Genetic Dissection of Brain Reward Circuits

描述（由申请人提供）：中皮质边缘多巴胺（DA）回路被认为是对自然奖励和滥用药物的行为反应的重要途径之一。该回路中导致药物寻找行为的稳定改变被认为涉及通过nmda型谷氨酸受体（NMDAR）的信号传导，但实际上对DA神经元内这种信号转导级联的细胞特异性要求一无所知。为了研究缺乏NMDAR功能亚基NR1的小鼠在DA神经元内对NMDAR信号的细胞特异性需求。一种新的小鼠模型也将产生，这种模型将允许细胞特异性的、可逆的神经活动失活。这种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，将促进我们对成瘾所需的奖赏通路中神经元活动依赖性的理解。加深对成瘾的神经机制和神经回路的了解，有望为成瘾患者提供更好的治疗方法，并设计出治疗慢性剧烈疼痛和其他使人衰弱的疾病的药物，而不必担心产生依赖。

DESCRIPTION (provided by applicant): 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 Pharmaceuticals to treat chronic severe pain and other debilitating illnesses without fear of developing dependence.