Genetic Dissection of Brain Reward Circuits

描述（由申请人提供）：被认为对自然奖励和滥用药物的行为反应很重要的主要途径之一是中皮质边缘多巴胺（DA）回路。该回路中导致药物寻求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，然而实际上对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NMDAR信号传导的细胞特异性需求，将研究在DA神经元内缺乏NMDAR的功能亚基NR1的小鼠。还将产生一种新的小鼠模型，该模型将允许神经活性的细胞特异性可逆失活。这种方法基于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的活性依赖性的理解。对成瘾的神经机制和电路的深入了解将有望为成瘾者提供更好的治疗，并设计药物来治疗慢性严重疼痛和其他使人衰弱的疾病，而不必担心产生依赖性。

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.