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Last days to submit your video to the FENS Forum 2012 Video Contest- Do not miss your chance to win €1000!

EJN Admin — Tue, 08 May 2012 10:15:54 +0000

Submit your video now!

Did you know? FENS launched a video contest on the occasion of the FENS Forum 2012 in Barcelona. Apply now to this video contest to win great prizes.

FINAL DEADLINE: May 15, 2012

WHO CAN APPLY:

Open to individual neuroscientists or teams of neuroscientists, who include at least one PhD student or postdoctoral fellow registered to the FENS Forum 2012.

PRIZES

Up to eight (8) prizes will be awarded: the top four (4) winners will receive €1,000 each and the other four, €700 each. For videos produced by teams, prizes will be equally divided between the filmmakers.

WINNERS ANNOUNCEMENT

• Winners will be announced during the 2012 FENS Forum in Barcelona at the EJN Social event (Tuesday July 17, 2012 at 18 h 45, CCIB room 129).

• Winning videos will be played during the FENS Forum 2012 and will be featured on the EJN blog, as well as on the FENS social network pages.

VIDEO CONTEST RULES

• At least one of the participants of the video must be a PhD student or postdoctoral fellow registered for the FENS Forum 2012.

• Content MUST be related to neuroscience (videos can be funny), including, but not limited to: protocol videos, educational presentations, data presentations, life in the lab…

• Videos must be original work and not previously published.

• If videos use music or images, they must be rights-free or must have permission from copyright owner.

• Videos must be no longer than three (3) minutes in length (excluding credits).

• Videos must be in English.

• All participants of the videos must sign a release form (http://www.ejnblog.org/wp-content/uploads/2011/12/release-form2.pdf) and winners will have to provide the original copies of these forms.

SUBMISSION PROCEDURE

To enter your video into the contest, please upload it on YouTube as an unlisted video and send us the link via email:

1. Create a YouTube account if you do not have one

2. Create a channel in your YouTube account

3. Click on Upload menu (top menu)

4. Upload video file

5. Under Privacy, select “Unlisted” and click “Save Changes” at the bottom of the page

6. To view the link to your video, click on the Share tab (i.e. http://youtu.be/xxxxxxx)

7. Send the title of your video, the link of the video, as well as your full name and registration information to britta.morich@fens.org and to editorial.office@ejneurosci.org with the subject “FENS Forum 2012 video competition”.

New Featured Article: Circadian [Ca2+]c Waves and Long-range Network Connections in Rat Suprachiasmatic Nucleus

EJN Admin — Tue, 08 May 2012 07:15:31 +0000

Featured article of EJN issue 35-9: Circadian [Ca2+]c Waves and Long-range Network Connections in Rat Suprachiasmatic Nucleus

Jin Hee Hong, Byeongha Jeong, Cheol Hong Min, and Kyoung J. Lee
Center for Cell-dynamics and Department of Physics, Korea University, Seoul, Korea

A model planar wave front in the presence of varying degree of long-range direct cell-to-cell connections. (A) no connection, (B) 25% connection, and (C) 50% connection. (top row) A planar phase wave is moving along the vertical direction. (middle row) ΔZT vs. distance plots and (bottom row) density maps are corresponding to cases in the top row. The cellslinked by solid black lines form a phase-synchronized sub-network. The phase of each sub-network is chosen randomly. The filled colors represent the specific phases. Scale bar: 100 µm.

The suprachiasmatic nucleus (SCN) is the master clock in mammals governing the daily physiological and behavioral rhythms. It is composed of thousands of clock cells with their own intrinsic periods varying over a wide range (20~28 h). Despite this heterogeneity, an intact SCN maintains a coherent 24 h periodic rhythm through some cell-to-cell coupling mechanisms. This study examined how the clock cells are connected to each other and how their phases are organized in space by monitoring the cytosolic free calcium ion concentration of clock cells using the calcium binding fluorescent protein, cameleon. Extensive analysis of 18 different organotypic slice cultures of SCN showed that the SCN calcium dynamics is coordinated by phase-synchronizing networks of long-range neurites as well as by diffusively propagating phase waves. The networks appear quite extensive and far-reaching, and the clock cells connected by them exhibit heterogeneous responses in their amplitudes and periods of oscillation to TTX treatments. Taken together, our study suggests that the network of long-range cellular connectivity has an important role for SCN achieving its phase and period coherence.

Read full-text article: click here

Commentary:

Read the corresponding commentary by Rae Silver on this article: Phase Waves in the Suprachiasmatic Nucleus.

Biographical notes:

	Jin Hee Hong received her PhD degree in Neurophysiology in the Department of Life Sciences at Ewha Womans University and started this research project as a postdoctoral fellow in the laboratory of Kyoung Jin Lee. Her current research interest is to understand the dynamics of cytosolic calcium concentration and the network properties in SCN as related to the circadian rhythm generation, synchronization, and phase coherence.
	Byeongha Jeong graduated with BS/MS degrees from the Department of Physics at Korea University and is currently working for his PhD degree in the laboratory of Kyoung Jin Lee. He has built a cameleon FRET imaging system and developed various image data analysis software. His major research concern is to find the relationship between the level of cytosolic calcium and that of clock genes, and understand their spatiotemporal wave dynamics.
	Cheol Hong Min graduated with BS degree from the Department of Physics, Korea University. As a PhD candidate, he belongs to the calcium dynamics group in Kyoung Jin Lee’s lab. He was involved in the studies investigating the origin of calcium puffs (transients) in SCN as well as in cultured networks of astrocytes. His current work is to decipher the mechanism responsible for the recurrent calcium waves in cultures of astrocytes.
	Kyoung J. Lee is currently the director of the Center for Cell Dynamics (CND) and full professor in the Department of Physics at Korea University in Seoul. He got his doctoral degree in physics (nonlinear dynamics) at the University of Texas at Austin in 1994 and got interested in biology beginning his postdoctoral career in Princeton University. Since then, he worked on various issues like cardiac wave instabilities, learning and memory of neural networks, cell motility and swarming, and circadian clock. Broadly speaking, he is interested in biophysical problems in which nonlinear dynamics and physics of complexity play an important role.

Supplemental Figure:

Upper panel is a schematic diagram illustrating the phase relationships and sub-networks of clock cells in a model SCN. The small arrows represent a specific circadian phase of a clock cell (small disk), while the large arrows represent the local mean of the phases. The yellow colored disks represent cameleon-expressing clock cells. Clock cells are not only diffusively coupled but also have long-range direct connections (yellow lines). Lower panel shows a typical YFP fluorescent image of a SCN slice culture expressing cameleon protein(3V: 3rd ventricle; OC: optic chiasm). A gene-gun was used for transfecting cameleon cDNA.

New- Interview Comment by Wolfram Schultz about the Special Issue of EJN on Reinforcement Learning

EJN Admin — Fri, 04 May 2012 12:13:28 +0000

Wolfram Schultz (Wellcome Trust Principal Research Fellow and Professor of Neuroscience at the University of Cambridge, UK) has greatly inspired the traditional reinforcement learning framework. What does Wolfram Schultz think about alternative mechanisms to prediction error learning rules to account for elements of reward-learning? To find out and read the Interview Comment of Wolfram …

Read the discussion about the EJN article “Effects of abstinence on accumbens activity” (Vol. 35, Issue 6, p. 940–951)

EJN Admin — Mon, 23 Apr 2012 16:04:19 +0000

A Comment by Serge H. Ahmed, Youna Vandaele and Karine Guillem (Université de Bordeaux, Bordeaux, France) on the article entitled “Cocaine abstinence alters nucleus accumbens firing dynamics during goal-directed behaviors for cocaine and sucrose” (Vol. 35, Issue 6, p. 940–951, March 2012) together with a Response from Courtney M. Cameron and Regina M. Carelli (The University of North Carolina, NC, USA) was published today in the Discussion Forum.

To share your thoughts and insights on the Discussion Forum, sign in to the social network account of your choice by clicking on “Sign in” or “Log in”.

One month left before the next deadline for NENS Travel Stipends for graduate students

EJN Admin — Wed, 18 Apr 2012 12:00:20 +0000

Alessio Fracasso, NENS trainee

NENS

The Network of European Neuroscience Schools (NENS) represents over 150 graduate schools and programs across 30 European countries that offer Masters, MD and PhD degrees in neuroscience. To access the NENS program directory, click here.

Are you a student in a NENS program who would like to gain international experience?

Nataliia Petrenko, NENS trainee

The NENS Stipends are intended for MSc and PhD students registered at NENS member schools. Applicants are expected to spend a period of one to three months at a NENS member school of their choice, in a different European country, for the purpose of methodological training. Applicants have the possibility to either conduct an individually-arranged internship at a NENS lab or take part in organized courses offered by NENS programs.

Stipends will cover travel and accommodation costs up to 2,000€. For application forms and details please visit the NENS Stipends page of the FENS website or contact: nens-office@unil.ch

Overall, my training stay at Ghent University was extremely interesting and productive. Despite an intensive training, learning a lot of new techniques for analyzing iEEG data, and piloting a new experimental design, I also enjoyed meeting new colleagues, to learn about their work, and have interesting discussions with different members of the department. Furthermore, I had the opportunity to attend a Social Neuroscience Symposium held in Brussels while I was doing my training stay in Ghent.” Leonie Koban, trainee 2011

Next deadline is June 15th, 2012

Exercise and Drug conditioning

EJN Admin — Wed, 11 Apr 2012 14:52:56 +0000

A recently published study in EJN from ML Mustroph, DJ Stobaugh, DS Miller, EK DeYoung, and JS Rhodes, about the effect of Exercise on Addiction has been highlighted today in The New York Times.

Click here to view The New York Times article.

Click here to read the original full-text EJN article.

Special Issue – Beyond the Simple Reinforcement Learning Framework

EJN Admin — Thu, 05 Apr 2012 23:25:46 +0000

Neural computational accounts of reward-learning have been dominated by the hypothesis that dopamine neurons behave like a reward-prediction error and thus facilitate reinforcement-learning in striatal target neurons. While this framework is consistent with a lot of behavioral and neural evidence, this theory fails to account for a number of behavioral and neurobiological observations. In this special issue of EJN we feature a combination of theoretical and experimental papers highlighting some of the explanatory challenges faced by simple reinforcement-learning models and describing some of the ways in which the framework is being extended in order to address these challenges. (From the Editorial written by John O’Doherty, guest editor of the Special Issue)

The new Special Issue of EJN entitled “Beyond Simple Reinforcement Learning: the Computational Neurobiology of Reward-Learning and Valuation” has been published online. Click here to access full-text articles of the issue.

Interview video series
Interview of John O’Doherty (California Institute of Technology), Guest Editor of the Special Issue, giving an overview of the issue
Interview of Kent Berridge (The University of Michigan), contributor of the Special Issue,defining an alternative theory (incentive salience) to the traditional prediction error hypothesis of phasic dopamine
Interview of Cyriel Pennartz (University of Amsterdam), Associate Editor of EJN, giving a brief introduction to Reinforcement Learning

Interview Comment by Wolfram Schultz

Wolfram Schultz’s work has greatly inspired the traditional reinforcement learning framework.

1) Biographical Note

I am a Wellcome Trust Principal Research Fellow and Professor of Neuroscience at the University of Cambridge. We work on reward and decision making. We use neurophysiology and neuroimaging to study reward and decision signals in single neurons and in human brain structures. We employ specific behavioural tasks that are designed to explore neuronal mechanisms and test them in relation to specific concepts from behavioural theories, such as animal learning theory and behavioural economics.

2) Could you please give us a brief overview of your view on reinforcement learning?

The term derives from machine learning and refers to operant learning in artificial agents. It is often used in neuroscience to describe Pavlovian and operant conditioning and their derivatives. Reinforcement is a major mechanism governing the acquisition or change of behavioural responses following rewards (positive reinforcement) and punishers (negative reinforcement).

3) In the special issue, the possibility of alternative mechanisms to prediction error learning rules are considered to account for elements of reward-learning. Do you think all reward-learning processes in the brain can be explained by prediction-error driven learning models, or do you think other additional (or alternative) mechanisms may be at work?

There are several ways in which behaviour toward reward is learned. All of them combine current evidence with knowledge of the world to update expectations and behaviour. They include error driven forms like reinforcement learning and motor learning, Bayesian learning based on likelihood ratios, and other forms such as observational learning and perceptual learning. At least reinforcement learning and motor learning are driven by a prediction error, which is the difference between the evidence (what I see or obtain) and the prediction. The evidence could derive from a reward (for reward prediction error), a punisher (for punisher prediction error) or a target reached by a movement (the delta learning rule). The prediction includes knowledge of the world, which can be as simple as a stimulus predicting a reward, or a more elaborate state, rule or other information that is often termed a model of the world. According to the original descriptions, Pavlovian and operant learning occurs only when the subject directly experiences a reward or punisher. These learning forms are captured by the Rescorla-Wagner (RW) rule and its derivatives, which allow precise experiments with good interpretations. More advanced and broadly defined learning models like Sutton & Barto’s temporal difference (TD) learning, as described in their book (1998), include higher order reinforcers and models of the world, which include more real life situations.

