■通过表达正确的行为来回应社会信号不仅在自闭症中受到挑战,而且在自闭症患病率高的疾病中,比如Prader-Willi综合征(PWS).临床证据表明,鼻内催产素(OXT)或加压素(AVP)可以调节患者的异常亲社会行为。然而,在社会厌恶的背景下,受损的行为反应背后的神经元机制是什么,以及如何纠正它们,仍然很大程度上未知。
■使用PWS的Magel2敲除(KO)小鼠模型(与CRE依赖性转基因品系杂交),我们设计了光遗传学,社会恐惧条件范式中的生理和药理策略。OXT和AVP信号传导的通路特异性作用在侧隔(LS)上进行了研究,接收密集下丘脑输入的区域。
■OXT和AVP信号在LS中促进抑制性突触传递,Magel2KO小鼠的失败抑制了生长抑素(SST)神经元并破坏了社交恐惧的灭绝。OXT和AVP缺陷的来源特别定位在Magel2KO小鼠的视上核→LS途径中,破坏了社交恐惧灭绝,可以通过LS中SST神经元的光遗传学或药理学抑制来纠正。有趣的是,LSSST神经元也门控了攻击行为的表达,可能作为超出局部间隔电路的功能单元的一部分。
■SST细胞在孤独症中整合和表达破坏的神经肽信号中起着至关重要的作用,从而改变表达安全与恐惧的平衡。我们的结果揭示了在社会厌恶的背景下功能障碍的新机制,并为自闭症谱系障碍的未来治疗提供了新的框架。
UNASSIGNED: Responding to social signals by expressing the correct behavior is not only challenged in autism, but also in diseases with high prevalence of autism, like Prader-Willi Syndrome (PWS). Clinical evidence suggests aberrant pro-social behavior in patients can be regulated by intranasal oxytocin (OXT) or vasopressin (AVP). However, what neuronal mechanisms underlie impaired behavioral responses in a socially-aversive context, and how can they be corrected, remains largely unknown.
UNASSIGNED: Using the Magel2 knocked-out (KO) mouse model of PWS (crossed with CRE-dependent transgenic lines), we devised optogenetic, physiological and pharmacological strategies in a social-fear-conditioning paradigm. Pathway specific roles of OXT and AVP signaling were investigated converging on the lateral septum (LS), a region which receives dense hypothalamic inputs.
UNASSIGNED: OXT and AVP signaling promoted inhibitory synaptic transmission in the LS, which failure in Magel2KO mice disinhibited somatostatin (SST) neurons and disrupted social-fear
extinction. The source of OXT and AVP deficits mapped specifically in the supraoptic nucleus→LS pathway of Magel2KO mice disrupting social-fear
extinction, which could be corrected by optogenetic or pharmacological inhibition of SST-neurons in the LS. Interestingly, LS SST-neurons also gated the expression of aggressive behavior, possibly as part of functional units operating beyond local septal circuits.
UNASSIGNED: SST cells in the LS play a crucial role in integration and expression of disrupted neuropeptide signals in autism, thereby altering the balance in expression of safety versus fear. Our results uncover novel mechanisms underlying dysfunction in a socially-aversive context, and provides a new framework for future treatments in autism-spectrum disorders.