Finlay Janet M, Dunham Ginger A, Isherwood Analiesse M, Newton Chelsea J, Nguyen Thuyanh V, Reppar Patricia C, Snitkovski Ilana, Paschall Sarah A, Greene Robert W
Department of Psychology, Behavioral Neuroscience Program, Western Washington University, Bellingham, WA, USA.
Department of Psychology, Behavioral Neuroscience Program, Western Washington University, Bellingham, WA, USA.
Brain Res. 2015 Mar 10;1600:70-83. doi: 10.1016/j.brainres.2014.10.037. Epub 2014 Oct 29.
Glutamate N-methyl-D-aspartate receptors (NMDARs) in the medial prefrontal cortex (mPFC) and hippocampus may play an integral role in complex cognitive and social deficits associated with a number of psychiatric illnesses including autism, mood disorders, and schizophrenia. We used localized infusions of adeno-associated virus Cre-recombinase in adult, targeted knock-in mice with loxP sites flanking exons 11-22 of the NR1 gene to investigate the effects of chronic NMDAR dysfunction in the mPFC and CA3 hippocampus on cognitive and social behavior. A 5-choice serial reaction time task (5-CSRTT) was used to monitor aspects of cognitive function that included attention and response inhibition. Social behavior was assessed using Crowley׳s sociability and preference for social novelty protocol. Chronic NMDAR dysfunction localized to the anterior cingulate/prelimbic mPFC or dorsal CA3 hippocampus differentially affected the response inhibition and social interaction. mPFC NR1-deletion increased perseverative responding in the 5-CSRTT and enhanced preference for social novelty, whereas CA3 NR1-deletion increased premature responding in the 5-CSRTT and decreased social approach behavior. These findings suggest that mPFC and CA3 NMDARs play selective roles in regulating compulsive and impulsive behavior, respectively. Furthermore, these findings are consistent with emerging evidence that these behaviors are mediated by distinct, albeit overlapping, neural circuits. Our data also suggest that NMDARs in these regions uniquely contribute to the expression of normal social behavior. In this case, mPFC and CA3 NMDARs appear to inhibit and facilitate aspects of social interaction, respectively. The latter dissociation raises the possibility that distinct circuits contribute to the expression of social intrusiveness and impoverished social interaction.
内侧前额叶皮质（mPFC）和海马体中的谷氨酸N-甲基-D-天冬氨酸受体（NMDARs）可能在与多种精神疾病（包括自闭症、情绪障碍和精神分裂症）相关的复杂认知和社交缺陷中发挥不可或缺的作用。我们在成年靶向敲入小鼠中使用腺相关病毒Cre重组酶进行局部注射，这些小鼠的NR1基因外显子11 - 22两侧带有loxP位点，以研究mPFC和海马体CA3区慢性NMDAR功能障碍对认知和社交行为的影响。采用5选串行反应时任务（5-CSRTT）来监测包括注意力和反应抑制在内的认知功能方面。使用克劳利社交性和对社交新奇性偏好方案评估社交行为。局限于前扣带回/前额叶前边缘皮质mPFC或背侧海马体CA3区的慢性NMDAR功能障碍对反应抑制和社交互动有不同影响。mPFC中NR1基因缺失增加了5-CSRTT中的持续性反应，并增强了对社交新奇性的偏好，而CA3区NR1基因缺失增加了5-CSRTT中的过早反应，并减少了社交接近行为。这些发现表明，mPFC和CA3区的NMDARs分别在调节强迫行为和冲动行为中发挥选择性作用。此外，这些发现与新出现的证据一致，即这些行为由不同但重叠的神经回路介导。我们的数据还表明，这些区域的NMDMDMDARs对正常社交行为的表达有独特贡献。在这种情况下，mPFC和CA3区的NMDARs似乎分别抑制和促进社交互动的各个方面。后一种分离增加了不同神经回路导致社交侵扰和社交互动匮乏表达的可能性。
