The Role of Midbrain to Prelimbic Cortex Glutamatergic projections in Stress-induced Drug Seeking

总结 尽管创伤后应激障碍（PTSD）和物质使用障碍之间存在公认的相关性， (SUD)目前尚不清楚创伤暴露和物质使用如何相互作用，以改变个体的概率 发展成这两种疾病中的任何一种虽然一些研究表明腹侧参与了 在PTSD和SUD中，被盖区（VTA）和内侧前额叶皮层（mPFC），尚不清楚是否 创伤性事件的经历改变了这两个结构之间的交流， 增加获得SUD的风险。已知VTA对mPFC的预测在 可卡因成瘾的发展;其他研究表明，PTSD的发病机制诱导 杏仁核（VTA）、mPFC和海马体之间相互作用的神经生理学变化。 最近的研究表明，共同释放多巴胺的腹侧被盖区多巴胺能神经元向核投射 前边缘皮层（PL）。有趣的是，VTA-NAc神经元投射参与了 在奖励寻求行为中的作用;但VTA-PL神经元投射在奖励寻求中的作用仍然是 未知这项研究的总体目标是了解大脑的机制和适应性 当暴露于导致SUD获得易感性增加的创伤性事件时。更具体地说， 目的是阐明腹侧被盖区神经元投射到后外侧的神经元是如何受到应激的影响的， 这影响雄性和雌性大鼠的可卡因寻找行为。我们初步的行为数据显示， 可卡因自我给药前的应激增加可卡因获得和可卡因诱导的恢复， 与无应激组比较。我们的中心假设是压力会加强突触 VTA-PL神经元能突触的传递，从而增强对 可卡因，并导致增加可卡因寻求行为。为了验证这一假设，我们将首先评估 暴露于可卡因之前的恐惧条件反射对可卡因获得和恢复的行为影响- 目标1a）。第二，我们将评估海马神经元投射的神经生理学变化， 使用具有全细胞膜片钳记录（离体）的光学刺激将VTA连接到PL，以测量突触 可卡因暴露大鼠VTA-PL神经元能突触的变化（AMPA与NMDA比率）， 优先应力（目标1b）。这些实验将揭示VTA如何调节PL神经元的存在下， 压力以及压力如何反过来影响寻求药物的行为。

SUMMARY Despite the recognized correlation between post-traumatic stress disorder (PTSD) and substance use disorder (SUD), it is unknown how trauma exposure and substance use may interact to alter the probability of an individual to develop either of these two disorders. Although some studies have revealed participation of the ventral tegmental area (VTA) and the medial prefrontal cortex (mPFC) in both PTSD and SUD, it is not yet known if the experience of a traumatic event alters the communication between these two structures in a way that may increase the risk of acquiring SUD. VTA projections to the mPFC are known to play an important role in the development of cocaine addiction; and other studies have shown that PTSD pathogenesis induces neurophysiological changes in the interaction between the amygdala, (VTA), mPFC, and hippocampus. Recently, studies showed that VTA glutamatergic neurons that co-release dopamine project towards the nucleus accumbens (NAc) and the prelimbic cortex (PL). Interestingly, VTA-NAc glutamatergic projections are involved in reward-seeking behavior; but the role of the VTA-PL glutamatergic projections in reward-seeking is still unknown. The overall goal of this investigation is to understand the mechanisms and adaptations of the brain when exposed to a traumatic event that leads to increased susceptibility of SUD acquisition. More specifically, the objective is to elucidate how the VTA glutamatergic projections into the PL are affected by stress and how this influences cocaine-seeking behavior in male and female rats. Our preliminary behavioral data show that stress prior to cocaine self-administration increases cocaine acquisition and cocaine-induced reinstatement, compared with the no-stress group in male rats. Our central hypothesis is that stress will strengthen synaptic transmission in the VTA-PL glutamatergic synapses, thus enhancing sensitivity to the reinforcing effects of cocaine and leading to increased cocaine-seeking behavior. To test this hypothesis, we will first evaluate the behavioral effects of fear conditioning prior to cocaine exposure on acquisition and reinstatement of cocaine- seeking (Aim 1a). Secondly, we will assess the neurophysiological changes of glutamatergic projections from the VTA to the PL using optical stimulation with whole cell patch-clamp recordings (ex-vivo) to measure synaptic changes (AMPA to NMDA ratio) in the VTA-PL glutamatergic synapses from cocaine-exposed rats with or without prior stress (Aim 1b). These experiments shall reveal how VTA modulates the PL neurons in the presence of stress and how this in turn, influences the drug seeking behavior.