‘Happiness is only real when shared’ marks the end of the motion picture Into the Wild, named after the corresponding book by Jon Krakauer. Conversely, the lack of social interaction causes adverse effects. This relationship has been subject to a vast number of psychological studies. A new study led by Zhen Yan and colleagues at the State University of New York Buffalo's Jacobs School of Medicine and Biomedical Sciences (Yan et al., 2024) now provides important insights into how early-life social isolation affects the mammalian genome, hence potentially the human genome, shaping stress responses and stress-related aggression. In their study, Yan et al. (2024) identified an epigenetic mechanism underlying heightened aggression in mice that experienced the stressor of social isolation early in life compared with animals housed in groups. They revealed increased deacetylation of histones in neurons of the prefrontal cortex, which is ultimately considered to change the expression of genes without altering the DNA sequence. In humans, epigenetics has already been identified to play a role in psychiatric disorders such as major depressive disorder. The present data provide important new insights into how early-life social stress might also alter gene expression in humans and underlie maladaptation in the stress response.

In a series of elegant experiments ranging from slice electrophysiology to animal behaviour, Yan et al. (2024) find that the altered histone acetylation is accompanied by an increased excitatory postsynaptic current in socially isolated male mice upon exposure to acute stress, putatively resulting in a change of prefrontal activity underlying the behavioural phenotype. This is very well in line with a role for histone deacetylation in synaptic plasticity, in addition to the effect of stress to modulate prefrontal activity rapidly in mice and humans (Gräff & Tsai, 2013). Thus, their data strongly point towards early-life social isolation leading to a hyperactivity within frontal networks, putatively underlying the impulsive action and heightened aggressive behaviour in response to the acute stressors.

Importantly, using histone-deacetylation inhibitors to treat these behavioural symptoms pharmacologically resulted in a vast attenuation of the aggressive stress response in mice that were socially isolated in early life. Consistent with improved animal behaviour, the group found the increased excitation upon acute stress in frontal regions in socially isolated mice to be reduced to baseline levels, highlighting not only the effects of epigenetics on synaptic plasticity and finally animal behaviour, but also the effectiveness of pharmacological interventions targeting epigenetics.

These results contribute to earlier and recent findings in which epigenetic changes, such as DNA methylation and histone deacetylations, were described in response to social isolation stress and where the use of histone-deacetylation inhibitors was shown to facilitate extinction learning in animals that went through fear conditioning experiments (Bludau et al., 2023). Including the present study by Yan et al. (2024) in this issue of The Journal of Physiology, this epigenetic mechanism has now been observed in several brain regions involved in the response to stress and fear, potentially assigning histone deacetylation to be a general mechanism in the precipitation of stressful situations during life. Collectively, this corroborates not only the significance of epigenetics for social stress, but also the use of histone-deacetylation inhibitors in the treatment of stress-related psychiatric manifestations.

Histone-deacetylation inhibitors constitute known tools in the treatment of various cancers, where they are able to suppress the rapid growth of tumour cells and, in combination with other drugs, reveal effectiveness in a broad range of different tumour classes. The two drugs used by Yan et al. (2024), romidepsin and MS-275, which target histone-deacetylation pharmacologically, are already in use in the context of cancer therapies (Bondarev et al., 2021). Romidepsin is already approved by the United States Food and Drug Administration, and MS-275 is currently in clinical trials and might show less side effects than romidepsin. Collectively, this raises the possibility of histone-deacetylation inhibition to constitute a new prominent avenue in the treatment of stress-related psychiatric disorders.

This is of particular interest for a post-pandemic society, in which adolescents ranging from kids to teenagers have been suffering from social isolation, and in a changing society that facilitates a lack of social interaction of human beings at any age. The costs of social isolation in the context of the coronavirus disease 2019 pandemic measures are yet to be calculated. In a society of rapidly growing cities with rapidly increasing anonymity, mankind consequently encounters elevated levels of social isolation, and the effects on mental health and well-being are already well described. Therefore, to tackle the disadvantages and the consequences of social isolation, identification of new tools and targets in the treatment of stress-related psychiatric disorders is particularly relevant. Collectively, the present research by Yan et al. (2024) will further strengthen the focus of the field on epigenetics and how to modulate and target the consequences of social stress on gene expression by the use of histone-deacetylation inhibition. It also illustrates the necessity to develop drugs targeting epigenetic modifications of gene expression with high specificity and minimal side effects (Park & Kim, 2020).

