Functional Neurogenesis

More specifically,

Can you enjoy a good cup of coffee when you have 8 straight hours of experimenting with maximum 10 minute breaks here and there but it takes you 5 minutes just to get to the lab kitchen from the behavior space let alone make a coffee and get back in time and you can’t make a coffee at home and bring it in a thermos or travel mug (which would be room temperature (the worst temperature for enjoying coffee) by the time you wanted it nay NEEDED it) because those items have already been moved to Canada where you’ll also soon be moving which explains why you couldn’t do these experiments according to a more relaxed schedule but instead have to get as much done as is humanly possible in the few weeks that remain?

SO? CAN YOU?

Yes:

*Stay tuned for “Can you enjoy a good meal when you have 8 straight hours of experimenting with maximum 10 minute breaks here and there but it takes you 5 minutes just to get to the lab kitchen from the behavior space let alone make a meal and get back in time and you can’t make a meal at home and bring it in a thermos or travel mug because it would lose its form upon being stuffed into a drinking vessel but then why are you so hung up on appearances stop being so superficial and just stuff it in a thermos.”

Previously, I wrote about new SFN data on the role for newborn neurons in regulating emotion. The second half of the SFN meeting rounded out the story because the bulk of the functional presentations focussed on the role of new neurons in that other, classic function of the hippocampus: memory. Spanning synaptic plasticity, circuit function, and then linking it all to behavior, we have quite a complete story here.

SYNAPTIC PLASTICITY IN YOUNG NEURONS

Every time I get worked up about all various neurogenesis findings I think about one acronym that returns me to a state of inner peace: ACSF-LTP. Yes, I plagiarized that last line from my previous post. We all know about LTP right? The ability of synapses to strengthen their connections in response to activity? It has been used for decades as a physiological model of memory formation. It’s pretty well accepted that newborn neuron ACSF-LTP is a unique form of LTP – one that is insensitive to GABAergic inhibition (hence “Artificial Cerebro Spinal Fluid” LTP, in contrast to LTP that also requires inhibition of GABA neurotransmission), one that requires a the NR2B subunit of the NMDA receptor, and one that is induced more easily than that of mature neurons. ACSF-LTP has quite a history:

1. It was first shown by Sabrina Wang in Martin Wojtowicz’s lab back in 2000. The first demonstration of a unique functional role for new neurons. That work was done in single neurons from rat, by patch clamping.
2. I followed up on that work in the Wojtowicz lab and found that this LTP could be observed in field recordings, i.e. this LTP stood out amongst the background of activity from all granule neurons when you stimulated their synaptic inputs. In fact, it was the only type of LTP observed in the absence of GABA blockers (making it pretty easy to identify and measure, even by novice electrophysiologists such as myself).
3. Ge et al (2007) confirmed these findings in single neurons in mice and characterized the “critical period”, showing that only immature neurons displayed this plasticity, and not older adult-born neurons.
4. Wang et. al (2008) did a nice trick and increased neurogenesis with fluoxetine and in turn increased ACSF-LTP. Irradiation abolished both.
5. Garthe et al (2009) used a chemical method for stopping neurogenesis. ACSF-LTP was gone.
6. Sahay et al (2011) also increased neurogenesis and therefore ACSF-LTP, via a novel transgenic method.

AND NOW, I saw a poster by Kheirback et. al, who now used a completely novel method to confirm the existence of this special form of plasticity in new neurons. They used Nestin CreER and a floxed NR2B to delete the NR2B subunit specifically from young neurons. This didn’t kill neurons, it didn’t affect plasticity in mature neurons, but it wiped out ACSF-LTP. This is not entirely surprising because the NR2B subunit is known to endow new neuron with their enhanced plasticity. It just was a novel, elegant and specific way to demonstrate it.

Whereas the behavioral data on new neurons is less advanced and more variable, the fact that ACSF-LTP has been demonstrated in different species (mouse and rat), is absent after using different methods to reduce neurogenesis (irradiation, chemical, transgenic), is enhanced after using different methods for increasing neurogenesis (fluoxetine, transgenic) arguably makes it the strongest support for a real, significant function for hippocampal neurogenesis.

Going back to these NR2B-deficient new neurons, these mice also had behavioral effects: they had impaired ability to behaviorally distinguish contexts during fear conditioning, reduced object exploration, and no preference for a novel object over a familiar object. There was also a tendency, albeit less robust, for these mice to be more innately anxious and fearful.

OPTOGENETICS

ACSF-LTP is so well documented because the anatomy and physiology of the inputs to granule neurons is not super complex. In contrast, if there’s one brain region that could really benefit from optogenetics, it’s the dentate gyrus output onto CA3. The connectivity is such that it is practically impossible to stimulate only new neurons with conventional techniques and record from their postsynaptic targets. At least the ones that are further away, like pyramidal neurons. This can be overcome by shining light on the dentate gyrus and ensuring that only new neurons are activated, through selective expression of channelrhodopsin or its variants. This is exactly what Gu et al did. They characterized, for the first time, mossy fiber LTP in new neurons and found that 4-week-old neurons have greater LTP than either 3 or 8-week-old cells. Using archaerhodopsin to inhibit new neurons they also found that these 4-week-old cells are especially important for memory retrieval in fear conditioning and water maze paradigms. The deficits were not huge, but they were consistent. Considering that they used viral methods to express archaerhodopsin, which probably only infects a small proportion of the total new neuron population, the effect these new neurons are having on behavior is quite remarkable.

