Natsubori Akiyo, Tsutsui-Kimura Iku, Nishida Hiroshi, Bouchekioua Youcef, Sekiya Hiroshi, Uchigashima Motokazu, Watanabe Masahiko, de Kerchove d'Exaerde Alban, Mimura Masaru, Takata Norio, Tanaka Kenji F
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo 160-8582, Japan.
Sleep Disorders Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
J Neurosci. 2017 Mar 8;37(10):2723-2733. doi: 10.1523/JNEUROSCI.3377-16.2017. Epub 2017 Feb 6.
The ventral striatum is involved in motivated behavior. Akin to the dorsal striatum, the ventral striatum contains two parallel pathways: the striatomesencephalic pathway consisting of dopamine receptor Type 1-expressing medium spiny neurons (D1-MSNs) and the striatopallidal pathway consisting of D2-MSNs. These two genetically identified pathways are thought to encode opposing functions in motivated behavior. It has also been reported that D1/D2 genetic selectivity is not attributed to the anatomical discrimination of two pathways. We wanted to determine whether D1- and D2-MSNs in the ventral striatum functioned in an opposing manner as previous observations claimed, and whether D1/D2 selectivity corresponded to a functional segregation in motivated behavior of mice. To address this question, we focused on the lateral portion of ventral striatum as a region implicated in food-incentive, goal-directed behavior, and recorded D1 or D2-MSN activity by using a gene-encoded ratiometric Ca indicator and by constructing a fiberphotometry system, and manipulated their activities via optogenetic inhibition during ongoing behaviors. We observed concurrent event-related compound Ca elevations in ventrolateral D1- and D2-MSNs, especially at trial start cue-related and first lever press-related times. D1 or D2 selective optogenetic inhibition just after the trial start cue resulted in a reduction of goal-directed behavior, indicating a shared coding of motivated behavior by both populations at this time. Only D1-selective inhibition just after the first lever press resulted in the reduction of behavior, indicating D1-MSN-specific coding at that specific time. Our data did not support opposing encoding by both populations in food-incentive, goal-directed behavior. An opposing role of dopamine receptor Type 1 or Type 2-expressing medium spiny neurons (D1-MSNs or D2-MSNs) on striatum-mediated behaviors has been widely accepted. However, this idea has been questioned by recent reports. In the present study, we measured concurrent Ca activity patterns of D1- and D2-MSNs in the ventrolateral striatum during food-incentive, goal-directed behavior in mice. According to Ca activity patterns, we conducted timing-specific optogenetic inhibition of each type of MSN. We demonstrated that both D1- and D2-MSNs in the ventrolateral striatum commonly and positively encoded action initiation, whereas only D1-MSNs positively encoded sustained motivated behavior. These findings led us to reconsider the prevailing notion of a functional segregation of MSN activity in the ventral striatum.
腹侧纹状体参与动机性行为。与背侧纹状体类似，腹侧纹状体包含两条平行通路：由表达1型多巴胺受体的中型多棘神经元（D1-MSNs）组成的纹状体中脑通路和由D2-MSNs组成的纹状体苍白球通路。这两条经基因鉴定的通路被认为在动机性行为中编码相反的功能。也有报道称，D1/D2基因选择性并非归因于两条通路的解剖学差异。我们想确定腹侧纹状体中的D1-和D2-MSNs是否如先前观察结果所声称的那样以相反的方式发挥作用，以及D1/D2选择性是否与小鼠动机性行为中的功能分离相对应。为了解决这个问题，我们将腹侧纹状体的外侧部分作为与食物激励、目标导向行为相关的区域进行研究，并通过使用基因编码的比率型钙指示剂并构建光纤光度测量系统来记录D1或D2-MSN的活动，并在持续行为过程中通过光遗传学抑制来操纵它们的活动。我们观察到腹外侧D1-和D2-MSNs中同时出现与事件相关的复合钙升高，特别是在试验开始提示相关和首次杠杆按压相关的时间。在试验开始提示后立即进行D1或D2选择性光遗传学抑制导致目标导向行为减少，表明此时这两类神经元群体对动机性行为进行共同编码。仅在首次杠杆按压后立即进行D1选择性抑制导致行为减少，表明在该特定时间D1-MSN具有特异性编码。我们的数据不支持在食物激励的目标导向行为中两类神经元群体进行相反编码的观点。表达1型或2型多巴胺受体的中型多棘神经元（D1-MSNs或D2-MSNs）在纹状体介导的行为中具有相反作用这一观点已被广泛接受。然而，最近的报道对这一观点提出了质疑。在本研究中，我们在小鼠食物激励的目标导向行为过程中测量了腹外侧纹状体中D1-和D2-MSNs的同步钙活动模式。根据钙活动模式，我们对每种类型的MSN进行了特定时间的光遗传学抑制。我们证明，腹外侧纹状体中的D1-和D2-MSNs共同且正向编码动作起始，而只有D1-MSNs正向编码持续的动机性行为。这些发现促使我们重新考虑腹侧纹状体中MSN活动功能分离的普遍观点。
