Date of Award

Fall 2021

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

David Mott

Second Advisor

Alexander McDonald

Abstract

The basolateral nuclear complex of the amygdala (BNC) – consisting of the lateral (LA), basolateral (BL), and basomedial nuclei (BM) – detects salient environmental stimuli (cue-detection) and motivates appropriate behavioral responses to their implied meaning (cue-guided behavior) via a precise pattern of internal circuitry. Glutamatergic signals representing environmental stimuli enter the LA and split into parallel streams that activate pyramidal neurons (PNs) in the anterior and posterior BL (BLa and BLp), which putatively mediate negative and positive emotions, respectively. The BL is the most densely innervated target of the cholinergic basal forebrain (CBF) and ACh transients (phasic ACh) in cortex are critical for cue-detection and cue-guided behavior. Despite the overlapping functions of the BNC and cortical phasic ACh, it is not known whether phasic ACh differentially impacts BLa and BLp PNs or their responses to LA inputs. The BNC is also a crucial storage site of associative emotional memories and ACh can facilitate learning and memory. NMDA receptors in the BNC are essential gatekeepers for the acquisition of associative emotional memories and ACh can facilitate long-term potentiation, the neuronal substrate of learning, by potentiating NMDA receptor currents in hippocampal PNs. Interestingly, despite similar cell types between the hippocampus and BNC, no studies have determined whether ACh also potentiates NMDA receptor currents in BL PNs. We addressed these critical knowledge gaps by employing confocal immunohistochemistry and brain slice electrophysiology combined with optogenetics and pharmacology. Three core findings emerged from these studies. First, phasic ACh temporally and associatively enhances the signal-tonoise ratio at the LA-BLa pathway. Phasic ACh depolarizes BL PNs via presynaptic α7 and α4β2 nAChRs on non-LA inputs before hyperpolarizing them via postsynaptic M1 muscarinic ACh receptors (M1Rs) coupled to GIRK channels, creating a biphasic response that bidirectionally modulates the ability of LA inputs to fire them by bringing their membrane potential closer to or farther from action potential threshold when they arrive. Second, M1Rs can reduce or potentiate NMDA receptor currents depending on whether they are stimulated by phasic ACh or bath-applied muscarine, respectively. The reduction and potentiation are mediated by GIRK and SK channels, respectively. Finally, the CBF preferentially impacts BLa over BLp PNs and their responses to LA inputs. M1R expression is substantially higher in the BLa; BLa PNs are more sensitive and have larger response components to phasic ACh; and BLa PNs have larger depolarizing responses to bath-applied muscarine. The effect of phasic ACh on LA-driven output was also more muted in BLp PNs, with no nicotinic facilitation and a smaller muscarinic reduction. Together, our results provide novel insight into the circuit- and molecular- mechanisms by which ACh signaling could modulate attention, learning and memory, and valence processing mediated by the BNC.

Available for download on Friday, December 15, 2023

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