“幸福只有在分享时才是真实的”标志着电影《荒野生存》的结尾，该电影以乔恩·克拉考尔（Jon Krakauer）的相应书籍命名。相反，缺乏社交互动会造成不利影响。这种关系已经接受了大量的心理学研究。纽约州立大学布法罗分校雅各布斯医学与生物医学学院的 Jen Yan 及其同事领导的一项新研究（Yan 等人，2024）现在提供了关于生命早期社会隔离如何影响哺乳动物基因组的重要见解，因此有可能人类基因组，塑造压力反应和与压力相关的攻击行为。在他们的研究中，Yan 等人。 ( 2024 ) 与群体饲养的动物相比，在生命早期经历过社会隔离压力的小鼠中，发现了导致攻击性增强的表观遗传机制。他们发现前额叶皮层神经元中组蛋白的脱乙酰作用增加，最终被认为可以在不改变 DNA 序列的情况下改变基因的表达。在人类中，表观遗传学已被确定在精神疾病（如重度抑郁症）中发挥作用。目前的数据提供了关于生命早期的社会压力如何改变人类基因表达并导致压力反应适应不良的重要新见解。

在一系列从切片电生理学到动物行为的优雅实验中，Yan 等人。 ( 2024 )发现，在受到急性应激时，社会孤立的雄性小鼠中，组蛋白乙酰化的改变伴随着兴奋性突触后电流的增加，推测导致行为表型背后的前额叶活动的变化。这非常符合组蛋白脱乙酰化在突触可塑性中的作用，以及压力对小鼠和人类快速调节前额叶活动的影响（Gräff & Tsai，2013）。因此，他们的数据强烈表明，早年的社会孤立导致了额叶网络的过度活跃，这可能是应对急性压力源的冲动行为和加剧的攻击行为的基础。

重要的是，使用组蛋白脱乙酰化抑制剂从药理上治疗这些行为症状，可以大大减弱早年被社会隔离的小鼠的攻击性应激反应。与动物行为的改善相一致，研究小组发现，社会孤立的小鼠额叶区域急性应激时的兴奋增加降低至基线水平，这不仅强调了表观遗传学对突触可塑性和最终动物行为的影响，而且还强调了药理学的有效性。针对表观遗传学的干预措施。

这些结果有助于早期和最近的发现，其中描述了DNA甲基化和组蛋白脱乙酰化等表观遗传变化是对社会隔离压力的反应，并且组蛋白脱乙酰化抑制剂的使用被证明可以促进经历恐惧的动物的灭绝学习调节实验（Bludau 等人，2023）。包括 Yan 等人目前的研究。 ( 2024 ) 在本期《生理学杂志》中，这种表观遗传机制现已在涉及压力和恐惧反应的几个大脑区域中观察到，可能将组蛋白脱乙酰化视为生活中压力情况沉淀的一般机制。总的来说，这不仅证实了表观遗传学对社会压力的重要性，而且证实了组蛋白脱乙酰化抑制剂在治疗压力相关精神表现中的应用。

组蛋白脱乙酰化抑制剂是治疗各种癌症的已知工具，它们能够抑制肿瘤细胞的快速生长，并与其他药物结合使用，显示出对多种不同肿瘤类别的有效性。 Yan等人使用的两种药物。 ( 2024 )、罗米地辛和 MS-275 均以组蛋白脱乙酰化为药理学目标，已在癌症治疗中使用 (Bondarev 等人，2021 )。罗米地辛已获得美国食品和药物管理局的批准，MS-275目前正在进行临床试验，可能比罗米地辛显示出更少的副作用。总的来说，这提出了组蛋白脱乙酰化抑制成为治疗应激相关精神疾病的新的重要途径的可能性。

这对于大流行后的社会尤其重要，在这个社会中，从儿童到青少年的青少年一直遭受社会孤立，而在一个不断变化的社会中，任何年龄段的人类都缺乏社会互动。 2019 年冠状病毒病大流行措施背景下的社会隔离成本尚未计算。在一个城市快速发展、匿名性迅速增加的社会中，人类因此遇到了更高程度的社会孤立，这对心理健康和福祉的影响已经得到了很好的描述。因此，为了解决社会孤立的缺点和后果，确定治疗压力相关精神疾病的新工具和目标尤为重要。总的来说，Yan 等人目前的研究。 ( 2024 ) 将进一步加强该领域对表观遗传学以及如何通过使用组蛋白脱乙酰化抑制来调节和靶向社会压力对基因表达的影响的关注。它还说明了开发针对基因表达表观遗传修饰、具有高特异性和最小副作用的药物的必要性（Park & Kim，2020）。