Hormones and Stress Response

The brain controls hormone release

Hypothalamic releasing factors

Oxytocin and Vasopressin (ADH) are released by the posterior pituitary, others from the anterior pituitary.

Environmental factors influence hormone secretion Social Mating and breastfeeding both stimulate oxytocin release in females, allowing for formation of pair bonds with partners and offspring Defeat leads to a reduction in testosterone levels in male rhesus monkeys, can be reversed by exposure to a female companion Stressful Physical and psychic stresses (trauma, fear) lead to ACTH release and subsequent glucocorticoid release: these pathways can be strengthened by learning

Social anxiety, as determined in a questionnaire, profoundly affects the level of testosterone in males randomly selected to lose a face to face game with a predetermined outcome.

Biological rhythms influence hormone secretion Adrenal steroid hormones are released prior to periods of wakefulness and activity Waking Synaptic efficacy for “easy” learning LTP and memory retention Hunger (carbs especially) and food seeking Seasonal and circannual rhythms Menstrual and estrous cycles Breeding “season” testes growth

LEFT: circadian control of hormone secretion RIGHT: circadian control of learning and memory, short term recall, in phase with body temp and alertness.

Hormones act via receptors Peptide hormones (grehlin, oxytocin, VP) and amino acid derivatives that act as neuromodulators (norepinephrine) Bind cell surface receptors—2nd messenger cascades Steroid hormones (estrogen, progesterone), thyroid hormone, and glucocorticoids Bind cytoplasmic receptors which become activated and translocate to the nucleus where they act as transcription factors

Adrenal Steroids Left normal, right neonatal neglect.

Developmental Experiences Influence Later Responses to Anxiogenic Stimuli High Maternal Care in Rats Alters Adult Offspring Increased Glucocorticoid Receptor Expression in Hippocampus Enhanced Glucocorticoid Feedback Sensitivity Decreased Hypothalamic CRF expression Reduced HPA axis activity in response to Stressors

Impact of Maternal Care : Increases activation of 5-HT7 Receptors in Offspring: Linked to Gs proteins Increases expression of a transcription factor, NGFI-A, which binds to a site on a non-coding region of the Glucocorticoid Receptor gene. Changes methylation state of specific sites of promotor sequence of Glucocorticoid Receptor gene. NGFI-A binding induces DNA demethylation, which will lead to increased transcription.

Methylation of GR exon 1 Methylation of GR exon 1. NGFI binding site is circled. NGFI binding reduces methylation, leading to increased transcription

Experiment Hypothesis: Maternal care affects serotonin signaling, leading to increased NGIF transcription, decreased methylation of the GR, and more GR production in the HPC. Method: Grow two populations of mice, one high maternal care, one low maternal care, then cross foster the pups with the opposite care mother Monitor adult GR methylation

offspring show methylation pattern consistent with rearing mother rather than birth mother (low 5’ methylation for L-H). No effect at 3’ site. 2C. Increased association of aceytlated histone and NGFI-A binding with GR exon 1 in high-LG/ABN reared adult offspring.

Societal factors in humans Childhood abuse or neglect Trauma Urban upbringing Stress Interpersonal relationships Environmental factors, particularly during development, can alter susceptibility to mental disorders

Social Anatomy Figure 1 A simplified taxonomy of neural areas supporting human social functions, shown on lateral and medial surfaces (top and bottom, respectively). Yellow, social perceptual processes; red, emotional and motivational appraisal of social stimuli; green, social attribution processes; blue, social categorization processes. fMRI, lesion studies

Interactions that affect mental disorder phenotypes Genes—environment Genes—hormones Hormones—environment Social hormones Mediate pair bonding Gender specific responsiveness

Genetic variants of social hormones AVPR1a (vasopressin receptor) High levels in ventral pallidum of prairie voles mediates their monogamous behavior A genetic variant precludes expression in VP in meadow voles and they are promiscuous Replacing the variant with the prairie vole avpr1a gene induces pair bonding in meadow voles Human variants in avpr1a also exist and correlate with relationship success in men Environmental factors don’t act alone to modulate susceptibility to disease. There is genetic variability in the population that interacts with social and stressful cues to determine ones risk for any given disease/disorder.

Genetic variants of social hormones OXTR (oxytocin receptor) Single nucleotide polymorphisms (SNPs) in intron 3 are associated with decreased maternal sensitivity and empathy May be over-represented in autism Another variant is associated with increased depression and social anxiety A third, protective, variant is associated with decreased stress response, particularly in men

Role of Development Many mental illnesses are only observed at or after adolescence Extensive plasticity in the brain, pruning of connections, establishment of new connections Shift from parental support to peer support Initiation of romantic relationships :: prime time for interactions between genes and environment to occur -response to stress, develop and rely on supportive networks, coping mechanisms