4) Could you briefly summarize your own findings about the functions of dopamine in reward-processing?

About 70-80% of dopamine neurons show a short burst of action potentials when a ‘primary’ reward (unconditioned stimulus, US) is better than predicted (positive prediction error), or a short reduction of activity when a reward is worse than predicted (negative prediction error). They don’t respond to fully predicted rewards. Although the negative prediction error response occurs against low spontaneous activity and thus has limited absolute dynamic range in individual neurons, it constitutes a strong relative response and occurs synchronously in the population in a nicely graded manner. Thus the bidirectional response is compatible with the prediction error of RW and TD learning.

Most dopamine neurons respond also to reward predicting conditioned stimuli (CS), again bidirectionally relative to an earlier prediction. The response moves to the first reward predictor, with decrement by delay (temporal discounting). These responses are globally compatible with several implementations of Sutton & Barto’s TD learning.

About 10-20% of dopamine neurons show also a short burst of action potentials following aversive events (e.g. air puff). Thus, the neurons are driven by salient events rather than selectively by rewards. However, there are no aversive prediction error responses. More dopamine neurons (up to 65%) show bursts after aversive stimuli when stimulus generalisation or pseudoconditioning are not controlled for. Overall, most dopamine neurons are depressed in their activity by aversive events.

A large proportion of dopamine neurons show also increased activity following novel and physically salient stimuli when stimulus generalisation or pseudoconditioning are not controlled for. Only a few of these responses seem to remain with proper controls. There is no prediction error coding with these stimuli.

About 30% of dopamine neurons show a slower increase in activity later during a stimulus-reward interval that reflects the risk of obtaining the predicted reward. This response is not explained by RW or TD models in a biologically plausible manner and might function to modulate the reward prediction error response according to attentional learning rules derived from the RW model.

These data show that the dopamine reward prediction error response is obtained by experimental observation. It is not a ‘hypothesis’. It can be recorded in awake mice, rats, monkeys and humans with an electrode, amplifier, oscilloscope and computer during all kinds of simple or complicated behavioural tasks. The only requirement is an unpredicted reward with a sharp onset that respects the rapid time course of the response, or clearly discernible phasic stimuli carrying well defined reward predictions.

‘Hypothesis’ might refer to the use of the dopamine prediction error response in learning. The arguments in favor are pretty strong. Hundreds of lesioning and psychopharmacological studies have shown the important involvement of dopamine in learning, including in knock-out mice, with few exceptions. Furthermore, tens, maybe a hundred, studies have shown dopamine dependent plasticity in striatum, fontal cortex and other dopamine innervated structures. Together with the very special form of neuronal response coding the crucial error term of learning models, it appears quite likely that the dopamine prediction error response plays an important role in reward and reward learning. Results obtained with new methods like optogenetics and knock-outs of specific receptor types strengthen the argument.

5) To what extent do you think basic reinforcement learning models can account for the reward functions of dopamine?

Many laboratories, including our own, measure the phasic, bursting responses of dopamine neurons to reward prediction errors. The reward prediction can derive from gradual learning via simple delivery of reward, the most basic Pavlovian situation compatible with model-free reinforcement learning, or reflect states or rules about the world (reward distributions, time series, reversals), compatible with model-based reinforcement learning. In each case, the dopamine neurons code the extent to which the obtained reward differs from any of those reward predictions. Thus, the dopamine responses comply with the most simple form of Pavlovian RW conditioning and the more advanced, model-free and model-based versions of Sutton & Barto’s TD model.

One should mention that TD models do capture temporal discounting accurately by the gamma coefficient that reduces the value of delayed rewards. The dopamine response to reward predicting stimuli shows corresponding temporal value discounting with delays.

The TD models account also for the observation that rewards are only effective when occurring after the stimuli or actions they reinforce. This refers to the credit assignment problem, which explains learning by crediting specific events for the obtained reward. The TD model is particular good at credit assignment, by moving the conditioned reinforcer back to the earliest reward predicting event, which then acts on eligibility traces left from neurons activated by the event. Neurobiological correlates of eligibility traces include stimulus traces in the form of sustained activity in postsynaptic neurons in striatum and cortex, and intracellular molecular traces, such as IP3 identified recently in dopamine neurons.

Dopamine neurons would be involved in learning to the extent that reward prediction errors occur. Thus dopamine neurons would be involved in learning both goal-directed behaviour and habits as far as prediction errors occur. Habits take time to develop, and prediction errors are likely to occur well before habits are established. But dopamine neurons would not be central for the specific differences between goal-directed behaviour and habits; they would just report prediction errors as they arise.

As mentioned above, there are many ways of reward learning. To the extent that they don’t use or generate prediction errors, the phasic dopamine response is unlikely to be involved. It remains to be determined which role these other forms play in reward learning.

6) As pointed out by Kent Berridge, a number of studies using either genetic or pharmacological manipulations have found that some types of reward-learning can be preserved in hypodopaminergic animals — to what extent do you think these findings challenge the reward-prediction error hypothesis?

Hundreds of lesioning and psychopharmacological studies demonstrate learning deficits with impaired dopamine transmission. But there are occasional studies showing intact learning despite reduced dopamine function. One explanation may be that other reward systems take over the learning function when dopamine fails. This may occur within seconds, minutes, hours or days after lesions or drug applications. Also, it is unclear whether dopamine neurons would be activated in the learning situations employed in the negative studies. An own study by Berridge in which learning was maintained despite impaired dopamine function involved reward devaluation by taste aversion. It is unclear how dopamine neurons would respond in this rather sophisticated situation, in addition to their weak processing of aversive events. However, when the dopamine involvement was studied, lesion deficits occurred only in those learning situations that engaged dopamine neurons, as shown in a recent experiment by Kent Berridge’s colleague Terry Robinson on sign vs. goal tracking rats. Recent work by Palmiter knocked out the burst generating NMDA receptors on dopamine neurons and showed substantial deficits in reward learning, suggesting that the bursting dopamine response to prediction errors is necessary for the tested forms of learning. The result relates to the long debated functional distinction between tonic and phasic dopamine firing (the reward prediction error burst would comply with phasic firing). Recent work by Morikawa showed an involvement of NMDA receptors in the acquisition of dopamine burst responses to conditioned stimuli when the crucial stimulus-reward delay was respected. The important point is not that one can get some reward learning without dopamine but that learning impairments do arise, and plenty of them.

EJN Review: Exploration and modulation of brain network interactions with noninvasive brain stimulation in combination with neuroimaging

EJN Admin — Mon, 19 Mar 2012 08:18:24 +0000

Complex brain functions involve interactions between different brain regions and it is believed that alterations in these network connections may be involved in neurological disorders. In this review written by M.M. Shafi, M.B. Westover, M.D. Fox and A. Pascual-Leone, the authors address how the combination of neuroimaging with noninvasive brain stimulation can be used to study functional connectivity networks and how they can selectively be manipulated. Learn about the potential therapeutic applications of the combination of these techniques….

To access full text article: click here.

In this figure 5 (click to enlarge): BOLD fMRI and EEG responses to TMS. (A) Bold fMRI response to rTMS of left dorsal premotor cortex. Six transverse sections showing activity changes in the cingulate gyrus, ventral premotor cortex, auditory cortex, caudate nucleus, left posterior temporal lobe, medial geniculate and cerebellum. (Modified with permission from Bestmann et al, 2005). (B) EEG response to single-pulse stimulation of left sensorimotor cortex. Top panels: Scalp potential with head shown as a two dimensional projection. The contour lines depict constant potentials; positive potentials are red, negative potentials are blue. Bottom panels: Current-density distributions: the calculated current-density at each time point is depicted as a percentage of the maximum current-density at that time point. For this subject, at 11 ms, the activation had spread from below the coil center to involve the surrounding frontal and parietal cortices. Contralateral activation emerged at 22 ms, and peaked at 24 ms. (Modified with permission from Komssi et al, 2002.) See full-text article for full references.

Featured Article: The Unfolded Protein Response in Models of Human Mutant G93A Amyotrophic Lateral Sclerosis

EJN Admin — Tue, 06 Mar 2012 10:14:46 +0000

Featured article of EJN issue 35-5: The Unfolded Protein Response in Models of Human Mutant G93A Amyotrophic Lateral Sclerosis

T. Prell¹, J. Lautenschläger¹, O.W. Witte¹, M.T. Carri^2,3, J. Grosskreutz¹¹Hans-Berger Department of Neurology, Friedrich-Schiller-University Hospital Jena, Erlanger Allee 101, D-07747 Jena, Germany²Department of Biology, University of Rome “Tor Vergata”, Rome, Italy³ Fondazione Santa Lucia IRCCS, Rome, Italy

Figure_1. Click on image to enlarge

Recent studies indicate that endoplasmic reticulum (ER) stress is involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle (ERMCC) is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, the cell engages the unfolded protein reaction (UPR). While activation of the UPR was shown in some ALS models and tissues, ER stress elements have not been studied directly in motor neurones. Here we investigated the expression of XBP1, ATF6α and phosphorylation of eiF2α and their modulation in mutated SOD1^G93A cell and animal models of ALS. Expression of XBP1 and ATF6α mRNA and protein is enhanced in SOD1^G93A NSC34 cells. Activation of ATF6α, XBP1 and phosphorylation of eiF2α was detectable in mutated SOD1^G93A motor neurones, but not in wild type motor neurones. Treatment with the ER stressor thapsigargin enhanced phosphorylation of eiF2α and expression of ATF6α, XBP1, and sXBP1 in NSC34 cells and motor neurons in a time dependent manner. The present study thus shows the activated UPR directly in motor neurones which overexpress human pathogenic mutant SOD1^G93A, providing evidence that ER stress plays a major role in ALS.

Read full-text article: click here

Commentary:

Read the corresponding commentary by Ludo Van Den Bosch on this article: Endoplasmic reticulum stress plays an important role in amyotrophic lateral sclerosis (ALS).

Biographical notes:

	Tino Prell graduated in 2007 at the University of Magdeburg (Germany) and got his medical doctoral degree in 2009 (citrullination of proteins in schwann cells). During training as a specialist neurologist he became involved in medical attendance of ALS patients. From a clinical point of view he is interested in the molecular pathophysiology of motor neuron diseases. He is focused on protein misfolding and calcium disturbance in the context of the endoplasmic reticulum mitochondria calcium cycle (ERMCC). Working in the NEDIG (Neurodegenerative Diseases Group) at the University Hospital Jena, he is involved in several projects concerning the clinical characteristics, MRI biomarkers and cellular pathophysiology of motor neurone diseases.
	Janin Lautenschlaeger studied pharmacy from 2004 to 2009 at the Friedrich-Schiller-University of Jena, Germany. Following her diploma at the clinical pharmacology, she started in the NEDIG (Neurodegenerative Diseases Group) of Julian Grosskreutz her PhD thesis. She is focusing on the analysis of calcium dynamics in motor neurons regarding pathologic features of ALS. Evaluation of the dynamics between the endoplasmic reticulum and mitochondria could give further insights in the ongoing process and may providing new therapeutic principles in motor neuron disease.
	Maria Teresa Carrì graduated in 1981 at the University of Rome Sapienza. After her first years as a PhD student, she became involved in projects concerning the structure, mechanisms of action and regulation of the expression of the enzyme SOD1 in eukaryotes. In 1994 she became interested in human SOD1 mutants and amyotrophic lateral sclerosis, a field in which she contributed with more than 50 papers published in International Peer Review Journals. She is also working on the biochemical mechanisms of other neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Spinal cerebellar ataxia type 1). At present, she is a Full Professor of Biochemistry at the University of Rome Tor Vergata and Head of the Lab of Neurochemistry at the Fondazione Santa Lucia.
	Otto W. Witte is the head and Full Professor of Neurology at the Hans Berger Department of Neurology at the University Hospital Jena. With more than 200 papers published in International Peer Review Journals he is involved in several projects with a special focus on neuronal plasticity after cerebral lesions and the understanding of functional and structural brain connectivity by using advanced MRI techniques.
	Julian Grosskreutz finished medical school in 1997 and got his medical doctoral degree in 1999 describing the electrophysiological properties of biopsied human sural nerves. He continued to pursue peripheral nerve excitability studies in vitro and in vivo in Syndey (AU) and Graz (A) while training as a specialist neurologist. From 2001 on he studied on ligand gated ion channels, in particular in AMPA receptors, and AMPAR mediated selective motor neuron death at the Hannover Medical School Hospital with partners in Leuven (BE). Using advanced fluorescent imaging techniques in motor neuron cocultures he developed the model of the ER mitochondria calcium cycle (ERMCC) as key affected pathway in amyotrophic lateral sclerosis. After a fellowship abroad in Sheffield (UK) 2006-2007 he received his Habilitation in 2007 and took up a consultant specialist position and lecturer as head of the neuromuscular unit of the Hans Berger Department of Neurology at the University Hospital Jena. He runs the NEDIG (Neurodegenerative Diseases Group) which serves tertiary care for ALS patients, participates in clinical trials, and studies clinical characteristics, MRI biomarkers and cellular pathophysiology of motor neuron diseases.

