November 16, 2011

In Anxiety, the PFC-ventral Hippocampus-Amygdala Sync Up (extended version)

Shortened vesion on Nature Neuroscience blog here
Ever since the functional double dissociation (also here) between the dorsal (dHPC) and ventral hippocampus (vHPC), a lot of research after has focused mainly on the dHPC and spatial memory/processing; however, less research has been done on the ventral portion.  This region is known to be largely in charge of mediating anxiety-like behaviors.  Some interesting findings have been presented on the poster floor here at Society for Neuroscience (2011).  I had the pleasure to see a few posters that relate to anxiety and this brain region.  The emerging story is that the vHPC interacts closely with the prefrontal cortex to regulate anxiety behaviors through the oscillatory pattern known as the theta rhythm, whereby the amygdala also plays a crucial role, along with the VTA.  This synchronized rhythm between multiple brain areas is how these regions coordinate neural communication with each other.

read more for the poster info on the brain regions and diagrams I made - they're pretty professional!

On the second day of SfN, I stopped by three interesting posters all related to this general theme. I'll only cover two, as space is limited and hopefully can post more either here or at my blog. Two of the most interesting ones are from J. A. Gordon's lab at Columbia.  The first poster by Likhtik examined the three areas involved with fear-related behaviors and the ability to discriminate (or predict) between neutral and aversive situations.  The inability to discriminate such situations or contexts can lead to anxiety, and thus a generalized response to fear/threat.  In 129/SvEv mice, local field potentials were recorded from the vHPC, mPFC, dHPC , and the basolateral nucleus of the amygdala (BLA).  Single unit recordings were taken from the BLA as these mice learnt to discriminate between a stimulus that leads to a shock (CS+) and one that does not (CS-).  Some of the mice were very good at learning this and discriminating between the two stimuli, while others were poorer.  These mice good at the discrimination showed a great increase in theta rhythm when presented with the CS+, or aversive stimulus, as compared to the CS-, or neutral/safe stimulus.  Animals that were not so great at the discrimination, as showing equal freezing to both stimuli, did not show a difference in theta power, as compared to a baseline condition (no stim).  What I found really cool was that, in animals that were subsequently good at this discrimination task, before handling any of the mice, the "Discriminator" mice had higher theta coupling in the BLA and mPFC as compared to the animals that were not good at this discrimination, the "Generalizers"!  Taking it a step further, they found a correlation between more freezing and coupling between the mPFC, BLA, and vHPC (not the dHPC, though, which also lends more support to the behavioral double dissociation mentioned at the top of this post).  You guessed it, the same as before handling, the "Discriminators" still had higher theta synchrony between all three of these regions even after handling, as compared to the "Generalizers".  Using some fancy algorithms and stuff I don't understand, they were able to determine the flow in which this theta activity occurred; it appears that, during baseline (no stim), the mPFC sets the tempo (or "leads") for theta activity reaching the BLA.  During the time that the aversive stimulus (CS+) is presented, BLA seems to lead the theta rhythm flow to the mPFC.  In the "Generalizers", though, during the safe stimulus (CS-), you get the same pattern, in which the BLA leads the mPFC theta, whereas this is not the case for the "Discriminators".  The "Generalizers" seem to be sending out generalization signals, whereas the "Discriminators" are better at thresh-holding their theta activity flow.  Upon taking a look at the flow of information between the vHPC and the mPFC, it appears that the vHPC sends out the information to the mPFC during baseline and during stimulus presentation, which makes sense given that the vHPC-mPFC directionality seems to be uni-directional (mentioned above).

This is how I envisaged the "leading" of theta while I was viewing the poster.
Picture courtesy of MS Paint & L. R. Glover Designs

 The second poster, presented by Aadhikari, examined whether, in 129-SvEv mice, the synchronization between the medial prefrontal cortex (mPFC), specifically the prelimbic area, and the vHPC can distinguish between safe and aversive areas in the 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 as to avoid falling, whereas the open arms are those that are wall-less (or have very small walls) in order to promote anxiety and fear of the height.  In order to explore whether these areas could distinguish between the safe (aka closed) arms and averse (aka open) arms, they recorded from multiple mPFC neurons while simultaneously monitoring (via local field potentials) how the vHPC responds.  What they find is, the mPFC neurons can distinguish between the arms, regardless of whether they were open or closed.  mPFC neurons that fired in the closed arms began to decrease their firing rate when the mouse was transition to an open arm and units that fired preferentially in open arms started to decrease their firing upon transitioning to the closed arm.  Here enters the vHPC.  They find that the mPFC neurons that respond more strongly to either set of arms is also highly coupled with theta activity in the vHPC.  This direction of vHPC to mPFC signalling has been shown to be uni-directional.

In terms of how the mice behaved on the EPM, they find that animals that tended to avoid the open arms had less, I repeat less, mPFC neurons that distinguished between the arm types.  Why the heck would animals that avoid open arms have less mPFC neurons that distinguish the two types of arms -- it's counter-intuitive (but is science not usually?). Interestingly, overall firing rate in avoidant mice (those that tended to stay in the closed arms) was higher than the rates from the less-avoidant mice. Why?  An answer was given in the form that, it is quite possible the mPFC neurons that respond more strongly to the closed arms generalized over open and closed arms, thereby increasing the total firing rate, as it then would appear that there would be no distinguishing neurons (e.g. they fire equally to the open and closed arms wildly).

Picture courtesy of MS Paint & L. R. Glover Designs

To back this up, the team did additional experiments in 5-HT1A receptor knockout mice and in a modified EPM where brightly-lit arms were the aversive stimulus, not the height, but, for sake of brevity, I'll leave it at that.

In the first poster, the avoidant mice (you could say good discriminators) had the "Warning: Dangerous Environment" signal activated and this spread throughout mPFC neurons, as to make it appear that they did not distinguish between arms, but, really, they did!  In the second poster, we can see the directionality of the flow, such that during presentation of a threatening cue, the BLA signals a "threat", sends information to the vHPC, which then is relayed to the mPFC.

To tie this all together: the vHPC appears to pick up the signal of "danger" and "anxious state".  This is expected based on previous behavioral work.  This message is sent uni-directionally to the mPFC, via this high synchronous coupling between the BLA-vHPC-mPFC.  mPFC neurons can and do discriminate the environment in safe and aversive zones normally.  However, when the mPFC gets the "danger" signal, through this theta rhythm coupling from vHPC, increased firing occurs in all the mPFC neurons, not only those that are aversive-prefering neurons.  Mice that are poor at discriminating threatening situations, so called Generalizers, appear to have the information flow almost backwards, thereby generalizing contexts! What do I think of this flow?  I think that the mPFC and BLA work together to define what's aversive vs. safe.  The information supplied is sent to the vHPC for a "checking" state, maybe to signal any conflict that occurs and/or to assign a specific context to the signal it's receiving.  This then is passed onto the mPFC, and the cycle continues. Where the information goes from here, further studies will tell!  I saw other posters that related some of this information to the VTA and other such regions.  The entire brain is a network and each part influences the other part.


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