Functional Neurogenesis

Now that I have something to show for it, let this be a formal announcement that I’ve returned to Toronto to join Paul Frankland’s lab (and therefore the larger Josselyn-Frankland group). I’ve always liked their work and one of the techniques I’m excited to learn is the use of viruses to alter gene expression in neurons. BECAUSE THIS WILL ALLOW ME TO TAKE PRETTY PICTURES!!! I will also say that this will be a short (but hopefully sweet) stay as I’ll be leaving at the end of the year to start my own lab in the Psychology Department at the University of British Columbia (!).

Now, on with the pictures! As always, I recommend high-res viewing (click on the image to view it, bigger, on Flickr).

Using a retrovirus, which infects dividing cells, I made the amazing discovery of four adult-born cells which all had the exact same shape and were located right next to each other!
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The idea that adult neurogenesis protects individuals from depression is perhaps the single greatest motivator driving neurogenesis research. Not surprisingly, “neurogenesis depression” is the most common behavioral keyword that brings people to this blog (followed closely by “pattern separation”). So I’m excited to say that we will soon be publishing what (I think) is the best evidence that impaired adult neurogenesis actually causes depressive symptoms (in mice). The neurogenesis-depression hypothesis is over 10 years old and yet there is largely only correlational evidence linking neurogenesis to depression and no direct evidence that impaired adult neurogenesis leads to depressive symptoms. Naturally, this has led to skepticism (e.g. see this paper by Robert Sapolsky, and discussion by fellow bloggers: scicurious, neurocritic, neuroskeptic). A key factor in our study was stress: mice that lacked neurogenesis often seemed very normal when they were happily going about their business (as in previous studies by other groups). However, following stress, mice lacking neurogenesis had elevated levels of stress hormones and they also showed more depressive behaviors (or depressive-like, if you prefer). I hope to go into more detail soon.

For now, here is the abstract:

Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Jason S. Snyder, Amélie Soumier, Michelle Brewer, James Pickel & Heather A. Cameron. National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.

Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness. In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis. Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking. Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to specifically inhibit adult neurogenesis, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic–pituitary–adrenal (HPA) axis. Relative to controls, neurogenesis-deficient mice showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.

*image is of GFAP-driven thymidine kinase in a mouse brain (GFAP in green and thymidine kinase in red). In the presence of ganciclovir, any cell that expresses thymidine kinase dies when it attempts to divide. In this case those cells would be the radial glial stem cells that produce new neurons. These were the mice used to stop neurogenesis in the majority of the experiments.

UPDATE: Ed Yong at Discover Magazine and Scicurious at Scientific American have great summaries of the findings and their significance. And the Drugmonkey blog attacks the question of whether or not a depression study in mice can be relevant for humans.

…and now for what is probably my final pre-SFN post. Posters dealing with mossy fiber function! Read the rest of this entry »

I have 62 items in my itinerary and I expect to add to it in the following weeks. There are always great presentations I find out about last minute and undoubtedly others that never see the light of (my) day. So fill me in if you have any tips. It’s not always the data that’s the most interesting part but often the presenter themselves, their ideas, methods, or the fact that you’ve known them since undergrad and you want to see baby pictures. My plan here is to share some of the potentially (you never know til you’re there) interesting presentations in my itinerary, bit by bit, over the next couple weeks.

1) 99.8/JJJ44 - The hippocampus is required for social recognition but not object recognition in Octodon degus
*T. UEKITA¹, K. OKANOYA²;
¹Doshisha Univ., Kyotanabe City, Japan; ²RIKEN BSI, Lab. for Biolinguistics, Wako City, Japan

Huh? Octogon what? They’re rodents unlike any other rodent. They perform communal digging, nurse each other’s young, are born with their eyes open, and are intolerant of sugar and get diabetes. Even more interesting is the fact that they can switch their circadian rhythms between nocturnal or diurnal patterns and they’re apparently able to use tools (at least according to Wikipedia). So, basically I want to chat about Degus with these guys.

