A novel habenulo-mesencephalic circuit in aversive signaling

描述（由申请人提供）：中脑多巴胺（DA）神经元对奖赏过程和药物成瘾的发展至关重要。它们放电频率的变化似乎是对刺激值的编码;理想的物质或刺激（如食物、水和成瘾药物）会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）则会抑制这些神经元。直到最近，这种抑制的来源还是未知的。现在假设，外侧缰核（LHb）中的丘脑能神经元（上丘脑的遗传保守部分）负责这种抑制。然而，因为LHb神经元是兴奋性的，所以必须有干预抑制性GABA神经元，当LHb兴奋时，其降低DA神经元的放电率。虽然存在与DA神经元紧密接近的GABA神经元，但其数量太少，无法解释所观察到的DA神经元的广泛抑制。一个新描述的核，中桥脑头内侧被盖核（RMTg）似乎具有所需的特性，以履行这一作用，它是由几乎完全的GABA神经元，从LHb接收大量的输入，并严重项目中脑DA神经元。本申请的中心目标是测试RMTg在向中脑DA神经元传递厌恶信号中可能发挥的作用。在LHb输出的电刺激后，将进行DA细胞的切片记录，通常导致DA神经元广泛抑制的条件。从切片制备物中解剖RMTg将检测该区域是否是出现这种抑制所必需的（特定目标1）。我们将通过检测即时早期转录因子c-Fos来观察RMTg的激活，该转录因子c-Fos响应于有和没有来自LHb的输入的厌恶刺激（特异性目标2）。最后，我们将测试RMTg的存在是否是LHb刺激诱导条件性位置厌恶所必需的，条件性位置厌恶是对与厌恶刺激配对的特定环境的回避，并降低可卡因诱导条件性位置偏好的能力（具体目标3）。预期该研究将阐明厌恶性刺激对奖赏神经回路的影响。这些信息将帮助我们了解为什么尽管继续使用毒品会产生负面副作用，但个人可能会重新吸毒，并制定治疗吸毒成瘾的新方法。

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.