Chang Hsin-Tzu, Cheng Kuan-Hsiang, Hung Yu-Chieh, Hsu Kuei-Sen
Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan City, 70101, Taiwan.
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan.
J Biomed Sci. 2025 Mar 17;32(1):37. doi: 10.1186/s12929-025-01130-0.
Social interaction is crucial for mental health across animal species. Social experiences, especially in early-life stages, strongly influence brain function and social behavior later in life. Acute social isolation (SI) increases motivation to seek social interaction, but little is known about its underlying neuronal and circuitry mechanisms. Here, we focus on oxytocin signaling in the ventral tegmental area (VTA), a vital node of the brain's reward network, as a potential mechanism for SI-induced craving for social interaction.
Adolescent (4-week-old) or adult (14-week-old) male C57BL/6J mice underwent a 1-week SI. Free interaction, object exploration, three-chamber social approach, and habituation tests were used to assess social and non-social behavior changes. Viral vectors were used to decipher the underlying neural circuitry, and chemogenetic techniques were applied to modify neuronal activity.
We found that in male C57BL/6J mice, SI during adolescence, but not adulthood, leads to increased craving for social interaction and object exploration, accompanied by impaired social habituation, social novelty preference, and social recognition memory (SRM). SI-induced craving for social interaction and SRM deficit is still observed upon regrouping. Through cell-type-specific manipulations with designer receptors exclusively activated by designer drugs (DREADD), we show that oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVN) are crucial for SI-induced social behavior changes. Chemogenetic activation of PVN oxytocin neurons recapitulates social behavior changes observed in SI mice, whereas chemogenetic inhibition of oxytocin neurons prevents social behavior changes caused by SI. Moreover, we found that dopaminergic neurons in the VTA mediate SI-induced craving for social interaction through their projections to the medial prefrontal cortex (mPFC), but not to the nucleus accumbens. Injection of a specific oxytocin receptor antagonist L368,899 into the VTA or chemical lesions of dopaminergic axon terminals in the mPFC with local application of 6-hydroxydopamine ameliorates SI-induced social behavior changes.
These findings suggest that adolescent SI has enduring effects on social behaviors in male mice through an oxytocinergic modulation of the VTA-to-mPFC dopaminergic circuit activity.
社会互动对所有动物物种的心理健康都至关重要。社会经历，尤其是在生命早期阶段，会强烈影响大脑功能和后期的社会行为。急性社会隔离（SI）会增加寻求社会互动的动机，但对其潜在的神经元和神经回路机制知之甚少。在这里，我们关注腹侧被盖区（VTA）中的催产素信号传导，它是大脑奖赏网络的一个重要节点，作为SI诱导的对社会互动渴望的一种潜在机制。
对青春期（4周龄）或成年（14周龄）雄性C57BL/6J小鼠进行为期1周的SI。使用自由互动、物体探索、三室社会接近和习惯化测试来评估社会和非社会行为的变化。使用病毒载体来解析潜在的神经回路，并应用化学遗传学技术来改变神经元活动。
我们发现，在雄性C57BL/6J小鼠中，青春期而非成年期的SI会导致对社会互动和物体探索的渴望增加，同时伴有社会习惯化、社会新奇偏好和社会识别记忆（SRM）受损。重新分组后仍可观察到SI诱导的对社会互动的渴望和SRM缺陷。通过使用仅由设计药物（DREADD）激活的设计受体进行细胞类型特异性操作，我们表明下丘脑室旁核（PVN）中的催产素神经元对SI诱导的社会行为变化至关重要。PVN催产素神经元的化学遗传学激活重现了在SI小鼠中观察到的社会行为变化，而催产素神经元的化学遗传学抑制则可防止SI引起的社会行为变化。此外，我们发现VTA中的多巴胺能神经元通过其向内侧前额叶皮质（mPFC）而非伏隔核的投射来介导SI诱导的对社会互动的渴望。向VTA注射特定的催产素受体拮抗剂L368,899或在mPFC中局部应用6-羟基多巴胺对多巴胺能轴突终末进行化学损伤可改善SI诱导的社会行为变化。
这些发现表明，青春期SI通过对VTA到mPFC多巴胺能回路活动的催产素能调节，对雄性小鼠的社会行为产生持久影响。
