Genetic Dissection of Brain Reward Circuits

描述(由申请人提供)：被认为对自然奖赏和滥用药物的行为反应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找行为的稳定变化被认为涉及通过NMDA型谷氨酸受体(NMDAR)发出信号，然而几乎不知道DA神经元内这一信号转导级联的细胞特异性要求。为了研究NMDAR信号转导小鼠的细胞特异性需求，我们将对DA神经元中缺乏NMDAR功能亚单位NR1的小鼠进行研究。一种新的小鼠模型也将被产生，该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奖励通路中神经元的活动依赖性的理解。对成瘾的神经机制和回路有了更深入的了解，有望为成瘾患者带来更好的治疗，并导致药物的设计，以治疗慢性剧烈疼痛和其他虚弱的疾病，而不必担心形成依赖。

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.