More images from the Authors:

Images of three-dimensional cultures of motor neurons, generated from spinal ventral cords of 13-day old wild-type (WT) mouse embryos, as in the article. Click on images to enlarge.

	SMI32 staining with colored depth coding (red on the top and blue at the bottom of the cell).
	Cultures were stained for SMI32 (in gray) and DAPI (in blue).
	Cultures were stained for SMI32 (in gray) and DAPI (in blue).
	Cultures stained for SMI32 (in gray) and DAPI (in blue).

How many neurons do we have?

EJN Admin — Tue, 21 Feb 2012 12:05:14 +0000

100 billion, right?

We learn in school that there are 100 billion galaxies in the universe, 100 billion stars in our galaxy and that the human brain contains 100 billion neurons… How convenient!

In a recent publication of EJN, Robert Lent et al. revisit some dogmas of quantitative neuroscience: Click here to access the full text article

About the Alzheimer’s Drug Discovery Foundation (ADDF)

EJN Admin — Wed, 08 Feb 2012 17:35:46 +0000

MISSION

The Alzheimer’s Drug Discovery Foundation (ADDF) is a non-for-profit organization that provides funding for drug discovery and development research programs in the field of Alzheimer’s disease (AD), related dementias and cognitive aging. The ADDF seeks to fill the critical translational funding gap between basic research and later stage drug development by funding promising drug discovery and development programs (Figure 1). In addition to funding academic programs, the ADDF also invests in and creates early stage biotechnology companies for which funding is typically made as a program-related investment . The ADDF also co-sponsors conferences to stimulate new ideas and approaches in areas of interest to the Foundation.

Figure 1: The role of the ADDF in funding drug development. The ADDF specifically funds drug discovery programs from the stage of screening through to phase II clinical trial, in the field of Alzheimer’s disease and related dementias. ADDF funding takes risk, bridging the gap between traditional government funding of basic research and later stage venture capital and private equity investment during clinical development.

METRICS

The ADDF has granted $51 million to fund over 370 Alzheimer’s drug discovery programs and clinical trials in academic centers and biotechnology companies in 18 countries. Subsequent to the ADDF’s critical initial funding, our grantees have received commitments in excess of $2 billion in follow-on funding from government, pharmaceutical companies and venture capital firms to further advance their drug research.

FUNDING MECHANISMS

The ADDF does not commit to any single scientific method, institution, approach, or solution. Our strategy is to support the most promising, diverse, novel research projects anywhere in the world and to develop a network of partnerships that will increase opportunities for developing effective, disease-modifying Alzheimer’s drugs. Our programs include:

Academic Drug Discovery and Development Program creates and supports innovative translational programs in academic medical centers and universities.
Biotechnology Development Program supports qualified scientific projects in existing, private and public, early-stage biotechnology companies. The ADDF will provide support for qualified projects in more advanced companies if a clear need for non-profit funding to support the project can be demonstrated and justified. Funding is typically made as a program-related investment.
Biotechnology Founders Technology Transfer Program supports the start-up of new biotechnology companies from both academic and other sources. Up to 35% of funds from these awards may be employed for expenses related to company formation, such as administrative, legal, patent and third-party vendor costs.
Conference Grants support innovative scientific conferences that stimulate discussion around novel targets.

The ADDF scientific staff, comprised of our Chief Scientific Officer and 3 PhD level neuroscientists, together with our expert Scientific Review Board and Business Advisory Board, carefully reviews each grant application and provides:

consultation for development of the proposed drug discovery research program, including access to services and resources
establishes milestones and monitors program progress on a semi-annual basis
strategic management assistance

FUNDING PRIORITIES

The ADDF funds four different categories of research: Drug Discovery (target validation; high throughput screening; medicinal chemistry, including hit to lead development and lead optimization; in vitro and in vivo studies of efficacy, ADME, toxicology, pharmacokinetics and pharmacodynamics; and in vivo proof-of-concept with lead compounds and biologics), Early Detection (development of biomarkers to accelerate drug development and early diagnosis), Clinical Trials (innovative pilot, primarily phase 2aclinical trials) and Prevention (targeted pharmacological and non-pharmacological approaches to prevention). We do not provide funding for basic science.

2012 REQUEST FOR PROPOSALS (RFP)

For a detailed description of our open RFPs, please visit: http://www.alzdiscovery.org/index.php/research-programs/grant-opportunities

GENERAL RFP

The ADDF is interested in novel targets and therapeutic approaches for Alzheimer’s disease, related dementias and cognitive aging, These areas include, but are not limited to: Energy utilization/mitochondria function, insulin sensitivity, protein degradation/autophagy, ApoE function and cholesterol metabolism, vesicular trafficking, inflammatory pathways, synaptic function/morphology, calcium regulation, myelin changes, ischemia and oxidative stress, vascular injury, the blood-brain barrier interface, and translatable biomarkers. For more information regarding priority areas (http://www.alzdiscovery.org/wp-content/uploads/2011/11/2012-general-rfp-and-funding-priorities1.pdf)

Strategic areas of particular interest include:

Repurposing – Testing drugs approved for other indications in Alzheimer’s disease preclinical models or in human clinical trials.
Developing new compounds and biologics for Alzheimer’s disease – Requires BOTH a medicinal chemist and a biologist as co-PIs/collaborators.
Preclinical proof-of-concept – Testing of novel lead compounds in animal models. Whenever possible, studies should include pharmacokinetics (PK) and pharmacodynamics (PD) testing, an a priori hypothesis and primary and secondary outcomes measures, and a statistical design plan including power analysis.

PROGRAM TO ACCELERATE CLINICAL TRIALS (PACT) RFP

PACT provides funding for early stage proof of concept, primarily phase 1 and phase 2a clinical studies, testing novel therapies in human patients. The program must include biomarkers in the study design that are related to the mechanism of the drug being tested (http://www.alzdiscovery.org/wp-content/uploads/2011/04/2011-pact-rfp.pdf).

2012 ADDF/CHARLES RIVER/CEREBRICON JOINT RFP: Use of aged rats as a relevant preclinical model for the development of therapeutics for cognitive aging and Alzheimer’s disease

Aging is the primary risk factor for Alzheimer’s disease. The ADDF seeks to capitalize on new knowledge regarding the biology of aging for translation research to develop new drugs. To accelerate the discovery of new drugs for cognitive aging and Alzheimer’s disease, the Alzheimer’s Drug Discovery Foundation (ADDF) has partnered with Charles River Discovery and Imaging Services/Cerebricon to co-develop and implement a grant program to fund pre-clinical studies focused on proof-of-concept testing of novel compounds in aged rats that employ novel outcome measures (http://www.alzdiscovery.org/wp-content/uploads/2011/07/2011_charles-river_addf_rfp.pdf).

Charles River/Cerebricon. has made available and will cover the cost for aged rats (up to 22 months old) if the applicant chooses to contract services for the purposes of this RFP. Alternatively, investigators can purchase aged rats from Charles River/Cerebricon and/or utilize animals and services from their own institutions or from other providers.

ADDF/ASSOCIATION FOR FRONTOTEMPORAL DEGENERATION (AFTD)/ RFP

Research investigating the pathologic mechanisms of neurodegeneration in frontotemporal degeneration (FTD) and related disorders is advancing, creating new potential targets for drug discovery, with implications for Alzheimer’s disease as well. The ADDF and the AFTD seek to accelerate and support drug discovery for FTD and related dementias through this targeted RFP for development of new compounds, biologics, and biomarkers for FTD (http://www.alzdiscovery.org/wp-content/uploads/2011/06/2011-addf-aftd-ftd-rfp.pdf).

APPLICATION PROCESS

All applications must be submitted electronically at (http://www.alzdiscovery.org/index.php/research-programs/grant-opportunities). Full information on the application process and RFP details can be found at the above address. Submission of a Letter of Intent (LOI) is required at least 2 weeks prior to the application deadline. Deadlines for 2012 are as follows:

General RFP/PACT: Jan 18^th, April 10^th, July 10^th and Oct 10^th
ADDF/Charles River/Cerebricon Ltd. RFP: July 10^th
ADDF/AFTD RFP: Sept 20^th

The ADDF typically supports one year of research at a time, with potential for future follow-on funding. Funding averages $150,000 per year and must be justified based on the scientific work plan. The PACT program is an exception where applications up to $1,000,000 per program will be accepted. The ADDF will attempt to make a determination of interest within 90 days of receipt of the application.

SCIENTIFIC RESOURCES

In addition to providing programmatic and scientific support to funded investigators the in house scientific staff are continuously generating resources to address critical unmet needs in the field that include:

Public-Private partnerships: Development of strategic industry relationships and public-private partnerships to leverage resources and secure follow on funding (pharma and VCs) for ADDF investigators.
Resource database: The ADDF staff are continuously developing relationships with industry partners to better connect investigators with contract research organizations (CROs) and negotiate discounted services.
Annual Drug Discovery for Neurodegeneration Conference: An intensive course on translating drugs into research. The course sees participants from both an academic and industry backgrounds and covers topics ranging from medicinal chemistry, hit to lead optimization, ADMET and preclinical animal model studies to financing models (http://www.worldeventsforum.com/addf/drugdiscovery).
Annual International Conference on Alzheimer’s Drug Discovery: Annual investigators meeting open to academics, industry and investment groups (http://www.worldeventsforum.com/addf/addrugdiscovery).
Online drug discovery tutorial: A web-based tutorial has been developed in conjunction with the annual Drug Discovery for Neurodegeneration conference. The site will go live in 2012 providing comprehensive reference material on the drug development lifecycle. The link can be found (http://www.alzdiscovery.org).
Catalyst conferences: the ADDF helps to develop and co-sponsor catalyst conferences in specific therapeutic areas in development.. Through a partnership with the NY Academy of Sciences the ADDF holds conferences throughout the year on target themes of interest (http://www.nyas.org/).
Scientific publications:
- Review articles: The ADDF scientific staff regularly publishes meeting reports and scientific reviews on the Alzheimer’s disease therapeutic landscape.
- Best Practices for Preclinical Animal Studies: The ADDF scientific staff developed guidelines for design of preclinical animal model efficacy studies (Shineman et al (2011). Alzheimer’s Research and Therapy 28;3(5):28)

For application submission inquiries:

Niyati Thakker
Grants Associate
Phone: +1 212-901-8019
nthakker@alzdiscovery.org

For program related inquiries:

Diana Shineman, PhD
Assistant Director for Scientific Affairs
Phone: +1 212-901-8007
dshineman@alzdiscovery.org

Rachel Lane, PhD
Scientific Program Manager
Phone:+1 212-901-8017
rlane@alzdiscovery.org

Attend the FENS Forum 2012 in Barcelona, July 14 – 18, 2012

EJN Admin — Mon, 06 Feb 2012 10:25:15 +0000

The FENS Forum is the largest neuroscience meeting in Europe. It is a must for neuroscientists from all over the world.

First register and then submit your abstract: click here

FENS Forum 2012 homepage

Graduate students and post-doctorate investigators:

Don’t miss the Young Investigator Training Programme! The programme includes summer research stays in Spanish laboratories, career development and professional networking opportunities.

http://fens2012.neurosciences.asso.fr/pages/index2.php?sub=27&left=110

And discover the great students activities: participate in the scientific photography and video contests with amazing prizes, bring your band to the Science Rock Party, meet your peers in a great Rock venue at the traditional Jump the FENS party and much more.

The EJN App is now available through the iTunes App Store for FREE!

EJN Admin — Wed, 01 Feb 2012 06:00:26 +0000

You can now keep up with the latest research and news from EJN with the new EJN App on iPhones and iPads!

Receive the latest EJN articles and Blog posts directly to your device

Optimized interface for easy browsing of content, including videos
Create your own ‘reading list’ which can be emailed to colleagues quickly and easily
Add your own notes to content within the App

Featured Article: Increased stress reactivity is associated with reduced hippocampal activity and neuronal integrity along with changes in energy metabolism

EJN Admin — Tue, 31 Jan 2012 06:30:10 +0000

For each printed issue of EJN, the Editors-in-Chief select a manuscript as a Featured article, based on significance and interest of the article. Featured articles are highlighted by a short commentary in the printed issue and online version of the journal, as well as in the blog now.

