Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada; Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada.
Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.
Neurobiol Dis. 2023 Jul;183:106179. doi: 10.1016/j.nbd.2023.106179. Epub 2023 Jun 3.
Aggressive behaviour (AB) may occur in patients with different neuropsychiatric disorders. Although most patients respond to conventional treatments, a small percentage continue to experience AB despite optimized pharmacological management and are considered to be treatment-refractory. For these patients, hypothalamic deep brain stimulation (pHyp-DBS) has been investigated. The hypothalamus is a key structure in the neurocircuitry of AB. An imbalance between serotonin (5-HT) and steroid hormones seems to exacerbate AB.
To test whether pHyp-DBS reduces aggressive behaviour in mice through mechanisms involving testosterone and 5-HT.
Male mice were housed with females for two weeks. These resident animals become territorial and aggressive towards intruder mice placed in their cages. Residents had electrodes implanted in the pHyp. DBS was administered for 5 h/day for 8 consecutive encounters prior to the interaction with the intruder. After testing, blood and brains were recovered for measuring testosterone and 5-HT receptor density, respectively. In a second experiment, residents received WAY-100635 (5-HT antagonist) or saline injections prior to pHyp-DBS. After the first 4 encounters, the injection allocation was crossed, and animals received the alternative treatment during the next 4 encounters.
DBS-treated mice showed reduced AB that was correlated with testosterone levels and an increase in 5-HT1 receptor density in the orbitofrontal cortex and amygdala. Pre-treatment with WAY-100635 blocked the anti-aggressive effect of pHyp-DBS.
This study shows that pHyp-DBS reduces AB in mice via changes in testosterone and 5-HT1 mechanisms.
攻击性行为（AB）可能发生在患有不同神经精神障碍的患者中。尽管大多数患者对常规治疗有反应，但一小部分患者尽管进行了优化的药物治疗管理，仍持续出现 AB，被认为是治疗抵抗。对于这些患者，已经研究了下丘脑深部脑刺激（pHyp-DBS）。下丘脑是 AB 神经回路的关键结构。血清素（5-HT）和类固醇激素之间的不平衡似乎会加剧 AB。
通过涉及睾酮和 5-HT 的机制，测试 pHyp-DBS 是否可以减少小鼠的攻击行为。
雄性小鼠与雌性小鼠一起饲养两周。这些常驻动物会对放置在其笼子中的入侵小鼠产生领地和攻击性。常驻动物的 pHyp 中植入了电极。在与入侵者互动之前，每天进行 5 小时的 DBS 治疗，共进行 8 次连续遭遇。测试后，回收血液和大脑，分别用于测量睾酮和 5-HT 受体密度。在第二个实验中，常驻动物在接受 pHyp-DBS 之前接受 WAY-100635（5-HT 拮抗剂）或生理盐水注射。在前 4 次遭遇后，交叉分配注射，动物在接下来的 4 次遭遇中接受替代治疗。
接受 DBS 治疗的小鼠表现出攻击性行为减少，这与睾酮水平相关，并增加了眶额叶皮质和杏仁核中的 5-HT1 受体密度。WAY-100635 的预先治疗阻断了 pHyp-DBS 的抗攻击作用。
这项研究表明，pHyp-DBS 通过改变睾酮和 5-HT1 机制减少了小鼠的 AB。
