Chp. 6: Neuroendocrinology of the Stress-Response

1. What is stress? How do we define stress, stressors and the stress-response. The nervous system plays a critical role in the stress-response: perception of events as stressful activation of the HPA axis-->secretes glucocorticoids activation of the ANS-->secretes catecholamines (epinephrine and norepinephrine) activation of pathways within the brain important for other responses (e.g., locomotion) Numerous events occur during an acute stress-response: changess in energy metabolism, heart rate, breathing, digestive processes, growth, analgesia, regulation of immune system, and behavior these changes are considered adaptive as they occur for short periods of time and they allow an individual to take appropriate action in a threatening situation However, chronic exposure to stress can alter these responses in specific ways that leads to the development of physical disease, and in humans, psychiatric illness. This relationship is influenced by genetic and experiential variables--vulnerability!! Chp. 6: Neuroendocrinology of the Stress-Response

2. Definitions: stressor: anything that disrupts the body’s physiological balance stress-response: the body’s adaptations designed to re-establish balance stress: general state of stressors provoking a stress-response Stress-Response What is stress? Physical Psychological no job promotion grizzly bear Negative injury (hemorrhaging) physical abuse public speaking meeting a deadline exercise Positive

3. Stress-Response Nervous System Hormones activation of the HPA axis glucocorticoids activation of the ANS (sympathetic division) Fight or Flight Reactions plasma catecholamines perception of an event as “stressful” activation of additional pathways in NS motor responses (locomotion)

4. Hypothalamo-Pituitary-Adrenocortical Axis (HPA axis): stress is perceived by limbic system neurons in the limbic system activate the HPA axis CRH neurons in hypothalamus release CRH at median eminence CRH stimulates release of ACTH from cells in the anterior pituitary ACTH stimulates both synthesis and release of glucocorticoids from adrenal cortex glucocorticoids act, in part, to mobilize energy for the fight or flight response glucocorticoids also act to restrain the HPA axis by inhibiting hormone release at the level of the hypothalamus, pituitary, and higher brain regions (limbic system) LIMBIC SYSTEM HPA Axis HYPO CRH Neuron CRH ANT PIT glucocorticoid negative feedback ACTH ADRENAL CORTEX glucocorticoids mobilize energy CRH: corticotrophin-releasing hormone ACTH: adrenocorticotrophin hormone

5. Parasympathetic Division “vegetative functions” increased digestion increased saliva decreased heart rate decreased breathing increased blood flow to gut restful state Autonomic Nervous System (ANS) The ANS consists of two main divisions--the parasympathetic and sympathethic divisions. These divisions have opposite effects on many physiological processes. Sympathetic Division “fight or flight response” decreased digestion decreased saliva increased heart rate increased breathing shunting of blood from gut to other tissues--skeletal muscle, heart, & brain heightened arousal & vigilance sweating

6. Neurons within the hypothalamus control the activity of neurons in the brainstem and lower spinal cord. Neurons within the brainstem and SC project to neurons within ganglia located close to target tissue. Acetylcholine (ACh) is the neurotranmitter that is released at the synapse in the ganglion and at the target tissue. Parasympathetic Division ganglion brainstem target tissue hypothalamus ACh lower spinal cord ACh target tissue

7. Neurons within the hypothalamus control the activity of neurons in the intermediolateral cell column (IML) of the spinal cord. Neurons within IML project to neurons within ganglia located close to the spinal cord. Neurons within the ganglia project to target tissues. Acetylcholine (ACh) is the neurotransmitter released at synapse in ganglion and norepinephrine (NE) is released at target tissues. In addition, neurons within IML project directly to the adrenal medulla where they release ACh which stimulates release of epinephrine (E) into blood. sympathetic chain of ganglia Sympathetic Division IML of spinal cord target tissue hypothalamus ACh NE E (bloodstream) Adrenal Medulla

