Date of Award

Fall 2021

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Alexander J. McDonald

Abstract

The ability to appropriately respond to and store memories of emotionally salient events is a critical feature of survival. The basolateral amygdala (BLA) is a temporal lobe structure that is essential in mediating emotional behaviors, learning, and memory. Important to circuit function are synchronized neuronal oscillations. Different oscillatory signatures are implicated in mediating different aspects of behavior and learning and memory processes: theta frequency (3-12 Hz) oscillations represent “online” states and are important for information encoding and learning, and sharp wave ripples (SWRs) represent more “offline” states that are important for the consolidation of memory. In the BLA, both of these oscillatory events are observed during different behaviors, although it is not known mechanistically how these occur in BLA circuits.

The neurotransmitter acetylcholine is implicated in emotional behaviors, learning, and memory. The BLA receives some of the densest cholinergic innervation from the basal forebrain and these inputs are important for a range of emotional processes. Basal forebrain neurons exhibit different firing patterns during a range of behaviors. It is not clear how acetylcholine release from these different patterns of basal forebrain neuron activity impacts BLA circuits. To address this, we utilized optogenetics to release acetylcholine in BLA brain slice preparations. Different physiological patterns of activity were used to explore the circuit mechanisms by which acetylcholine temporally modulates BLA network activity in a cell and receptor subtype specific manner. We found that large phasic cholinergic stimulations induced theta oscillations of the local field potential (LFP) in BLA slices via a muscarinic receptor-mediated mechanism. These oscillations were produced via large rhythmic inhibition of cholecystokinin-expressing interneurons (CCK INs), which were more sensitive to acetylcholine than parvalbumin-expressing (PV) or somatostatin-expressing (SOM) INs. On the other hand, low frequency small cholinergic stimuli evoked SWRs in the BLA. This mechanism of SWR induction has not previously been reported in any brain area. SWRs were induced via nicotinic receptor signaling and recruitment of ripple frequency (150-200 Hz) excitatory and inhibitory events. PV INs were critically involved in these SWRs.

Taken together, these results show that differential patterns of activity in basal forebrain cholinergic neurons, as is observed over a variety of behaviors, produce differential network events in the BLA through different cell and receptor subtypes. This work suggests that acetylcholine signaling is able to control opposing network states in the BLA depending on the nature by which they are firing: “online” theta oscillations important for encoding and “offline” SWRs important in memory consolidation. BLA circuits were shown to be uniquely sensitive to these network changes by acetylcholine, outlining a preferential impact of acetylcholine on amygdalar behaviors, such as fear or extinction learning and memory. These results offer important implications for disorders associated with altered amygdala activity, such as post-traumatic stress disorder (PTSD) and anxiety disorders.

Rights

© 2021, Joshua Xavier Bratsch-Prince

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