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Biological Pathways Linking Social Environment to Health.

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1 Biological Pathways Linking Social Environment to Health

2 Routes for biological embedding Everything interconnected, so hard to establish a beginning. Somewhat arbitrarily: 1.Embodiment & epigenetics 2.Endocrine system – hormonal messengers 3.Limbic system emotions, meaning and learning 4.The autonomic nervous system, closely linked to endocrine system & hormone secretions 5.Immune system 6.Life course perspective.


4 ‘Embodiment’ The processes whereby our physical bodies incorporate traces of lived experiences (+ & -). Ecosocial & life course perspective; bodies as active agents in adaptation Brain & mind involved: neural substrates of our learning (body memory); driving becomes automatic… Culturally learned bodily expression of emotions Neuroses & psychological effects of trauma Social embodiment = patterned responses to situations: reinforce social bonds: smiling, reach out a hand in greeting Shaped epigenetically - environment modifies gene expression (rather than changing the genes themselves) to modify phenotype.

5 Genotypes, Phenotypes & Plasticity Genes code for proteins, building blocks for everything we will discuss Variants of genes (alleles) lead to diversity Expression of a gene is strongly influenced by environment

6 How does a genotype express a phenotype? Transcription – Portion of DNA unravels – Messenger RNA (mRNA) created from part of DNA – mRNA exits nucleus into cytoplasm of the cell Translation – Transfer RNA (tRNA) uses mRNA’s information to create proteins – Using amino acid materials from our diet (e.g. essential ones) or manufactured in the cell Proteins used in most structures, and also functions throughout the body. E.g. many hormones are built from proteins

7 From DNA to Protein Strings of 3 DNA nucleotides = 1 Codon 1 of 20 Amino Acids Assembled into peptide Protein

8 Proteins More than 50% of dry weight in most cells Drive and regulate all bodily processes Genes “act” via the proteins they code for Structural Storage Transport Receptors Contractile Defensive Hormonal Enzymatic PROTEIN TYPES

9 Factors Influencing Phenotype 1.Dominance 2.Polygenic Inheritance – Multiple genes involved 3.Environment (epigenetics) The observable physical or physiological trait

10 Side-bar: Genetic disorders Important, but not the main focus today. Dominant genetic disorders; rare. E.g., – Huntington’s – Hemophilia Polygenetic; you inherit genes that predispose you to the disorder; will not necessarily get it. – Diabetes – Asthma – Breast cancer, etc.

11 3. Environment Environment influences gene action in many ways: – Proteins must use elements from the environment to build structures – Influences gene regulation (temperature, light, nutrients, toxins, stress, etc.) – Demonstrated in genetically identical plants, twin studies (e.g., Tim Spector)

12 Genetics: Phenotypic plasticity A critical idea is that of “phenotypic plasticity,” which refers to the capacity of a single genome to produce a range of physically or functionally adaptive traits. – For example, fetuses that experience poor maternal nutrition adapt by incorporating energy- saving metabolic changes that anticipate a post- natal environment that is also characterized by food scarcity. These children often become obese.

13 Nature via Nurture Changing thinking over relative contributions of genes and environment Biological determinism wrong: genes provide a range of phenotypic possibilities Epigenetics The combination of genetics and epigenetics blends evolutionary and developmental biology. This has been termed ‘evo-devo’: the one leads to invariant outcomes and the other to individual differences.

14 Epigenetics Our cells contain full DNA code, but produce only cells of their own type. Cookbook & recipe metaphor. DNA transcription & translation regulated by ‘supervisory’ enzymes which determine type, amount & timing of protein produced Enzyme regulation influenced by many factors, including environment. Epigenetics studies these mechanisms, which lead to persistent changes in gene activities and effects, but without changing DNA base sequences

15 Epigenetic mechanisms DNA string is long & is tightly wound on ‘spools’. To be transcribed the relevant section needs to be unwound. The spools are made of histone proteins; these can change shape to allow or forbid access. Enzymes control this, in a dynamic balancing act of promoting & inhibiting access, e.g. – Methylation tightens the DNA & impedes transcription – Acetylation loosens the bonds. These enzymes are influenced by internal milieu, including health, stress levels, chemical exposures, etc. A critical point is that the methylation can be lasting, so that early exposures & experiences (including in utero) can lead to lifelong changes in gene expression. It can also be passed on to offspring.

