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

项目摘要/摘要 视前外侧区(LPO)是一种功能未知的下丘脑结构。的确有 有证据表明，刺激LPO可以引起运动，并且这个结构支持颅内自我 这表明LPO可能是“大脑奖赏系统”的一部分。LPO还发送强大的 投射到腹侧被盖区(VTA)，这是大脑奖励回路的关键成员。这进一步增加了头寸 LPO被认为是大脑奖励系统的潜在成员，特别是作为VTA活动的调节器。 这一点意义重大，因为调节VTA活性的结构已被证明在 寻找可卡因；VTA多巴胺神经元活性增加会引发复发(即增加寻求毒品)， 反之，减少则减少寻求。目前尚不清楚LPO是否在功能上调节VTA神经元的活动 和寻找可卡因的行为。 本提案的目的是了解LPO是否以及如何调节VTA神经元的活动(AIM 1)和可卡因寻找行为(目标2)。此外，该建议亦会研究劳工事务主任的贡献- VTA通路在任何观察到的作用，以及神经递质(GABA或谷氨酸)的参与。 这将通过操纵(增加或减少)LPO和LPO-VTA的活性来实现 这将决定这种结构和途径是否足以和/或必要地调节 VTA神经元的活动与可卡因寻找行为。活动将使用三种方法进行操作： 药理学、化学遗传学和光遗传学。 VTA神经元(GABA和多巴胺)的活性将通过活体细胞外记录来评估 麻醉大鼠。可卡因寻求将在可卡因自我管理后进行评估，通过检查 在没有可卡因的情况下做出反应。还将对蔗糖寻觅进行测试，以检验这是否起到作用 结构和路径延伸到寻求自然回报。LPO-VTA的神经化学性质 将通过(I)使用药理学、(Ii)通过测量突触电流和(Iii)通过执行 免疫组织化学。 我们预测，刺激LPO增加了VTA中多巴胺神经元的活动，并寻求 行为。这是通过GABA能的LPO-VTA途径发生的。具体地说，LPO发出抑制性GABA能 对VTA的预测。这些突触连接到VTA的GABA神经元，导致解除抑制(即 多巴胺神经元的兴奋)。 我们期望这些研究将确立LPO作为VTA神经元活动的关键调节器的新角色，并 寻找可卡因的行为。这对理解电路和机制有很大的进步 上瘾的人。此外，这些研究将通过发现大脑的一种作用，促进我们对大脑的理解 其功能在很大程度上未知的结构。

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.