Modulation of ventral periaqueductal gray dopamine neurons Public Deposited

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  • March 22, 2019
  • Li, Chia
    • Affiliation: School of Medicine, UNC Neuroscience Center, Neuroscience Curriculum
  • Dopamine (DA) neurons within the ventral periaqueductal gray (vPAG) regulate reward, as well as negative emotional behaviors that often lead to addiction relapse. Due to the cell-type heterogeneity of the vPAG, little is known about the functional properties of these neurons, or how drugs of abuse, such as opioids and alcohol, modulate them. In these studies, transgenic mouse lines were used to evaluate the properties, projection, and functional modulation of vPAG DA neurons. Alcohol modulation of synaptic transmission was examined; acute alcohol had minimal effects on GABA transmission, but resulted in a robust enhancement of glutamatergic transmission onto vPAG dopamine neurons, as well as an increase in firing rate of these neurons. Interestingly, chronic intermittent alcohol exposure produced no significant alterations on either inhibitory or excitatory synaptic transmission, suggesting that alcohol has both region- and cell-type-dependent effects on function. Negative emotional behaviors during withdrawal, a critical component of drug addiction, can often lead to relapse, making the study of such behaviors relevant and essential. The kappa opioid receptor (KOR) system has been implicated in disruption of affective behaviors including depression, anxiety, and drug abuse, some of which are mediated via dopamine signaling. Previous studies have shown that stress-induced dysphoria can augment KOR expression in dopamine-rich brain regions, providing a link between kappa opioid modulation and dopamine signaling. Due to the link between dopamine, drug abuse, and the behavioral relevance of the ventral periaqueductal gray (vPAG), this work aimed to elucidate the mechanisms underlying opioid modulation of GABAergic inputs onto vPAG DA neurons. In this study, activation of KOR significantly reduced GABAergic inhibition of vPAG DA neurons. In addition, mechanistic investigation suggested that this effect was mediated via pre-synaptic mechanisms of the G-protein coupled receptor beta-gamma subunit. Finally, this work demonstrated that the vPAG DA neurons are glutamatergic, and project to the bed nucleus of stria terminalis (BNST), a part of the extended amygdala that regulates stress-related behavior. Using viral tools, the potential of vPAG dopamine neurons in modulating behaviors, as well as activity of projection targets were demonstrated. Therefore, this work provides insight into the regulation of negative affective behavior for potential improvement in treatments for emotional disorders and drug abuse.
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  • In Copyright
  • Kash, Thomas
  • Doctor of Philosophy
Graduation year
  • 2013

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