16 Epigenetic influences Gene-environment interactions are especially relevant at sensitive periods of infant and child development. We carry alleles that can be turned on or off via environmental triggers. Birth cohort studies increasingly showing links between child experiences and later life sickness. For example: – There is a genetic polymorphism in the monoamine oxidase A (MAO-A) promoter region of the genome, which seems to contribute to aggression. The Dunedin birth cohort study showed that a low activity allele in association with severe maltreatment in childhood led to antisocial outcomes in 85% of males. – British 1958 birth cohort study studies methylation of 20,000 genes by categories of SES. Methylation more closely linked to childhood SES than to adult (N Borghol, 2012).

17 Genetics and Behaviour Evidence that genes influence behaviour – “Innate” behaviours we observe in many different species – Changes to biological structures, such as brain areas, may lead to change in behaviour – Behaviours of closely related species, e.g. humans and chimpanzees Behaviours are highly complex traits, and likely involve many genes

18 Example: Tobacco Use Nicotine binds to nicotinic-acetylcholine receptors in the brain, which in turn modulate release of dopamine The gene CHRNA4 codes for one subunit of the nicotine receptor – There are several different forms of this gene Feng et al 2004 found a form of the gene to be protective against nicotine addiction Genetics may influence susceptibility to nicotine-addiction


20 Made up of all hormone-secreting cells in the body: glands Secrete directly into bloodstream (vs. exocrine glands) Internal communication system between brain and body (complementary to nervous system) Maintains homeostasis and long-term control – Regulates slower processes than nervous system (e.g., growth, stress response) The Endocrine System

21 Hormones “A substance produced by one tissue and transported to another tissue where it induces a specific physiological response.” More than 50 known human hormones Grouped into 3 classes: – Peptides (short chains of amino acids) – Amines – Steroids (lipids derived from cholesterol)

22 Hormone Action Hormones trigger actions in specific target cells These have receptor molecules that hormones bind to (lock & key analogy) Steroid hormones act inside the cell, while peptide and amine hormones bind with receptors on the cellular membrane Binding changes the shape of the receptor, eliciting a chemical/physiological response

23 Action of Steroid Hormones Steroids can enter cell since they are lipids and can cross the cellular membrane

24 Action of Non-Steroid Hormones Peptides and amines cannot cross the cell membrane Bind to receptor on membrane, causing chemical signal (second messenger) inside the target cell

25 Homeostasis and Regulation Negative feedback regulates secretion of almost every hormone

26 Most elements of the internal environment are controlled by hormones which have simple, negative-feedback relations with the products or processes that they regulate (e.g., blood glucose & insulin). A disturbance in a process stimulates hormonal secretion: the hormone corrects the disturbance so removing the stimulus for its own secretion. This occurs without neural involvement. But hormones are also controlled by the brain, via the autonomic nervous system, sympathetic & parasympathetic branches. E.g., pancreas, kidneys & adrenal glands all linked to ANS. The hypothalamus also secretes hormones (ACTH, oxytocin, GH and a dozen others). These act on numerous organs. Hence, controls occur via local, neural and neural-hormonal pathways. Why? In part so that the body can respond in anticipation of metabolic fluctuations. E.g. anticipatory insulin release in anticipation of food. In part so that the brain can exert overriding control, ‘resetting the thermostat’.