Featured article of EJN issue 35-3: Increased stress reactivity is associated with reduced hippocampal activity and neuronal integrity along with changes in energy metabolism

Alana Knapman, Sebastian F. Kaltwasser, Daniel Martins-de-Souza, Florian Holsboer, Rainer Landgraf, Christoph W. Turck, Michael Czisch, and Chadi Touma

Patients suffering from major depression have repeatedly been reported to have dysregulations in hypothalamus–pituitary–adrenal (HPA) axis activity along with deficits in cognitive processes related to hippocampal and prefrontal cortex (PFC) malfunction. Here, we utilized three mouse lines selectively bred for high (HR), intermediate, or low (LR) stress reactivity, determined by the corticosterone response to a psychological stressor, probing the behavioral and functional consequences of increased vs. decreased HPA axis reactivity on the hippocampus and PFC. We assessed performance in hippocampus- and PFC-dependent tasks and determined the volume, basal activity, and neuronal integrity of the hippocampus and PFC using in vivo manganese-enhanced magnetic resonance imaging and proton magnetic resonance spectroscopy. The hippocampal proteomes of HR and LR mice were also compared using two-dimensional gel electrophoresis and mass spectrometry. HR mice were found to have deficits in the performance of hippocampus- and PFC-dependent tests and showed decreased N-acetylaspartate levels in the right dorsal hippocampus and PFC. In addition, the basal activity of the hippocampus, as assessed by manganese-enhanced magnetic resonance imaging, was reduced in HR mice. The three mouse lines, however, did not differ in hippocampal volume. Proteomic analysis identified several proteins that were differentially expressed in HR and LR mice. In accordance with the notion that N-acetylaspartate levels, in part, reflect dysfunctional mitochondrial metabolism, these proteins were found to be involved in energy metabolism pathways. Thus, our results provide further support for the involvement of a dysregulated HPA axis and mitochondrial dysfunction in the etiology and pathophysiology of affective disorders.

Read full-text article: click here

Commentary:
Read the corresponding commentary by James P. Herman, Diana Lindquist and Richard A. Komoroski on this article: Linking cerebral metabolic function to stress vulnerability

Biographical note: Chadi Touma studied Biology and Biochemistry in Muenster and Hanover, Germany. His doctoral studies focussed on the development, validation and application of a non-invasive technique to monitor stress hormones in mice. He graduated with ’summa cum laude’ at the University of Muenster and in 2004 joined the Max Planck Institute of Psychiatry in Munich. In 2010, he was appointed Head of the Research Group of Psychoneuroendocrinology at the Max Planck Institute of Psychiatry. The focus of this research group is to generate and characterise clinically relevant animal models of inborn (trait) emotionality and stress reactivity in order to elucidate behavioural, neurobiological, endocrine and molecular-genetic mechanisms underlying affective disorders such as major depression.

Featured Article: Projections and interconnections of genetically defined serotonin neurons in mice

EJN Admin — Tue, 03 Jan 2012 08:46:14 +0000

FEATURED ARTICLE OF EJN ISSUE 35-1

by Sun Jung Bang, Patricia Jensen, Susan M. Dymecki and Kathryn G. Commons.

Fig. 6. Projections of r1-Pet1 neurons (green) to other groups of serotonin neurons, identified by immunolabeling for TPH2 (red).

Brain serotonin neurons are heterogeneous and can be distinguished by several anatomical and physiological characteristics. Toward resolving this heterogeneity into classes of functional relevance, subtypes of mature serotonin neurons were previously identified based on gene expression differences initiated during development in different rhombomeric (r) segments of the hindbrain. This redefinition of mature serotonin neuron subtypes based on the criteria of genetic lineage, along with the enabling genetic fate mapping tools, now allows various functional properties, such as axonal projections, to be allocated onto these identified subtypes. Furthermore, our approach uniquely enables interconnections between the different serotonin neuron subtypes to be determined; this is especially relevant because serotonin neuron activity is regulated by several feedback mechanisms. We used intersectional and subtractive genetic fate mapping tools to generate three independent lines of mice in which serotonin neurons arising in different rhombomeric segments, either r1, r2 or both r3 and r5, were uniquely distinguished from all other serotonin neurons by their expression of enhanced green fluorescent protein. Each of these subgroups of serotonergic neurons had a unique combination of forebrain projection targets. Typically more than one subgroup innervated an individual target area. Unique patterns of interconnections between the different groups of serotonin neurons were also observed and these pathways could subserve feedback regulatory circuits. Overall, the current findings suggest that activation of subsets of serotonin neurons could result in topographic serotonin release in the forebrain coupled with feedback inhibition of serotonin neurons with alternative projection targets.

Read full-text article

Read the corresponding commentary by Ali Jahanshahi, Yasin Temel and Harry W. M. Steinbusch.

Biographical Information

Sun Jung Bang	Sun Jung Bang received her PhD degree in Behavioral Neuroscience in the Department of Psychology at Yale University in 2009, under the supervision of Dr. Thomas Brown. She is currently a postdoctoral fellow in the laboratory of Dr. Kathryn Commons, and this study was the first project she worked on when she joined the lab. “It was a great project to learn about serotonin, neuroanatomy of the brain and microscopy techniques”.
Patricia Jensen	Patricia Jensen started this project as a postdoctoral fellow in the laboratory of Susan Dymecki, and continued it as she began her own independent research program at the NIEHS. Patricia is one of several junior faculty trained in the laboratory of Susan Dymecki in mouse genetics. The current focus of Patricia’s research is in understanding the development of the noradrenergic system. Lab website: http://neuroscience.nih.gov/Lab.asp?Org_ID=507
Susan Dymecki	Dr. Dymecki, a Professor in the Department of Genetics at Harvard Medical School, is developing and using innovative mouse genetic strategies to identify and manipulate specific groups of neurons to better understand their function. These approaches are currently being applied in the Dymecki lab to understand if dysfunction of particular groups of serotonin neurons generates unique functional deficits. Lab website: http://genepath.med.harvard.edu/~dymecki/joinus.html
Kathryn Commons	Dr. Commons is currently an Associate Professor at Children’s Hospital Boston and Harvard Medical School.The network of feedback connections between serotonin neurons in this study was a particular interest to Kathryn Commons. Serotonin neurons have many feedback regulatory mechanisms, but it is poorly understood at a systems level how these shape activity within the serotonin system. Lab website: http://www.childrenshospital.org/cfapps/research/data_admin/Site2586/mainpageS2586P0.html

Tips by the Authors

Determining the best imaging method

One of the difficult phases of this project was in determining what the best method was to identify eGFP-containing axons throughout the brain. Axons, and particularly axons from serotonin neurons, can be very fine and difficult to identify with a cytoplasmic marker. Eventually we found that the best sensitivity was attained by immunolabeling using the ABC-elite kit from Vector Labs coupled with the DAB (3,3′-Diaminobenzidine) substrate, and visualizing the sections using dark-field illumination. Dark-field illumination increases the ability to detect axons for two reasons. First it’s easier for the eye to detect sparse bright objects in a field of black, like stars in the night sky, rather than a few dark objects on a field of white. Second, in dark-field, the visible photons are ones scattered off the objects in the field, this slightly decreases resolution but also makes objects appear slightly larger and therefore more visible.

Lipofuscin in Mice

In the second part of the study, we wanted to use immunoflourescence techniques to visualize the relationship between eGFP containing axons and serotonin cells. A problem we found in this part of the study was autoflourescence produced by lipofuscin. Lipofuscin appears as small perisomatic particles that can be easily identified because they are detected in all the flourescent channels simultaneously. In addition, they tend to be more abundant in large serotonin neurons than neighboring cells. Lipofuscin can be a major problem for flourescence methods, particularly when using tissue from primates or humans. Methods have been published to reduce lipofuscin-produced fluorescence (Schnell et al., J Histochem Cytochem. 47(6):719-30; 1999; PMID:10330448). Mice tend to have more lipofuscin than rats, and different strains of mice can have different levels of lipofuscin as well. However, we knew that the accumulation of lipofuscin is age-dependent, and therefore, to reduce this problem we were careful to collect and study mice that were about 28 days old.

Tips for immunohistochemistry, by the Editors of EJN

EJN Admin — Wed, 07 Dec 2011 09:48:24 +0000

Immunohistochemistry is like cooking. There are many recipes out there, but some of them do not work out well. However, when they do, they are great! You need the right ingredients, a dose of experience, a few tricks from old cooks, and a grain of common sense. Read more to learn about traps to avoid, and important information to report when you publish your findings.

The problem

The validity of scientific results depends to a large extent on the use of appropriate methods providing the required precision and sensitivity, as well as controlled specificity of reagents and procedures. This statement is particularly valid for immunohistochemistry, where sensitivity and specificity of the antibodies, as well as technical procedure are crucial to avoid false-positive and false-negative results.

When using immunohistochemistry, several factors can cause false-negative or false-positive results and all should be verified as much as possible in each experimental set-up used. In particular, primary antibodies can fail to detect their target antigen even if the antigen is present in the tissue for many reasons, including conformation changes induced by fixation/embedding, steric hindrance by interacting proteins/post-translational modifications, low affinity of the antibody for the target, or failure of the antibody to penetrate into the tissue. Conversely, antibodies can bind non-specifically to other targets or tissue components. This observation holds true for both primary and secondary antibodies.

The problem is further confounded by the vast literature describing various procedures – such as the use of distinct “blocking” reagents and antigen-retrieval – to minimize these pitfalls and ensure high-fidelity binding of antibodies. This makes it difficult to choose the adequate method, and testing alternatives can be laborious. However, blindly following an established protocol might prove insufficient. It requires considerable experience, rational thinking and evidence from other methods to determine whether a given staining pattern obtained by immunohistochemistry is likely specific or non-specific. For instance, antibodies directed against a synaptic protein should produce no staining of the cell nucleus (unless this protein plays an additional, previously not described role in this compartment). In such case of wrong labeling, either the antibody or the staining protocol may be unsuitable.

The solutions

Here, we provide a practical guide of what should be tested and what should be reported in order to provide convincing evidence for the validity of immunohistochemical experiments. This includes dealing with the three main steps that can lead to false negative and false positive results:

Detection of the antigen of interest by the primary antibody
Detection of the primary antibody by secondary antibodies
Tissue preparation

1) Primary antibody specificity

The most stringent specificity test is performed in tissue devoid of the antigen of interest (knockout mouse). When not feasible, the best alternative is to show that two antibodies raised against different epitopes of the antigen of interest yield the same staining pattern. A third control includes inactivation of the antibody by incubation with its antigen prior to use for immunohistochemistry. This control does not exclude, however, that several targets sharing a common epitope are detected by this antibody. If doubts remain, additional information about the expression and localization of the antigen of interest should be provided by alternative methods.

As a consequence of the requirement by the Journal of Comparative Neurology to provide detailed characterization of primary antibodies, there is now a large collection of commercially-available antibodies that fulfill these criteria. To avoid unnecessary duplication, the Journal of Comparative Neurology has published an Antibody database listing all these products, which can be considered as being well characterized. Keep in mind, however, that polyclonal antibodies can vary considerably in their affinity and specificity from batch to batch, even when sold under the same catalog number. Every new batch ought to be tested to avoid bad surprises.

2) Secondary antibody specificity

Secondary antibodies are raised against immunoglobulins (typically IgGs) of the species in which primary antibodies were raised. As they are used in fairly high concentration, the likelihood that they bind non-specifically to tissue components (extracellular matrix proteins, blood vessels, etc) is higher than for primary antibodies. Further, they might cross-react with IgGs from other species, which is particularly relevant in multiple-labeling experiments. To minimize cross-reactivity, whenever available, it is best to use highly cross-adsorbed secondary antibodies.

Influence of immunoglobulins in lesioned tissue. Immunoperoxidase staining with secondary antibody binding to IgGs potentiated by tissue lesion. Sections were stained for a marker of microglia in the mouse hippocampus following injection of kainic acid. Left: section from wild-type mouse; Right: section from mouse devoid of IgGs (Zattoni et al., 2011)

To test for specificity, secondary antibodies should be applied in the absence of primary antibodies: all residual staining can be considered as being non-specific. In immunofluorescence experiments, beware of possible autofluorescent molecules that may be contained in tissues, their presence can be detected best in the absence of secondary antibodies. Note, however, that non-specific binding to tissue components depends both on the antibody and the tissue type. Embryonic/neonatal brain tissue has much more non-specific binding than adult tissue, and lesions, which cause damage to the blood-brain-barrier and leakage of serum proteins into brain parenchyma, also increase non-specific binding of secondary antibodies. The same can be said for weak tissue fixation over extended time (e.g., poor perfusion-fixation, fixation by immersion, etc.).

3) Influence of tissue preparation

Relative to antibody specificity, this issue is more versatile and complex and it can result in both, false-positive and false-negative results, even when using highly specific and well-characterized antibodies. As noted above, these effects arise mainly from epitope masking due to fixation-induced conformational changes and failure of the antibody to penetrate the tissue, as well as from non-specific binding of secondary antibodies, which can mask the specific signals. Furthermore, it needs to be emphasized that when antibodies do not recognize or do not have access to their epitope, they will typically bind non-specifically to other tissue components, and therefore produce false-positive results. Finally, it is important to realize that control tests performed with knockout tissue only provide information about false-positive results, but not false-negatives.

