Date of Award
Doctor of Philosophy (PhD)
Interdepartmental Neuroscience Program
Animal survival relies in part on the ability to learn the outcomes that environmental stimuli predict and recall those associations to make decisions later in life. Learning is not monolithic, but instead is mediated by different brain regions depending on the type of information processed. Learning can happen at happen at different speeds, and memories can vary in their longevity. Much is still unknown about the neurobiology underlying learning and memory, thus further research into these processes is necessary to build foundational understanding of these critical phenomenon, and also to develop novel treatments for patients suffering from learning and memory related disorders such as Alzheimer’s Disease, addiction, and post-traumatic stress disorder. Memories that have a positive or negative emotional association are powerful and long-lasting. The basolateral amygdala (BLA) is a brain area involved in emotional processing, including associating initially neutral cues with the appetitive or aversive stimuli they come to predict. Acetylcholine (ACh), a neuromodulator with abundant release in the BLA, is implicated in many processes throughout the brain and body, not least of which is learning and memory. The following chapters detail my exploration of the connection between BLA ACh signaling and cue-reward learning. After explaining the background behind and rationale for the approach (Chapter 1), I briefly describe the development of a cue-reward learning task used to study the role of cholinergic signaling in appetitive learning (Chapter 2). Then, I discuss experiments we performed to record (Chapter 3) and manipulate (Chapter 4) BLA cholinergic signaling during this cue-reward learning. I conclude by integrating the results from recording and manipulation studies and attempt to reconcile these results internally and with external findings to move toward a more comprehensive understanding of the effect of BLA ACh signaling during reward learning (Chapter 5). The primary behavioral paradigm used in the following chapters was a cue-reward learning task in which mice must learn to nose poke during presentation of an auditory tone to receive a food reward. In Chapter 3, we used a genetically-encoded fluorescent ACh sensor to record ACh dynamics in the BLA as animals learned the task contingency. We found that ACh was released in the BLA in response to salient events during the task and evolved with task performance. In order to isolate the source of the ACh, we also recorded calcium dynamics in the BLA-projecting cholinergic terminal fibers of nucleus basalis of Meynert (NBM), a basal forebrain nucleus that is a main contributor of ACh to the BLA. The pattern of activity in these terminal fibers was similar to that observed for ACh signaling, suggesting that the NBM is responsible, at least in part, for cue-reward ACh signaling. Importantly, these shifts in time-locking were tightly correlated to acquisition of the task contingency. We also recorded the activity of BLA output cells, which revealed they were excited following reward-retrieval initially, but their response shifted to the reward-predictive tone after acquisition. Next, in Chapter 4, we optogenetically and pharmacologically modulated cholinergic signaling in the BLA and systemically investigated the effect of manipulating cholinergic signaling on reward learning. We found that both behaviorally-contingent and non-contingent stimulation of BLA ACh release enhanced cue-reward learning. Systemic antagonism of muscarinic, but not nicotinic, ACh receptors impaired task acquisition. Interestingly, nicotine administration led to a modest improvement in performance of the cue-reward task. The studies described here advance the understanding of how ACh might be involved in cue-reward learning and challenge notions of the precise timing required for neuromodulatory input to affect the formation of associations between stimuli.
Crouse, Richard Blake, "Acetylcholine Signaling in the Basolateral Amygdala During Reward Learning" (2021). Yale Graduate School of Arts and Sciences Dissertations. 32.