The lateral preoptic area: a novel regulator of VTA activity and cocaine seeking

项目概要/摘要 外侧视前区（LPO）是下丘脑的结构，其功能在很大程度上是未知的。有 有证据表明，刺激LPO eliminates运动，而这种结构支持颅内自我， 这表明LPO可能是“大脑奖励系统”的一部分。IPO也发出了强有力的 腹侧被盖区（VTA）是大脑奖赏回路的关键成员。这进一步表明， LPO作为大脑奖励系统的潜在成员，特别是作为VTA活性的调节剂。 这是重要的，因为调节VTA活性的结构已被证明在以下方面起关键作用： 可卡因寻求; VTA多巴胺神经元活性的增加触发复发（即增加药物寻求）， 而减少则减少了搜索。LPO是否在功能上调节腹侧被盖区神经元的活动尚不清楚 和寻求可卡因的行为 本提案的目的是了解LPO是否以及如何调节腹侧被盖区神经元的活动（Aim 1)和可卡因寻求行为（目标2）。此外，该提案将审查法律专业干事的贡献- VTA通路中任何观察到的效应，都与神经递质（GABA或谷氨酸）有关。 这将通过操纵（增加或减少）LPO和LPO-VTA的活性来实现 这将确定该结构和途径是否足以和/或必需用于调节细胞的生长。 腹侧被盖区神经元的活动和可卡因寻求行为。将使用三种方法操纵活动： 药理学、化学遗传学和光遗传学。 VTA神经元（GABA和多巴胺）的活性将在体内细胞外记录下评估。 麻醉大鼠。可卡因寻求将在可卡因自我给药后通过检查 在没有可卡因的情况下做出反应。还将测试蔗糖寻求，以检查这一作用是否 结构和途径延伸到寻求自然回报。LPO-VTA的神经化学性质 将（i）使用药理学，（ii）通过测量突触电流，和（iii）通过执行 免疫组化 我们预测，刺激LPO增加腹侧被盖区多巴胺神经元的活动， 行为这通过GABA能LPO-VTA途径发生。具体来说，LPO将抑制性GABA能 预测VTA。这些突触到VTA的GABA神经元上，导致去抑制（即， 多巴胺神经元的兴奋。 我们希望这些研究能为LPO作为腹侧被盖区神经元活动的关键调节剂确立一个新的作用， 寻求可卡因的行为这为理解电路和机制提供了重大进展 上瘾的人此外，这些研究将通过发现大脑中的一个作用， 其功能在很大程度上是未知的。

Project Summary/Abstract The lateral preoptic area (LPO) is a hypothalamic structure whose function is largely unknown. There is evidence that stimulating the LPO elicits locomotion, and that this structure supports intracranial self- stimulation, suggesting that the LPO could be part of the “brain reward system”. The LPO also sends strong projections to the ventral tegmental area (VTA), a key member of the brain reward circuit. This further positions the LPO as a potential member of the brain reward system and, in particular, as a modulator of VTA activity. This is significant because structures that modulate VTA activity have been shown to play a critical role in cocaine seeking; increases in VTA dopamine neuron activity trigger relapse (i.e. increase drug seeking), whereas decreases reduce seeking. It is unknown if the LPO functionally regulates the activity of VTA neurons and cocaine seeking behavior. The objective of this proposal is to understand if and how the LPO regulates the activity of VTA neurons (Aim 1) and cocaine seeking behavior (Aim 2). In addition, the proposal will examine the contribution of the LPO- VTA pathway in any observed effect, and the neurotransmitters (GABA or glutamate) involved. This will be achieved by manipulating (increasing or decreasing) the activity of the LPO and LPO-VTA pathway; this will determine if this structure and pathway are sufficient and/or necessary for regulating the activity of VTA neurons and cocaine seeking behavior. Activity will be manipulated using three approaches: pharmacology, chemogenetics, and optogenetics. The activity of VTA neurons (GABA and dopamine) will be evaluated with in vivo extracellular recordings in anesthetized rats. Cocaine seeking will be evaluated after cocaine self-administration, by examining responding in the absence of cocaine. Sucrose seeking will also be tested, to examine if the role of this structure and pathway extends to seeking for natural rewards. The neurochemical nature of the LPO-VTA pathway will be probed (i) using pharmacology, (ii) by measuring synaptic currents, and (iii) by performing immunohistochemistry. We predict that stimulating the LPO increases the activity of dopamine neurons in the VTA and seeking behavior. This occurs via a GABAergic LPO-VTA pathway. Specifically, the LPO sends inhibitory GABAergic projections to the VTA. These synapse onto GABA neurons of the VTA resulting in dis-inhibition (i.e. excitation) of dopamine neurons. We expect these studies to establish a novel role for the LPO as a key modulator of VTA neuron activity and cocaine seeking behavior. This provides a significant advancement in understanding circuits and mechanisms of addiction. In addition, these studies will advance our understanding of the brain, by discovering a role of a structure whose function is largely unknown.