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

项目总结/摘要 中脑边缘多巴胺系统，从腹侧被盖区（VTA）投射到核团 强烈地控制着在环境中寻求奖励的动机，包括滥用药物， 改变体液和能量平衡的奖励。长期以来发生的内部状态的自然不平衡 时间过程，如饥饿和口渴的感觉，对于动机行为的表达至关重要。 然而，在不同的稳态下，基底神经节回路活动的回路机制 仍不清楚随着单神经元分辨率成像工具的最新发展， 传感器和光学神经递质传感器，腹侧中脑以及 腹侧纹状体很容易测量。这项工作的目标是确定选择性活动 腹侧被盖区多巴胺神经元的模式在不同的内部状态下发生变化， 活动驱动中脑背外侧核中多棘输出神经元放电模式的差异 在行动选择中。为了解决这个问题，我将使用一个自由移动的提示方法音调辨别任务， 在执行单神经元解析时， 使用头戴式微型显微镜对多巴胺神经元钙活性进行成像。我假设 多巴胺神经元将优先响应于被剥夺的线索和奖励，同时也弱地响应于 非剥夺刺激，这将取决于上游大脑区域的活动， 口渴的表情此外，我假设多巴胺细胞活性的这种差异将导致双向的 纹状体输出活动的调节，跟踪局部多巴胺释放和剥夺诱发的行动 选择.这项工作将建立在我们实验室对纹状体回路以及内感受性神经元的先前研究的基础上。 其他实验室的电路。我将学习在体内记录技术以及行为的技能 设计和数据分析。通过这个项目，我希望能进一步了解突触前和突触后的基础。 状态依赖性动机中多巴胺能活动的电路机制。

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.