Investigating the Recruitment of Lateral Hypothalamic Circuits for Encoding Fear Memories Following Experience with Reward Learning

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PROJECT SUMMARY Decades of elegant research has led to development of rich models of how we encode fear memories. The fear circuit that has emerged from this research is complex. However, at the center of nearly all models of fear learning is the basolateral amygdala. Activity in basolateral amygdala neurons tracks fear learning, and glutamatergic signaling in this region is necessary for the acquisition and expression of conditioned fear. Indeed, it has been demonstrated that the “fear engram” in basolateral amygdala can be targeted and erased to reduce fear. This has led to efforts to develop treatments to erase problematic memories in a manner that may eventually translate to humans experiencing pathological fear as a result of maladaptive fear memories. However, we have recently shown that a neuronal population usually restricted to learning about rewards, can be recruited to encode fear memories as well (Sharpe et al., 2021, Nature Neuroscience). Specifically, GABAergic neurons in the lateral hypothalamus are not necessary to encode fear memories in experimentally- naïve rats. Yet if rats have had recent experience with reward learning, which is dependent on hypothalamic function, these neurons become critical to encode the fear memory. Importantly, this is in the context of an experimental design that controls for many experimental variables associated with experiencing fear and reward learning experiences. This suggests that reward learning primes the hypothalamus to encode fear memories. We will examine the impact that recruitment of the lateral hypothalamus has for the well-documented role of the basolateral amygdala in encoding fear memories. Our preliminary data suggest that reward learning shifts the fear circuit away from the basolateral amygdala and towards the lateral hypothalamus. We further hypothesize that there is a temporal gradient to the involvement of the lateral hypothalamus in fear, such that this role will decay with time from the reward learning experience. To formally test this, we will use cell-type specific optogenetics and fiber photometry of a genetically-encoded calcium sensor to manipulate and record basolateral amygdala pyramidal neurons and lateral hypothalamic GABAergic neurons. We will do this during fear learning in rats with or without reward learning experience, while varying the delay between reward and fear learning procedures. This will begin to characterize a novel fear circuit comprising lateral hypothalamus, expanding models of fear learning, and giving insight into how rewarding experience influences fear encoding. This work is important to human mental health. We know that enhancements in basolateral amygdala activity is produced by traumatic events, and correlated with subsequent enhancements in fear learning. Further, increased amygdala activity to fear cues is seen in humans with post-traumatic stress disorder (PTSD). Thus, a shift away from amygdala towards hypothalamic circuits to encode fear could confer resilience against problematic fear memories. This work will expand our understanding of where fear memories are acquired and stored, and will also reveal recruitment of a novel neural circuit that could confer resilience against problematic fear memories.