小鼠幼年炎症痛致社交缺陷，脑刺激可逆转

研究做了什么

这项研究关注一个具体问题：生命早期的疼痛经历，会不会改变成年后负责社交行为的脑系统。研究团队来自首都医科大学宣武医院，第一作者为Xiangdong Wan，论文发表在《Translational Psychiatry》。他们选择前扣带皮层作为观察对象，这一脑区既参与处理社交信息，也参与疼痛中令人不适的情绪成分。该区域正常运作依赖兴奋性神经元与抑制性神经元之间的平衡。

实验使用雄性和雌性实验室小鼠，包括经过基因改造、可以分别标记或操控兴奋性、抑制性神经元的品系。小鼠出生第10天时，一组被注射完全弗氏佐剂到一只后爪，造成炎症并使爪子对压力和热更敏感；对照组注射生理盐水。为检验时间窗口，另一些小鼠分别在6、9、12、15、18或21天龄接受同样注射。

社交缺陷与脑活动变化

到成年期，这些小鼠对压力和热的敏感度已恢复正常，但早期经历疼痛的小鼠表现出社交缺陷。正常小鼠在“陌生小鼠所在的隔间”和“空笼子所在的隔间”之间会更偏好前者，而疼痛组没有表现出这种偏好。缺陷在雌雄两性中都出现，至少持续到16周龄，并且只在12天龄及以前接受注射的小鼠中出现。

这种缺陷看起来不是普遍的焦虑或记忆问题：疼痛组小鼠对新引入的小鼠仍有正常兴趣，也没有表现出比对照组更多的焦虑样行为。作者据此认为，这更接近社交动机的特异性下降。

在疼痛组小鼠接近陌生小鼠时，前扣带皮层的兴奋性神经元活动比对照组更弱。对照组中，该区域的抑制性神经元在社交接近时通常会降低活动，而疼痛组这种下降幅度更小，使该区域相对更受抑制。化学递质测量也呈现一致模式：社交接近时兴奋性递质谷氨酸释放更少，抑制性递质GABA的下降幅度更小；疼痛组该区域兴奋性神经元数量更少、抑制性神经元更多。

逆转缺陷的几种操作

研究者用光遗传学和化学遗传学手段增强兴奋性神经元活动，或压低抑制性神经元活动，疼痛组小鼠的社交缺陷得到恢复。在健康小鼠身上做相反方向的操控，则会产生社交缺陷。把增强谷氨酸信号或阻断GABA受体的药物直接注入该区域，也能改善社交行为，但改善并不完全。

最后，研究者在前扣带皮层植入电极进行深脑刺激。在他们选定的参数下，刺激增强了兴奋性神经元活动，只轻度激活抑制性神经元；在测试期间施加刺激，逆转了疼痛组小鼠的社交缺陷。较高的刺激参数使部分小鼠出现类似癫痫的反应。作者在结论中称，早期疼痛通过造成前扣带皮层“低兴奋、高抑制”状态损害社交功能，而深脑刺激可以纠正这种失衡。

解读时需要保留的边界

这是小鼠研究，不是人类研究。小鼠与人类共享许多遗传和生理特征，但仍是不同物种；幼鼠一次短暂的炎症性损伤，也不等同于儿童的慢性疼痛。论文讨论的深脑刺激虽已在人类临床使用，但本研究中它只在小鼠身上测试，且效果仅在刺激开启时被观察到，益处能否持续尚不清楚。

研究还有几项方法上的限制：测试时研究者知道每只小鼠属于哪一组，未设盲；没有追踪雌鼠的动情周期，而这一周期可能影响社交行为。因此，这项研究提供的是关于早期疼痛、前扣带皮层兴奋/抑制平衡与社交行为之间关系的机制线索，不能直接转化为对儿童疼痛或社交困难的临床建议。

Deep brain stimulation may reverse social deficits caused by early-life pain, mouse study suggests

A study on mice found that inflammatory pain early in life led to lasting deficits in social behavior, along with an imbalance between excitatory and inhibitory activity in a brain region called the anterior cingulate cortex. Boosting the region’s excitatory neurons, quieting its inhibitory neurons, or applying deep brain stimulation reversed the social deficits. The paper was published in Translational Psychiatry.

The human brain develops through a complex interaction between genetic instructions and experiences from the environment. This interaction is especially important in early years of life, when the developing brain is highly plastic and particularly sensitive to outside influences. Adverse experiences during childhood, such as abuse, neglect, social isolation, or chronic stress, can interfere with normal brain development and leave lasting changes in both brain structure and function.

Research has linked such experiences to alterations in areas involved in memory, emotional regulation, decision-making, and responses to stress, including the hippocampus, amygdala, and prefrontal cortex. These changes may help explain why early-life adversity is associated with a greater risk of psychological and behavioral difficulties later in life.