There are a number of published examples of pitfalls resulting from the influence of tissue preparation, notably fixation and the need in some cases, to use stringent methods for unmasking epitopes, in particular for postsynaptic proteins (Fritschy et al., 1998; Watanabe et al., 1998; Lorincz & Nusser, 2008).

The following aspects should be considered, when aiming at improving immunohistochemistry procedures because of apparent false-negative or false-positive results produced by an antibody. Typically, a compromise between preservation of the (ultra)-structure and staining sensitivity should be sought.

Reduce (or enhance) tissue fixation: type of fixative, pH, concentration, duration of the fixation (and postfixation), use of additives (e.g. picric acid). These effects are age-dependent (neonatal, but not adult, brain tissue benefits from a longer postfixation) and related to the nature of the antigen (soluble proteins tend to diffuse away in weakly fixed tissue).
When fixation has deleterious effects, consider using weak fixation by brief immersion of tissue slices or tissue sections, as described in detail in (Schneider Gasser et al., 2006).
Antigen-retrieval methods (e.g., heating/boiling tissue in acidic buffer; enzymatic digestion).
Use of detergent or repeated freeze/thaw to enhance penetration of the antibodies into the tissue.
Use of blocking solutions before and during primary antibody incubation. Note that in perfusion-fixed tissue, good results can be obtained without any pre-blocking step (see Fritschy & Mohler, 1995).
Temperature and duration of incubation in primary antibody and secondary antibody solution, as well as duration of the rinsing steps between antibody solutions. Here, an increase in signal-to-noise ratio can be achieved, sometimes with striking reduction of non-specific binding to tissue components.

	Standard perfusion-fixation for detection of neurochemical markers. Double immunofluorescence staining for calbindin (green), a cytoplasmic marker of Purkinje cells and vesicular glutamate transporter type 2 (red), a marker of climbing fiber terminals. Staining was performed on perfusion-fixed, free-floating tissue sections (Fritschy et al., 2006).
	High sensitivity detection of postsynaptic markers by antigen-retrieval (pepsin treatment). Double-immunofluorescence staining for postsynaptic markers (green; left, PSD-95; right, gephyrin) and presynaptic markers (red; left, vesicular glutamate transporter type 1; right, vesicular GABA transporter) in the hippocampus. Staining was performed using pepsin-mediated antigen retrieval. See Tyagarajan et al., 2011 for details.
	Combined detection of soluble cytoplasmic protein (eGFP) and postsynaptic markers in weakly fixed tissue. Triple-immunofluorescence staining showing the presence of GABAergic postsynaptic proteins – GABA_A receptor a2 subunit (red) and gephyrin (blue) – in relation to newborn granule cells in the olfactory bulb, selectively expressing eGFP (green) upon transduction with a lentivirus. The combination of eGFP and gephyrin immunofluorescence was achieved by preparing live tissue slices that were briefly fixed by immersion in a paraformaldehyde solution; see Panzanelli et al., 2009 for details.

Submitting to EJN

In the Author guidelines, EJN emphasizes the need to provide enough information in the Materials and Methods section to enable proper evaluation of the results and reproduction of the data. With regards to immunohistochemistry, detailed information about the antibodies used and about control experiments validating their specificity and the sensitivity of the method is mandatory. Authors should indicated which exact antibody was used (catalog and batch number, species of origin, immunogen information) and should provide information on the characterization of the antibody (description -or reference to experiments previously reported- performed to test its specificity, see EJN author guidelines). These requirements are in line with the policy of the Journal of Comparative Neurology, which refuses publication of articles that do not provide detailed characterization of antibodies used for immunohistochemistry. EJN encourages its contributors to consult the antibody database of the Journal of Comparative Neurology when selecting antibodies for experiments and when reporting their use in their manuscripts.

Despite these pitfalls of immunohistochemistry, only a minority of articles submitted to EJN fulfills these explicit requirements of the author guidelines. In 2008, in order to improve this situation, EJN published a technical spotlight emphasizing the necessity to check whether negative findings (failure to detect the antigen of interest in the sample analyzed) might be due to the method – in particular, tissue fixation – used for analysis (Fritschy, 2008).

We hope this article will help you to prepare and analyze your immunohistochemistry experiments. Please feel free to ask questions!

Useful resources:

The antibody database of the Journal of Comparative Neurology

Is my antibody staining specific? (Fritschy and Sarter, 2008)

References:

Fritschy, J.M. (2008) Is my antibody-staining specific? How to deal with pitfalls of immunohistochemistry. Eur. J. Neurosci., 28, 2365-2370.

Fritschy, J.M. & Mohler, H. (1995) GABA_A-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J. Comp. Neurol., 359, 154-194.

Fritschy, J.M., Panzanelli, P., Kralic, J.E., Vogt, K.E. & Sassoè-Pognetto, M. (2006) Differential dependence of axo-dendritic and axo-somatic GABAergic synapses on GABA_A receptors containing the a1 subunit in Purkinje cells. J. Neurosci., 26, 3245-3255.

Fritschy, J.M., Weinmann, O., Wenzel, A. & Benke, D. (1998) Synapse-specific localization of NMDA- and GABA_A-receptor subunits revealed by antigen-retrieval immunohistochemistry. J. Comp. Neurol., 390, 194-210.

Lorincz, A. & Nusser, Z. (2008) Specificity of immunoreactions: the importance of testing specificity in each method. J. Neurosci., 28, 9083-9086.

Panzanelli, P., Bardy, C., Nissant, A., Pallotto, M., Sassoè-Pognetto, M., Lledo, P.M. & Fritschy, J.M. (2009) Early synapse formation in developing interneurons of the adult olfactory bulb. J. Neurosci., 29, 15039-15052.

Schneider Gasser, E.M., Straub, C.J., Panzanelli, P., Weinmann, O., Sassoè-Pognetto, M. & Fritschy, J.M. (2006) Immunofluorescence in brain sections: simultaneous detection of presynaptic and postsynaptic proteins in identified neurons. Nature Protocols, 1, 1887-1897.

Tyagarajan, S.K., Ghosh, H., Yevenes, G.E., Nikonenko, I., Ebeling, C., Schwerdel, C., Sidler, C., Zeilhofer, H.U., Gerrits, B., Muller, D. & Fritschy, J.M. (2011) Regulation of GABAergic synapse formation and plasticity by GSK3beta-dependent phosphorylation of gephyrin. Proc. Natl. Acad. Sci. USA, 108, 379-384.

Watanabe, M., Fukaya, M., Sakimura, K., Manabe, T., Mishina, M. & Inoue, Y. (1998) Selective scarcity of NMDA receptor channel subunits in the stratum lucidum (mossy fibre-recipient layer) of the mouse hippocampal CA3 subfield. Eur. J. Neurosci., 10, 478-487.

Zattoni, M., Mura, M.L., Deprez, F., Schwendener, R., Engelhardt, B., Frei, K. & Fritschy, J.M. (2011) Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy. J. Neurosci., 31, 4037-4050.

Featured Article: The integrity of cholinergic basal forebrain neurons depends on expression of Nkx2-1

EJN Admin — Tue, 29 Nov 2011 12:17:15 +0000

The transcription factor Nkx2-1 belongs to the homeobox-encoding family of proteins that have essential functions in prenatal brain development. Nkx2-1 is required for the specification of cortical interneurons and several neuronal subtypes of the ventral forebrain. Moreover, this transcription factor is involved in migratory processes by regulating the expression of guidance molecules. Interestingly, Nkx2-1 expression was recently detected in the mouse brain at postnatal stages. Using two transgenic mouse lines that allow prenatal or postnatal cell type-specific deletion of Nkx2-1, we show that continuous expression of the transcription factor is essential for the maturation and maintenance of cholinergic basal forebrain neurons in mice. Notably, prenatal deletion of Nkx2-1 in GAD67-expressing neurons leads to a nearly complete loss of cholinergic neurons and parvalbumin-containing GABAergic neurons in the basal forebrain. We also show that postnatal mutation of Nkx2-1 in choline acetyltransferase-expressing cells causes a striking reduction in their number. These degenerative changes are accompanied by partial denervation of their target structures and results in a discrete impairment of spatial memory.

Article by: Lorenza Magno, Oliver Kretz, Bettina Bert, Sara Ersözlü, Johannes Vogt, Heidrun Fink, Shioko Kimura, Angelika Vogt, Hannah Monyer, Robert Nitsch and Thomas Naumann.

Read the full article on Wiley Online Library.

Also of interest

Read the corresponding commentary by Oscar Marin: A postnatal function for Nkx2-1 in basal forebrain integrity.

Editorial – EJN in the digital age: introducing the ‘EJN blog’

EJN Admin — Mon, 28 Nov 2011 14:00:21 +0000

One may ask, do we still need journals, and what are the advantages of journals having distinct identities? Should we simply deposit our manuscripts on the web, and let the scientific community judge their significance over time, on the basis of the number of citations? Given the increasingly specialized subfields in our rapidly maturing science, the number of scientists who are capable of judging the merits of a particular paper is exceedingly small. Therefore, when you read a paper outside your primary field of expertise, you trust that the journal ensures a level of scientific quality, making it worthwhile for you to read this paper and to stay informed about the larger neuroscience. More importantly, scientists already have a lot on their plate, and cannot afford to review the methods of each article that they read to judge whether the data are scientifically sound. A shared peer-reviewing system thus remains critical, and this can only be accomplished if journals have the proper staff and editorial boards…

This Editorial by Jean-Marc Fritschy and Martin Sarter explains why the EJN blog was created.

Access full-text article: download PDF

EJN now accepts PDF files for original submissions!

EJN Admin — Wed, 23 Nov 2011 14:21:20 +0000

When you submit a manuscript to EJN for the first time (original submission), you may now upload a single PDF file containing text and figures.

Please note this does not apply to revisions or resubmissions.

For full details please see author guidelines.

Special Issue: Molecular Mechanisms of Neuronal Differentiation

EJN Admin — Mon, 21 Nov 2011 09:39:33 +0000

What are the precise molecular and cellular mechanisms that the human brain exploits to encode consciousness, identity and thought? This remains undoubtedly one of the greatest scientific challenges facing mankind. This Special Issue addresses with eminent precision the rules that dictate the structural and functional diversity of neurons as well as the molecular principles that integrate these cells into coherent and dynamic networks during development. Read more…

Dystonia, An Attractive Field of Research

EJN Admin — Fri, 11 Nov 2011 02:18:50 +0000

What is Dystonia?

Dystonia is an umbrella term for a group of movement disorders in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. It is the third most common movement disorder, after Parkinson’s disease and tremor. The movements are involuntary, sometimes painful and can be incapacitating.

Symptoms may affect a single muscle, a muscle group (such as the arm, leg, or the neck), or the entire body including limbs, trunk, head, and face. Dystonia can affect several parts of the body. Early symptoms may include a deterioration in handwriting, foot cramps, and/or an abnormal gait often due to posture of the foot. The neck may turn or pull involuntarily, especially with fatigue or stress. Sometimes the eyes will blink uncontrollably or be involuntarily closed for a sustained period, causing functional blindness. Other possible symptoms are voice or speech difficulties due to muscle contractions of the larynx. Some patients develop a tremor. Initial symptoms of dystonia may be mild. The symptoms may intensify over time and spread to additional, often adjacent, areas of the body. In other cases, there is little or no progression. The earlier the age of onset, the more likely the form will be severe.

Several areas of the brain have been implicated in dystonia including the basal ganglia, cerebellum, thalamus, and cortex. Several neurotransmitters have also been implicated including GABA, dopamine, and acetylcholine. Secondary dystonia can result from environmental or disease-related damage to the basal ganglia. Birth injury, infection, drug exposure, heavy-metal or carbon monoxide poisoning, trauma, or stroke can cause dystonic symptoms. Dystonia can also occur as the symptom of other diseases, some of which may be hereditary. Many cases of dystonia have no connection to disease or injury and are classified as primary or idiopathic dystonia. Of the primary dystonias, some cases appear to be inherited in a dominant manner and with reduced penetrance. Several forms of dystonia have multiple genes or multiple mutations that are associated with symptoms. Some dystonias may have different types of hereditary patterns, including recessive and x-linked.

Dystonia is a Rubik’s cube of molecular, cellular, developmental, structural, functional, and medical facets. H. A. Jinnah, MD, PhD, Professor at Emory University and Principal Investigator of the Dystonia Coalition, explains how he came to be interested in studying dystonia and parts of the puzzle yet to be solved.

At the moment there is no cure for dystonia. Current pharmacological treatments are aimed at lessening the symptoms of muscle contractions, pain, and abnormal postures. In the most common and severe form of inherited dystonias (early-onset generalized dystonia), pharmacological treatment is often ineffective. However, clinical research has shown that deep brain stimulation (DBS) of the globus pallidus internus (GPi) nuclei is highly effective for these patients (first reports in the late 90′s). DBS surgery consists in the implantation of electrodes in the GPi, connected to a battery, implanted under the skin in the chest or abdomen. DBS treatment involves delivering high-frequency, low-voltage current in the grey nuclei. Recent studies have shown that benefits may be maintained over 10 years after initial surgery. The mechanism of action of DBS on dystonia remains unknown.

