Noradrenergic Regulation of BDNF Release; Problems With Interpreting Data On BDNF and Neurogenesis in the Hippocampus

I was going to mention that the changes in BDNF levels in the amygdala and hippocampus (increase in the amygdala and decrease in hippocampus) in that article (http://www.ncbi.nlm.nih.gov/pubmed/18614692), in response to folate depletion in normal mice, could, when viewed alongside the increases in noradrenaline levels in the hippocampus, be the result of a chronically-increased firing rate or activation of noradrenergic neurons in the locus ceruleus. Noradrenergic activity is an important factor that regulates BDNF release in different parts of the brain. The mice in that study were showing evidence of "behavioral despair" and anxiety, and increases in noradrenaline release in the amygdala and hippocampus, in response to exaggerated increases in the firing rates of neurons in the locus ceruleus that project to the amygdala and hippocampus, would be consistent with that type of chronic stress/HPA axis hyperactivation paradigm. Here's a really interesting article showing that BDNF is especially-strongly regulated by noradrenergic activity (more specifically, beta-adrenoreceptor activation by noradrenaline or adrenaline) in response to exercise and other stimuli:

http://www.ncbi.nlm.nih.gov/pubmed/12759116

A chronic increase in the firing rates of neurons in the locus ceruleus could decrease beta-adrenoreceptor responses in one part of the brain and increase them in another (explaining the site-specific effects on BDNF release) or something like that. I think BDNF release, per se, is sort of too dynamic to interpret easily, and any drug (or stimulus like physical exercise) that increases noradrenergic transmission in the brain can transiently elevate (or otherwise influence) BDNF release or expression. Here's an article claiming that doses of caffeine, in animals, that are comparable to those consumed by humans (2-3 cups of coffee) increase BDNF levels in the hippocampus, but I wonder if those effects would persist for more than a week or two:

http://www.ncbi.nlm.nih.gov/pubmed/18620014

The increases in the proliferation of hippocampal neuronal progenitor cells ("neurogenesis") in response to exercise [as mentioned briefly in the article I cited above (http://www.ncbi.nlm.nih.gov/pubmed/12759116)] or antidepressants or other drugs tend to be not that significant or meaningful, in a lot of cases. Here's an article that gets at that controversy: (http://www.ncbi.nlm.nih.gov/pubmed/16889797). This doesn't mean neurogenesis is unimportant in the adult brain, but it just means that a lot of the proliferating neuronal progenitor cells don't differentiate into new neurons. And a lot of the studies on hippocampal volume in relation to depression or other conditions are very inconsistent, and there tends to be significant variation, between individuals, in the so-called "normal" hippocampal volume. When researchers have used MRIs to try to correlate structural brain changes with neuropsychiatric symptoms, the results have very frequently not ended up being reproducible. Also, an increase in BDNF is sort of a catch-all indicator of neuronal activity and doesn't really tell you much. Here's an interesting article that looks critically at the problems with a simplistic model for the role that BDNF release may have in psychiatric conditions: (http://www.ncbi.nlm.nih.gov/pubmed/17700574).