Instinctive behaviours such as defence, feeding and reproduction have evolved across animal phyla and ensure survival of both the individual and its kin. A brainstem region central to the initiation of virtually all instinctive behaviours is the periaqueductal gray (PAG). Although stereotyped to some degree, the expression of instinctive behaviours exhibits significant variability within and across individuals. Previous work has mostly focussed on behavioural variability arising from plasticity mechanisms occurring in forebrain regions projecting to the PAG, including the hypothalamus, amygdala and cortex. Here, we asked whether the PAG itself possesses the molecular machinery to support synaptic plasticity and neuromodulation. We used a label-free LCMS-based proteomics approach with data-independent acquisition to compare tissue from the PAG and two other highly plastic brain regions: neocortex and hippocampus. We analysed differences in the PAG proteome of male and female mice in two housing conditions (single- versus group-housed) as a means to induce plasticity. This comprehensive proteomic dataset, containing ~10,000 proteins per sample, allows us to posit that 1) the PAG expresses all proteins critical for postsynaptic plasticity and 2) changes in the social environment lead to significant differential expression of the majority of the PAG proteome. Third, we identified specific protease inhibitors, linked to the extracellular matrix, that are strongly upregulated in males throughout the brain. These proteins have been associated with Alzheimer’s disease (AD) and may point to a molecular mechanism of sex-specific AD vulnerability. In summary, we reveal how sex and social environment influence the proteome of the PAG.