27 Individual variability in hormone secretion: Some people are habitual low excretors of hormones; others are higher. Secretion has also been studied in relation to coping styles, showing that when characteristic coping approach fails hormone secretions change abruptly. (Sterling & Eyer)


29 Structure Part of the brain that translates ideas and affects into feelings and emotions Connects to frontal lobes (‘thinking brain’) and also to endocrine system The limbic system is closely connected to organs of perception (olfaction; memory) and plays a role in appraisal of the environment and hence in interpreting the stressfulness of a threat. It seems to be involved in processing the meaning of perceptions. Comprises an upper and lower circuit, which connect the neocortex (thinking brain) to parts of the endocrine system

30 The Limbic System

31 Functions Upper circuit appears to be involved in feeling states, while the lower circuit is involved in emotional states specific to survival (flight or fight response) Functions include: – Olfaction – Arousal, motivation, etc. – Regulation of homeostasis through the autonomic and endocrine systems – Coding in laying down new memories – Emotional responses, learning and higher control over exchanges between the body and the external world through emotions

32 Loosely defined About the size of a walnut (larger in women than men) Evidence on functions comes from brain- damaged animals and people The Limbic System


34 Amygdala – Receives sensory information from other regions – Organization of emotional information – Role in memory (damage results in amnesia for non-procedural memories) – Connected to olfactory bulb – memory of odours is strong – Stimulation causes aggression, damage leads to passivity and lack of reaction to fearful stimuli


36 Hippocampus – Involved in converting short-term memory (things in your mind) into long-term memory – Damage prevents formation of new memories


38 Thalamus – A relay station that channels sensory impulses from the nervous system to appropriate parts of the cerebral cortex. – Links “thinking brain” with sensory and emotional areas – Damage results in emotional apathy


40 Hypothalamus – Linked to pituitary gland – the master gland and thereby the endocrine system. The p ituitary releases hormones related to growth, reproduction, metabolism – Important in homeostatic regulation (the body’s thermostat) – Regulates drives (hunger, thirst, sex), autonomic nervous system (stress response), aggressive behaviour – Plays a central role in the stress response via secreting CRH, which causes the pituitary to secrete ACTH, which stimulates the adrenal medulla to release epinephrine. The “HPA” (see below).

41 Are connected to organs of perception (olfaction; memory) and play a role in appraisal of the environment and hence in interpreting the stressfulness of a threat Are involved in processing the meaning of perceptions Set emotional tone & add emotional dimensions to stress perception: fear, anger, anxiety Store emotional components of memory Facilitate bonding: damage prevents animals from bonding with young Regulate motivation and drive via orchestrating the SAM and HPA responses (see below). Together, these structures:

42 The brain system for appraising threats Limbic system: –Adds emotional dimensions to stress perception: fear, anger, anxiety –Especially centered in the hypothalamus


44 Nervous system Central nervous system (CNS) Peripheral nervous system (PNS) BrainSpinal cord Autonomic nervous system (ANS) (involuntary muscles) Somatic nervous system (voluntary muscles) Sympathetic (mobilizes & expends energy; prepares for fight or flight) Parasympathetic (conserves energy; undertakes ‘housekeeping’) Overview of structures involved (See next slide)

45 Divisions of the autonomic nervous system

46 How do the Nerves work? SYNAPSES Note idea of synaptic memory: well-used pathways. Others are disused & may store emotions & hidden memories

47 Neurotransmitters Dopamine o Natural Amphetamine o Motor coordination, cognition, mood, attention and learning, metabolism (BP, MR, digestion) – positive reinforcement Serotonin (Peripheral & Central NS) o Provides a healing, nourishing, satisfied feeling in the body – allows you to sleep naturally, enjoy time and think rationally GABA o Chief inhibitory neurotransmitter o Relaxation, anti-anxiety, involved in endorphin production Acetylcholine o Cognition, memory, arousal o Deficiency = lower creativity, learning

48 ANS structure: Adrenal Glands Adrenal glands On top of the kidneys Two parts: –Outer covering (cortex) –Inner part (the medulla) Both parts secrete stress hormones These perform complementary roles in up- and down-regulation.

