File:Human-Social-Genomics-pgen.1004601.g002.jpg

English: (A) A simple (acyclic) social signal transduction pathway maps adverse social conditions onto activation of the conserved transcriptional response to adversity (CTRA) in leukocytes. Brain-mediated perceptions of social threat activate the sympathetic nervous system (SNS), leading to release of norepinephrine (NE) at SNS nerve terminals, activation of β-adrenergic receptors on adjacent cells, and stimulation or repression of specific transcription factors in response to the cyclic 3′-5′ adenosine monophosphate/protein kinase A (cAMP/PKA) signaling pathway. β-adrenergic-responsive transcription factors induce the CTRA gene expression program by stimulating transcription of genes encoding proinflammatory cytokines and suppressing transcription of genes encoding Type I interferons and IgG antibodies. CTRA gene expression programs prepare the body to respond to wounding injury and bacterial infections but may promote chronic illnesses such as cardiovascular disease (CVD), Alzheimer disease (AD), Type II diabetes (T2D), and metastatic cancer while undermining host resistance to virally mediated infectious diseases (ID). (B) Superimposed effects of reciprocal endogenous and exogenous recursive feedback on the social signal transduction pathway can propagate the impact of a transient adverse environmental shock. In this system, a transient environmental threat activates the core social signal transduction pathway to stimulate transcription of proinflammatory cytokine genes, as part of the CTRA. Arc 1 shows an endogenous biological feedback loop in which the proinflammatory gene products signal the brain to activate a programmed set of sickness behaviors that include reduced social motivation, fatigue, anhedonia, and negative emotional states. Arc 2 shows how the resulting reductions in individual social behavior and altered social niche selection evoke less supportive and more hostile responses from the surrounding social network and thereby create a more adverse social environment. Effects of the exogenous social recursion loop (Arc 2) are propagated via the core social signal transduction cascade into continued CTRA activation and continued endogenous biological recursion (Arc 1). Reciprocating feedback may thus maintain the system in a new dynamic equilibrium that maintains altered endogenous inflammation and exogenous social influence long after the initiating transient shock has passed. Similar recursive feedback can occur at every level of the social signal transduction cascade, resulting in complex systems dynamics that can trigger persistent sequelae such as PTSD and biological embedding of early life social conditions without requiring any durable genomic modification (e.g., mutation or epigenetic marking). Abbreviations: CHD, coronary heart disease; CNS (central nervous system); IRF, interferon regulatory factor.