Synaptic and circuit mechanisms of fear suppression

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Fear behavior, also known as defensive behavior, promotes survival when it is rapidly deployed in response to perceived danger. The perception of danger is informed by previous experiences in similar situations. When these previous experiences are heterogeneous, with some associated with danger and others with safety, the brain faces the computational challenge of simultaneously retrieving conflicting memories of similar situations, rapidly weighing them against the current situation, and immediately deploying a fear response if deemed necessary. A possible solution for this computational challenge is provided by oscillatory activity, which can rapidly promote and gate information flow through neural circuits. Accordingly, experience-dependent fear behavior correlates with various patterns of oscillatory activity in limbic brain regions. Which of these correlations reflect causal contributions of oscillatory activity, and how these contributions are enacted, remains unclear. The goal of this proposal is to gain a mechanistic understanding of how two different patterns of oscillatory activity promote the retrieval of two competing memories of the same context, one associated with danger and the other with safety. The hypotheses tested under this proposal are based on a working model in which two mutually exclusive oscillatory states control information flow through parallel limbic circuits that connect the basolateral amygdala (BLA), the medial prefrontal cortex (mPFC), and the ventral hippocampus (vHIP). Mice will be subjected to consecutive fear conditioning and extinction trials in the same context. This paradigm leads to spontaneous alternation of freezing and exploratory behavior in this context, reflecting competing fear and extinction memories. The retrieval of the fear memory is promoted by one pattern of oscillatory activity in the BLA, while the retrieval of the extinction memory is promoted by a different pattern of oscillatory activity in the BLA. The first aim will test the hypothesis that the two different BLA oscillations synergistically interact with two different BLA engrams, thereby promoting the retrieval of the two memories. For this, fear engram neurons and extinction engram neurons in the BLA will be recorded or manipulated. The second aim will test the hypothesis that different BLA oscillations recruit different mPFC neurons in an experience-dependent manner. For this, functionally defined mPFC neurons will be recorded or manipulated. The third aim will test the hypothesis that the BLA controls parallel vHIP-mPFC pathways during fear and extinction memory retrieval. Neurons in the vHIP that project to the mPFC will be recorded or manipulated during manipulations of BLA activity, oscillations, or engram neurons. Combined, these aims study synergistic relationships between oscillatory activity and engram neurons, thereby increasing the mechanistic understanding of how limbic circuits can rapidly and appropriately deploy, or suppress, experience-dependent fear behavior. This increased mechanistic understanding will facilitate the rational design of novel therapeutic treatments for excessive fear that use targeted induction of oscillatory activity patterns.