Neurogenesis and the septotemporal axis at #SFN11

As I’ve alluded, science, and therefore the SFN meeting where much science is unveiled, is a cycle of confusion and clarification. Currently, confusion may be prevailing in the adult hippocampal neurogenesis field since new neurons have been implicated in everything mammals do – spatial and nonspatial memory, anxiety, depression, addiction, social behavior, stress regulation, blinking etc. This should not be entirely surprising since the hippocampus itself, where these young neurons reside, has many different functions. But how can we reconcile these seemingly disparate functions?

Every time I get worked up about all these neurogenesis findings I think about two words that return me to a state of inner peace, calmness, and….mental turmoil that all of my experiments will have to be performed twice: Septal and Temporal. Neurogenesis aside, the septal and temporal ends of the hippocampus are connected to different brain structures that cause the septal hippocampus to be more involved in spatial processing/cognition and the temporal hippocampus to be more involved in regulating stress and emotion. Which has the potential to explain everything.

Two posters today did a great job of analyzing neurogenesis in these different parts of the hippocampus and relating these findings to function. First, Tanti et al. showed that while a chronic stress model of depression reduced neurogenesis along the entire septotemporal axis, the antidepressant fluoxetine (aka Prozac) rescues this deficit specifically in the temporal hippocampus. In contrast, environmental enrichment, which may be viewed as more of a spatial and cognitive stimulus, selectively (and massively!) increased neurogenesis in the septal hippocampus with no effect in the temporal hippocampus. A nice dissociation where different classes of stimuli (drugs that regulate emotion vs. knowledge about objects and environments) regulate plasticity in different parts of the hippocampus.

This was complemented by a thorough study by Lehman et al., who recently showed that new neurons aid in the recovery from psychosocial stress, they asked whether “depressed” mice that suffered social defeat showed regional differences in neurogenesis. The prediction would be that neurogenesis should be specifically reduced in the temporal hippocampus, since this is the region that regulates the stress and emotional responses. They too were curious about the effects of environmental enrichment, since they’ve previously found that enrichment can rescue mice from a depressed state, but only if neurogenesis was present. The story sounds complicated when I tell you that they did all these experiments in normal mice and mice that had their adrenal glands removed, and had low levels if stress hormones (glucocorticoids). But a surprisingly clear picture emerged:

Social defeat (getting beaten up by a big bully mouse and then having to constantly live next to him) increased glucocorticoids and led to anxiety/depressive behaviors. Furthermore, social defeat specifically reduced neurogenesis in the temporal (i.e. “emotional”) hippocampus. The culprit was glucocorticoids – by removing glucocorticoids both the “depression” and neurogenesis impairments could be reversed. In a complementary experiment, they found that environmental enrichment is also a stressor, but a good stressor. Environmental enrichment increased glucocorticoids yet its other effects were beneficial – the mice were less anxious, less depressed, and they had increased neurogenesis. And just as with social defeat, the effects of environmental enrichment were also dependent on glucocorticoids: when glucocorticoids were removed, environmental enrichment did not reduce anxiety/depression and it did not increase neurogenesis.

The take home message is that stress hormones have bad effects on behavior and neurogenesis in the context of social stress, but they have good effects on behavior and neurogenesis in the context of environmental enrichment. And while we don’t yet know if septal neurogenesis is more important for spatial/cognitive behaviors and temporal hippocampus for emotional regulation, both of these posters did a great job of convincing me that this is a direction we need to pursue if we are to understand the many functions of new neurons. They also made it clear that there are complex interactions between stress, neurogenesis and behavior. To the point that I can live (for a little bit) with not knowing exactly how these neurons are working, but knowing that these diverse functions are clearly possible.