The Freaky and Wonderful Hippocampus

8 Dec

OK, I’m about to dork out on you big time.

I’ve been writing a paper this week about neurogenesis in the hippocampus and how it relates to depression. It’s possible that I lost you right about at the point where I said “neurogenesis in the hippocampus.” Stick with me – this is cool stuff.

Image from Wikipedia

The hippocampus, a small temporal-limbic structure generally associated with memory consolidation and retrieval , is unusual in its ability to continually support neurogenesis (the production of new neurons) in the adult brain. Very briefly, here’s how the process goes down: precursor cells form in the subgranular zone of the dentate gyrus, a flexed, layered region that is located near the center of the hippocampus. The precursor cells then migrate into another layer of the dentate gyrus known as the granule cell layer to mature. It’s assumed that the hippocampus must continually generate these new neurons in order to form distinctive episodic memories without interference from older neurons.

Neurogenesis in the hippocampus seems to be highly sensitive to a lot of factors. For example, neurogenesis declines in response to advancing age and stress, and it increases in response to estrogen levels, learning, and physical activity. Major depression appears to be related to reductions in hippocampal neurogenesis, while sustained use of antidepressants is associated with increased neurogenesis – correlations that have been highly interesting  to depression researchers, clinicians, and even tired graduate students.

We know that severe or chronic stress often precedes major depression in people who are genetically prone to the disorder. Given the particularly potent effects of stress on hippocampal neurogenesis, which have been demonstrated in a lot of animal studies, it seems likely that stress plays a key role in initiating the neurogenesis inhibition associated with depression. More disturbingly, chronic or severe stress – and the depressed behavior associated with it – has also been linked to problems with neuron survival in animal hippocampi. While current technology doesn’t allow us to safely study neurogenesis in living people , human studies do show that hippocampal volumes (and presumably hippocampal neurogenesis and neuron survival) are negatively affected by prolonged major depression. Atrophy in the hippocampus can persist for decades after remission, and the magnitude of volume loss may be as high as 20%.

If the hippocampus is implicated in depression, we’re faced with a chicken-or-the-egg question: do problems with hippocampal neurogenesis and neuron survival make people vulnerable to depression? Or does depression inhibit neurogenesis and neuron survival in the hippocampus? Most evidence seems to support the latter. A study by MacQueen and colleagues (2003) found that patients who had experienced only one major depressive episode didn’t differ from matched controls in hippocampal volume, while patients who had experienced multiple episodes demonstrated significantly smaller hippocampal volumes than controls. These changes weren’t accounted for by increasing age, providing support for the idea that reductions in hippocampal volume don’t precede depression. In a study by Santarelli and colleagues (2003), focused radiation was applied to the hippocampi of mice to end neurogenesis, a procedure that should have resulted in observably depressed behavior if inhibited hippocampal neurogenesis initiated depression. However, the behavior of mice that had undergone the procedure didn’t differ from the behavior of mice in the control condition. Interestingly, the procedure did appear to block the ability of the antidepressant fluoxetine (Prozac) to produce its usual behavioral effects. If the functional aspects of recovery from depression depended solely on changes in the neurotransmitter mechanisms that antidepressants target, halting hippocampal neurogenesis shouldn’t have impacted the effectiveness of the Prozac. This finding suggests that while hippocampal neurogenesis may not contribute significantly to the development of depression, it may be crucial to recovery from depression. Almost all antidepressants have been shown to stimulate hippocampal neurogenesis and/or improve neuron survival, and it’s probably not a coincidence that the typical delay in antidepressant effectiveness (about 6 weeks) is about the same length of time as the maturation time of new neurons in the hippocampus. Frodl and colleagues (2008) found that people who took antidepressants regularly over the course of a three-year period demonstrated increased hippocampal volume, while subjects who did not take antidepressants consistently didn’t demonstrate these gains, regardless of whether or not their depression was in remission.

It’s important to note that the role that the hippocampus plays in depression is still a matter of some debate, and it’s widely acknowledged that there are undoubtedly other factors that play a crucial role in the regulation of neurogenesis in the adult hippocampus that have yet to be identified or understood. We also have to remember that most studies of hippocampal neurogenesis during depression are animal studies, and depression among animals – usually measured via tests involving response to food – may not be a perfect counterpart to the complex condition that is human depression. The conclusions drawn from animal studies must be applied to humans with caution.

