Functional Neurogenesis

As I’ve alluded, science, and therefore the SFN meeting where much science is unveiled, is a cycle of confusion and clarification. Currently, confusion may be prevailing in the adult hippocampal neurogenesis field since new neurons have been implicated in everything mammals do – spatial and nonspatial memory, anxiety, depression, addiction, social behavior, stress regulation, blinking etc. This should not be entirely surprising since the hippocampus itself, where these young neurons reside, has many different functions. But how can we reconcile these seemingly disparate functions?

Every time I get worked up about all these neurogenesis findings I think about two words that return me to a state of inner peace, calmness, and….mental turmoil that all of my experiments will have to be performed twice: Septal and Temporal. Neurogenesis aside, the septal and temporal ends of the hippocampus are connected to different brain structures that cause the septal hippocampus to be more involved in spatial processing/cognition and the temporal hippocampus to be more involved in regulating stress and emotion. Which has the potential to explain everything. Read the rest of this entry »

It’s hard to explore SFN when you’ve got your own poster to tend to. I thought I could hop around the development section before things got busy but there was no “before things got busy.” The design of the conference also can work against presenters because the presentations you’d like to see the most are being displayed simultaneously with your own. So next year I vow to present something really boring.

Of course, much can be learned while pinned down at your own poster. When you work in one lab, or one institution, your thoughts about the brain tend to have a specific focus based on the ideas of the people around you. Of course, new papers come out that challenge those thoughts but, man, papers move slooooowly. Scientists have not done a stellar job of using the internet to quickly communicate ideas. However, once a year at SFN a whole bunch of people come to your poster and give you their thoughts on the brain. Sometimes their thoughts are only presented in the language of distorted eyebrows and raised inflections but this is way better than typical social interactions with strangers, which usually go something like “You study brain cells/memory? Dude, I sure could use some more of those/that!”

So, what did my visitors think?

I had several visitors who specifically came by because they knew about me through the blog and through Twitter. Thank you for stopping by! You often never know if your online thoughts are useful, but I was happy to hear that several of you have used the blog as a teaching tool and a way to keep up with the field. I wish I could have these interactions with my readers more often than once a year at SFN. Then again I’d probably never be able to keep up with the comments so…no I didn’t say that – get engaged! I also heard one person, who does in vivo electrophysiology on my favorite brain regions, tell me that they’d tweet about neuroscience but they have nothing interesting to add to the conversation! Bollocks! Do you know how many in vivo electrophysiologists are on Twitter? Like, one? And how many experts are reviewing the literature on Research Blogging? Your knowledge is valuable. I would follow you in an instant.

“At first there was agreement on the behavioral function of neurogenesis but now everything is going in different directions.” Yes! Adult neurogenesis is a great example of the more you learn the more confused you get! Things may have seemed congruent 5 years ago but that was when there was only half a dozen studies that had examined the problems that arise when new neurons are ablated. Since then people have gone on to study more types of behavior and, as is also the case with the hippocampus, new neurons have been found to contribute to more and more types of behaviors. This has also given us additional opportunities for failed replication, and therefore doubt and confusion. One visitor commented on the recent paper that found memory impairments only if you kill new neurons after learning and we agreed that killing new neurons before behavioral testing could allow for other neurons to compensate, and make it appear that these new neurons are not doing anything significant. Of course, we have shown that often (e.g. at “baseline”) new neurons may be dispensable but that when an animal is stressed they are critical. And so explanations are emerging as to why some observe a behavioral function for new neurons and others do not, it’s just that it seems to be unbearably slow or remarkably fast depending on your mood.

I learned that there’s someone out there studying neurogenesis as related to maternal behavior….IN SHEEP! And they find that these neurons mature very slowly, like, primate slow. I love it when we think we have things completely figured out and then the data goes a totally different direction when you throw wool into the equation. Like, if we put cute little wool sweaters on our mice, would that make new neurons mature slower? One of the next big questions. Testable. Do it.

For those that missed my poster, fear not, for I have submitted it to Nature Precedings and will notify you here when they’ve posted it (couple days). For those that came to my poster today, sorry, you didn’t have to come to my poster.