Pain experienced during childhood or adolescence can also act as a powerful and persistent source of stress during sensitive stages of development. When pain becomes chronic, its consequences may extend far beyond physical discomfort and affect education, social relationships, later employment, and overall quality of life. Despite this, much less is known about how painful experiences early in life influence the development of brain systems responsible for complex social behavior.

Study author Xiangdong Wan of Xuanwu Hospital, Capital Medical University, in Beijing and colleagues set out to examine the long-term effects of early-life pain on social behavior. They focused on the anterior cingulate cortex, a region toward the front of the brain that is involved both in processing social information and in the emotional, unpleasant side of pain. The region’s normal function depends on a precise balance between excitatory neurons, which increase activity in the networks they connect to, and inhibitory neurons, which dampen it. The researchers hypothesized that early-life pain disrupts this balance, leading to social deficits.

The researchers used male and female laboratory mice, including genetically modified strains that allowed them to target excitatory or inhibitory neurons specifically. In these mice, the researchers could make one type of neuron glow so it could be counted, record its activity, or switch it on or off using light (optogenetics) or a designer drug that acts only on engineered receptors (chemogenetics).

When the mice were 10 days old, the researchers injected a substance called Complete Freund’s Adjuvant into one hind paw of mice in one group, producing inflammation that made the paw more sensitive to pressure and heat. A control group received a saline injection instead. To find out whether timing mattered, the researchers also gave the injection to other groups of mice at 6, 9, 12, 15, 18, or 21 days of age.

By adulthood, the mice’s sensitivity to pressure and heat had returned to normal, but those that had experienced early-life pain showed social deficits. Unlike control mice, which preferred a chamber containing an unfamiliar mouse over one containing an empty cage, they showed no preference between the two. The deficit appeared in both males and females, persisted to at least 16 weeks of age, and occurred only when the injection was given at 12 days of age or younger.

The mice that had experienced early-life pain still showed normal interest in a newly introduced mouse, and they did not show more anxiety-like behavior than control mice. The authors suggest this points to a specific loss of social motivation rather than general anxiety or memory problems.

When the pain-exposed mice approached an unfamiliar mouse, excitatory neurons in their anterior cingulate cortex became less active than those of control mice. In control mice, inhibitory neurons in the region normally quieted down during social approach, but this drop was smaller in pain-exposed mice, leaving the region relatively more inhibited. Measurements of chemical messengers showed a matching pattern, with less release of the excitatory messenger glutamate and a smaller drop in the inhibitory messenger GABA during social approach, and the pain-exposed mice also had fewer excitatory and more inhibitory neurons in the region.

Boosting the activity of excitatory neurons or dampening the activity of inhibitory neurons, using light or designer drugs, rescued the social deficit in pain-exposed mice. In healthy mice, the opposite manipulations produced social deficits. Infusing drugs that enhance glutamate signaling or block GABA receptors directly into the region also improved social behavior, although not fully.

Finally, the researchers implanted an electrode in the anterior cingulate cortex to deliver deep brain stimulation, a technique already in clinical use in humans. At the setting they selected, stimulation increased the activity of excitatory neurons while only mildly activating inhibitory ones, and applying it during testing reversed the social deficit in pain-exposed mice. A higher setting caused seizure-like reactions in some mice.

“This study unveils a core mechanism whereby early-life pain impairs social function by inducing a state of hypoexcitation [reduced activation] and hyperinhibition [increased inhibition] in the ACC [anterior cingulate cortex]. Furthermore, we establish that DBS [deep brain stimulation] can effectively rectify this ACC imbalance, providing a novel theoretical basis and a potential translational strategy for intervening in social deficits associated with developmental trauma,” study authors concluded.

The study contributes to the scientific understanding of the importance of early experiences for adult life. However, it should be noted that the study was conducted on mice, not on humans. Although mice and humans share many genetic and physiological similarities, they are still very different species, and a brief inflammatory injury in mouse pups is not the same as chronic pain in children.

In addition, the researchers were not blinded to which mice were in which group during testing, and the stimulation was tested only while it was switched on, so it is not known whether its benefits last. The researchers also did not track the estrous cycle in female mice, which can affect social behavior.

The paper, “Deep brain stimulation ameliorates social deficits from early-life pain by restoring excitatory/inhibitory balance in the anterior cingulate cortex,” was authored by Xiangdong Wan, Tao Du, Dou Yang, Zaiying Jiang, Xiangyu Zhang, Yunjian Huang, Siyi Liu, Shiyun Xu, He Zhang, Guang Lu, Bing Ni, and Hongwei Zhu.