Role of functional and anatomical heterogeneity in ventral pallidum circuits underlying behavioral reinforcement

奖赏处理功能障碍是主要神经精神疾病的常见症状， 成瘾精神分裂症和抑郁症神经元多巴胺信号的扰动与 在这种症状的病因学中，并且是当前药物治疗的目标。我们对它是如何运作的知之甚少 神经精神症状表现在多巴胺信号传导改变的下游，或者是 多巴胺信号首先会受到干扰。腹侧苍白球（VP）是一个主要的怀疑， 受到越来越多的关注。VP是Nucleus Bensors（NAc）的主要输出，也是返回到 腹侧被盖区（VTA）。VP活动对享乐刺激敏感，并能有效地驱动动机 行为。然而，VP是异质性的，包含具有不同神经递质和投射的神经元 目标的例如，VP谷氨酸和GABA神经元共享相似的投射模式，但驱动相反 强化任务的行为模式。NAc D1型和D2型中型多刺的光遗传激活 神经元可以类似地双向影响强化，但如何定义NAc和定义VP细胞类型 联系是未知的。在目标1中，我们采用光遗传学辅助的电生理学和报告小鼠， 在NAc和VP之间建立小区类型特定的连接。Aim 2将使用体内钙成像， 评估所定义的VP群体响应于正和负效价刺激的内在活性， 关联的上下文。这些研究将建立在我们最近的工作，解决关键的知识差距，并促进 VP回路异质性在奖赏加工和神经精神病学中作用的程序性评估 病

Dysfunctional reward processing is a symptom common of major neuropsychiatric disorders including addiction, schizophrenia and depression. Perturbations in neuronal dopamine signaling have been implicated in the etiology of this symptom and is a target of current pharmacotherapies. Less is known about how neuropsychiatric symptoms manifest downstream of altered dopamine signaling, or the mechanisms by which dopamine signaling becomes perturbed in the first place. The ventral pallidum (VP) is a prime suspect that is receiving increasing attention. The VP is the major output of nucleus accumbens (NAc) and a key input back to the ventral tegmental area (VTA). Activity in VP is sensitive to hedonic stimuli and can potently drive motivated behaviors. Yet the VP is heterogeneous containing neurons with diverse neurotransmitters and projection targets. For example, VP glutamate and GABA neurons share similar projection patterns but drive opposite patterns of behavior on reinforcement tasks. Optogenetic activation of NAc D1-type and D2-type medium spiny neurons can similarly bi-directionally influence reinforcement, but how defined NAc and defined VP cell types are connected is unknown. In Aim 1 we employ optogenetic-assisted electrophysiology and reporter mice to establish the cell-type-specific connectivity between NAc and VP. Aim 2 will use in vivo calcium imaging to assess the intrinsic activity of defined VP populations in response to positive and negative valence stimuli and associated contexts. These studies will build on our recent work, address key knowledge gaps, and facilitate a programmatic assessment of the role of VP circuit heterogeneity in reward processing and neuropsychiatric illness.