Sunday, May 11, 2025
5/11/2025
Locus coeruleus ensembles in active avoidance and reward seeking - PROJECT SUMMARY Knowing how to act in response to cues in our environment is a critical behavior. Making optimal choices involves engaging the necessary neural networks to seek rewards (e.g., food etc.), avoid negative outcomes (e.g., injury etc.), and ignore irrelevant information. Aberrant network activity in response to cues leads to maladaptive behavioral responses, something characteristic in many psychiatric disorders including PTSD, addiction, autism spectrum disorder, and schizophrenia. The brainstem nucleus locus coeruleus (LC) and brain-wide levels of norepinephrine (NE), a majority of which originates from LC, are vital for engaging appropriate behaviors in response to cues. Recent discoveries emphasize the unexplored complexity in the organization of LC and its role in responding to cues that elicit behavior. Distinct ensembles of LC neurons encode different cognitive processes and behaviors. Furthermore, discrete LC subcircuits are required to parse various LC functions. My long-term goal is to dissociate the complex role of LC and NE in regulating adaptive and maladaptive behaviors. The specific objective of this proposed research is to identify the functional LC neural ensembles and projection targets necessary to appropriately respond to positive and negative reinforcement cues. To achieve this goal, I will (1) characterize LC neural activity acquired from high density electrophysiology probes and (2) identify and modulate LC projections with an activity dependent viral labelling strategy during an active avoidance and reward seeking task. My central hypothesis is that opposing cue-outcome associations recruit separate LC neuron ensembles and circuits necessary for appropriate behavioral responses, even when outcome-associated behaviors are similar. In Aim 1 I will analyze large scale electrophysiology data obtained from high-density Neuropixel probes to characterize LC neuronal activity during active avoidance and reward cue presentation. I hypothesize that there will be separate and distinct ensembles of neurons that respond to cues prompting similar actions to either receive a positive outcome vs avoid a negative outcome. In Aim 2 I will use calcium-dependent genetic tagging, Cal-Light, to identify and inhibit discrete LC projections driven by behavior-evoking cues. I hypothesize that LC ensembles for active avoidance and reward seeking cues preferentially target different brain regions forming functional subcircuits. Furthermore, I will test my hypothesis that activity in these LC subcircuits is necessary for appropriate behavior. The proposed research will identify LC ensembles and projections underlying optimal behavior, highlight circuits that may contribute to maladaptive behavior, and inform circuit- based treatment targets for PTSD and other psychiatric disorders.
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