Nong Yi, Stoppel David C, Johnson Mark A, Boillot Morgane, Todorovic Jelena, Shen Jason, Zhou Xinyu, Nadler Monica J S, Rodriguez Carrie, Huo Yuda, Nagakura Ikue, Kasper Ekkehard M, Anderson Matthew P
Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02115, USA.
Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02115, USA.
bioRxiv. 2023 Mar 1:2023.02.28.530462. doi: 10.1101/2023.02.28.530462.
The circuit origins of aggression in autism spectrum disorder remain undefined. Here we report -expressing glutamatergic neurons in ventrolateral division of ventromedial hypothalamus (VMHvl) drive intermale aggression. Aggression is increased due to increases of gene dosage in the VMHvl neurons when modeling autism due to maternal 15q11-13 triplication. Targeted deletion of increased copies in VMHvl reverses the elevated aggression adult mice. VMHvl neurons form excitatory synapses onto hypothalamic arcuate nucleus AgRP/NPY neurons through a NRXN1-CBLN1-GluD1 transsynaptic complex and UBE3A impairs this synapse by decreasing gene expression. Exciting AgRP/NPY arcuate neurons leads to feedback inhibition of VMHvl neurons and inhibits aggression. Asymptomatic increases of UBE3A synergize with a heterozygous deficiency of presynaptic or postsynaptic (both ASD genes) to increase aggression. Targeted deletions of in arcuate AgRP neurons impairs the VMHvl to AgRP/NPY neuron excitatory synapses while increasing aggression. Chemogenetic/optogenetic activation of arcuate AgRP/NPY neurons inhibits VMHvl neurons and represses aggression. These data reveal that multiple autism genes converge to regulate the VMHvl-arcuate AgRP/NPY glutamatergic synapse. The hypothalamic circuitry implicated by these data suggest impaired excitation of AgRP/NPY feedback inhibitory neurons may explain the increased aggression behavior found in genetic forms of autism.
自闭症谱系障碍中攻击行为的神经回路起源仍不明确。在此，我们报告腹内侧下丘脑（VMHvl）腹外侧区中表达 - 的谷氨酸能神经元驱动雄性间的攻击行为。在模拟因母亲15q11 - 13三联体导致的自闭症时，VMHvl神经元中 基因剂量的增加会导致攻击行为增强。靶向删除VMHvl中增加的 拷贝可使成年小鼠的攻击行为恢复正常。VMHvl神经元通过NRXN1 - CBLN1 - GluD1跨突触复合体与下丘脑弓状核AgRP/NPY神经元形成兴奋性突触，而UBE3A通过降低 基因表达来损害这种突触。刺激AgRP/NPY弓状神经元会导致对VMHvl神经元的反馈抑制，并抑制攻击行为。UBE3A的无症状增加与突触前 或突触后 （均为自闭症相关基因）的杂合缺陷协同作用，增加攻击行为。靶向删除弓状AgRP神经元中的 会损害VMHvl到AgRP/NPY神经元的兴奋性突触，同时增加攻击行为。对弓状AgRP/NPY神经元进行化学遗传学/光遗传学激活会抑制VMHvl神经元并抑制攻击行为。这些数据表明，多个自闭症相关基因共同作用来调节VMHvl - 弓状AgRP/NPY谷氨酸能突触。这些数据所涉及的下丘脑神经回路表明，AgRP/NPY反馈抑制性神经元的兴奋受损可能解释了自闭症遗传形式中发现的攻击行为增加。