SO WE HAVE SYNAPSES AND BEHAVIOR, BUT WHAT’S IN THE MIDDLE?

The most commonly-proposed, but least understood, cognitive function for new neurons is pattern separation. Originally a computational term, it refers to the process by which neurons take similar inputs (spatiotemporal patterns of incoming synaptic activity) and maximize their differences. When brains do this well we are able to distinguish very similar experiences in our memory. When it fails you spend 30 minutes looking for your car before you remember that you parked in a different lot. The discrimination of safe from dangerous contexts during fear conditioning is used more and more as a behavioral test of pattern separation. While it may depend on pattern separation by new neurons, this has never been shown. To get at this, Niibori et al. used the catFISH method to see what is happening in CA3 neuronal ensembles when mice don’t have neurogenesis. catFISH uses the spatiotemporal patterns of activity-dependent gene expression to identify neuronal populations that were activated by different experiences. It’s been shown that when rodents are put into 2 different contexts, distinct ensembles of CA3 neurons are activated by the 2 experiences. The memory traces are kept distinct in order to not confuse the experiences. If new neurons are indeed performing a pattern separation function then you’d predict that, in their absence, the same population of CA3 neurons is activated by the 2 experiences. And this is exactly what Niibori et al found. Furthermore, confirming that new neurons are not just performing this separation function, but are actually required to behaviorally distinguish the 2 environments, mice lacking neurogenesis showed similar levels of fear behavior in both a context that was paired with shock as well as a context that had never been paired with shock. And so the hypothesized role for new neurons in pattern separation just got a whole lot stronger.

WHERE ARE WE AT?

There’s only so much functional work going on out there. Some behavior, less electrophysiology, a new method for measuring circuit properties. Your study of a phenomenon feels complete when you’ve seen presentations that cover function at these different levels of analysis. When they replicate and then build upon previous findings it’s even more of a confirmation that progress is being made. I have to say I think it was a pretty good meeting for adult neurogenesis.

How do the physiological properties of new neurons translate to a behavioral role? Are they just like mature neurons or are they unique? One idea that’s been thrown around is that their plastic period, their critical period, might endow them with an enhanced ability to associate information and contribute to memory formation. While we know that hippocampal neurons are already plastic and very capable of physiologically linking together different stimuli the big hope seems to be that maybe immature neurons are even better at this.

A related question is how fewer synapses and unique inhibitory connectivity affects their information processing capabilities. The verdict is out on whether new neurons are more or less involved in information processing than their mature counterparts. Currently, the best information we have is from studies looking at activity, measured by immediate early gene expression, in response to behavioral stimulation. The true measure of whether a neuron is involved in information processing / representation is if it spikes, i.e. fires action potentials, in response to a specific stimulus. Since new neurons have fewer synapses it’s very possible that they aren’t able to represent many different types of information, and therefore aren’t capable of associating information during memory formation. On the other hand, new neurons synapses are more plastic, perhaps making them better able to associate information even if they have fewer synapses. Read the rest of this entry »

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

Update: The poster is now available at Nature Precedings.

Still acquiring histological images for my SfN poster. My recurring problem is that I end up taking pictures of things because they’re pretty and not because they have anything to do with the task at hand. Today’s case in point:

Well, this does relate to my SfN poster a little bit. Red shows cell nuclei, most of which are dentate gyrus granule neurons. And white is GFAP immunostaining, which largely labels astrocytes but in this part of the brain also labels radial glia, the stem cells (or to be less controversial, “precursor” cells) of the hippocampus. Radial glia can be identified by the long process (almost like a dendrite) that they extend through the granule cell layer. There are a few in the above picture. Read the rest of this entry »

The annual most insanely huge neuroscience meeting is rapidly approaching and I am pleased to announce that I will be blogging about the meeting again this year, here at Functional Neurogenesis. The meeting will be held at the Washington DC convention center, located in “China” town, which is cool because in addition to learning about neuroscience attendees will have the opportunity to also learn the Chinese characters for “Starbucks” and “TGI Fridays.”  Below is a list of the “official” neurobloggers, chosen by SFN, where you can keep up with some of the most exciting neuroscience presented and discussed at the meeting. For the most part, only 1 neuroblogger was chosen per theme and so you can be sure that there wil be a lot of non-official coverage throughout Twitter and the blogosphere. For starters I would stay tuned to the official hashtag #SFN11 but also check out this list of active bloggers and tweeters that will be covering the meeting. Nature Publishing Group will also be aggregating posts at the Action Potential blog. And the bloggers are:

A: Development – Functional Neurogenesis – @jsnsndr

B: Neural Excitability, Synapses, and Glia: Cellular Mechanisms – Brainteresting – @brainteresting

C: Disorders of the Nervous System – Neurobytes – @neurobytes @rimrk

C: Disorders of the Nervous System – Scicurious: Scientific American Scicurious: Scientopia – @scicurious

D: Sensory and Motor Systems – Paula’s Piece of Mind – @Paulineddra

E: Homeostatic and Neuroendocrine Systems – Dormiviglia – @Beastlyvaulter (protected)

F: Cognition and Behavior – Future Dr. Science Lady – @Drsciencelady

G: Novel Methods and Technology Development – Guitchounts – @Guitchounts

H: History, Teaching, Public Awareness, and Societal Impacts in Neuroscience – Neuroflocks – @Scipleneuro

SUN: Student Undergrad Neurobloggers – SUN – @Astroglia