Video showing DBS surgery performed by the team of Philippe Coubes, MD, PhD, at the Gui de Chauliac University Hospital, Montpellier, France. The video presents MRI-based bilateral stereotactic electrode implantation, under general anesthesia.

What is the Dystonia Coalition?

The Dystonia Coalition is a collaboration of medical researchers and patient advocacy groups supported by the Office of Rare Diseases and The National Institute of Neurological Disorders and Stroke at the NIH. The mission is to advance the pace of clinical and translational research in the dystonias to find better treatments and a cure. The objectives are to develop a fuller understanding of the many different features of dystonia and how they change over the years, to develop validated diagnostic strategies and rating tools for diagnosis and monitoring patients in clinical trials, to establish a biorepository where samples of blood and other materials can be stored and distributed for research, to catalyze clinical trials for promising new treatments, and to promote education and awareness.

The Dystonia Coalition uses an open-door policy in which new investigators and institutions may join the effort at any time. Each of these centers may participate in ongoing research projects, submit proposals for new projects, or nominate candidates for career development awards.

Emory University serves as the Central Coordinating Center for the Dystonia Coalition’s activities. Three main research projects are directed through three Project Centers. Joel Perlmutter at Washington University in St. Louis is directing the Natural History with Linked Biorepository project encompassing all of the focal dystonias. Cynthia Comella at Rush University in Chicago is directing the project involving Development of Comprehensive Rating Tools for Cervical Dystonia. Christy Ludlow at James Madison University in Harrisonburg, VA is directing the development of a project involving Diagnostic and Rating Tools for Spasmodic Dysphonia. In addition to the four centers outlined above, the Dystonia Coalition has more than 40 Participating Clinical Centers distributed throughout North America and Europe. The Dystonia Coalition uses an open-door policy in which new investigators and institutions may join the effort at any time. Each of these centers may participate in ongoing research projects, submit proposals for new projects, or nominate candidates for career development awards.

H. A. Jinnah, MD, PhD discusses the origins of the Dystonic Coalition and some of the challenges of better understanding this disorder. The Dystonia Coalition is a collaboration of medical researchers and patient advocacy groups supported by the Office of Rare Diseases and The National Institute of Neurological Disorders and Stroke at the NIH. The mission is to advance the pace of clinical and translational research in the dystonias to find better treatments and a cure.

Integral to the mission are the patient advocacy groups. Each of the patient advocacy groups is encouraged to be involved in the yearly meeting of the Dystonia Coalition, participant in the Pilot Projects Program or Career Development Program, and refer patients to our centers for participation in studies or expert treatment, and help keep patients and providers well informed. The Dystonia Medical Research Foundation also serves as an administrative center.

The primary goal of the Dystonia Coalition is to conduct research relating to dystonia. The academic centers in the Dystonia Coalition all have a special interest in dystonia research as well as expertise in its diagnosis and treatment of all forms of dystonia. Patients come to these centers for both research opportunities and expert clinical care. The Dystonia Coalition welcomes patients to come for either or both.

Studying Dystonia Offers Great Opportunities for Neuroscientists. William Dauer, MD explains some of the factors that make dystonia an exciting and important topic worthy of greater attention from the neuroscience community. Known genes, lack of cell death, and abnormal connectivity of multiple motor system structures provide great incentive to study fundamental neuroscience problems. Dystonia is an ideal field for young investigators ready to engage in a complex and fascinating problem and ultimately help thousands of patients in the process.

Bios:

Philippe Coubes, MD, PhD, completed his Neurosurgery residency at the University Medical School of Montpellier (France) in 1989. He then received a PhD in Biomedical Sciences in 1995 at the University of Montpellier after being a trainee at the Cleveland Clinic (USA) in the departments of Neurological Surgery and Nuclear Medicine. Coubes is currently a Professor of the departments of Functional and Stereotactic Neurosurgery and Pediatric Neurosurgery at the Gui de Chauliac University Hospital in Montpellier, France. He is also the director of a Research Lab working on Movement Disorders (URMA) at the IGF institute, INSERM U661, CNRS UMR 5203, Montpellier. Coubes was one of the first neurosurgeons to adapt DBS for the treatment of dystonia. His work is focused on the mechanisms of action and long-term effects of DBS. Coubes receives public funding for patient care and his research is mostly supported by French patient foundations.

William Dauer, MD is an Elinor Levine Associate Professor of Neurology & Cell and Developmental Biology at the University of Michigan. He serves on a number of advisory boards including the Dystonia Medical Research Foundation (DMRF) Medical & Scientific Advisory Council. Dauer is a recipient of the DMRF’s most prestigious grant, the Stanley Fahn Award. The central goal of William Dauer’s studies is to unravel the molecular and cellular mechanisms of diseases that disrupt the motor system. The primary focus is on Parkinson’s disease and DYT1 dystonia. For each of these projects, special focus is directed toward disease genes that cause these disorders, employing a range of molecular, cellular, and whole animal studies to dissect the normal role of disease proteins, and how pathogenic mutations lead to disease. http://www.dauerlab.org/

H. A. Jinnah, MD, PhD received his BS from Duke University in 1985 and combined MD/PhD degrees in Neurosciences via the NIH-sponsored Medical Scientist Training Program at the University of California in San Diego in 1993. He completed a Neurology Residency and Fellowship in Movement Disorders at Johns Hopkins University in 1997. He is currently a Professor in the Departments of Neurology, Human Genetics & Pediatrics at Emory University, Atlanta. Jinnah’s research interests are in the biological basis for neurological and behavioral disorders with a special interest in the biological basis of dystonia. The research strategy involves two complementary approaches. One approach entails studies of biological mechanisms responsible for dystonia in Lesch-Nyhan disease, a rare neurogenetic disorder for which the genetic mutations and biochemical defects are known. The other approach involves the investigation of biological mechanisms shared by different forms of dystonia, with the goal of identifying final common molecular and neural pathways. His laboratory takes a multidisciplinary approach that encompasses molecular genetics, biochemistry, cell biology, anatomy and histopathology, neuropharmacology, and animal models. The laboratory programs are linked with a clinical research program that addresses the same problems in humans and their treatments. Jinnah has received both private and NIH funding for his research programs since 1997. He has served on a number of advisory boards including the Dystonia Medical Research Foundation.

ADDITIONAL LINKS

Dystonia Medical Research Foundation

http://www.dystonia-foundation.org

Faces of Dystonia

http://www.dystonia-foundation.org/faces_of_dystonia

Dystonia Coalition

http://rarediseasesnetwork.epi.usf.edu/dystonia

We wish to thank the members of the Dystonia Medical Research Foundation (DMRF) for helping put this content together, as well as the video participants.

FENS EJN Award 2012

EJN Admin — Fri, 04 Nov 2011 15:05:10 +0000

Winner 2012: Barry Everitt, Professor of Behavioral Neuroscience at the University of Cambridge and Master of Downing College

The FENS EJN Award is given in recognition of outstanding scientific work in all areas of neuroscience. The award is a personal prize of £10,000, sponsored by Wiley-Blackwell (publishers of EJN). This prize is awarded once every two years and is presented to the recipient at the occasion of the FENS forums of Neuroscience.

We are pleased to announce that Barry Everitt, Professor of Behavioral Neuroscience at the University of Cambridge and Master of Downing College, is the 2012 winner of the FENS EJN Award.

Barry Everitt’s research has contributed immensely to our understanding of the neural mechanisms of reward mechanisms, drug-seeking behavior and relapse. Dr. Everitt’s work has had a tremendous impact on the field as indicated, for example, that he is among the world’s 100 most highly cited neuroscientists.

Barry Everitt will be honored at the occasion of a special lecture to be given by the awardee at the 2012 FENS Forum of Neuroscience in Barcelona (July 14-18, 2012).

Preparation of neuronal cell cultures

EJN Admin — Fri, 04 Nov 2011 14:35:50 +0000

This video shows how to prepare rat embryonic cultures of hippocampal neurons, step by step and how the neurons should look like once cultured in vitro. This video was made by the Fritschy Lab at the University of Zurich.

Dowload pdf protocol

How to Get Funding in the Non-Profit Landscape

EJN Admin — Fri, 04 Nov 2011 14:15:49 +0000

Ashley E. Brady, Ph.D., is Associate Director of Foundation Relations at Vanderbilt University.

Perhaps now, more than ever before, a successful independent research career depends not only on your skills as a scientific investigator, but also on your ability to identify and navigate various complex funding mechanisms in order to compete successfully for grants and awards to support your work. For this reason, it is important to consider all of your options for obtaining research support and to broaden your portfolio of funding by including awards from both the government and non-profit organizations.

Non-Profit Foundations

Foundations offer a number of research grants to scientists that vary widely in their size and scope, but with each organization having its own quirks and personality, navigating the foundation landscape can prove to be a full time job in itself. There are a few key points to keep in mind when considering seeking support from a foundation or other non-governmental organization.

Foundations are often focused on advancing research into a particular disease, so it is critical that you understand what the goal of the foundation is in order to make sure you gear your work to that priority. This may require you to challenge yourself by thinking much more broadly about your area of research as well as considering the translation potential of the work you propose.

If you are a young trainee or new faculty member, this can be an ideal time for you because foundations are often very interested in supporting young investigators. In many cases, foundations are not able to fund at the level of larger, government awards, so they look for a niche where they can have the most impact. Often, this comes by helping to grow the number of new researchers in their field of interest. They realize that a modest amount of funding in the early years can keep a budding scientist in the game long enough to gain traction.

Foundations are also particularly interested in supporting riskier, out-of the box- ideas that may be supported by little preliminary data, but which may have a significant impact on the field if they succeed.

This may allow you the flexibility to do something entirely new that you haven’t been able to try before. Furthermore, many foundations are public charities which garner most of their financial resources from public fundraising so they need success stories to take back to their donors to show them that they have used their money wisely and gained a significant return on their investment.

Balancing your funding portfolio with foundation funding is also a great idea because it allows you the opportunity to forge a long term relationship with a foundation. The benefits of this may be invitations to attend private meetings with other awardees, networking opportunities with various experts in your field, requests to serve on the scientific review committee, or to speak at a conference for patients and caregivers. Many foundation awards carry a great deal of prestige and can enhance recognition in your field. If you have been funded by one foundation, then the next may be even more willing to take a chance on you.

Advice to graduate students and post doctoral fellows:

As a trainee, if you are serious about a successful career in research, it is critically important to start taking advantage of the independent funding opportunities that are available to you at this stage in your career. I often hear the phrase “past performance predicts future success”, so there is no better time to start to build your credentials in this arena. This is an excellent time to sit down and map out a long term plan for the different awards you should plan to compete for in order to position yourself for full independence.

The earlier you begin to secure funding, the easier it will be later in your career.

Furthermore, writing grants, especially good ones, is a learned skill that will improve the more you do it, so make this part of your overall training experience. Moreover, during your training period, you are only seeking funding for your (often) modest salary, and you do not need much more in the way of support for the actual research. As such, there are generally more awards to go around and the competition is not quite as tough.

One piece of advice that I had not considered when I was training is to cultivate a relationship with someone who is an expert in your field, but not a former mentor or collaborator and who is not at your institute, who could write a reference letter for you attesting to your contribution to the field and potential to impact the future of research in this area. This may be someone who has seen you speak at a national meeting, or you who have actively sought as a mentor to review your manuscripts and give you guidance. This can be viewed as a particularly strong recommendation by the reviewers, and is even a requested component of some privately funded award applications.

Keep in mind as you prepare your application that awards at this level are granted for training purposes, meaning that they are as much about your mentor as they are about you. Make sure that you work with your mentor to develop a strong training plan in which you describe specific and tangible training opportunities that will be available to you.

Some Tips for Successful Proposals:

Do your Research:

Identify the mission of the organization and write to this mission.

No matter how good your idea or grant is, if it is outside the scope of their mandate, you will not be successful.

Review past funded projects to make sure that your proposed work fits well. If all the projects that have been supported have a translational or clinical component to them, a completely basic research program may not be of interest.
Contact the program officer or grants director ahead of time to discuss your proposal idea. This can prove beneficial no matter what type of organization you are seeking funding from, as this person can guide you and may encourage you to submit an idea you had not considered.
Know who your audience is by researching your reviewers. This is especially true of foundation applications where there may or may not be a scientific review committee, and even if there is, they may not be experts in your particular area.

