Early-life pain led to lasting social deficits in mice, and brain stimulation reversed them

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.

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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.