2) 100.19/KKK35 – Hippocampal granular neuron recruitment during the evocation of a recent or remote object recognition memory
P. C. BELLO-MEDINA¹, *V. RAMIREZ-AMAYA²;
¹Neurobiologia Conductual y Cognitiva, Inst. de Neurobiologia, Univ. Nacional Autonoma de Mexico, Queretaro, Mexico; ²Neurobiologia Conductual y Cognitiva, Inst. de Neurobiologia UNAM, Queretaro, Mexico

Victor Ramirez-Amaya has done some interesting work on learning-related structural plasticity in the hippocampus and he’s also shown that the plasticity-related protein Arc is expressed in a delayed fashion after experience, probably as a part of the process of memory consolidation. Since there’s an emerging role for the dentate gyrus and neurogenesis in long-term memory I’m interested in this poster, which looks at activity-dependent Arc expression in the dentate gyrus and in young neurons after recent and remote(ish) memory retrieval.

3) 101.6/KKK46 – Spatial representation along the proximo- distal axis of CA1
*E. J. HENRIKSEN¹, C. A. BARNES^2,1, M. P. WITTER¹, M.-B. MOSER¹, E. I. MOSER¹;
¹Kavli Inst. Sys Neurosci, Ctr. Biol of Memory, NTNU, Trondheim, Norway; ²Univ. Arizona, NSMA, Tuscon, AZ

The hippocampus is a convenient structure to study because its anatomical boundaries are distinct – the dentate gyrus doesn’t abut any other principal cell layers. CA3 and CA1 are easily distinguished from each other based on cell packing density. Probably for this reason there has emerged the assumption that these subregions are homogeneous in function. However, at least for the dentate gyrus it has become clear that it’s two blades are very different. And now, this abstract reports that the CA1 neurons that border region CA3 carry more spatial information than those at the other end, near the subiculum. I’m not entirely sure why I’m interested in this, but it may be because it suggests a certain level of care must be taken in future experiments (e.g. being consistent in where measurements are made) and it argues for better reporting in methods sections as to how measurements were made (because we now know that not all areas of CA1 are equivalent).

If you’ve been paying attention to the adult hippocampal neurogenesis literature at all, you noticed that “pattern separation” is gaining popularity as a research topic. A few quick searches on Pubmed confirm that a trend is indeed afoot.  For the years prior to 1999, only 15 Pubmed-indexed papers answer to the keyphrase “pattern separation.”  This number holds roughly steady through about 2003, and then it begins to take off.  As of this moment (September 24, 2010 @ 3:27pm CST), we are up to 81 papers. According to my back-of-the-envelope calculations, we are in a period of exponential growth.  Should this trend hold –and I see no signs of it abating– we can expect upwards of 370 million pattern separation papers by 2050. Can you imagine what a comprehensive exam will be like?  Your child (grandchild?) will face a stack of journal articles almost 500 miles high!  Al Gore, from atop his famous scissor lift, will inveigh against the massive deforestation wreaked by our prolific little research community.  What’s that you say? We’ll all be using iPads? Fair enough.
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And here we have the latest, craziest hypothesis of granule cell function. Crazy not because the authors have lost their minds but because the story of the dentate gyrus, where adult neurogenesis occurs, is becoming more peculiar every day. The underlying premise of this paper by Alme et al. (which we will examine later) is that granule neurons go through a critical period during their development when they are more likely to contribute to memory encoding. Here it’s hypothesized that, once the critical period is over, they shut down. Forever. Hundreds of thousands of neurons never to be used again. It’s not every day you get to read such bold and novel ideas. Their hypothesis has similarities with that proposed by Aimone 2006, that adult neurogenesis causes different cohorts of neurons to be immature at different phases of an animal’s life, thereby separating memories according to time. The question here is whether these neurons can be reactivated once their critical period is over. Read the rest of this entry »