CAREER: Reward Learning Shapes the Fear Circuit

University Of California-Los Angeles, Los Angeles CA

Investigators

Abstract

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). Neuroscience research tends to conceptualize particular brain regions as specialized to encode particular types of memories. This has led to concerted efforts to locate specific memory engrams in the brain that we could eventually manipulate at will. For example, we often think about fear memories as being exclusively encoded in the brain’s “fear center”, called the amygdala. If we could locate the fear engram in the amygdala, one day we might be able to erase problematic fear memories. However, our recent work has challenged this idea of regional specialization. Specifically, we found that a brain region usually restricted to encoding rewarding memories, the hypothalamus, can be recruited to encode future fear memories if subjects have recently experienced something rewarding. Now, we will 1) investigate if this constitutes a shift away from the traditional amygdala fear circuit, 2) reveal the wider circuit that supports hypothalamic regions in the encoding of fear memories, and 3) expose whether the recruitment of hypothalamic circuits to encode fearful memories is permanent or transient. Together, this work will reveal a more fluid approach to conceptualizing memory formation in the brain. We will disseminate this knowledge to the wider community in an undergraduate seminar course while trialing the teaching philosophy “learning by observing and pitching in”, which is designed to accommodate the educational needs of the diverse student population at UCLA. Further, this project will support paid research opportunities for undergraduate students to work on the proposed experiments and prepare them for careers in scientific research. We generally conceive of particular neural circuits as being specialized to encode particular types of information. However, we have recently revealed a phenomenon that calls this into question. We have shown that lateral hypothalamus (LH) can be recruited to encode fear memories, given appropriate prior experience (Sharpe et al., 2021, Nature Neuroscience). That is, LH GABAergic neurons are not necessary to encode fear memories in experimentally-naïve rodents. However, if rodents have had experience in reward learning, which is dependent on LH function, LH GABAergic neurons become critical for the encoding fear. This showed that reward learning “primes” LH to encode fear memories. We hypothesize that reward learning recruits a novel LH fear circuit to encode fear, which constitutes a shift away from the traditional amygdala circuit, in a manner that degrades with time since reward learning experience. We will use cell-type specific optogenetics and fiber photometry of a genetically-encoded calcium sensor, to investigate the causal and correlative dynamics of this phenomenon. We propose to examine: 1) if reward learning reduces the role of basolateral amygdala in encoding fear, 2) where the LH receives the necessary aversive teaching signal to encode fear memories, and 3) if increasing the delay between reward and fear procedures attenuates the involvement of LH GABAergic neurons in encoding fear. This will reveal a dynamic system that shifts between circuits that encode information depending on prior experience, which may have evolved to help us adapt to changing environments by utilizing existing cognitive schema from recent learning episodes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.