Date of Award

Spring 2018

Project Type

Thesis

Program or Major

Biological Sciences

Degree Name

Master of Science

First Advisor

Arturo A Andrade

Second Advisor

Win H Watson

Third Advisor

Jill A McGaughy

Abstract

Anxiety is linked to dysregulation of neuronal activity in several brain regions including the infralimbic (IL) area of the medial prefrontal cortex (mPFC) and the basolateral nucleus of the amygdala (BLA). Disruptions to the balance of excitatory and inhibitory signaling in these regions are implicated in anxiety-like behaviors in animals and anxiety disorders in humans. The neuronal circuitry between excitatory neurons, known as pyramidal cells (P-cells), and inhibitory neurons, known as interneurons (INs), is a primary target for anxiety modulation at the cellular level. INs, particularly the subtype that contain the neuropeptide cholecystokinin (CCK+INs), form inhibitory synapses around P-cells. Through GABAergic neurotransmitter release, CCK+INs regulate P-cell activity and subsequent anxiety-related neuronal output. Two protein complexes, the N-type calcium channel (CaV2.2) and the type-1 cannabinoid receptor (CB1), are expressed in the presynaptic terminal of CCK+INs. CaV2.2 and CB1 have been shown to regulate neurotransmitter release from CCK+INs in the hippocampus, but it is not known if this role is conserved in the anxiety-related neuronal circuits of the BLA and IL. CaV2.2 has also been shown to regulate the intrinsic firing properties of P-cells in the hippocampus and deep cerebellar nuclei, but this role has not been demonstrated in the IL. To investigate these neuronal circuits, I used a combination of transgenic mouse models, confocal microscopy, patch-clamp electrophysiology, optogenetics, and pharmacology. In the first chapter of my thesis, I investigated the role of CaV2.2 in CCK+IN/P-cell synapses in the BLA. In the second chapter of my thesis, I investigated the role of CB1 in regulating GABA release from CCK+INs in the BLA. In the third chapter of my thesis, I assessed the regulation of GABA release and intrinsic firing by CaV2.2 in the IL. I present electrophysiology data which demonstrate GABA release from CCK+INs is partially CaV2.2-dependent in the BLA. I obtained preliminary electrophysiology recordings which suggest CB1 receptors modulate GABA release in CCK+IN/P-cell synapses in the BLA. I found that neurotransmitter release from GABAergic INs is partially CaV2.2-dependent in the IL. I found that GABA release from CCK+INs is not CaV2.2-dependent in this region. Lastly, I observed that CaV2.2 plays a minimal role in the intrinsic firing properties of P-cells in the IL. My findings suggest that CaV2.2 differentially regulates GABA release and intrinsic firing properties across brain regions, suggesting there are region-specific implications of CaV2.2 modulation in anxiety-related neuronal output.

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