PDF(Pubmed)
Abstract：
UNASSIGNED: Neurodevelopmental disorders (NDDs) can cause debilitating impairments in social cognition and aberrant functional connectivity in large-scale brain networks, leading to social isolation and diminished everyday functioning. To facilitate the treatment of social impairments, animal models of NDDs that link N- methyl-D-aspartate receptor (NMDAR) hypofunction to social deficits in adulthood have been used. However, understanding the etiology of social impairments in NDDs requires investigating social changes during sensitive windows during development.
UNASSIGNED: We examine social behavior during adolescence using a translational mouse model of NMDAR hypofunction (SR-/-) caused by knocking out serine racemase (SR), the enzyme needed to make D-serine, a key NMDAR coagonist. Species-typical social interactions are maintained through brain-wide neural activation patterns; therefore, we employed whole-brain cFos activity mapping to examine network-level connectivity changes caused by SR deletion.
UNASSIGNED: In adolescent SR-/- mice, we observed disinhibited social behavior toward a novel conspecific and rapid social habituation toward familiar social partners. SR-/- mice also spent more time in the open arm of the elevated plus maze which classically points to an anxiolytic behavioral phenotype. These behavioral findings point to a generalized reduction in anxiety-like behavior in both social and non-social contexts in SR-/- mice; importantly, these findings were not associated with diminished working memory. Inter-regional patterns of cFos activation revealed greater connectivity and network density in SR-/- mice compared to controls.
UNASSIGNED: These results suggest that NMDAR hypofunction - a potential biomarker for NDDs - can lead to generalized behavioral disinhibition in adolescence, potentially arising from disrupted communication between and within salience and default mode networks.
UNASSIGNED: We examine social behavior during adolescence using a translational mouse model of NMDAR hypofunction (SR-/-) caused by knocking out serine racemase (SR), the enzyme needed to make D-serine, a key NMDAR coagonist. Species-typical social interactions are maintained through brain-wide neural activation patterns; therefore, we employed whole-brain cFos activity mapping to examine network-level connectivity changes caused by SR deletion.
UNASSIGNED: In adolescent SR-/- mice, we observed disinhibited social behavior toward a novel conspecific and rapid social habituation toward familiar social partners. SR-/- mice also spent more time in the open arm of the elevated plus maze which classically points to an anxiolytic behavioral phenotype. These behavioral findings point to a generalized reduction in anxiety-like behavior in both social and non-social contexts in SR-/- mice; importantly, these findings were not associated with diminished working memory. Inter-regional patterns of cFos activation revealed greater connectivity and network density in SR-/- mice compared to controls.
UNASSIGNED: These results suggest that NMDAR hypofunction - a potential biomarker for NDDs - can lead to generalized behavioral disinhibition in adolescence, potentially arising from disrupted communication between and within salience and default mode networks.
摘要：
■神经发育障碍（NDDs）可导致大规模脑网络中社会认知和异常功能连接的衰弱性损害，导致社会孤立和日常功能减弱。为了促进社会障碍的治疗，已经使用了将N-甲基-D-天冬氨酸受体（NMDAR）功能减退与成年期社会缺陷联系起来的NDD动物模型。然而,了解NDD中社会损害的病因需要调查发育过程中敏感窗口期间的社会变化。
■我们使用敲除丝氨酸消旋酶（SR）引起的NMDAR功能减退（SR-/-）的翻译小鼠模型来检查青春期的社会行为，制造D-丝氨酸所需的酶，一个关键的NMDAR协同剂。物种典型的社会互动是通过全大脑神经激活模式维持的；因此，我们使用全脑cFos活动映射来检查由SR删除引起的网络级连通性变化.
■在青少年SR-/-小鼠中，我们观察到对熟悉的社交伴侣的新型特定和快速的社交习惯的抑制社交行为。SR-/-小鼠还在高架迷宫的开放臂中花费了更多时间，这通常指向抗焦虑行为表型。这些行为发现表明，在SR-/-小鼠的社交和非社交环境中，焦虑样行为普遍减少；重要的是，这些发现与工作记忆降低无关.cFos激活的区域间模式显示，与对照组相比，SR-/-小鼠的连通性和网络密度更高。
■这些结果表明，NMDAR功能减退-NDD的潜在生物标志物-可导致青春期的普遍行为抑制，可能是由于显著网络和默认模式网络之间和内部的通信中断引起的。
■我们使用敲除丝氨酸消旋酶（SR）引起的NMDAR功能减退（SR-/-）的翻译小鼠模型来检查青春期的社会行为，制造D-丝氨酸所需的酶，一个关键的NMDAR协同剂。物种典型的社会互动是通过全大脑神经激活模式维持的；因此，我们使用全脑cFos活动映射来检查由SR删除引起的网络级连通性变化.
■在青少年SR-/-小鼠中，我们观察到对熟悉的社交伴侣的新型特定和快速的社交习惯的抑制社交行为。SR-/-小鼠还在高架迷宫的开放臂中花费了更多时间，这通常指向抗焦虑行为表型。这些行为发现表明，在SR-/-小鼠的社交和非社交环境中，焦虑样行为普遍减少；重要的是，这些发现与工作记忆降低无关.cFos激活的区域间模式显示，与对照组相比，SR-/-小鼠的连通性和网络密度更高。
■这些结果表明，NMDAR功能减退-NDD的潜在生物标志物-可导致青春期的普遍行为抑制，可能是由于显著网络和默认模式网络之间和内部的通信中断引起的。