49 Adrenals

50 Stress response: SAM & HPA Operates via two interrelated systems: SAM (Sympathetic-adrenomedullary – the medulla) HPA (hypothalamic-pituitary-adrenocortical – the cortex). These balance each other Both are triggered by the hypothalamus

51 SAM Adrenal medulla (the inner part) releases hormones epinephrine (adrenaline) and norepinephrine Epinephrine Stimulates rapid mobilization of metabolic resources: increased heart rate, increased rate of respiration, inhibition of digestive system, release of glucose, increased alertness, etc. "Rapid response"

52 HPA Hypothalamus secretes corticotropin-releasing hormone (CRH)  pituitary, stimulates release of adrenocorticotropic hormone (ACTH)  adrenal cortex, stimulates release of glucocorticoid (GC) & mineralocorticoid (MC) hormones. These form a “back-up response"; slower effect – Cortisol involved in regulating metabolism, immune response, and general homeostasis. – Protein & fat are metabolized into glucose; this suppresses immune response; raises BP Receptors = GRs and MRs Targets the brain Also changes gene expression

53 GR and MR Receptors The glucocorticoids from HPA bind to specific mineralocorticoid (MR) or glucocorticoid (GR) receptors on the target organs. GRs mediate most of the stress response; MRs mediate basal responses such as regulating neurotransmitters, BP, circadian rhythm GR effects therefore often oppose MR effects. This leads some to argue that vulnerability to stress is affected by the ratio of GR to MR receptors and their activation Such ratios set by gene expression, susceptible to epigenetic influences.

54 Function Normal homeostasis (body temperature, etc) is maintained within relatively narrow limits. By contrast, the stress response maintains homeostasis over a far wider range of adaptive circumstances, and in responding to challenges. This is 'allostasis': achieving stability through change. It occurs via the 'stress response'.

55 Anabolism & Catabolism The hormones suppressed during arousal are ones that promote synthetic or "anabolic" processes requiring energy. – Anabolic processes include energy storage, growth, synthesis of proteins, repair, and surveillance against infectious agents & malignant cells. Most of the hormones that increase during arousal are ones that promote degradative or "catabolic" processes directed at the immediate mobilization of energy. – Epinephrine, growth hormone, glucagon, and cortisol all promote carbohydrate, fat, and protein breakdown. The effects of this shift in overall hormonal pattern is all the more powerful because each hormone has multiple effects that reinforce the others.

56 HPA: Animal evidence Evidence from rodent models shows that infant rearing modifies activation of HPA response. For example, when a mother rat grooms her offspring this stimulates the development of GR receptors, which therefore allows more efficient control of HPA system activation. This epigenetic effect illustrates how neurobiology can be modified by social experience in critical periods of infant development. Pups reared by nurturing mothers, yet which are given freedom to explore, become more stress resilient. The ratio of their GR : MR receptors is different from rat pups that experienced maternal separation. This epigenetic mechamism involves methylation of a region of DNA that regulates HPA axis function, and also higher-order executive functions in the brain.

57 Weiss & Rats under stress Rats received electric shocks & got ulcers. 4 factors predicted level of ulceration: – If warned by a buzzer that shock was coming, ulcers lessened. Unpredictable = bad. – Rats with control over shock (by pressing a level) had fewer ulcers. – Reinforcement: a signal that the control behavior was correct led to fewer ulcers. – Demand level: if rat had to press lever several times fast, ulcers were worse. (Weiss J. Sci Am 1971; 226: 104 )

58 Human evidence Humans in insecure relationships show elevated cortisol and heart rate in response to HPA activation: i.e., their stress reaction is prolonged. Children who receive supportive care appear to have reduced stress responses "that may buffer or protect the developing brain and result in a more stress-resilient child." (Gunnar & Quevedo) Studies of Romanian orphans: after neglect during the first 6 mos. in orphanages, children tended to become high cortisol reactors and to suffer profound social-emotional, as well as cognitive, developmental disturbances that persist at least into early adolescence. "Responsive caregiving allows children to elicit help by expressing negative emotions, without triggering the endocrine component of the stress response": plausibly a modified limbic system reaction. Infants lacking maternal attachment show more reactive HPA and less adaptive behaviors.

