State-dependent regulation of mesolimbic dopamine and ventral striatal neuron activity

项目总结/文摘

PROJECT SUMMARY/ABSTRACT The mesolimbic dopamine system, projecting from the ventral tegmental area (VTA) to the nucleus accumbens, strongly controls motivation to seek rewards in the environment, including drugs of abuse and rewards that alter fluid and energy balance. Natural imbalances in internal state that occur over prolonged timecourses, such as the sensations of hunger and thirst, are critical for expression of motivated behavior. However, the circuit mechanisms underlying basal ganglia circuit activity during different homeostatic states remains unclear. With the recent development of single neuron resolution imaging tools, optical calcium sensors, and optical neurotransmitter sensors, dopamine activity in the ventral midbrain as well as in the ventral striatum can be easily measured. The goal of this work is to determine how selective activity patterns in VTA dopamine neurons change during different internal states and how those changes in activity drive differences in firing patterns of medium spiny output neurons in the nucleus accumbens during action selection. To address this, I will use a freely-moving cued approach tone discrimination task in which food- and water-predictive cues are randomly delivered while performing single-neuron resolution imaging of dopamine neuron calcium activity using a head-mounted mini-microscope. I hypothesize that dopamine neurons will preferentially respond to the deprived cue and reward while also weakly responding to the non-deprived stimuli, and that this will depend on activity in upstream brain regions required for hunger and thirst expression. Further, I hypothesize that this difference in dopamine cell activity will lead to a bidirectional modulation of striatal output activity that tracks local dopamine release and deprivation-evoked action selection. This work will build on prior research done on striatal circuits in our lab as well as on interoceptive circuitry in other labs at our institution. I will learn skills in in vivo recording techniques as well as behavioral design and data analysis. With this project, I hope to further understand fundamental pre- and post-synaptic circuit mechanisms underlying dopaminergic activity in state-dependent motivation.