Functional Neurogenesis

So, it turns out that neurogenesis in primates is quite a bit different than in rodents. It’s been over 10 years since adult neurogenesis was first described in the adult primate hippocampus and yet much of the basic work has yet to be done. That’s where this new study by Kohler et al. come in. The data are not so new actually — they were first presented at the Society for Neuroscience meeting back in 2005.

Their question was simple: at what rate do newborn neurons mature in nonhuman primates? Their methods were also simple and easy to compare to previous studies in rodents: they used BrdU to label newborn cells and then they colabeled the BrdU+ cells with immature (DCX) and mature (NeuN) neuronal markers at different cell ages: 2 days, 2 weeks, 6 weeks, 11 weeks and 23 weeks.

First, they found that after labeling with BrdU the number of BrdU+ cells increased over the next 6 weeks. This fits well with the data from Gould and suggests that precursor cells in primates may divide much more infrequently, taking up the BrdU label at injection, retaining it for several days or weeks and then giving rise to additional BrdU+ cells upon redivision, etc etc until the BrdU is diluted. Read the rest of this entry »

“Random” roundup because any posts linking to articles or ideas I’ve recently found noteworthy will never occur on a regular basis (as others manage to do – I applaud you) but only when enough interesting material has accrued and I have a spare moment. The links will, however, not be random. For example, you can expect many links to point to articles on adult neurogenesis or hippocampal function but will likely find few links directing you to photos of puppy dogs.

Dopaminergic Modulation of Cortical Inputs during Maturation of Adult-Born Dentate Granule Cells. A pretty thorough examination of dopaminergic modulation of synaptic transmission and synaptic plasticity in the dentate gyrus. Dopamine reduced synaptic transmission in both immature and mature granule neurons, but through different receptor subtypes. Additionally, dopamine reduced long-term plasticity in immature neurons but not mature neurons. Given the suggestion that dopamine could gate the entry of information into long-term memory, these findings suggest young and old neurons could have quite different behavioral functions.

Mu Y, Zhao C, & Gage FH (2011). Dopaminergic Modulation of Cortical Inputs during Maturation of Adult-Born Dentate Granule Cells. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (11), 4113-23 PMID: 21411652

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Lidocaine attenuates anisomycin-induced amnesia and release of norepinephrine in the amygdala. Memory consolidation is the phenomenon by which memories are encoded through enduring structural changes in the brain and is often demonstrated by showing that memory loss occurs when you inhibit protein synthesis around the time of learning. This paper shows that one of the most commonly-used protein synthesis inhibitors, anisomycin, leads to increased norepinephrine release in the amygdala which could, by itself, impair memory.  The interesting final experiment showed that the effects of anisomycin on memory and norepiniphrine were reduced when the amygdala was totally shut down with lidocaine.

Sadowski RN, Canal CE, & Gold PE (2011). Lidocaine attenuates anisomycin-induced amnesia and release of norepinephrine in the amygdala. Neurobiology of learning and memory PMID: 21453778

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Evidence for the Re-Enactment of a Recently Learned Behavior during Sleepwalking. I’ve written a number of times about how neuronal firing patterns observed during waking experience are replayed during sleep, and could therefore reflect consolidation of memory and even dream content. Of course no one knows what rats are experiencing during sleep or whether they dream like us. To get around this problem, these authors trained sleepwalkers on a motor task with very defined arm movements and then examined sleepwalking behavior on the following night. Indeed, a video shows one subject who wakes up the following night and, for a few seconds, seems to be performing the same stereotyped task movements. Only one subject but tantalizing evidence and a cool experimental strategy nonetheless.

