Contributions of Genetically Defined Cell Populations in the Extended Amygdala to Emotional Behavior Public Deposited

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  • March 20, 2019
  • Mazzone, Christopher
    • Affiliation: School of Medicine, UNC Neuroscience Center, Neuroscience Curriculum
  • Emotional disorders, including anxiety, remain pervasive and debilitating conditions throughout the world despite decades of progress in the development of pharmacological treatments. Limitations in treatment efficacy exist, in part, due to our lack of understanding of the precise neural pathways and mechanisms underlying emotional disorders. Here I focus on the extended amygdala, an area of the brain that has long been implicated in the regulation of emotional behaviors. In this dissertation work, I use combinatorial approaches to determine the cellular identity and receptors that contribute to anxiety so that we may better develop more selective drug treatments for emotional disorders. In Chapter 2, I use Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to manipulate G protein-coupled signaling pathways in a population of inhibitory cells of the bed nucleus of the stria terminalis (BNST), a component of the extended amygdala. This approach allowed us to identify that activation of Gq-coupled signaling pathways within inhibitory cells of the BNST is sufficient to induce an anxiety-like state in mice. I then identified endogenous Gq-coupled receptors expressed by inhibitory cells of the BNST, ultimately creating a list of potential candidate receptors for alleviating anxiety. In Chapter 3, I further dissect BNST anxiety circuitry by focusing on the impact of serotonin on BNST corticotropin-releasing factor (CRF) expressing neurons. I show that the serotonergic input from the dorsal raphe (DR) nucleus to the BNST can induce both serotonin release and anxiety-like behavior. Using electrophysiological tools we found that serotonin produces opposing effects on membrane properties within BNST CRF neurons. Interestingly, selective serotonin reuptake inhibitors (SSRIs) are known to exacerbate learned fear responses and we found that inhibition of BNST CRF neurons is able to occlude the SSRI-induced enhancements of fear. These results highlight inhibition of BNST CRF neurons as a potential therapeutic strategy for SSRI-induced increases in anxiety seen in patients during the early stages of SSRI-based therapies. Together, these studies untangle part of the complex emotional circuits that may contribute to pathological emotional states and provide new therapeutic targets for the alleviation of both acute and SSRI-induced anxiety.
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  • In Copyright
  • Thiele, Todd
  • Smith, Spencer
  • Stuber, Garret
  • Kash, Thomas
  • Crews, Fulton
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017

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