Neuroanatomical Localization of the Dopaminergic Modulation of Clock Speed

描述（由申请人提供）：对秒到分钟范围的时间感知，间隔计时，是行为的基础。时间感知的改变是由各种药物的急性和慢性给药引起的，这种改变可能在这些药物的使用和滥用中起作用。例如，滥用多巴胺能药物，如甲基苯丙胺和可卡因，会导致对时间的感知发生变化，以至于感觉时间过得更慢了。这种效应与用于计时和时间感知的内部时钟速度的增加有关。了解间隔时间的心理和神经机制，以及吸毒带来的变化，可能会为吸毒背后的一系列过程提供重要的见解。例如，了解多巴胺在哪里以及如何改变对时间的感知可能有助于制定具体的治疗策略。虽然先前的研究表明皮质-纹状体-丘脑回路在间隔时间中的作用，但这些大脑结构的具体计算仍然未知。最近的间隔计时模型提出，皮层活动作为时间信号的来源，由纹状体整合，以估计时间。由于多巴胺能药物可以直接改变皮层和纹状体区域的神经活动，目前尚不清楚这些药物在大脑的哪个部位发挥作用。目前的建议将确定多巴胺调节内部时钟速度的位置。具体来说，我们建议微注射药物，增加或减少中脑初级多巴胺能核（即黑质和/或腹侧被盖区）的活性，并研究这些改变对间隔时间的影响。这些效果将通过训练受试者在特定时间对食物强化做出反应来评估，并评估在特定大脑区域给药后反应时间的变化。在对急性给药的效果进行评估之后，将对药物长期输注到这些核中的影响进行评估，因为以前使用慢性全身给药的工作已经表明，生物体适应不断改变的时间感知。通过评估这些对时钟速度慢性变化的适应发生在哪里，我们将更好地了解计时过程是否遵循与药物强化和运动行为相似的适应模式。滥用药物已被证明会以急性和慢性的方式改变对时间的感知。确定这些时间变化的神经位置，以及它们在长期使用后的适应性，将提供有关药物使用、滥用和依赖所涉及的一系列神经变化的重要信息。

DESCRIPTION (provided by applicant): The perception of time in the seconds to minutes range, interval timing, is fundamental to behavior. Alterations in temporal perception result from the acute and chronic administration of a variety of drugs, and such alterations may play a part in the use and abuse of these drugs. For instance, dopaminergic drugs of abuse, such as methamphetamine and cocaine, cause alterations in the perception of time, such that time feels as though it is passing more slowly. This effect has been associated with an increase in the speed of an internal clock used for timing and time perception. Understanding the psychological and neural mechanisms of interval timing, as well as the changes brought on by drug use, may provide important insights into the range of processes that underlie drug use. For instance, understanding where and how dopamine is altering the perception of time may allow development of specific treatment strategies. While previous work has suggested a role for cortico-striatal-thalamic loops in interval timing, the specific computations performed by these brain structures remain unknown. A recent model of interval timing has proposed that cortical activity serves as the source of a temporal signal that is integrated by the striatum in order to estimate time. As dopaminergic drugs can directly alter neural activity in both cortical and striatal regions, it remains unclear where in the brain these drugs are exerting their effects. The current proposal will determine the location(s) in which dopamine modulates the speed of the internal clock. Specifically, we propose to microinject pharmacological agents that will increase or decrease the activity of the primary dopaminergic nuclei of the midbrain, (i.e., the substantia nigra and/or ventral tegmental area), and investigate the effects of these alterations on interval timing. These effects will be evaluated by training subjects to respond at specific times for food reinforcement, and evaluating the change in response times following drug administration into specific brain regions. Following an assessment of the effects of acute administration, the impact of chronic infusion of pharmacological agents into these nuclei will be assessed, as previous work using chronic systemic administration has shown that organisms adapt to a continually altered perception of time. By evaluating where these adaptations to chronic alterations in clock speed occur, we will better understand whether timing processes follow similar adaptation patterns as drug reinforcement and locomotor behaviors. Drugs of abuse have been shown to alter the perception of time in both an acute and chronic fashion. Determining the neural locations of these changes in timing, as well as their adaptation following chronic use will provide important information regarding the array of neural changes involved in the use, abuse, and dependence of drugs.