Characterizing in-task corticostriatal circuit operation during habit learning

习惯学习过程中任务中皮质纹状体回路操作的特征

• 批准号: 8526235
• 负责人: Nuné Martiros
• 金额: $ 4.22万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526235
• 关键词: Address; Affect; Anatomy; Area; Automobile Driving; Behavior; Behavior Control; Brain; Corpus striatum structure; Data; Disease; Dopamine; Dorsal; Elements; Excision; Goals; Habits; Knowledge; Learning; Lesion; Life; Modeling; Motor; Motor Cortex; Nature; Neurons; Obsessive compulsive behavior; Optics; Pattern; Performance; Rattus; Recording of previous events; Rewards; Role; Sensory; Series; Site; Structure; Synapses; Techniques; Testing; Thalamic structure; Training; Training Activity; addiction; base; experience; flexibility; habit learning; motor learning; neocortical; novel; operation; optogenetics; programs; public health relevance; relating to nervous system; research study; response

DESCRIPTION (provided by applicant): The striatum is an evolutionarily ancient brain structure that receives the most dopamine input of any structure in the brain (41,43). Despite the emergence of frontal neocortical areas, it remains the primary structure responsible for much of implicit reward-based habit learning that is essential for everyday life but can become maladaptive resulting in addiction, compulsive behaviors, and other disorders (11,16,24,31,32). Based on recent findings, we now believe that there may be neural activity patterns in dorsal striatum that are signatures of habit formation. In dorsomedial striatum (DMS), neural responses are seen early in habit learning during decision points of a task (45). In dorsolateral striatum (DLS), neural responses are seen later in learning and concentrated at the initiation and termination of motor habits (9,10,27,45). These patterns are consistent with the roles of DMS and DLS defined by lesion studies (6,15,38,49,50,51,53) and are promising candidates as the neural bases of habit formation; however, it is still unclear what these patterns represent. More importantly, we cannot understand their function unless we consider their role within the corticostriatal circuit and eventually the entire cortico-striatal-pallidal-thalamic circuit, the pimary brain circuit involving striatum (1,42). So far studies have only recorded from isolated sites within these circuits without addressing the how the different regions interact in- task or have focused on exploring the anatomy of the circuit outside of behavior. In order to bridge this gap, we must deconstruct these circuits by defining how the task responses at each point in the circuit emerge. In the proposed studies, I will address whether the previously described DMS and DLS activation patterns generalize across a range of habitual tasks and clarify their relationship to motor habit behavior using a novel lever press sequence task. I will then address how this activity emerges within the corticostriatal circuits. Based on existing knowledge that cortex provides major excitatory input to striatum (1,42), that the cortical areas projecting to DMS and DLS are different (13,35,39), and that corticostriatal plasticity is necessary for habit learning (14,52,53) I hypothesize that cortical input is driving the striatal task responses and tht sculpting of corticostriatal synaptic strengths with experience produces the learning related changes in striatal task responses. To test this hypothesis I will record single unit activity simultaneously in cortical sites and their target striatal sites while using local optogenetic inhibition of the cortical input to identify which of the striatal task responses are dependent upo this input. This combined approach will help me determine not only which striatal task responses are driven by cortical input, but how the activity of neurons in cortex may be driving them. These experiments would be the first to begin constructing a model of the mechanisms of function of corticostriatal circuits within behavior incorporating task and learning dynamics. Ultimately, developing in-depth understanding of habit learning circuits will be key to our long term goal of finding precise circuit manipulations to alleviate debilitating maladaptive behaviors that occur when habits become too fixed.

描述（由申请人提供）：纹状体是一种进化上古老的大脑结构，在大脑中的任何结构中，它接收最多的多巴胺输入（41，43）。尽管出现了额叶新皮层区域，但它仍然是负责大部分内隐奖励习惯学习的主要结构，这种习惯学习对日常生活至关重要，但可能会变得适应不良，导致成瘾，强迫行为和其他疾病（11，16，24，31，32）。基于最近的研究结果，我们现在相信背侧纹状体中可能存在神经活动模式，这是习惯形成的标志。在背内侧纹状体（DMS）中，在任务的决策点期间，在习惯学习的早期观察到神经反应（45）。在背外侧纹状体（DLS）中，神经反应在学习后期出现，并集中在运动习惯的开始和结束时（9，10，27，45）。这些模式与损伤研究（6、15、38、49、50、51、53）所定义的DMS和DLS的作用一致，并且是有希望作为习惯形成的神经基础的候选者;然而，仍然不清楚这些模式代表什么。更重要的是，我们无法理解它们的功能，除非我们考虑它们在皮质纹状体回路中的作用，并最终考虑它们在整个皮质-纹状体-苍白球-丘脑回路中的作用，即涉及纹状体的主要脑回路（1，42）。到目前为止，研究只记录了这些回路内的孤立部位，而没有解决不同区域如何在任务中相互作用，或者专注于探索行为之外的回路解剖。为了弥合这一差距，我们必须通过定义电路中每个点的任务响应如何出现来解构这些电路。在拟议的研究中，我将解决以前描述的DMS和DLS激活模式是否在一系列习惯性任务中推广，并使用一种新的杠杆按压序列任务来澄清它们与运动习惯行为的关系。然后，我将讨论这种活动是如何出现在皮质纹状体回路。基于现有的知识，即皮质向纹状体提供主要的兴奋性输入（1，42），投射到DMS和DLS的皮质区域是不同的（13，35，39），皮质纹状体可塑性是必要的习惯学习（14，52，第五十三章）我假设皮质输入驱动纹状体任务反应，皮质纹状体突触强度的塑造与经验产生学习纹状体任务反应的相关变化。为了验证这一假设，我将同时记录皮质部位及其靶纹状体部位的单个单位活动，同时使用皮质输入的局部光遗传学抑制来识别哪些纹状体任务反应依赖于该输入。这种结合的方法不仅可以帮助我确定哪些纹状体任务反应是由皮层输入驱动的，还可以帮助我确定皮层神经元的活动如何驱动它们。这些实验将是第一个开始构建一个模型的皮质纹状体电路的功能机制的行为，包括任务和学习动力学。最终，深入了解习惯学习回路将是我们长期目标的关键，即找到精确的回路操作，以减轻当习惯变得过于固定时发生的适应不良行为。