Oudiette D, Constantinescu I, Leclair-Visonneau L, Vidailhet M, Schwartz S, & Arnulf I (2011). Evidence for the Re-Enactment of a Recently Learned Behavior during Sleepwalking. PloS one, 6 (3) PMID: 21445313

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Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. One of the biggest questions in the neurogenesis field is whether adult-born neurons are important for behavior. Usually this is tested by examining behavior in animals that lack adult neurogenesis but many studies have correlated increased neurogenesis in enriched or athletic animals with “improved” behavior (smarter, less depressed etc). Of course, the major confound is that enrichment and exercise do many other things besides increasing neurogenesis. To get around this Sahay et al. made a mouse in which neurogenesis could be specifically increased in adulthood. These mice were better at discriminating between related contexts and, after exercise, showed much greater exploratory activity in an open field.

Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, & Hen R (2011). Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature PMID: 21460835

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Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates. This study potentially bridges a big big gap by extending the role of adult neurogenesis in the antidepressant response from rodents all the way to monkeys. Chronic stress induced anhedonic and subordinate behaviors and these effects could be reversed with fluoxetine, but not in irradiated monkeys that had reduced neurogenesis. Could someone follow this up with a transgenic model?

Perera, T., Dwork, A., Keegan, K., Thirumangalakudi, L., Lipira, C., Joyce, N., Lange, C., Higley, J., Rosoklija, G., Hen, R., Sackeim, H., & Coplan, J. (2011). Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates PLoS ONE, 6 (4) DOI: 10.1371/journal.pone.0017600

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Systemic 5-bromo-2-deoxyuridine induces conditioned flavor aversion and c-Fos in the visceral neuraxis. OH NOOO! Rats don’t like BrdU! These authors show that pairing a BrdU injection with exposure to a sweet palatable drink causes rats to avoid that drink in the future. It also leads to a mildly elevated stress response and elevated c-fos expression in areas of the brain that represent viscera, consistent with the possibility that BrdU could be exerting unpleasant effects in the gut, where there is a lot of cell division. The authors conclude that the effects on behavior in subsequent days and weeks are probably minimal (phew!), but I’d certainly keep these data in mind when considering injecting BrdU around the time of behavioral testing.

Kimbrough A, Kwon B, Eckel LA, & Houpt TA (2011). Systemic 5-bromo-2-deoxyuridine induces conditioned flavor aversion and c-Fos in the visceral neuraxis. Learning & memory (Cold Spring Harbor, N.Y.), 18 (5), 292-5 PMID: 21498563

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Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice. In an interesting study of plasticity following neurogenesis reduction, these authors find that LTP was dramatically reduced after arresting neurogenesis, but only transiently. LTP recovered within weeks, possibly because of compensatory reductions in inhibition and enhanced survival of neurons born before neurogenesis ablation. Hat tip to Sil for this one.

Singer BH, Gamelli AE, Fuller CL, Temme SJ, Parent JM, & Murphy GG (2011). Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice. Proceedings of the National Academy of Sciences of the United States of America, 108 (13), 5437-42 PMID: 21402918

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That’s it.

Some facts on neuronal excitability:

1. Excitable: the ability to fire action potentials.
2. More excitable: fires action potentials, but more.
3. More LTP: not the same as more excitable.
4. Less inhibition: also not the same as more excitable, though the two may go hand in hand.
5. The Scholarpedia page on neuronal excitability, which was last modified on 13 August 2009, has been accessed 49,025 times, and contains no information (peer review is slow).

One of the claims that is often made is that adult-born neurons are more plastic and more excitable than older neurons.  This despite there being little evidence (until recently) that new neurons indeed are more excitable. But, hey, “excitable” sounds great alongside “plastic”. The Schmidt-Hieber paper did show that new neurons are more excitable, though it wasn’t their main focus and it is only occasionally referenced as evidence for greater excitability.

