A novel habenulo-mesencephalic circuit in aversive signaling

描述(申请人提供)：中脑多巴胺(DA)神经元是奖赏过程和药物成瘾发展的中枢。它们的放电频率的变化似乎编码了刺激的价值；理想的物质或刺激(如食物、水和成瘾药物)提高了这些神经元的放电，而不希望的物质或刺激(如轻度休克、停药)抑制了这些神经元的放电。直到最近，这种抑制的来源还不清楚。现在的假设是，外侧缰核(LHb)中的谷氨酸能神经元负责这种抑制，外侧缰核是上皮神经元中系统发育保守的部分。然而，由于LHb神经元是兴奋性的，所以当LHb兴奋时，必然存在干预的抑制性GABA神经元，从而降低DA神经元的放电频率。虽然在DA神经元附近有GABA神经元，但数量太少，不能解释观察到的DA神经元的广泛抑制。新发现的中脑桥脑头内侧被盖核(RMTg)似乎具有完成这一功能所需的特征；它几乎完全由GABA神经元组成，接受来自LHb的大量输入，并大量投射到中脑DA神经元。这项应用的中心目标是测试RMTG在将厌恶信号传递到中脑DA神经元中可能扮演的角色。将对电刺激LHb输出后的DA细胞进行切片记录，这种情况通常会导致DA神经元的广泛抑制。从切片制备中解剖RMTG将测试该区域是否对于这种抑制的出现是必要的(特定目标1)。我们将通过检测即时早期转录因子c-Fos来研究RMTg的激活，以响应有和没有LHb输入的厌恶刺激(特定目标2)。最后，我们将测试RMTG的存在是否对于LHb刺激诱导条件性位置厌恶是必要的，这是对与厌恶刺激配对的特定环境的避免，并降低可卡因诱导条件位置偏好的能力(特定目标3)。预计这项拟议的研究将阐明厌恶刺激对奖赏神经回路的影响。这些信息将有助于我们理解为什么尽管继续使用毒品会产生负面影响，但个人可能会重新使用药物，并开发治疗药物成瘾的新方法。 公共卫生相关性：多巴胺(DA)的激活与奖赏过程和成瘾的发展密切相关。然而，大脑如何抑制DA活动，潜在地降低奖励物质的价值，并对奖励过程施加“刹车”，目前还不是很清楚。在这里，我们研究了一个新描述的大脑回路，它可能负责抑制DA神经元。这样的研究将有助于我们了解为什么一些人更容易吸毒，以及以前吸毒者重新吸毒的倾向。

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.