Tag Archives: gage

Random roundup

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“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.

Studies of adult hippocampal neurogenesis in humans

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

#SFN10 Itinerary Pt. 2

Continuing on…

1) 31.20/C37 – Dentate network activity modulates integration of newborn granule cells
*F. KLEINE BORGMANN1, J. GRÄFF2, N. TONI3, I. M. MANSUY4,5, S. JESSBERGER1;
1Inst. of Cell Biology, Swiss Federal Inst. of Technol. (ETH), Zürich, Switzerland; 2Brain Res. Inst., Univ. of Zürich, Zürich, Switzerland; 3Univ. of Lausanne, Lausanne, Switzerland; 4Brain Res. Inst., Univ. of Zurich, Zürich, Switzerland; 5Swiss Federal Inst. of Technol. (ETH), Zürich, Switzerland

This looks interesting because there is so little known about how neuronal activity regulates neurogenesis. In 2007 Toni et al. suggested that dendritic filopodia on new neurons form synapses with presynaptic boutons that have already formed a synapse onto a different (presumably mature) neuron. The question addressed here is whether altering excitability/plasticity at those pre-existing synapses affects the subsequent formation of new neuron synapses. In other words, if you make old neurons more plastic, will they outcompete new neurons for synaptic space? Seems maybe they do.

2) 203.9/KKK52 – Coding of temporal context in the hippocampus: Do rate codes offer insight into a time-of-day signature?
F. T. SPARKS*1, E. A. MANKIN*2, B. SLAYYEH2, R. J. SUTHERLAND1, *J. K. LEUTGEB2;
1Dept of Neurosci., Univ. of Lethbridge, Lethbridge, AB, Canada; 2Ctr. for Neural Circuits and Behavior, Neurobiol Section, Div. of Biol Sci., UCSD, LA JOLLA, CA

We all know the hippocampus is important for episodic (-like) memory yet activity in hippocampal neurons is usually only measured in relation to spatial information. Memories also often contain temporal information and Rob Sutherland (one of the authors) has shown that rats indeed integrate time-of-day information into their memories. Here, measuring electrophysiological activity in hippocampal neurons, it is reported that 1) hippocampal neurons fire when a rat is in a specific spatial location, as expected; 2) when nearby contextual features are altered (square vs circular exploration chamber) the same population of neurons are active in the same places but they fire at different rates (rate coding); 3) what is unique here: hippocampal neurons also used a rate code to differentiate between a given context explored in the morning vs the afternoon. Thus, time-of-day is a contextual feature that is encoded in the hippocampus. Interestingly, it is reported that the rate codes for spatial and temporal information are carried by different populations of neurons.

3) 330.6/A6 – Experience specific information encoding by newborn neurons of the adult dentate gyrus
*G. D. CLEMENSON, JR, F. H. GAGE;
Salk Inst., La Jolla, CA

This presentation builds on Kee 2007, who showed that 10-week-old neurons are only activated in the water maze if they were functional at the time of the original water maze training, and Tashiro 2006 who claimed that, when a mouse re-experiences something, it is new neurons that were in their critical period during the original experience that are activated. We still have a ways to go before we understand how faithful new neurons are in their responding to different experiences – their enhanced plasticity and unique physiology has caused some speculation that they could be promiscuous, participating in many different experiences. This study seems like it may have the best evidence that young neurons are in fact quite selective in what they encode.

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?

Everything you always wanted to know about neurogenesis timecourses (but were afraid to ask)

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

addition of new neurons

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.

Continue reading Everything you always wanted to know about neurogenesis timecourses (but were afraid to ask)