Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Department of Pharmacology and Toxicology, Indiana University School of Medicine, 320 W. 15th Street, NB-400C, Indianapolis, IN, 46202, USA.
Sci Rep. 2021 Mar 18;11(1):6345. doi: 10.1038/s41598-021-85513-x.
The medial (DMS) and lateral (DLS) dorsal striatum differentially drive goal-directed and habitual/compulsive behaviors, respectively, and are implicated in a variety of neuropsychiatric disorders. These subregions receive distinct inputs from cortical and thalamic regions which uniquely determine dorsal striatal activity and function. Adenosine A receptors (A1Rs) are prolific within striatum and regulate excitatory glutamate transmission. Thus, A1Rs may have regionally-specific effects on neuroadaptive processes which may ultimately influence striatally-mediated behaviors. The occurrence of A1R-driven plasticity at specific excitatory inputs to dorsal striatum is currently unknown. To better understand how A1Rs may influence these behaviors, we first sought to understand how A1Rs modulate these distinct inputs. We evaluated A1R-mediated inhibition of cortico- and thalamostriatal transmission using in vitro whole-cell, patch clamp slice electrophysiology recordings in medium spiny neurons from both the DLS and DMS of C57BL/6J mice in conjunction with optogenetic approaches. In addition, conditional A1R KO mice lacking A1Rs at specific striatal inputs to DMS and DLS were generated to directly determine the role of these presynaptic A1Rs on the measured electrophysiological responses. Activation of presynaptic A1Rs produced significant and prolonged synaptic depression (A1R-SD) of excitatory transmission in the both the DLS and DMS of male and female animals. Our findings indicate that A1R-SD at corticostriatal and thalamostriatal inputs to DLS can be additive and that A1R-SD in DMS occurs primarily at thalamostriatal inputs. These findings advance the field's understanding of the functional roles of A1Rs in striatum and implicate their potential contribution to neuropsychiatric diseases.
内侧（DMS）和外侧（DLS）背侧纹状体分别驱动目标导向和习惯性/强迫性行为，并且与多种神经精神疾病有关。这些亚区从皮质和丘脑区域接收不同的输入，这些输入独特地决定了背侧纹状体的活动和功能。腺苷 A 受体（A1R）在纹状体中大量存在，并调节兴奋性谷氨酸传递。因此，A1R 可能对神经适应过程具有区域特异性影响，这些影响最终可能会影响纹状体介导的行为。目前尚不清楚 A1R 驱动的可塑性是否会出现在背侧纹状体的特定兴奋性输入上。为了更好地理解 A1R 如何影响这些行为，我们首先试图了解 A1R 如何调节这些不同的输入。我们使用体外全细胞、贴附式膜片钳切片电生理学记录，在 C57BL/6J 小鼠的 DLS 和 DMS 中的中间多刺神经元中，评估了 A1R 对皮质和丘脑纹状体传递的抑制作用，同时结合了光遗传学方法。此外，我们还生成了条件性 A1R KO 小鼠，这些小鼠在 DMS 和 DLS 的特定纹状体输入中缺乏 A1R，以直接确定这些突触前 A1R 在测量的电生理反应中的作用。激活突触前 A1R 会导致兴奋性传递在雄性和雌性动物的 DLS 和 DMS 中产生显著且持久的突触抑制（A1R-SD）。我们的发现表明，DLS 的皮质纹状体和丘脑纹状体传入的 A1R-SD 可以是累加的，而 DMS 的 A1R-SD 主要发生在丘脑纹状体传入中。这些发现推进了我们对 A1R 在纹状体中的功能作用的理解，并暗示它们可能对神经精神疾病有潜在贡献。
