Date

9-2015

Document Type

Dissertation

Degree Name

Ph.D.

Department

Neuroscience Graduate Program

Institution

Oregon Health & Science University

Abstract

The suprachiasmatic nucleus (SCN) of the anterior hypothalamus is the central circadian pacemaker of the body. Besides several neuropeptides, SCN neurons express the neurotransmitter γ−aminobutryic acid (GABA), and local GABAergic nerve terminals are abundant within the SCN. Despite the prevalence of GABA and GABA receptors in the SCN, the physiological and functional roles of GABA within the SCN remain unclear. GABA signaling has been proposed to mediate synchrony, desynchrony, phase shifts, synaptic gain, and has been observed to be both inhibitory and excitatory within the SCN neural network. My dissertation work has investigated the physiological and functional roles of GABA transmission in the SCN.

The results presented in Chapter 2 provide new insight into the functional role of SCN GABA transmission. I show that that genetic deletion of the vesicular GABA transporter (VGAT), and therefore disruption of synaptic release of GABA from SCN neurons, results in the deterioration of behavioral rhythmicity in vivo and concurrent cellular desynchonry in vitro. Therefore, the results presented here indicate that local GABA transmission is essential for the synchronization of SCN neurons that is necessary for coherent circadian output.

In the central nervous system, GABA transmission is normally inhibitory, but several groups have observed excitatory GABA transmission in the adult SCN. However, studies across labs have disagreed on the circadian phase, neuronal location and prevalence of excitatory GABA transmission. GABA has been reported to be exclusively inhibitory, inhibitory during the day and excitatory during the night, and excitatory during the night and inhibitory during the day. The intracellular concentration of chloride ([Cl−]i) is the ultimate determinant of GABA’s physiological action. In Chapter 3, I present results obtained from two independent techniques to address the regulation of [Cl−]i in SCN neurons. Together, my results indicate that the potassium-chloride cotransporters (KCCs) have a significant role in SCN [Cl−]i regulation, while the sodiumpotassium- chloride cotransporter type 1 (NKCC1) has a relatively minor role. Further, I have observed that [Cl−]i is differentially regulated in AVP- and VIP-expressing neurons, and have found direct evidence for a circadian component to [Cl−]i regulation in AVPexpressing neurons.

Membrane excitability has been linked to the molecular clock in SCN neurons. Therefore, the regulation of [Cl−]i in SCN neurons addressed in Chapter 3 may be a key regulator of the circadian synchrony of SCN neurons investigated in Chapter 2. Both of these projects have made use of novel genetic approaches to address complex questions in SCN physiology. These techniques represent the forefront of neuroscience research, and have once again been shown to be invaluable for dissecting neural circuitry.

Identifier

doi:10.6083/M4BK1B9B

School

School of Medicine

Available for download on Saturday, September 15, 2018

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