Date of Award

Summer 2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Sheryl G. Beck

Abstract

Anxiety disorders are prevalent in human and veterinary medicine yet the underlying mechanism is poorly understood. Because serotonin (5-HT) neurons of the dorsal raphe (DR) are thought to play a prominent role, my goal was to understand the changes in DR 5-HT neurons that underlie anxiety and other stress-related disorders. Two DR subdivisions were studied in a series of experiments: the ventromedial DR (vmDR), a well characterized subfield with a high density of 5-HT neurons, and the lateral wing DR (lwDR), a largely uncharacterized subfield with a more sparse distribution of 5-HT neurons. Many stress paradigms activate 5-HT neurons of the lwDR more so than 5-HT neurons of the vmDR, suggesting a unique role for lwDR 5-HT cells in stress circuits. However, it is not known if lwDR 5-HT neurons possess physiological characteristics that contribute to their increased propensity to be activated by a stressor. I found that lwDR 5-HT neurons demonstrated increased intrinsic excitability, increased glutamatergic input, and similar GABAergic input when compared to vmDR 5-HT neurons. Using the chronic social defeat model of anxiety, the distinctions between lwDR and vmDR neurons were explored further. Social defeat induced anxious behavior and stress-associated pathological changes in the peripheral organs of intruder mice. For the first time, investigation into the neural mechanisms of social defeat has focused on 5-HT neuron physiology, revealing subregion-specific effects within the DR. Increased excitability was seen in the vmDR neurons of the most anxious mice. This was accompanied by a decrease in GABAergic input to vmDR 5-HT neurons potentially mediated by both presynaptic and postsynaptic changes. The lwDR 5-HT neurons demonstrated distinct stress-induced changes limited to the slower kinetics of postsynaptic GABAAR. The differential effect of social stress on inhibitory input to vmDR or lwDR neurons suggest that the 5-HT output in brain regions targeted by each subfield is differentially affected in anxiety disorders. Collectively these findings help fill the gap in our understanding of local DR circuitry, the heterogeneity of 5-HT neurons, and the distinct regulation of vmDR and lwDR neurons in the circuits that mediate stress and contribute to the pathophysiology of anxiety.

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