Genetic Dissection of Brain Reward Circuits

被认为对自然奖赏和药物的行为反应很重要的主要途径之一 滥用的是中皮质边缘多巴胺(DA)回路。这一回路内稳定的变化导致药物 寻找行为被认为涉及通过NMDA型谷氨酸受体(NMDAR)发出信号， 然而，对于这种信号转导级联的特定细胞要求，我们几乎一无所知。 在DA神经元内。为研究缺乏NMDAR信号转导的小鼠的细胞特异性需求 我们将研究多巴胺神经元内NMDAR的功能亚基NR1。一种新的鼠标模型，将允许 细胞特异性的、可逆的神经活动失活也将产生。此方法基于 一种对神经递质释放至关重要的蛋白质的化学二聚化和失活，将促进我们的 了解成瘾所需奖赏通路中神经元的活动依赖性。获得 加强对成瘾的神经机制和神经回路的了解将有望带来更好的 对成瘾患者的治疗并导致药物治疗的设计 慢性剧烈疼痛和其他使人衰弱的疾病，无需担心发展成依赖。

One of the major pathways thought to be important for behavioral responses to natural rewards and drugs of abuse is the mesocorticolimbic dopamine (DA) circuit. Stable alterations within this circuit that lead to drug seeking behavior are thought to involve signaling through the NMDA-type glutamate receptor (NMDAR), however virtually nothing is known about the cell-specific requirements of this signal transduction cascade within DA neurons. To study the cell-specific requirements of NMDAR signaling mice which lack the functional subunit of NMDAR, NR1, within DA neurons will be studied. A new mouse model that will allow for the cell-specific, reversible inactivation of neural activity will also be generated. This approach, based on the chemical dimerization and inactivation of a protein critical for neurotransmitter release, will advance our understanding of the activity-dependence of neurons within reward pathways required for addiction. Attaining an enhanced understanding of the neural mechanisms and circuitry of addiction will hopefully lead to better treatments for individuals who suffer from addiction and lead to the design of Pharmaceuticalsto treat chronic severe pain and other debilitating illnesses without fear of developing dependence.