Your health is in your head Social status impacts T-cell responses through synapse strength in prefrontal cortex

Social status is a powerful predictor of health, yet the mechanisms linking social rank to immune function remain poorly understood. Previous work has implicated the dorsolateral medial prefrontal cortex (dl-mPFC) in governing social hierarchical behavior, but whether this region also shapes immunity was unknown. In this thesis, I investigated this link in laboratory mice, combining social hierarchy assessment with DNA vaccination to measure antigen-specific CD8+ T-cell responses. I further compared mouse models with different levels of AMPA-receptor-dependent synaptic plasticity and used AAV (adeno-associated virus) vectors to rescue or knock down GluA1 in specific brain regions, evaluating the effect on the immune system. In groups of four male mice, rank correlated with immunity: second-ranked mice mounted the strongest T-cell expansion, independent of stress hormone levels. In mice lacking the AMPA-receptor subunit GluA1, social status no longer influenced T-cell responses, indicating that the brain translates rank into immune output through GluA1-dependent plasticity. Restoring GluA1 selectively in dl-mPFC neurons boosted T-cell responses even in socially isolated mice, revealing a causal, social-context-independent role for dl-mPFC synapse strength. Conversely, depleting GluA1 in the dl-mPFC enhanced T-cell responses only in solitary mice, showing this regulation depends on social context and plasticity in additional brain regions. A separate line of work revealed roles for GluA1- and GluA3-containing AMPA-receptors in hippocampal formation and reactivation of contextual fear memories. Together, these findings establish AMPA-receptor plasticity as a tool to probe brain-behavior relationships and show that social status shapes T-cell immunity through prefrontal synapse strength, offering insight into health inequality.