Functional Neurogenesis

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 »

Kitamura et al. (2009) Adult Neurogenesis Modulates the Hippocampus-Dependent Period of Associative Fear Memory. Cell. 139:814-827.

It’s great to see this paper finally in print. At SFN 2008 the authors had a poster that generated a lot of excitement, at least in our circles.  And the poster was quite a sight: there was such a profusion of data that the poster poured off the easel, nearly reaching the floor. With 27 (!) supplemental figures in the final article, one has to wonder if this is the final straw that led to this article.

The authors use an ingenious approach to address an idea that has been floating around for a while: that adult neurogenesis regulates memory turnover in the hippocampus. Read the rest of this entry »