Play by the Rules:

Read the directions carefully and follow them. While seemingly trivial, you do not want your application tossed out on a technicality before a reviewer has even seen it. This can be especially important with proposals to foundations, where there may be very specific requirements. For example, in addition to length, font, and other formatting rules, they also may require multiple hard copies, with or without staples or clips, or for electronic submissions, they may require the files to be named very specifically.
Verify eligibility ahead of time. If you are unsure, contact the organization. Often there are very specific rules as to what other awards you may currently hold or apply for, as well as how many years you have been in your faculty or training position.
Be aware of deadlines and submission requirements. Some organizations will require electronic submission only, others will require a hard copy, or even both. Does the organization require the application to be postmarked by the deadline, or physically in the office?
Watch carefully for ‘Letter of Intent’ deadlines which may be weeks to months prior to the full proposal deadline. These are becoming more and more common as funders try to streamline the amount of work and effort on both their end and yours.

Sell your Idea:

Explain how funding will impact the area in which you are working and will help to move it forward in new and important ways.
Point out why the particular funding mechanism you are seeking is ideal for your proposed studies. If you are applying to a foundation for seed funding for a pilot study, indicate how this work might not otherwise be supported, but that successful completion of the proposed aims will help move the project to the next level.
Demonstrate your ability to carry out the project, highlighting your past successes and unique skills, carefully selecting appropriate collaborators and/or consultants (include letters of support), and describing support, resources and infrastructure available at your research institute.
If you are applying for a career development award, make sure to point out how obtaining this award will impact your career and allow you to learn skills, publish, and engage colleagues such that you will be even more competitive for other awards. Do not take “training opportunities” for granted, and be specific. Cite journal clubs, departmental seminars, lab meetings, regular meetings with your mentor or career development committee, departmental retreats, classes you can audit, national meetings you plan to attend, opportunities to speak in front of peers and your plans for publication etc…

Write it Well:

No matter how great your idea is, it must be well written or it will not be successful. Plan ahead and do not wait until the last minute- it will show in your writing. Engage others to help you revise and polish.
If you are not instructed otherwise, set up the first page of your document so that it clearly and concisely lays out the significance of the studies you want to undertake, your main hypothesis, and the aims/ methods you propose to test your theory. This section should captivate your audience because sometimes this may be all that the reviewer has time to read.
Your proposed aims should be specific, testable, and never dependent on one another. Each should stand alone such that you can continue with the next aim if the first fails.
Never ask the reader to “figure it out”. Make your rationale clear. Just because it is in your head, does not mean the reader can infer it, or wants to take the time to put the pieces together. Always strive to make the reader’s job as easy as possible.
Never blow off the abstract. This may also be one of the few pieces of the grant that is actually read by busy and overworked reviewers. Especially with foundations, when a lay abstract is requested, take this seriously and prepare it with thought. There are times when a layperson will serve on the review committee and selling that person on your proposal may pay in dividends. Enlist a friend who is not a scientist to read your lay abstract and provide comments.

Stand Out Among Others:

(These tips are perhaps most important when dealing with foundation awards, as opposed to government grants)

Submit your progress reports on time. Be respectful of others’ time and never make them chase you down.
Remember to cite each organization’s support of your work in your manuscripts and posters
Consider writing a “Thank you” letter. This can be done when you first receive your funding and at the end of the funding period. Even when your grant is not funded, you may want to send a note thanking the reviewers for taking the time to read and process your grant, especially if you received feedback. You never know how far this might go if you resubmit at a later time.
After the grant is completed, continue to update the organization on your progress. If you receive a large award or honor, or contribute to an important publication, let the funding organization know and thank them for their support so they know you appreciate their prior investment in you.
Be willing to help if asked. Organizations that have supported you may ask you to serve on their review board or study section, speak at a conference, or moderate an event. Be generous with your time.

Resources:

Grant Searches:

Community of Science: www.cos.org
Research Professional: www.researchprofessional.org

Writing:

Zeiger, M. Essentials of Writing Biomedical Research Papers. 2^nd Ed. McGraw-Hill. 2000.

Russell, S.W. and Morrison, D.C. The Grant Application Writer’s Workbook: Successful Proposals to Any Agency. Grant Writers’ Seminars and Workshops. 2005. (available at www.grantcentral.com)

Gopen, G.D. and Swan, J.A. “The Science of Scientific Writing.” American Scientist. 78:550-559. 1990.

Articles:

Powell, K. Making the Cut. Nature. 467:383-385. 2010.

Websites:

Guide for Writing a Funding Proposal: S. Joseph Levine, Michigan State University

http://www.learnerassociates.net/proposal/

Guidelines for writing grant applications from Frontiers in Bioscience:

http://www.bioscience.org/current/grant.htm

The Author:

Ashley E. Brady, Ph.D., is Associate Director of Foundation Relations at Vanderbilt University where she has served for the past two years. She is an experienced biomedical research scientist with expertise in molecular pharmacology, drug discovery and translational neuropharmacology. Prior to her current role, she obtained her Ph.D. in Pharmacology from Vanderbilt University in 2003 where she was supported by a PhRMA Foundation pre-doctoral fellowship. After completing her Ph.D., she received the Chateaubriand Fellowship from the French Embassy which allowed her to pursue a year of post-doctoral studies at the Institute de Génomique Fonctionnelle (IGF) at the Centre Nationale de Researche Scientifique (CNRS) in Montpellier, France. She then returned to Vanderbilt where she continued her post-doctoral training in the Department of Pharmacology and was awarded an individual Ruth L. Kirschstein National Research Service Award (NRSA) from the National Institute of Mental Health. In her current role, she identifies funding opportunities and reviews grants for faculty and trainees and is often invited to speak at various workshops and symposia at Vanderbilt University on the topic of successfully seeking and applying for research funding.

FENS EJN Young Investigator Award

EJN Admin — Fri, 04 Nov 2011 09:40:32 +0000

2012 winner: Oscar Marin, Professor of Developmental Neurobiology at the Neuroscience Institute, joint centre of the Spanish research Council (CSIC) and the Miguel Hernandez University (UMH).

The FENS EJN Young Investigator Award is a biennial prize and given in recognition of outstanding scientific work in all areas of neuroscience to a researcher under 40 years of age at the time of application. The award is a personal prize of £7,00, sponsored by Wiley-Blackwell (publishers of EJN). This prize is presented to the recipient at the occasion of the FENS forums of Neuroscience.

We are pleased to announce that Oscar Marin, Professor of Developmental Neurobiology at the Neuroscience Institute, joint centre of the Spanish research Council (CSIC) and the Miguel Hernandez University (UMH), is the 2012 winner of the FENS Young Investigator Award.

Oscar Marin is a leading researcher in the field of cortical development. He has made several seminal discoveries about the specification, migration, and functional integration of GABAergic interneurons in the neocortex during ontogeny. His research also focuses on harnessing neuronal progenitors derived from the ganglionic eminence for neuron-replacement therapies.

Oscar Marin is also a Founding member of the Scientific Council of the European Research Council and has contributed tremendously to the success of ERC grants, which are among the most prestigious research grants of the EU.

Oscar Marin will be honored at the occasion of a special lecture to be given by the awardee at the 2012 FENS Forum of Neuroscience in Barcelona (July 14-18, 2012).

Welcome to the EJN blog!

EJN Admin — Thu, 03 Nov 2011 14:49:45 +0000

The Editorial Office Team of EJN introduces you to the EJN blog.

Why would you pay to get published?

EJN Admin — Thu, 27 Oct 2011 14:42:41 +0000

An enormous number of ‘Open Access’ (OA) journals have emerged in recent years, and these compete for your publications in neurosciences. This Editorial by Jean-Marc Fritschy and Martin Sarter touches on the OA environment and how EJN fits in the landscape.

Read this Editorial in full on Wiley Online Library.

Combined delivery of Nogo-A antibody, neurotrophin-3 and the NMDA-NR2d subunit establishes a functional ‘detour’ in the hemisected spinal cord

EJN Admin — Thu, 13 Oct 2011 13:59:14 +0000

To encourage re-establishment of functional innervation of ipsilateral lumbar motoneurons by descending fibers after an intervening lateral thoracic (T10) hemisection (Hx), we treated adult rats with the following agents: (i) anti-Nogo-A antibodies to neutralize the growth-inhibitor Nogo-A; (ii) neurotrophin-3 (NT-3) via engineered fibroblasts to promote neuron survival and plasticity; and (iii) the NMDA-receptor 2d (NR2d) subunit via an HSV-1 amplicon vector to elevate NMDA receptor function by reversing the Mg²⁺ block, thereby enhancing synaptic plasticity and promoting the effects of NT-3. Synaptic responses evoked by stimulation of the ventrolateral funiculus ipsilateral and rostral to the Hx were recorded intracellularly from ipsilateral lumbar motoneurons. In uninjured adult rats short-latency (1.7-ms) monosynaptic responses were observed. After Hx these monosynaptic responses were abolished. In the Nogo-Ab + NT-3 + NR2d group, long-latency (approximately 10 ms), probably polysynaptic, responses were recorded and these were not abolished by re-transection of the spinal cord through the Hx area. This suggests that these novel responses resulted from new connections established around the Hx. Anterograde anatomical tracing from the cervical grey matter ipsilateral to the Hx revealed increased numbers of axons re-crossing the midline below the lesion in the Nogo-Ab + NT-3 + NR2d group. The combined treatment resulted in slightly better motor function in the absence of adverse effects (e.g. pain). Together, these results suggest that the combination treatment with Nogo-Ab + NT-3 + NR2d can produce a functional ‘detour’ around the lesion in a laterally hemisected spinal cord. This novel combination treatment may help to improve function of the damaged spinal cord. Read the full article on Wiley Online Library.

Also of interest

Read the corresponding commentary by Jacqueline C. Bresnahan & Michael S. Beattie on this article: Spinal cord injury: taking a detour to recovery

Neuroscience Peer Review Consortium

EJN Admin — Sat, 01 Oct 2011 11:00:36 +0000

EJN is member of the Neuroscience Peer Review Consortium (NPRC). The Consortium is an alliance of neuroscience journals that have agreed to share manuscript reviews, at the author’s request. Its goal is to speed and enhance thorough peer review by reducing the number of times that manuscripts are reviewed.

Manuscripts that are not accepted for publication in a Consortium journal can be submitted to another Consortium journal after appropriate revision and have their reviews forwarded to facilitate the second evaluation process. By reducing or eliminating the need for new reviews at the second

The Neuroscience Peer Review Consortium has been formed to reduce the time and effort involved in the peer review of original neuroscience research reports.

journal, this process has the potential to reduce workloads and speed the publication of new data.

Journals members of NPRC do not accept “confidential comments to the editors” anymore in order to achieve a more transparent review process.

A complete list of Consortium journals and details of the review-sharing process can be found at the Consortium’s website, which is hosted by the International Neuroinformatics Coordinating Facility. Although the Consortium provides a valuable new opportunity, no one is required to take part. If authors do not wish to have their reviews forwarded, nothing will be exchanged between journals, and authors can submit their manuscript to another journal without its history being known. Similarly, if reviewers do not want their identity revealed to editors at a second journal, they have the option of remaining anonymous to external editors.

Towards a Comparative Understanding of Adult Neurogenesis

EJN Admin — Mon, 19 Sep 2011 11:00:55 +0000

Guest Editors: L. Bonfanti and G Zupanc

Despite the considerable enthusiasm for research on adult neurogenesis, there are a strikingly low number of comparative studies in this field. However knowledge from comparative studies may provide clues about the biological function of adult neurogenesis, which remains largely elusive in the intact mammalian brain. This Special Issue summarizes recent findings derived from a cross-species comparative perspective. Read more…

NIH-funded authors and EJN

EJN Admin — Thu, 01 Sep 2011 14:42:11 +0000

From April 2008, the NIH is mandating grantees to deposit their peer-reviewed author manuscripts in PubMed Central, to be made publicly available within 12 months of publication. The NIH mandate applies to all articles based on research that has been wholly or partially funded by the NIH and that are accepted for publication on or after April 7, 2008. In order to help authors comply with the NIH mandate, for papers accepted for publication in European Journal of Neuroscience after this date Wiley-Blackwell will post the accepted manuscript (incorporating all amendments made during peer review, but prior to the publisher’s copy-editing and typesetting) of articles by NIH grant-holders to PubMed Central at the point of acceptance by the journal. This version will then be made publicly available in PubMed Central 12 months after publication. Following the deposit Wiley-Blackwell authors will receive further communications from the NIH with respect to the submission. For further information, see here.

If authors wish to make their final published article openly accessible and without a 12 month embargo, they can choose to publish via the OnlineOpen service.

Wellcome and HHMI grantees can find out further information here.

