Category Archives: reviews of papers

New neurons mature slower in the temporal/ventral dentate gyrus

I’ve previously written about the functional differences between the septal (aka dorsal aka rostral¹ aka posterior²) and temporal (ventral/caudal/anterior) hippocampus and how studies are increasingly not treating the hippocampus as a single homogeneous structure. Myself and others have extended this perspective to studies of adult neurogenesis and now I’m happy to report that we had a new paper come out on the topic last week.

The study was a bit of a fun learning experience for me for several reasons. As many of you know I recently changed labs and will be starting my own lab soon. So things are on the go and I haven’t had the time to dive deep into a study that is going to take several years to complete. But some research projects can be done quickly and still are able to produce very useful results. As I prepare for my own lab I was probably thinking, “What kind of projects could a Master’s student accomplish??”. And indeed we had a strong postbaccalaureate fellow in the lab for about a year who fit this description pretty well (she’s the middle author). Also, we had lots of tissue remaining from a recent study where we compared neurogenesis in mice and rats that could be used to answer other questions, thereby saving time, money and importantly, animals. So we decided to ask whether the maturation and survival of adult-born neurons differ between the aforementioned functionally-distinct hippocampal subregions.

The basic idea of the study.

experimental designBrdU was injected to birthdate+label new neurons and at various intervals kainate was given to “activate” all the neurons that had integrated into the circuitry, and formed synapses. This integration (a major step in the new neuron maturation process) can then be measured by immunohistochemically staining for gene products such as Arc that are expressed after synaptic activity. Our tissue was cut in the coronal plane, however, which is not ideal for isolating the septal and temporal ends of the hippocampus (though others have found that there are meaningful differences along this rostrocaudal axis). Since the rostral sections are purely septal (see blue portions, above) this subregion was not a problem. We then decided to basically “cut” the caudal sections in half and by analyzing only the ventral portion we were able to specifically target neurons located in the far temporal dentate gyrus (shown in red). We were also able to investigate whether new neurons are more likely to survive in one subregion than another, by counting the number of cells present before (at 7d old) and after (at 28d old) the period of cell death.

Since this article is completely open access you can see the actual data for yourself here. The short story is that new neurons matured faster in the septal dentate gyrus (all cells could express Arc by 3w of age whereas in the temporal dentate gyrus this didn’t occur until somewhere between 4-10w of age). The other new finding was that there were many more new neurons initially added to the infrapyramidal blade of the dentate gyrus but these neurons were much less likely to survive than neurons born in the suprapyramidal blade.

What is the significance of these findings? To me, they provide a framework for future studies. If you want to investigate new neurons specifically during their immature stage (when they might have unique functions) you certainly have to consider the anatomical location. But what if the main function for new neurons is not realized until they are fully mature? Well, if you plan to ablate or silence new neurons and examine behavioural effects, then you might want to wait longer if you’re planning on investigating emotion/stress-related behaviours that might rely more heavily on the temporal hippocampus. They also suggest that new neurons in the temporal dentate gyrus might have an extended unique role since they remain immature for longer. The peculiar survival difference between the infrapyramidal and suprapyramidal blades doesn’t do much to clarify the functions of these two regions, but it adds to the ever-growing list of differences that suggests they are truly distinct.

Often findings across labs do not match up as well as one would like so I am rather happy that Piatti et al. have found similar maturation differences in another species (mice) and using different methods (electrophysiological recordings from virally-labelled new neurons). So this is probably for real!

Lastly, a reviewer pointed out something very helpful, which is that it can be very difficult to discern the two blades of the dentate gyrus in caudal coronal sections (like this or those slightly more caudal where the dentate gyrus is essentially a blob). I spent a fair bit of time looking perplexed as I played with 3D paper models of the dentate gyrus but felt pretty cool doing so because similar strategies have been used by some of the foremost neuroanatomists of our time – see here. A 3D computer model that incorporated the blades of the dentate gyrus would have been very convenient (talking to you, Allen). In any case, we decided to remove our caudal blade analyses from the paper and instead only focussed on the septal infrapyramidal vs. suprapyramidal differences.

Reference: Snyder JS, Ferrante SF, Cameron HA (2012) Late Maturation of Adult-Born Neurons in the Temporal Dentate Gyrus. PLoS ONE 7(11): e48757. PMID: 23144957

¹in rodents

²in humans

Impaired adult neurogenesis leads to depression – is it realistic?

depressionAbout a year ago we published a paper linking adult neurogenesis to depression. A causal sort of ‘linking’, right? I mean, we found that, when adult neurogenesis was eliminated, mice had elevated glucocorticoids in response to stress and showed depressive-like behaviours1. So doesn’t this mean that impaired adult neurogenesis could lead to depression in humans, in the real world?

Well, it could…and we did end our paper with the following:

Because the production of new granule neurons is itself strongly regulated by stress and glucocorticoids, this system forms a loop through which stress, by inhibiting adult neurogenesis, could lead to enhanced responsiveness to future stress. This type of programming could be adaptive, predisposing animals to behave in ways best suited to the severity of their particular environments. However, maladaptive progression of such a feed-forward loop could potentially lead to increased stress responsiveness and depressive behaviours that persist even in the absence of stressful events.

We had to end it somehow – I was just happy that after 3 years of work we were DONE2! But our final speculation makes it clear that, while this chapter may be done, the story is not. And this fact was rightly pointed out in a recent commentary by Lucassen et al. in Molecular Psychiatry3, where they continue the discussion and bring up some good points. Here is a loose elaboration on some of the outstanding issues they bring up. Continue reading Impaired adult neurogenesis leads to depression – is it realistic?

Forming and recalling memories. Artificially.

Memory manipulation has become one of the most hotly pursued topics in neuroscience. After all, much or of who are is based on what we’ve learned, including memories that we can consciously recall as well as acquired desires and habits that can lead to problems like addiction. In rodents, we’ve known for decades that damage to the hippocampus can erase recently-formed memories. Studies of reconsolidation have shown us that when a memory is retrieved it becomes labile and allows for new information to be added, thereby creating an updated version. More recently we (humans) have been able to identify the neurons involved in memory formation and show that killing them, and only them, results in memory erasure. Bringing us even closer to the stuff of movies, studies by Garner et al. in Science and Liu et al. in Nature have now artificially controlled memory formation and recall. We’re essentially talking about reactivating memory by pushing a button. Yes – you can say “dude, whoah” now. Continue reading Forming and recalling memories. Artificially.

New neurons mature very slowly in monkeys

ResearchBlogging.orgSo, 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. Continue reading New neurons mature very slowly in monkeys

Random roundup

random roundup banner

“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


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


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


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


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


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


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


That’s it.

Are new neurons really more excitable? (yes)

ResearchBlogging.orgSome 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. Continue reading Are new neurons really more excitable? (yes)

How does the brain pick which neurons to use?

ResearchBlogging.orgWiring. 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. Continue reading How does the brain pick which neurons to use?

Pattern separation: 370,000,000 papers 2050?

pubmed 2If 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.
Continue reading Pattern separation: 370,000,000 papers 2050?

Someone finally dissects the role new neurons play in fear conditioning

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)

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

Do new neurons go through a critical period and then retire, never to be used again? 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. Continue reading Do new neurons go through a critical period and then retire, never to be used again?