Limitations aside, the research literature does offer an interesting perspective on depression and has potentially exciting implications for treatment. Given the convincing body of evidence suggesting that hippocampal neurogenesis must be present for antidepressants to produce at least some of their desired effects, new types of medication may be worth exploring. Most existing antidepressants target reuptake of the neurotransmitters serotonin or norepinephrine; hippocampal neurogenesis is just a nice side effect. There are, however, several promising new compounds that have been shown to stimulate hippocampal neurogenesis and that may eventually be capable of producing antidepressant effects without the negative side effects (drowsiness, decreased libido, etc.) that so often accompany traditional antidepressants. At any rate, the superior effects of long-term antidepressant treatment suggest that clinicians should continue to strongly encourage clients who have begun antidepressant regimens to stay on their meds for at least the requisite six weeks. It’s possible that clients might be more willing to persist in taking meds despite crappy initial side effects if they’re aware of the (theoretical) role of the hippocampus in the efficacy of antidepressants and the amount of time required for successful neurogenesis to take place.

The research on this subject also offers possible new directions for our understandings of other treatments that have been shown to be effective for depression, including exercise, stress reduction and mindfulness techniques, and even electroconvulsive therapy, all of which have been associated with improvements in neurogenesis. Could hippocampal neurogenesis stimulation be the common thread underlying all of these treatments? Of course, this line of thought raises many more questions. If hippocampal neurogenesis is the mechanism underlying successful treatment, could treatments have additive effects on the hippocampus? For example, do clients who take Prozac and exercise regularly experience faster neurogenesis or better neuron survival than clients who use only one treatment? What are the limits of hippocampal neurogenesis, and what implications do these limits have for long-term use of antidepressants? Can a hippocampus generate too many new neurons? What happens if it does? And if reductions in hippocampal volume are associated with memory problems common to depression, could long-term use of antidepressants result in improvements in memory?

Ted says that he thinks science is like throwing rocks at a thing in the dark and trying to guess the shape of it by listening to the sounds the rocks make. While we still don’t know the exact shape of the relationship between the hippocampus and depression, “rocks” are being thrown with great enthusiasm – a search for “hippocampal neurogenesis” on a handful of research databases brings up a list of 1128 research articles published after 2000, many of which directly address mood and motivation – and the field has already produced findings that promise to have important ramifications for the way depression is understood and treated in the future.

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If you’re as interested in this stuff as I am and have loads of free time to read research articles (lol!), here are some articles that I found especially interesting:

Balu, D. T., & Lucki, I. (2009). Adult hippocampal neurogenesis: Regulation, functional implications, and contribution to pathology. Neuroscience and Behavioral Reviews, 33, 232-252.

Becker, S., & Wojtowicz, J. M. (2007). A model of hippocampal neurogenesis in memory and mood disorders. Trends in Cognitive Sciences, 11(2), 70-76.

Frodl, T., Jager, M., Smajstrlova, I., Born, C., Bottlender, R., Palladino, T., Reiser, M., Moller, H., Meisenzahl, E. M. (2008). Effect of hippocampal and amygdala volumes on clinical outcomes in major depression: a 3-year prospective magnetic resonance imaging study. Journal of Psychiatry and Neuroscience, 33(5), 423-430.

Hanson, N., Owens, M., & Nemeroff, C. (2011). Depression, antidepressants, and neurogenesis: A critical reappraisal. Neuropsychopharmacology, 36(13), 2589-2602.

MacQueen, G. M., Campbell, S. , McEwen, B. S., Macdonald, K., Amano, S., Joffe, R. T., Nahmias, C., & Young, L. T. (2003). PNAS, 100(3), 1387-1392.

Marcussen, A. B., Flagstad, P. P., Kristiansen, P. G., Johansen, F. F., & Englund, U. U. (2008). Increase in neurogenesis and behavioural benefit after chronic fluoxetine treatment in Wistar rats. Acta Neurologica Scandiniavica, 117(2), 94-100.

Santarelli, L., Saxe, M., Gross, C., Surget, A., Battagila, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., Belzung, C., Hen, R. (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science, 301(5634), 805-809.

Sapolski, R. M. (2001). Depression, antidepressants, and the shrinking hippocampus.  PNAS, 98(22), 12320-12322.

Van Bokhoven, P. P., Oomen, C. A., Hoogendik, W. G., Smit, A. B., Lucassen, P. J., & Spijker, S. S. (2011). Reduction in hippocampal neurogenesis after social defeat is long-lasting and responsive to late antidepressant treatment. European Journal of Neuroscience, 33(10), 1833-1840.

Yan, H. C., Cao, X., Gao, T. M., & Zhu, X. H. (2011). Promoting adult hippocampal neurogenesis: A novel strategy for antidepressant drug screening. Current Medicinal Chemistry, 18, 4359-4567.

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