A novel habenulo-mesencephalic circuit in aversive signaling

描述（由申请人提供）：中脑多巴胺（DA）神经元是奖励过程和药物成瘾发展的核心。它们放电频率的变化似乎对刺激的价值进行了编码；理想的物质或刺激（如食物、水和成瘾性药物）提高这些神经元的放电，而不理想的物质或刺激（如轻度休克、药物戒断）抑制相同的神经元。直到最近，这种抑制的来源还是未知的。现在的假设是，侧链（LHb）中的谷氨酸能神经元（系统发育上保守的上皮体的一部分）负责这种抑制。然而，由于LHb神经元是兴奋性的，因此必然存在干预的抑制性GABA神经元，当LHb兴奋时，会降低DA神经元的放电速率。虽然GABA神经元靠近DA神经元，但数量太少，无法解释所观察到的DA神经元的广泛抑制。一种新发现的核，中孔庭上内侧被盖核（RMTg）似乎具有完成这一角色所需的特征；它几乎完全由GABA神经元组成，接收来自下丘脑的大量输入，并大量投射到中脑DA神经元。本应用的中心目标是测试RMTg在向中脑DA神经元传递厌恶信号中可能发挥的作用。电刺激LHb输出后的DA细胞切片记录，通常会导致DA神经元的广泛抑制。从切片制备中剥离RMTg将测试该区域是否对这种抑制的出现是必要的（Specific Aim 1）。我们将通过检测即时早期转录因子c-Fos来观察RMTg在有或没有LHb输入的厌恶刺激下的激活（Specific Aim 2）。最后，我们将测试RMTg的存在是否对LHb刺激诱导条理性地方厌恶（即回避与厌恶刺激配对的特定环境）是必要的，并降低可卡因诱导条理性地方偏好的能力（specific Aim 3）。预期本研究将阐明厌恶刺激对奖赏神经回路的影响。这些信息将帮助我们理解为什么个人可能会重新使用药物，尽管继续使用有负面的副作用，并开发新的方法来治疗药物成瘾。

DESCRIPTION (provided by applicant): Midbrain dopamine (DA) neurons are central to reward processes and the development of drug addiction. Changes in their firing rate appear to encode the value of a stimulus; desirable substances or stimuli (e.g. food, water, and addictive drugs) elevate the firing of these neurons while undesirable substances or stimuli (e.g. mild shock, drug withdrawal) inhibit the same neurons. Until recently, the source of such inhibition was unknown. It is now hypothesized that glutamatergic neurons in the lateral habenula (LHb), a phylogenetically conserved part of the epithalamus, are responsible for such inhibition. However, because LHb neurons are excitatory there must be intervening inhibitory GABA neurons that, when excited by the LHb, decrease the firing rate of DA neurons. While there are GABA neurons in close proximity to the DA neurons, there are too few to account for the widespread inhibition of DA neurons observed. A newly described nucleus, the mesopontine rostromedial tegmental nucleus (RMTg) appears to have the required characteristics to fulfill this role; it is comprised almost solely of GABA neurons, receives heavy inputs from the LHb, and projects heavily to midbrain DA neurons. The central goal of this application is to test the role the RMTg may play in the transmission of aversive signals to midbrain DA neurons. Slice recording of DA cells following electrical stimulation of the LHb outputs, conditions that normally lead to widespread inhibition of DA neurons, will be conducted. Dissection of the RMTg from the slice preparation will test whether this area is necessary for the appearance of such inhibition (Specific Aim 1). We will look at activation of the RMTg by detection of the immediate early transcription factor c-Fos in response to aversive stimuli both with and without input from the LHb (Specific Aim 2). Finally, we will test whether the presence of the RMTg is necessary for LHb stimulation to induce conditioned place aversion, which is the avoidance of a specific environment that have been paired with an aversive stimulus, and reduce the ability of cocaine to induce conditioned place preference (Specific Aim 3). It is anticipated that the proposed research will elucidate the influence aversive stimuli have on the neurocircuitry of reward. Such information will help us to understand why individuals may relapse into drug use, despite the negative side effects of continued use, and to develop new approaches to the treatment of drug addiction. PUBLIC HEALTH RELEVANCE: The activation of dopamine (DA) is heavily implicated in the reward process and the development of addiction. However how the brain inhibits DA activity, potentially decreasing the value of rewarding substance and applying a "brake" to the reward process, is not well understood. Here we investigate a newly described brain circuit that may be responsible for inhibition of DA neurons. Such research will help us to understand why some individuals are more susceptibility to drug addiction and the propensity of former drug users to return to drug use.