Herry et al vs Courtin et al
Seminar in Biopsych
It is a longstanding finding that cued fear conditioning leads to a marked increase in fear expression in mice, as indicated by a strong increase in freezing behavior (along with coupled autonomic responses, such as increased corticosterone, increased heart rate, etc.). Furthermore, it’s known that continuous presentation of the conditioned stimulus without the unconditioned stimulus is enough to dissociate the association between the CS and the US. Lastly, it’s been shown that reintroducing a contextual cue (the initial context that a mouse was conditioned in) is enough to recover the fear response that was extinguished. This is a good model for PTSD in humans, the most popular treatment for it — exposure therapy —, and its lack of efficacy: most people that undergo exposure therapy experience spontaneous recovery. What circuits mediate this behavior and what about the nature of the circuit leads to this strange series of behavioral changes? In other words, how do fear memories get stored and accessed, and when we try to forget them, why are they not efficiently forgotten?
Herry et al tried to unveil the inner workings of this fear circuit by taking a look at the basolateral amygdala (BLA), a brain structure previously implicated in fear memory consolidation and expression. By using an electrophysiological approach to record from these neurons, neurons with firing patterns correlated specifically with certain stimulus presentations were able to be dissected out. They segregated two groups of neurons that were responsive to the CS+ (that was originally paired with the US) either after fear conditioning or after fear extinction; these neurons will collectively be referred to as the fear ensemble and the extinction ensemble, respectively. Furthermore, they showed that the pattern of activity of either ensemble preceded the respective behavioral changes (freezing increase/decrease). Interestingly, they observed that fear renewal was coupled with a decrease in the activity of the extinction ensemble and a preferential recruitment of the fear ensemble, once again. This is in line with the hypothesis that this collection of “fear neurons” directly control the switch to a fearful state. An interesting question to ask is what the “extinction-resistant” population of neurons represents, and how they contribute to the modulation of this behavior, if at all. The BLA is a very heterogeneous brain region, so maybe it has nothing to do with fear at all.
Okay, so there are two discrete populations of neurons that are more highly active during fearful and “safety” states, but where do these properties of these neurons come from? Are they anatomically different? Herry et al showed that the hippocampus preferentially innervates the fear neurons in the BLA, and those neurons go on to project to the mPFC, while there is a reciprocal connectivity between the BLA extinction neurons and the mPFC. This kind of makes sense, considering the hippocampus has been implicated in memory acquisition, and the mPFC has been implicated in decision making. Lastly, they showed that inactivation of the BLA does not change the current fear state of the mouse, but removes the ability of a change in the emotional state of the mouse.
When Cyril Herry finished his post-doc, he continued to try to probe this fear circuit to understand what is leading to this differential emotional state after behavioral (or neuronal) manipulations. It’s been shown that the mPFC has many different neuronal subtypes, one of which includes parvalbumin interneurons. PV interneurons are a subtype of interneurons characterized by their expression of parvalbumin; they are fast-spiking in nature, and exhibit perisomatic influence on principal neurons. Using a combination of electrophysiological recordings (multi-unit and LFP) and optogenetics (activation and inactivation), Courtin et al was able to show that PV interneurons are necessary and sufficient for fear expression in mice (I hear necessary and sufficient gets you Nature papers). To gain control of just the parvalbumin neuron population in the mPFC, they used PV-cre mice and injected cre-dependent AAVs for optogenetic manipulation. They showed, in several ways, that manipulating the activity of the PVIN population altered the activity pattern of the principal neurons (PN) in the mPFC to, in turn, affect fear expression. They showed that PVIN inactivation reset the theta rhythm in the mPFC, which has previously (and since) been shown to be important for fear expression), and preferentially activated the PN population, to lead to an increase in fear behavior. Great, so there is a modulation of activity in the mPFC that relates to fear expression, but that doesn’t tell us how it fits into the grand scheme of the fear circuit. So lastly, Courtin et al showed that those mPFC PN neurons that were activated during PVIN inactivation targeted the BLA, as shown by antidromic activation of efferents to the BLA with concurrent recording of the mPFC neurons.
These two papers provided deep and thorough insight into the mechanistic nature of the fear circuit; however, how the fear circuit works in its entirety is yet to be unveiled. Herry et al found two segregated populations of neurons in the BLA that showed dichotomous firing patterns paired with dichotomous behaviors, while Courtin et al showed that PV interneuron activity modulates the communication of the mPFC to the BLA. But, where do the PV interneurons in the mPFC receive their projections from, and which BLA neurons get innervated by mPFC projections? It’s in the works!
Both papers ended with just about the exact same closing paragraph: the translational goal of this work, which is to help understand what goes on in anxiety disorders where fear expression regulation goes awry.