選擇性剔除前腦興奮性神經元coiled-coil and C2 domain containing 1a (Cc2d1a) 基因會導致雄性小鼠表現自閉症類群障礙(簡稱:自閉症)核心症狀:包含社交溝通功能缺失、反覆重複性行為的增加及認知功能缺失等。 除了核心症狀外，焦躁易怒行為也是廣泛出現在自閉症個案中，焦躁易怒行為是一種對於外在負面刺激過度反應的一種狀態。此外，許多神經精神症狀及神經系統疾病的致病機轉多和失調的催產素系統有關。我們觀察到在成年Cc2d1a基因剃除雄性小鼠下視丘內室旁核中表現較少的催產素表現神經元。然而目前對於異常的焦躁易怒行為是否因催產素系統異常及可能造成催產素系統異常的原因尚未明瞭。在一系列的研究中，我們發現雄性小鼠在類焦躁易怒行為測試中表現較強烈的類攻擊行為，且在攻擊行為評估試驗中看到有較具攻擊性的趨勢。給予催產素治療能有效得緩解因選擇性剃除Cc2d1a雄性小鼠所致之異常類焦躁易怒行為。接著我們利用免疫螢光染色法確認室旁核中催產素神經元減少並非因本身細胞剃除Cc2d1a。在早期發育階段抑制催產素神經元活性也能成功的模擬選擇性剃除Cc2d1a雄性小鼠在類焦躁易怒測試中的表現。我們利用電生理紀錄觀察到雄性基因剃除小鼠室旁核中催產素神經元失衡的興奮性是藉由前額葉-室旁核這條神經迴路所調控。此外，光纖光度測量的結果顯示雄性基因剃除鼠在內側杏仁核後腹側部所釋放的催產素較少；同時我們也觀察到在類焦躁易怒行為檢測後與攻擊行為相關的神經迴路在雄性基因剃除小鼠有過度活化的現象。我們也發現在雄性個體中類焦躁易怒行為多半是藉由室旁核中催產素神經元所調控；反之在卵巢摘除之雌性小鼠則藉由血管加壓素神經元來產生類焦躁易怒行為。綜合此等研究發現我們認為選擇性剃除Cc2d1a雄性小鼠所表現之過度的類焦躁易怒行為與異常的催產素神經元系統間有關。此研究對於因自閉症基因缺陷所致之類焦躁易怒行為提供新的細胞及神經網絡機制及未來治療的可能方向。

Male mice with conditional deletion of coiled-coil and C2 domain containing 1a (Cc2d1a) in forebrain glutamatergic neurons display core symptoms of autism spectrum disorder (ASD), including social communication deficits, excessive repetitive behaviors, and impaired cognitive function. Besides core symptoms, irritability is often seen in individuals with ASD, characterized by strong reactivity to negative emotional stimuli. Furthermore, the pathophysiology of several neuropsychiatric and neurological disorders, especially ASD, is closely linked to the dysregulation of the oxytocin (OXT) system. We have observed that male Cc2d1a cKO mice exhibit reduced OXT neuron expression in the paraventricular nucleus of the hypothalamus (PVN) in adulthood. However, it remains unclear whether the abnormal OXT system causes increased irritability and what mechanisms underlie these changes. First, we observed that conditional deletion of Cc2d1a has a sex-specific effect on aggression. Male Cc2d1a cKO mice showed increased irritability-like behavior in the bottle brush test (BBT) and mild aggressive-like behavior in the resident intruder test (RIT). OXT treatments successfully restored behavioral deficits induced by Cc2d1a deletion. We then conducted immunostaining to confirm that reduced PVN OXT neurons were due to cell-nonautonomous regulation. We also found that early inhibition of OXT neuronal activity could mimic the behavioral performance seen in male Cc2d1a cKO mice. Additionally, the imbalance ratio of excitatory/inhibitory (E/I) of the PVN OXT in male Cc2d1a cKO mice results from an altered medial prefrontal cortex (mPFC)-PVN pathway. Fiber photometry analysis of OXT sensor activity was reduced in the posteroventral part of the medial amygdala (MeApv) in male Cc2d1a cKO mice. Furthermore, neural circuits associated with aggressive-like behavior were hyperactivated in male mice with conditional deletion of Cc2d1a. Additionally, we found that irritability-like behavior in male mice is mainly regulated by PVN OXT neurons, whereas in ovariectomized (OVX) female mice, it is controlled by PVN arginine vasopressin (AVP) neurons. These findings strongly indicate a correlation between impaired OXT system and increased irritability-like behavior in Cc2d1a cKO mice. Overall, we offer new insights and a potential therapeutic approach for irritability-like behavior caused by an ASD-related gene mutation.

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