My misunderstanding that there are no thorough investigations of new neuron excitability was brought to an end recently when I was fortunate to have an infant-free moment (In which I was able to read two papers in the same evening, plus an entire New Yorker article over breakfast. Amazing.) One of the papers was Reliable Activation of Immature Neurons in the Adult Hippocampus by Mongiat et al. from Alejandro Schinder’s lab, which I really should have read long ago. 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 »

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.
Read the rest of this entry »

Based on a true story – how progress is made in the field of adult neurogenesis*

1. A group of scientists reduce neurogenesis and report a memory deficit.
2. A second group repeats the experiment, with only a few minor differences in protocol, and fails to find a memory deficit.
3. A third group, using the same species as the first group but a protocol more similar to the second group, replicates the original finding but only when the experiment is performed on Wednesdays.
4. Faith is restored.
5. Five groups report no such neurogenesis-dependent memory deficit.
6. It is reported that developmental exposure to strontium reduces adult neurogenesis by 40% AND produces the much sought after memory deficit. In a technical tour de force follow-up experiment, artisanal cheeses restore neurogenesis and reverse the memory deficits. Causation is established.
7. BDNF.
8. Everyone proclaims the role of neurogenesis in memory and is totally confused at the same time.
9. Someone systematically examines all of the variables in the memory test to determine whether or not the whole thing is a hoax and they should just change careers**.
10. We have never gotten this far.

Even at level 8, the neurogenesis-fear conditioning story was one of the more convincing arguments of new neuron functionality. With this study by Drew et al. we may soon be jumping for joy as we appear to be graduating to level 9.

The contribution of adult neurogenesis to contextual fear conditioning was greatest when mice were only given a brief training experience – mice lacking adult neurogenesis showed reduced fear of a context where they previously received a single footshock during a brief (3 min) exploration session. With longer exposures to the context, or additional footshocks, neurogenesis-deficient mice showed normal memory. This finding could be explained by the fact that young neurons have a lower threshold for synaptic plasticity, allowing them to encode fleeting experiences that would be forgotten if left to mature neurons.

So, brief training protocols may now likely be my first choice, at least when using mice. In fact, the only times I have observed contextual fear memory deficits in mice has been after brief training protocols almost identical to those used by Drew et al. So we just might have taken a big step forward. If not, check back in 5 years for my revised “How progress is made” list.

*or any other field for that matter

**this is not entirely a joke because, in this case, it both 1) appears to not be a hoax, and 2) marks the launch of the next phase of Michael Drew’s career (congrats)

Reference
Drew MR, Denny CA, & Hen R (2010). Arrest of adult hippocampal neurogenesis in mice impairs single- but not multiple-trial contextual fear conditioning. Behavioral neuroscience, 124 (4), 446-54 PMID: 20695644

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 »

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 »

Dendrites are the extensions of neurons that receive incoming information. Neurons have primary dendrites that further split off into secondary and tertiary dendritic branches. On each of these branches are thousands of synaptic connections with axons of neurons carrying incoming information. The result is a dendritic tree that is capable of receiving and integrating a wide array of information within a single neuron. This is one of the neurobiological mechanisms by which different components of a memory are thought to be joined.

Neurons are not born with dendrites and spines – they are acquired during a developmental process that takes many weeks (see here & here). During early development, the pattern of formation of dendrites and spines are sculpted by experience, as might be expected if dendrites and spines are anatomical structures involved in processing and storing sensory information. While a body of work has emerged suggesting adult-born neurons are involved in memory and behavior, no one has yet investigated whether experience is capable of altering the dendritic development of these new neurons. This paper by Tronel et al. is therefore very important because it is the first to look at this phenomenon. They show a dramatic acceleration of dendritic development in response to learning, suggesting a potentially powerful role for new neurons in storing and processing information.
Read the rest of this entry »

Studies of adult neurogenesis often begin with the following sentence: “Adult neurogenesis occurs in all mammals examined, including humans.” More detail-oriented papers might say, “Adult neurogenesis occurs in all mammals examined, including humans…but not bats.” Here, the similarities between bats and humans become more evident than one might expect: it could be an equally long time before we understand adult neurogenesis in either of these species. Bats are (relatively) easy enough to study experimentally, but how many studies will be required to understand why neurogenesis does not occur in the adult bat brain? With humans, we have the opposite problem: the one study in humans that used the unambiguous cell-birth marker, BrdU, found adult neurogenesis. The second study may never exist. Read the rest of this entry »