59 Summary "Stress reactivity is better understood as the result of intertwined biological and psychological processes that ultimately ensure an organism's survival." "There is a cost to frequent physiological adjustments (allostatic load)" “One of the most interesting findings emerging from the research... is that in the absence of supportive care, stressors experienced during sensitive periods of development can... leave permanent imprints in the neural substrate of emotional and cognitive processes.... the nervous system of mammals carries their singular epigenetic history and expresses it in unique but predictable ways”. Reference: Gunnar M, Quevedo K. The neurobiology of stress and development. Annu Rev Psychol 2007; 58:

60 Social Status & Physiological Responses Sapolsky (1997): baboons of higher rank had greater cortisol suppression, suggesting more effective glucocorticoid negative feedback Steptoe & Marmot: cardiovascular reactivity is generally greater in lower SES individuals Lupien et al. (2000): lower SES children had higher salivary cortisol levels than higher SES children Cohen et al. (2006): higher SES associated with lower levels of cortisol and epinephrine, independent of race, age, gender and body mass Allostatic load is a representation of how the cumulative wear and tear of life conditions can undermine host resistance.


62 How could psychological factors influence immunity and disease? Psychological characteristic or state CNS innervationsHormonal responseBehavioral change Immune change Disease susceptibility Stressful events Coping Smoking Poor dietary habits poor sleeping Cohen et al, Ann Rev Psychol, 1996

63 Immune Response Immune response elicited when foreign substance enters body Two types: – Innate or Non-specific: Called non-specific because the same response occurs regardless of the foreign material that enter the body Characterized by inflammation reaction – Acquired or specific: Tailored to specific pathogens that enter the body. Characterized by antibodies, T-cells (T-lymphocytes), and B-cells (B-lymphocytes)

64 Innate or Non-specific immunity (Note skin & mucous membranes = first line of defence) Bacterium or virus enters body through wound (or other route) Damaged cells release histamine resulting in increased blood flow and temperature: Pain, redness, swelling Platelets released from bloodstream to clot blood at wound site Complement System: proteins that cause pores in microorganism to open so that fluids and salts enter, causing cell to burst Neutrophils migrate to site and kill bacteria by phagocytosis (Link to YouTube video and another)videoanother Macrophages remove pathogens by phagocytosis and release hormones called cytokines Cytokines attract T-cells and B-cells to site and activate them.


66 Acquired or Specific Immunity Mnemonics: Antibody = anti foreign body (the good guys). Antigen = antibody generators; generates an immune response (the bad guys) Pathogens such as bacteria and viruses have unique proteins on their surfaces called antigens. After phagocytosis, cytokines signal T-cells and B-cells. Cytotoxic T-cells bind to infected cells and release chemicals that kill the pathogen Suppressor T-cells then inhibit immune response when no longer needed Helper T-cells assist in B-cell growth; B cells make the antibodies …

67 Acquired or Specific Immunity (2) … B-cells develop into either antibody-producing cells or memory cells. Antibodies are matched to the pathogenic antigen. They kill the pathogenic cells in a variety of ways: Secondary immune response: Memory cells remain in the body after the pathogen is eliminated. If a pathogen presenting the same antigen enters the body again, the immune response will be much faster and stronger than it was the first time. Vaccines work by introducing an inactivated virus into the body that elicits an immune response and causes memory cells to develop for that virus.


69 How can psychosocial state affect immunity? How does this affect health? Cytokines are hormones released by macrophages to attract and activate other immune cells. Pro-inflammatory cytokines such as interleukin-6 (IL-6) promote inflammation. Anti-inflammatory cytokines such as IL-10 decrease the immune response. Anxious and depressed moods increase the production of pro- inflammatory cytokines [2], [3]. IL-6 promotes the production of C-reactive protein, which is a risk factor for myocardial infarction [4].

