Department of Pharmacology, National Cheng-Kung University, Tainan, Taiwan; Department of Pharmacy, China Medical University Hospital, No. 2, Yude Rd., North Dist., Taichung, Taiwan.
Division of Natural Sciences, Center for General Education, Southern Taiwan University of Science and Technology, Tainan, Taiwan.
Eur J Pharmacol. 2024 Oct 15;981:176918. doi: 10.1016/j.ejphar.2024.176918. Epub 2024 Aug 17.
Maladaptive reactive aggression is a core symptom of neuropsychiatric disorders such as schizophrenia. While uncontrolled aggression dampens societal safety, there is a limited understanding of the neural regulation involved in reactive aggression and its treatment. High levels of aggression have been linked to low serotonin (5-HT) levels. Additionally, post-weaning socially isolated (SI) mice exhibit outbursts of aggression following encountering acute stress, and hyperactivated ventral hippocampus (vHip) involves this stress-provoked escalated aggression. Here, we investigated the potential role of the raphe nucleus projecting to the vHip in modulating aggressive behavior. Chemogenetically activating the dorsal raphe nucleus (DRN) soma projecting the vHip or DRN nerve terminals in the vHip reduced reactive aggression. The reduction of attack behavior was abolished by the pretreatment of 5-HT receptor antagonist SB-224289. However, activating the median raphe nucleus (MRN)-to-vHip pathway ameliorated depression-like behavior but did not affect reactive aggression. DRN→vHip activation suppressed the vHip downstream area, the ventromedial hypothalamus (VMH), which is a core aggression area. Intra-vHip infusion of 5-HT receptor agonists (anpirtoline, CP-93129) suppressed reactive aggression and decreased c-Fos levels in the vHip neurons projecting to the VMH, suggesting an inhibition mechanism. Our findings indicate that activating the DRN projecting to the vHip is sufficient to inhibit reactive aggression in a 5-HT receptor-dependent manner. Thus, targeting 5-HT receptor could serve as a promising therapeutic approach to ameliorate symptoms of reactive aggression.
适应不良的反应性攻击是精神神经障碍的核心症状，如精神分裂症。虽然不受控制的攻击会降低社会安全性，但人们对反应性攻击及其治疗的神经调节知之甚少。高水平的攻击性与低血清素（5-HT）水平有关。此外，断奶后社会隔离（SI）的小鼠在遇到急性应激后会爆发攻击性，而过度活跃的腹侧海马（vHip）涉及这种应激引起的攻击性升级。在这里，我们研究了投射到 vHip 的中缝核在调节攻击行为中的潜在作用。化学激活投射到 vHip 的中缝核（DRN）体或 DRN 神经末梢在 vHip 中减少了反应性攻击。5-HT 受体拮抗剂 SB-224289 的预处理消除了攻击行为的减少。然而，激活中缝核（MRN）到 vHip 的通路改善了抑郁样行为，但没有影响反应性攻击。DRN→vHip 激活抑制了 vHip 的下游区域，即腹内侧下丘脑（VMH），这是一个核心攻击区域。vHip 内注射 5-HT 受体激动剂（anpirtoline、CP-93129）抑制了反应性攻击，并降低了投射到 VMH 的 vHip 神经元中的 c-Fos 水平，表明存在抑制机制。我们的研究结果表明，激活投射到 vHip 的 DRN 足以以 5-HT 受体依赖的方式抑制反应性攻击。因此，靶向 5-HT 受体可能是一种有前途的治疗方法，可改善反应性攻击的症状。
