The lateral preoptic area regulates the ventral tegmental area and drives reinforcement and aversion




Gordon, Adam Girard

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The lateral preoptic area (LPO) is an understudied brain region that is interconnected with reward centers of the brain, but the role it plays in modulating these reward centers and the behaviors these centers underlie is unknown. The LPO is positioned to regulate the activity of the ventral tegmental area (VTA) through a direct projection to VTA GABA and VTA dopamine neurons and through indirect connections via intermediary structures, including the lateral habenula and rostromedial tegmental nucleus, which potently regulate VTA dopamine neuron activity. Correlational studies find that LPO neurons are excited by both rewarding and aversive events, and neuronal activity in this structure is sensitive to fluctuations in cocaine levels throughout self-administration. However, the role of the LPO in these behaviors is unknown. Throughout this dissertation, I demonstrate that the LPO functionally regulates the activity of VTA dopamine and GABA neurons, drives both reinforcement and aversion, and increases activity in response to aversive events. Specifically, I found that stimulation of the LPO with bicuculline leads to inhibition of VTA GABA neurons and excitation of VTA dopamine neurons and precipitates cocaine and sucrose seeking behaviors. I also found that stimulation of the LPO with optogenetics leads to inhibition of VTA GABA neurons and mixed effects on VTA dopamine neurons. In addition, stimulation of the LPO with optogenetics drives both reinforcement and aversion; it supports intracranial self-stimulation and drives real-time place aversion in the same subjects. However, I found that even though stimulation of the LPO does not drive place-preference per se, stimulation of the LPO is reinforcing in the real-time place preference procedure, because animals continue to obtain stimulation in the face of adversity. Finally, I found that, at the population level, the LPO increases its activity in response to aversive events and corresponding predictive cues, but not to rewarding events and corresponding predictive cues. Together, these results indicate that the LPO regulates the activity of VTA subpopulations, drives complex reward-related behaviors, and signals in response to aversive events, all of which argues that the LPO is a previously overlooked member of the brain reward circuit



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