Calcium Signaling in the Brain Reward Circuit and Drug Addiction

描述（由申请人提供）：中脑边缘多巴胺神经元在基于奖励的强化学习中发挥核心作用。最近的证据表明，一种病理形式的奖励为基础的学习有助于药物成瘾的发展。该建议旨在确定特定钙信号在调节多巴胺神经元的功能输出和可塑性中的作用。已知多巴胺神经元的动作电位放电在呈现奖励相关刺激时从强直性单峰活动转变为相位性爆发。这种放电模式转换被认为是由主要激活NMDA（N-甲基-D-天冬氨酸）型谷氨酸受体的兴奋性谷氨酸能输入触发的。由多巴胺神经元爆发引起的阶段性多巴胺释放用于促进靶脑区域中的突触可塑性，从而介导强化学习和药物成瘾的发展。然而，最近的证据表明，多巴胺神经元本身的突触可塑性也可能是这些学习过程所必需的。由突触后动作电位触发的钙信号在大脑突触的可塑性中起关键作用。因此，该提议的总体假设是，伴随动作电位爆发的大的钙瞬变介导NMDA受体介导的传递到多巴胺神经元的长时程增强（LTP）的诱导。将在急性制备的大鼠脑切片中进行电生理记录，结合细胞内钙的共聚焦成像和笼状化合物的闪光光解。第一个目的是确定促代谢神经递质输入和急性精神兴奋剂暴露对爆发诱导的钙信号的影响。第二个目的是检验NMDA受体介导的传递的LTP可以以依赖于由先前的代谢型神经递质输入增强的爆发诱导的钙信号的方式被诱导的假设。第三个目的是测试的假设，重复的精神兴奋剂暴露在体内增强爆发诱导的钙信号和NMDA受体介导的传输的可塑性，这可能会促进与药物经验相关的环境刺激的学习。从这个项目中获得的结果将提供新的信息，以促进我们对药物成瘾发展的神经机制的理解。大脑奖励回路中神经元之间连接强度的经验依赖性变化被认为是药物成瘾的关键神经机制之一，这可以被视为奖励学习的一种适应不良形式。因此，了解负责这些变化的细胞机制将有助于开发药物成瘾的治疗策略。该项目的目标是确定介导这些变化的关键细胞信号以及成瘾药物对其的调节。

DESCRIPTION (provided by applicant): Mesolimbic dopamine neurons play a central role in reward-based reinforcement learning. Recent evidence indicates that a pathological form of reward-based learning contributes to the development of drug addiction. This proposal seeks to define the role of specific calcium signals in regulating the functional output and plasticity of dopamine neurons. It is known that action potential firing of dopamine neurons transitions from tonic single-spike activity to phasic bursts upon presentation of reward-related stimuli. This firing mode transition is thought to be triggered by excitatory glutamatergic inputs predominantly activating NMDA (N-methyl-D-aspartate)-type glutamate receptors. The phasic dopamine release resulting from dopamine neuron bursts acts to promote synaptic plasticity in target brain areas, thereby mediating reinforcement learning and the development of drug addiction. However, recent evidence indicates that plasticity of synapses on dopamine neurons themselves may also be essential for these learning processes. Calcium signals triggered by postsynaptic action potentials are known to play a critical role in the plasticity of synapses in the brain. Therefore, the overarching hypothesis of this proposal is that large calcium transients accompanying bursts of action potentials mediate the induction of long-term potentiation (LTP) of NMDA receptor-mediated transmission onto dopamine neurons. Electrophysiological recording combined with confocal imaging of intracellular calcium and flash photolysis of caged compounds will be performed in acutely prepared brain slices from rats. The first aim is to determine the influence of metabotropic neurotransmitter inputs and acute psychostimulant exposure on burst- induced calcium signals. The second aim is to test the hypothesis that LTP of NMDA receptor- mediated transmission can be induced in a manner dependent on burst-induced calcium signals boosted by preceding metabotropic neurotransmitter inputs. The third aim is to test the hypothesis that repeated psychostimulant exposure in vivo enhances burst-induced calcium signals and the plasticity of NMDA receptor-mediated transmission, which may promote the learning of environmental stimuli associated with drug experience. The results obtained from this project will provide novel information to advance our understanding of the neural mechanisms underlying the development of drug addiction. Experience-dependent changes in the strength of connections between neurons in the brain reward circuit is thought to be one of the key neural mechanisms underlying drug addiction, which can be viewed as a maladaptive form of reward learning. Therefore, understanding the cellular machinery responsible for these changes would help to develop therapeutic strategies for drug addiction. The goal of this project is to determine the critical cellular signals mediating these changes and their regulation by addictive drugs.