Jason

Figshare is one of the greatest new tools for scientists. It allows you to publish any piece of data, no matter how small or insignificant, in a citable fashion. This is a big deal because ALL scientists have (tons of) data of this sort. Pilot experiments are performed to get the conditions right for the real experiments. And they never get published. The manuscript is written up or the paper is reviewed and some data is judged irrelevant or incomplete and is excluded. And never gets published. An experiment is performed and there is a null result, or the data are hard to interpret without further experiments, or the project doesn’t get funded, and so the project is dropped. And the experiment becomes nonexistent outside of the lab that performed it. There are many reasons why this should not be the case: 1) effort was spent on the experiment and so publishing it gives the scientist credit, 2) taxpayer money was spent on the experiment and so publishing these data gives back to the system that enables us to do this work in the first place, 3) data that are not useful or exciting to the scientist that acquired them can be incredibly useful and time-saving to other scientists that are working on related problems. The list could go on.

Figshare may not be the only option, and others will likely crop up in the near future, but it is a good example of a solution. We all know about the internet, right? A medium for immediately publishing anything you want? I’m a little baffled that this has taken so long.

For my part, in my spare time, I will be scouring my hard drive for findings that have been forgotten. The beauty of publishing in a place like Figshare is that it is easy. Most of these experiments have already been analyzed (I mean, they were graphed so that we could discuss what to do/not do with them, now it’s just a matter of uploading the already-presentable data). Also, there’s no obligation to discuss the data ad nauseum (you’ll see some data descriptions are pretty short) though some degree of explanation is required to make the data useful. Furthermore, should the story evolve, there’s no reason why it can’t be also published in a traditional journal format. Check out Nature Publishing Group’s policy – they’re ok with publishing data (even full manuscripts) on preprint servers prior to submitting to their journals.

Of course, some data may still not be “shareable” such as patient data or data that is closely related to an ongoing project. But interestingness should never be a factor in my mind, because you never know what will be valuable to others.

So, if you’re “just” a summer student who thinks your 2 months of work can’t possibly amount to hard, citable evidence, think again. Ask your boss first, but think again.

For obvious reasons, studying neurogenesis in primates is useful. Primates are phylogenetically more related to us than rodents, and so understanding their nervous system can better help us to understand our own. For over a decade we have known that neurogenesis continues in adulthood in primates and in many ways, the process is similar to what has been observed in rodents. For example, neurogenesis is reduced with age in primates, is decreased by stress, increased in pathological conditions such as epilepsy, and increased by antidepressant treatment.

My goal in compiling this list was to assess the magnitude of adult neurogenesis in primates. It’s definitely more challenging than assessing the magnitude of neurogenesis in rodents, which we know much more about, and so I had put it off. At this point I haven’t reached a clear conclusion but, in quickly skimming these papers, the number of proliferating cells and/or new neurons averages thousand(s) of cells in the young adult primate hippocampus. The range is much much larger, and many studies cannot be easily compared due to variability in the methods, which is partly understandable since primates are scarce and are often used in multiple studies, thereby limiting the analyses that can be performed.

Download the list

Everybody knows what the hippocampus is for: memory. And…maybe something about anxiety or depression? Yes – over the last 10 years or so many studies have been published showing that the hippocampus has these two roles and that the mnemonic and emotional functions of the hippocampus are associated with its septal (dorsal) and temporal (ventral) ends, respectively. This new knowledge means that we’ve had to reorient our perspective. What we see when we consider the septal hippocampus may not be the same if we only consider its temporal end. My goal here is not to provide a review of the memory vs. emotional functions of the hippocampus (btw this dichotomy is a vast oversimplification). Instead, I’d like to talk about how people have differentiated these two ends of the hippocampus in their analyses. I’m also happy to showcase a bunch of pretty anatomical images that will probably never be published in a traditional journal article. Read the rest of this entry »

Wiring. That’s one answer to this question. We know this from topographic maps in the thalamus and neocortex, where the basic units of sensory information are neatly represented in spatially-arranged populations of neurons – the various body parts are represented in specific locations, as are the different frequencies of sound, the different parts of the retina, and different odors and tastes. This basic sensory information has to be represented (i.e. we all need a faithful representation of visual elements, we all need to hear the various frequencies of sound that make up human speech etc.) so why not hard-wire it and make its representation the same for all of us?

It’s often thought that things change as you move into parts of the brain that represent more complex and abstract concepts. For example, in the hippocampus, many neurons receive the same inputs so it’s generally assumed that different neurons are equally capable of representing a given piece of information. While wiring between neurons must play a role in determining which neurons are activated, the diffuseness of the wiring means that related information need not be stored in spatially neighboring neurons as in the sensory regions of neocortex. Indeed, if you look at hippocampal neurons activated by a given experience they don’t appear to have any particular spatial arrangement but are randomly distributed, anatomically. Alternatively, it could be that certain hippocampal neurons are hard-wired to respond to specific stimuli, it’s just that we don’t understand the wiring. Read the rest of this entry »

