Nature Neuroscience | Action Potential

Synchronized Anxiety

This is a guest post in our #NPGsfn11 blog series and posted on behalf of Lucas Glover.

In 1999, the functional organization of the hippocampus became a little more complicated. A functional double dissociation was identified (also here) between the two parts of this structure, the dorsal (dHPC) and ventral hippocampus (vHPC.) Since then, much research has focused on the dHPC and its role in spatial memory processing, but much less has been done on the vHPC. The vHPC is known to be involved in mediating anxiety-like behaviors and I sought out a cutting edge update on this proposed functional role here at the Society for Neuroscience Annual Meeting. The emerging story: vHPC and prefrontal cortex (PFC) synchronize to a network oscillation known as “theta” to regulate anxiety behaviors.

Synchronization between multiple brain areas is how these regions coordinate neural communication and Josh Gordon’s lab captured my attention on this topic with two interesting posters. Likhtik et al examined three brain areas implicated in fear-predictive behaviors and tightly linked to the ability to discriminate between neutral and aversive situations. The inability to discriminate between such situations or contexts can lead to anxiety and perhaps even a more generalized response to the fear/threat. Local field potentials (local activity patterns from many neurons) were recorded from the vHPC, mPFC, dHPC in mice, as well as the basolateral nucleus of the amygdala (BLA). Single unit recordings (activity from an individual cell) were taken from the BLA while the mice learned to discriminate between stimuli that either led to a shock (CS+) or not (CS-).

Mice displayed some individual variability in the speed at which they learned this discrimination, with fast-learners exhibiting a greater increase in theta rhythm power (synchronization between areas) when presented with the CS+, or aversive stimulus, as compared to the CS-, or neutral/safe stimulus. In fact, even before learning this task, the “discriminators” already possessed higher theta coupling between the BLA and mPFC, as well as a stronger correlation between theta coupling in three of the four regions being recorded (not dHPC, though, which also lends more support to the behavioral double dissociation mentioned above) and freezing behavior itself. Mice that were poor discriminators initially reacted similarly to both stimuli, did not exhibit any theta modulation and were termed “generalizers.” “Direction of flow” analyses revealed significant differences in how information passed between brain areas in the “discriminators” vs. generalizers (more on this later.)

The second poster, Aadhikari et al, examined whether synchronization between mPFC and vHPC can signal the discrimination between safe and aversive areas in an elevated plus maze (EPM). The EPM, which is elevated off the ground, is a common behavioral apparatus used to induce stress and anxiety behaviors in rodents. It consists of two closed arms, which are the “safe” arms of the maze, where high walls surround the mouse to protect it from falling, as well as open arms, which are wall-less (or have very small walls) in order to promote anxiety and a fear of heights. Again, the authors employed single unit recordings, this time from mPFC neurons, while simultaneously monitoring local field potentials in the vHPC. Many mPFC neurons could distinguish between the arms, firing in open or closed sections, with firing rates changing as the rodent moved towards or away the neuron’s “preferred” space. The strongest-responding mPFC neurons, regardless of which condition set them off, were also highly coupled with vHPC theta activity, however, task-related neural activity was inversely-proportional to behavioral measures of anxiety.

So, let’s try to synthesize here. It seems the vHPC may pick up a signal representing “danger” and/or the “anxious state,” with this message sent uni-directionally to the mPFC via high synchronous coupling between the BLA-vHPC-mPFC. While mPFC neurons can and do discriminate between safe and aversive environments, in the presence of a “danger” signal, increased firing may occur in all mPFC neurons, regardless of their tuning to aversion. Mice that are poor at discriminating threatening situations appear to have an information workflow that is almost backwards, possibly leading to a generalization of contexts!

What do I think of this flow? I think the mPFC and BLA work together to define what’s aversive vs. safe. This information may then be supplied to the vHPC for a “gut-check,” (dare I say, “brain-check??,”) to perhaps signal conflict or to assign a specific context to the received signal. This may then be passed back to the mPFC and the cycle continues. Where the information goes from here, further studies will tell!

Lucas R Glover

Graduate student: joint-doctoral program between NIMH/NIH and Oxford

Lucas is a 1st year graduate student at the NIMH and Oxford, investigating the role of adult neurogenesis in stress and dentate gyrus-mediate functions.


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