The neural network of phantom sound changes over time: a comparison between recent-onset and chronic tinnitus patients

EJN Admin — Tue, 16 Aug 2011 14:03:54 +0000

Tinnitus is characterized by an ongoing conscious perception of a sound in the absence of any external sound source. Chronic tinnitus is notoriously characterized by its resistance to treatment. In the present study the objective was to verify whether the neural generators and/or the neural tinnitus network, evaluated through EEG recordings, change over time as previously suggested by MEG. We therefore analyzed the source-localized EEG recordings of a very homogenous group of left-sided narrow-band noise tinnitus patients. Results indicate that the generators involved in tinnitus of recent onset seem to change over time with increased activity in several brain areas [auditory cortex, supplementary motor area and dorsal anterior cingulate cortex (dACC) plus insula], associated with a decrease in connectivity between the different auditory and nonauditory brain structures. An exception to this general connectivity decrease is an increase in gamma-band connectivity between the left primary and secondary auditory cortex and the left insula, and also between the auditory cortices and the right dorsal lateral prefrontal cortex. These networks are both connected to the left parahippocampal area. Thus acute and chronic tinnitus are related to differential activity and connectivity in a network comprising the auditory cortices, insula, dACC and premotor cortex. Read the full article on Wiley Online Library.

Also of interest

Read the corresponding commentary by Rodolfo Llinas on this article: Tinnitus: where is the source

The diffusional properties of dendrites depend on the density of dendritic spines

EJN Admin — Tue, 19 Jul 2011 14:06:11 +0000

We combined computational modeling and experimental measurements to determine the influence of dendritic structure on the diffusion of intracellular chemical signals in mouse cerebellar Purkinje cells and hippocamal CA1 pyramidal cells. Modeling predicts that molecular trapping by dendritic spines causes diffusion along spiny dendrites to be anomalous and that the value of the anomalous exponent (d_w) is proportional to spine density in both cell types. To test these predictions we combined the local photorelease of an inert dye, rhodamine dextran, with two-photon fluorescence imaging to track diffusion along dendrites. Our results show that anomalous diffusion is present in spiny dendrites of both cell types. Further, the anomalous exponent is linearly related to the density of spines in pyramidal cells and d_win Purkinje cells is consistent with such a relationship. We conclude that anomalous diffusion occurs in the dendrites of multiple types of neurons. Because spine density is dynamic and depends on neuronal activity, the degree of anomalous diffusion induced by spines can dynamically regulate the movement of molecules along dendrites. Read the full article on Wiley Online Library.

Also of interest

Read the corresponding commentary by Chris I. De Zeeuw and Tycho M. Hoogland on this article: Anomalous diffusion imposed by dendritic spines

Spatiotemporal specificity of GABAA receptor-mediated regulation of adult hippocampal neurogenesis

EJN Admin — Mon, 04 Jul 2011 14:07:31 +0000

GABAergic transmission regulates adult neurogenesis by exerting negative feedback on cell proliferation and enabling dendrite formation and outgrowth. Further, GABAergic synapses target differentiating dentate gyrus granule cells prior to formation of glutamatergic connections. GABA_A receptors (GABA_ARs) mediating tonic (extrasynaptic) and phasic (synaptic) transmission are molecularly and functionally distinct, but their specific role in regulating adult neurogenesis is unknown. Using global and single-cell targeted gene deletion of subunits contributing to the assembly of GABA_ARs mediating tonic (α4, δ) or phasic (α2) GABAergic transmission, we demonstrate here in the dentate gyrus of adult mice that GABA_ARs containing α4, but not δ, subunits mediate GABAergic effects on cell proliferation, initial migration and early dendritic development. In contrast, α2-GABA_ARs cell-autonomously signal to control positioning of newborn neurons and regulate late maturation of their dendritic tree. In particular, we observed pruning of distal dendrites in immature granule cells lacking the α2 subunit. This alteration could be prevented by pharmacological inhibition of thrombospondin signaling with chronic gabapentin treatment, shown previously to reduce glutamatergic synaptogenesis. These observations point to homeostatic regulation of inhibitory and excitatory inputs onto newborn granule cells under the control of α2-GABA_ARs. Taken together, the availability of distinct GABA_AR subtypes provides a molecular mechanism endowing spatiotemporal specificity to GABAergic control of neuronal maturation in adult brain. Read the full article on Wiley Online Library.

Also of interest

Read the corresponding commentary by Angelique Bordey on this article: Adult-born neuron development is controlled by GABAA receptor subtypes

Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy

EJN Admin — Thu, 30 Jun 2011 14:12:27 +0000

Epilepsy is a heterogeneous neurological disease affecting approximately 50 million people worldwide. Genetic factors play an important role in both the onset and severity of the condition, with mutations in several ion-channel genes being implicated, including those encoding the GABA_A receptor. Here, we evaluated the frequency of additional mutations in the GABA_A receptor by direct sequencing of the complete open reading frame of the GABRA1 and GABRG2 genes from a cohort of French Canadian families with idiopathic generalized epilepsy (IGE). Using this approach, we have identified three novel mutations that were absent in over 400 control chromosomes. In GABRA1, two mutations were found, with the first being a 25-bp insertion that was associated with intron retention (i.e. K353delins18X) and the second corresponding to a single point mutation that replaced the aspartate 219 residue with an asparagine (i.e. D219N). Electrophysiological analysis revealed that K353delins18X and D219N altered GABA_A receptor function by reducing the total surface expression of mature protein and/or by curtailing neurotransmitter effectiveness. Both defects would be expected to have a detrimental effect on inhibitory control of neuronal circuits. In contrast, the single point mutation identified in the GABRG2gene, namely P83S, was indistinguishable from the wildtype subunit in terms of surface expression and functionality. This finding was all the more intriguing as the mutation exhibited a high degree of penetrance in three generations of one French Canadian family. Further experimentation will be required to understand how this mutation contributes to the occurrence of IGE in these individuals. Read the full article on Wiley Online Library.

Also of interest

Read the corresponding commentary by Christopher A. Reid and Dimitri M. Kullmann on this article: GABAA receptor mutations in epilepsy

Special Issue: Saccade, Search and Orient: The Neural Control of Saccadic Eye Movements

EJN Admin — Wed, 01 Jun 2011 13:35:49 +0000

One of the most important functions of the brain is to guide our behavior through an ever-changing environment. Circuitries executing and modulating saccadic eye movements represent an elegant model system for investigating how sensory information and goal-related information interact to control and coordinate behavior.

The articles in this Special Issue of EJN cover the full scope of research in this exciting field, ranging from midbrain, thalamic, striatal, and cortical circuitry controlling and influencing eye movements to oculomotor functions in REM sleep and learning.

Read the entire issue on Wiley Online Library.

Differentiable contributions of human amygdalar subregions in the computations underlying reward and avoidance learning

EJN Admin — Tue, 03 May 2011 14:13:41 +0000

To understand how the human amygdala contributes to associative learning, it is necessary to differentiate the contributions of its subregions. However, major limitations in the techniques used for the acquisition and analysis of functional magnetic resonance imaging (fMRI) data have hitherto precluded segregation of function with the amygdala in humans. Here, we used high-resolution fMRI in combination with a region-of-interest-based normalization method to differentiate functionally the contributions of distinct subregions within the human amygdala during two different types of instrumental conditioning: reward and avoidance learning. Through the application of a computational-model-based analysis, we found evidence for a dissociation between the contributions of the basolateral and centromedial complexes in the representation of specific computational signals during learning, with the basolateral complex contributing more to reward learning, and the centromedial complex more to avoidance learning. These results provide unique insights into the computations being implemented within fine-grained amygdala circuits in the human brain. Read the full article on Wiley Online Library.

Also of interest

Read the corresponding commentary by Kevin S. LaBar on this article: Cracking the almond

Neural correlates of Pavlovian-to-instrumental transfer in the nucleus accumbens shell are selectively potentiated following cocaine self-administration

EJN Admin — Wed, 20 Apr 2011 14:14:42 +0000

During Pavlovian-to-instrumental transfer (PIT), learned Pavlovian cues significantly modulate ongoing instrumental actions. This phenomenon is suggested as a mechanism under which conditioned stimuli may lead to relapse in addicted populations. Following discriminative Pavlovian learning and instrumental conditioning with sucrose, one group of rats (naive) underwent electrophysiological recordings in the nucleus accumbens core and shell during a single PIT session. Other groups, following Pavlovian and instrumental conditioning, were subsequently trained to self-administer cocaine with nosepoke responses, or received yoked saline infusions and nosepoked for water rewards, and then performed PIT while electrophysiological recordings were taken in the nucleus accumbens. Behaviorally, although both naive and saline-treated groups showed increases in lever pressing during the conditioned stimulus cue, this effect was significantly enhanced in the cocaine-treated group. Neurons in the core and shell tracked these behavioral changes. In control animals, core neurons were significantly more likely to encode general information about cues, rewards and responses than those in the shell, and positively correlated with behavioral PIT performance, whereas PIT-specific encoding in the shell, but not core, tracked PIT performance. In contrast, following cocaine exposure, there was a significant increase in neural encoding of all task-relevant events that was selective to the shell. Given that cocaine exposure enhanced both behavior and shell-specific task encoding, these findings suggest that, whereas the core is important for acquiring the information about cues and response contingencies, the shell is important for using this information to guide and modulate behavior and is specifically affected following a history of cocaine self-administration. Read the full article on Wiley Online Library.

Also of interest

Read the corresponding commentary by Kyle S. Smith on this article: Neuronal correlates of normal and drug-potentiated Pavlovian–instrumental transfer

Reduction in hippocampal neurogenesis after social defeat is long-lasting and responsive to late antidepressant treatment

EJN Admin — Thu, 14 Apr 2011 14:47:05 +0000

Major depressive disorder is a chronic disabling disease, often triggered and exacerbated by stressors of a social nature. Hippocampal volume reductions have been reported in depressed patients. In support of the neurogenesis theory of depression, in several stress-based animal models of depression, adult hippocampal neurogenesis was reduced and subsequently rescued by parallel antidepressant treatment. Here, we investigated whether repeated social defeat and subsequent individual housing for 3 months induces long-lasting changes in adult hippocampal neurogenesis in rats, and whether these can be normalized by late antidepressant treatment, as would match human depression. Neurogenesis was analysed by stereological quantification of the number of immature doublecortin (DCX)-immunopositive cells, in particular young (class I) and more mature (class II) DCX⁺ cells, to distinguish differential effects of stress or drug treatment on these subpopulations. Using this social defeat paradigm, the total DCX⁺ cell number was significantly reduced. This was most profound for older (class II) DCX⁺ cells with long apical dendrites, whereas younger, class I cells remained unaffected. Treatment with the broad-acting tricyclic antidepressant imipramine, only during the last 3 weeks of the 3-month period after social defeat, completely restored the reduction in neurogenesis by increasing both class I and II DCX⁺cell populations. We conclude that despite the lack of elevated corticosterone plasma levels, neurogenesis is affected in a lasting manner by a decline in a distinct neuronal population of more mature newborn cells. Thus, the neurogenic deficit induced by this social defeat paradigm is long-lasting, but can still be normalized by late imipramine treatment. Read the full article on Wiley Online Library.

Also of interest

Read the corresponding commentary by Carmen Sandi on this article: Extending the impact of stress on hippocampal neurogenesis

Reduction in hippocampal neurogenesis after social defeat is long-lasting and responsive to late antidepressant treatment

EJN Admin — Thu, 14 Apr 2011 14:15:41 +0000

Major depressive disorder is a chronic disabling disease, often triggered and exacerbated by stressors of a social nature. Hippocampal volume reductions have been reported in depressed patients. In support of the neurogenesis theory of depression, in several stress-based animal models of depression, adult hippocampal neurogenesis was reduced and subsequently rescued by parallel antidepressant treatment. Here, we investigated whether repeated social defeat and subsequent individual housing for 3 months induces long-lasting changes in adult hippocampal neurogenesis in rats, and whether these can be normalized by late antidepressant treatment, as would match human depression. Neurogenesis was analysed by stereological quantification of the number of immature doublecortin (DCX)-immunopositive cells, in particular young (class I) and more mature (class II) DCX⁺ cells, to distinguish differential effects of stress or drug treatment on these subpopulations. Using this social defeat paradigm, the total DCX⁺ cell number was significantly reduced. This was most profound for older (class II) DCX⁺ cells with long apical dendrites, whereas younger, class I cells remained unaffected. Treatment with the broad-acting tricyclic antidepressant imipramine, only during the last 3 weeks of the 3-month period after social defeat, completely restored the reduction in neurogenesis by increasing both class I and II DCX⁺ cell populations. We conclude that despite the lack of elevated corticosterone plasma levels, neurogenesis is affected in a lasting manner by a decline in a distinct neuronal population of more mature newborn cells. Thus, the neurogenic deficit induced by this social defeat paradigm is long-lasting, but can still be normalized by late imipramine treatment.

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Spatiotemporal specificity of GABAA receptor-mediated regulation of adult hippocampal neurogenesis

Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy

Special Issue: Saccade, Search and Orient: The Neural Control of Saccadic Eye Movements

Differentiable contributions of human amygdalar subregions in the computations underlying reward and avoidance learning

Neural correlates of Pavlovian-to-instrumental transfer in the nucleus accumbens shell are selectively potentiated following cocaine self-administration

Reduction in hippocampal neurogenesis after social defeat is long-lasting and responsive to late antidepressant treatment

Reduction in hippocampal neurogenesis after social defeat is long-lasting and responsive to late antidepressant treatment