The differential role of cortical neuron types in motor behaviour and their alterations in disease

新皮层及其靶结构纹状体中的脑功能障碍是神经退行性运动障碍如亨廷顿病（HD）的发展和进展的核心。先前的研究表明，HD相关的变化，兴奋性神经元的活动在皮层，可能与抑制性控制的损失，通过中间神经元。尽管其相关性，功能参与特定的神经元群体在HD仍然在很大程度上未被探索。为了表征4种主要皮质神经元亚型的贡献，我进行了慢性体内双光子钙成像：1。兴奋性皮质纹状体投射神经元（CSPN）以及抑制2。小清蛋白（PV），3.生长抑素（SST）和4.血管活性肠肽（VIP）群体的HD小鼠模型。HD小鼠的行为异常反映在抑制性神经元的异常活动中，VIP活性总体降低，SST活性增加。与VIP神经元类似，CSPN活性降低，特别是在运动开始时。我的研究结果表明，HD以细胞类型特异性的方式影响皮质回路，为靶向治疗干预开辟了新的可能性。使用靶向光遗传学刺激，初步结果证明了VIP活性的拯救。这种调节对大脑内下游通讯和行为的影响是一个悬而未决的问题：-VIP神经元的激活对皮质纹状体活动和小鼠行为有什么影响？- SST神经元活动的慢性抑制是否挽救了网络变化和行为缺陷？- 在HD小鼠模型中，纹状体中不同类型的细胞在功能上是如何受到影响的？随着我的沃尔特本杰明奖学金的延长，我打算与加州圣地亚哥大学（UCSD）的小宫山隆木教授合作解决这些问题。

The dysfunction of the brain in the neocortex and its target structure striatum is central to the development and progression of neurodegenerative movement disorders such as Huntington’s disease (HD). Previous studies have shown HD-related changes in excitatory neuron activity in the cortex, possibly related to a loss of inhibitory control through interneurons. Despite its relevance, the functional involvement of specific neuronal populations in HD remains largely unexplored. To characterize the contributions of 4 major cortical neuron subtypes, I performed chronic in vivo 2-photon calcium imaging in: 1. excitatory corticostriatal projection neurons (CSPN) as well as inhibitory 2. parvalbumin (PV), 3. somatostatin (SST) and 4. vasoactive intestinal peptide (VIP) populations in a HD mouse model. Behavioral abnormalities in HD mice were mirrored in aberrant activity of inhibitory neurons, with an overall reduction of VIP activity and an increase of SST activity. Similar to VIP neurons, CSPN activity was reduced, particularly at the onset of locomotion. My results indicate that HD affects cortical circuits in a cell-type specific manner, opening new possibilities for targeted therapeutic intervention. Using targeted optogenetic stimulation, preliminary results demonstrate a rescue of VIP activity. The consequences of this modulation on downstream communication within the brain and on behavior are open questions: - What consequences does activation of VIP neurons have on corticostriatal activity and mouse behavior? - Does the chronic inhibition of SST neuron activity rescue network changes and behavioral defects? - How are distinct cell types in the striatum functionally affected in HD mouse models? With an extension of my Walter Benjamin Fellowship, I intend to address these questions in collaboration with Prof. Takaki Komiyama at University of California San Diego (UCSD).