As we accumulate more and more data on adult neurogenesis in rodents I keep asking myself what kind of impact these new cells could have. The dearth of literature on primate and human adult neurogenesis seems to make these questions all the more relevant. As a starting point, I created a Pubmed collection of all the studies of adult hippocampal neurogenesis in humans. They’re also listed below in a Google spreadsheet. Note that human studies often do not directly measure neurogenesis but instead measure 1) cell proliferation (which usually correlates with neurogenesis in rodents, but assumes that proliferation results in surviving neurons in humans), 2) stem cell markers (such as nestin, which correlates with neurogenesis only if they indeed divide and produce new neurons), 3) immature neurons (which, technically speaking, is neurogenesis, but whether these neurons mature and become functional remains to be determined), or 4) other factors that correlate with neurogenesis, such as blood flow or stem cell biomarkers. So, while the conclusions of these studies may be exciting (or depressing), they have to be taken with a grain of salt at this point.

Download the list

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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A fundamental property of the hippocampus is its ability to rapidly encode memories while simultaneously keeping them distinct. Recording from hippocampal neurons one can clearly see that different populations of neurons are active as a rat explores two environments. This is thought to be one mechanism by which information is kept distinct in the brain.

For the last 15-20 years it has been thought that the dentate gyrus (DG), a major subfield of the hippocampus, serves to take small changes in incoming sensory information and orthogonalize them (i.e. make them more different). This idea was built in part on the fact that there are many more DG neurons than upstream cortical neurons. Thus, the DG could use completely different populations of neurons to represent different sets of incoming information and then pass on these representations to CA3, which may bind them into coherent events/memories (the interconnectedness of CA3 neurons, via “recurrent collatorals”, is thought to be a mechanism by which the different components of a memory are bound together).

However, a “problem” arose when Leutgeb et al. found that it is always the same population of dentate granule neurons (~1% of the total population) that are active as an animal explores different environments, even very different ones. This was a bit of a surprise. Still consistent with the proposed role of the DG in orthogonalizing information, however, was the fact that the DG neurons fired (i.e. generated action potentials, which transmit information from neuron to neuron) at different rates/frequencies in the different environments. Thus, changes in sensory information were represented by changes in patterns of activity within the same population of cells, not by recruiting different populations of cells. This is but one study – the question of how the DG encodes and extracts information is far from settled (e.g. what are the other 99% of granule neurons doing? Surely there is a situation in which they are active, no?). But the findings were robust and raise many questions, namely: How does the same population of DG neurons activate different populations of downstream CA3 neurons, during different experiences? Read the rest of this entry »

Most studies of adult neurogenesis are concerned with neuronal age. Or at least they should be. This is because new neurons develop from a stage where they have no excitatory synapses to one where they have many. If we assume the traditional view that information is stored at excitatory synaptic connections, then young neurons are initially useless and only become physiologically and behaviorally meaningful when they have matured to a point where they can relay and process information. It is therefore critical that the developmental timecourse of new neurons be mapped out, so we know when new neurons become functionally relevant, or whether they might even have different functions at different ages.

Below are what I hope to be comprehensive visual collages of all published timecourse experiments, where a certain property of new neurons is examined at multiple (≥ 3) different ages. They are grouped by studies of: 1) cell survival, 2) marker expression, 3) functionality, and 4) miscellaneous studies that do not quite fit into the first 3 categories. I’ve ordered the data roughly chronologically and have included the first author’s name and publication year so you can read deeper, if needed. Indeed, if you know these studies already, a brief look at the graphs will bring back the take home message. However, since the data is stripped of text, if the studies are unfamiliar, you’ll have to go to the original source to figure out what the heck they mean (use Pubmed to at least obtain abstracts for the original studies if I didn’t provide a direct link).

Personally, I like timecourse studies for the same reason I like to have all my music albums or books visible at the same time: at a single glance they provide a lot of information – each individual stage of maturation can be interpreted within a bigger picture. The result of these many hours of work will either be a) that the purpose of adult neurogenesis will become immediately clear, or b) that we’ll all have some fancy collages to pin on our bulletin boards and look intelligent.

The survival timecourse

New neurons are born and then many die. The survival timecourse answers the questions: How many new neurons are born? Where are they born and where do they end up, anatomically? How many of them survive and can their survival be altered? Survival timecourses are typically performed by injecting animals with a mitotic marker that will label new neurons as they’re being born, e.g. ³H-thymidine (old school), BrdU (tried and true – example), or a GFP-expressing retrovirus (new school). At a later date one can then detect these birthdated new neurons and count them, see where they’re located etc.

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