70 Conclusions No question that psyche, CNS and immunity are interrelated Psychological factors alters the immune system Effects of psychological factors on cancer onset or progression intermediated by the immune system is a question that remains unanswered

71 LIFE COURSE Part 6:

72 Sensitive Periods hypothesis Limited spans of developmental time when specific brain systems and the cognitive, emotional, or behavioral capacities they subserve are maximally receptive to environmental tuning and input. These allow both mundane and extraordinary experiences to get under the skin at critical times to affect biological function and hence perhaps alter life course trajectories. Sensitive periods in brain and biological development start in the prenatal period, reach a peak in the first few years of life, and continue at a declining rate throughout childhood and adolescence. – E.g., learning a second language best up to age 7 – Age of parental divorce is critical for impact on the children – E.g., epigenetic influences on rat gene that codes for establishment of glucocorticoid receptors; linked to anxiety in the pup.

73 Life Course Barker: exposures in utero lead to phenotypic adaptations (e.g. short stature or early menarche); these may entail lifelong susceptibilities = Developmental Origins of Health and Disease, or DOHaD Boyce: Social subordination, even in the very young, is associated with heightened cardiovascular, autonomic, and adrenocortical responses to stress and with disproportionately higher rates of chronic medical conditions and injuries.

74 Hertzman & Boyce Opportunities for biological embedding link closely to sensitive periods in the development of neural circuitry. Social environments and experiences get under the skin early in life, and do so in ways that affect the course of human development. Epigenetic regulation is the best example of operating principles relevant to biological embedding. Heart disease, diabetes, obesity, depression, substance abuse, school success, premature mortality, disability at retirement, accelerated aging and memory loss all have social determinants in early life

75 Hertzman & Boyce (2) Social causation is nonlinear and is nested within complex, dynamic accumulations of exposures over time, with interactions among multiple causal factors, and disease occurrence that is a nonlinear function of exposure. Social causation implicates symbolic processes. The psychosocial determinants of disease uniquely traffic in the meaning and affective valences of life experience. Social causation is nonspecific, unlike traditional epidemiology that links singular causes with singular outcomes. “Adverse social conditions yield broad, pluripotential pathogenicity rather than focal, specific morbidities.”

76 Hertzman & Boyce (3) Life experiences involve mundane, rather than exceptional, exposures: cf. the weathering metaphor. Physical and emotional abuse in childhood create serious health consequences, but it is often the less memorable but far more prevalent misfortunes of childhood that become embedded in neural circuitry and produce the vulnerabilities of adult life. Social causation is iterative and recursive: it involves repeated, self-amplifying exposures over time.

77 Developmental bio-programming Hertzman & Boyce: examples of biological embedding: – Early sensory stimulation activates genes in different parts of the brain to differentiate neuron functions and establish sensory pathways. – Sensory pathways, in turn, influence the development of neural pathways within the brain and other biological pathways, including the immune and endocrine systems. – Maternal attachment & stimulation drives the development of neural pathways that help the baby’s brain become attuned to its immediate environment: without attachment (grooming in primates, licking in rats) these pathways do not develop. – Child’s attachment to mother is critical; lack of early signaling of attachment can lead to failure to set up the reactions of positive attachment in the HPA and brain of the child. This deficit makes the child will be at risk of missing significant social cues. – Negative reinforcement loop: lack of response to social cues can make the child hard to relate to; this, in turn, can lead to deterioration of the child’s immediate social environment, making it more stressful.

78 Biological reactivity From early in life, ∼ 15% of children are more highly biologically reactive to their immediate social context than others are. The effects of being highly reactive biomedical outcomes are bivalent: they can be protective in some contexts and risk- augmenting in others. Those who are biologically sensitive to context are distributed across social strata, but the less privileged will tend to find themselves in risk-augmenting contexts, whereas those from more privileged backgrounds will tend to find themselves in protective environments.

79 Prefrontal cortex Biological incorporation of executive function: – Hertzman reports experimental studies of attention varying by SES: higher SES kids seem able to focus their attention and to be less distractable. – Lower SES kids tended to pay attention to irrelevant stimuli in a distraction experiment. This was then linked to higher cortisol secretions. Linked to the relative instability & chaos of early childhood environment, which varied by SES.

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