Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction.
Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction.
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DOI：
10.7554/elife.54838
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发表时间：
2020-12-04
期刊：
影响因子：
7.7
通讯作者：
Fuccillo MV
中科院分区：
文献类型：
--
作者：
Alabi OO;Davatolhagh MF;Robinson M;Fortunato MP;Vargas Cifuentes L;Kable JW;Fuccillo MV
目标导向行为对正常功能至关重要，在神经精神疾病中受到严重损害。尽管基因突变和这些疾病之间存在广泛的关联，但对目标导向功能障碍的分子贡献仍不清楚。我们在基于价值的选择范式中检查了Neurexin1α（一种神经精神疾病相关突触分子）组成性和脑区域特异性突变的小鼠。我们发现Neurexin1α基因敲除显示出对有益结果的选择减少，对昂贵选择的回避受损。强化模型表明，这是由价值更新和表现方面的缺陷驱动的。端脑兴奋性投射神经元中Neurexin1α的破坏，而不是丘脑神经元，概括了整体Neurexin1α敲除的选择异常。此外，Neurexin1α的选择性前脑兴奋性敲除扰乱了纹状体内的值调制神经信号，纹状体是基于反馈的强化学习的中心节点。通过将基于价值的决策缺陷与区域特异性Nrxn 1 α干扰和价值调节神经活动的变化相关联，我们揭示了神经精神疾病相关认知功能障碍的病理生理学的潜在神经基质。
Goal-directed behaviors are essential for normal function and significantly impaired in neuropsychiatric disorders. Despite extensive associations between genetic mutations and these disorders, the molecular contributions to goal-directed dysfunction remain unclear. We examined mice with constitutive and brain region-specific mutations in Neurexin1α, a neuropsychiatric disease-associated synaptic molecule, in value-based choice paradigms. We found Neurexin1α knockouts exhibited reduced selection of beneficial outcomes and impaired avoidance of costlier options. Reinforcement modeling suggested that this was driven by deficits in updating and representation of value. Disruption of Neurexin1α within telencephalic excitatory projection neurons, but not thalamic neurons, recapitulated choice abnormalities of global Neurexin1α knockouts. Furthermore, this selective forebrain excitatory knockout of Neurexin1α perturbed value-modulated neural signals within striatum, a central node in feedback-based reinforcement learning. By relating deficits in value-based decision-making to region-specific Nrxn1α disruption and changes in value-modulated neural activity, we reveal potential neural substrates for the pathophysiology of neuropsychiatric disease-associated cognitive dysfunction.