8. During a stress response, the sympathetic division of the ANS will be activated. norepinephrine (NE) will be released at target tissues (e.g., heart) epinephrine (E) will be released into the bloodstream to act throughout the body epinephrine and norepinephrine (plasma catecholamines) carry out the various events associated with “fight or flight response” decreased digestion, decreased saliva production, increased heart rate, increased breathing, shunting of blood from gut to other tissues, heightened arousal and vigilance, and sweating (among other responses) in addition, these hormones act to increase glucose levels within the bloodstream (energy metabolism) Autonomic Nervous System (ANS)

9. Acute Stress Response: considered adaptive--it allows us to deal with an emergency situation (short-lived) different responses will be seen in different situations, but the outcome will be the same-- survival (life, grades, etc…) grizzly bear: may freeze or run or climb a tree--your response will determine your survival poster presentation: may start early to make a really cool poster or wait until the absolute last minute to make it--your response will determine your grade (and potentially survival in this course!) Chronic Stress Response: considered maladaptive--detrimental affects on the body chronic stress can lead to physical disease: gastric ulcers, visceral obesity, decreased growth, increased risk for coronary heart disease chronic stress can also affect behavior: inhibition of reproduction in humans, chronic stress has been linked to psychiatric illness (depression) Stress-Response

10. Acute Stress Response: metabolic: to increase levels of glucose within the bloodstream cardiovascular/respiratory: to increase cardiovascular tone to speed delivery of mobilized glucose and oxygen to tissues that need it--heart, skeletal muscle and the nervous system analgesia: to decrease the perception of pain inhibition of behaviors and processes that might threaten the survival of the individual: inhibition of mating behavior inhibition of feeding inhibition of gastrointestinal processes inhibition of the immune system Stress-Response

11. Acute Stress Response: Metabolic Purpose: to increase levels of glucose within the bloodstream Background: energy substrates are stored in the body in several forms: 1) excess fats are stored in adipose tissue as triglycerides, 2) amino acids are stored throughout the body as proteins, and 3) glucose is stored throughout the body as glycogen two hormones secreted by the pancreas play an important role in controlling the levels of blood sugar (glucose): 1) -cells in the pancreas secrete insulin--a key hormone involved in storage of glucose and the synthesis of proteins and fatty acids, 2) -cells in the pancreas secrete glucagon--a key hormone for the release of glucose into the bloodstream secretion of insulin and glucagon maintain glucose homeostasis under low stress conditions Ex. After a meal, glucose levels are high and -cells secrete insulin allowing for the transport of glucose from blood into cells for storage; several hours after the meal, glucose levels drop and -cells secrete glucagon which then acts to increase the release of glucose from stores until the next meal. Stress-Response

12. Acute Stress Response: Metabolic Purpose: to increase levels of glucose within the bloodstream During stress, glucocorticoids and plasma catecholamines act to increase levels of glucose within the bloodstream: glucose uptake is inhibited and synthesis of proteins, fatty acids and glycogen is halted lipolysis: triglycerides (fatty acids) are broken down and flushed into bloodstream glycogenolysis: glycogen is degraded and glucose is flushed into the bloodstream proteolysis: proteins are degraded into amino acids and flushed into bloodstream gluconeogenesis: fatty acids and amino acids are converted into glucose within the liver E/NE acts at adrenergic receptors (membrane) to rapidly increase blood glucose levels via lipolysis, glycogenolysis, proteolysis, gluconeogenesis; in addition, these hormones act to inhibit secretion of insulin while increasing secretion of glucagon glucocorticoids act at intracellular receptors to increase the synthesis of enzymes (via gene transcription) that subsequently act to increase the process of gluconeogenesis; this effect is slower but can last for a longer period of time Stress-Response

13. Acute Stress Response: Cardiovascular/Respiratory Purpose: to increase cardiovascular tone to speed delivery of mobilized glucose and oxygen to tissues that need it--heart, skeletal muscle and the nervous system Activation of the sympathetic division of the ANS lead to release of norepinephrine in tissues and epinephrine (and to a lesser degree norepinephrine) within the bloodstream; these catecholamines mediate increases in cardiovascular tone. in crease in breathing rate increase in heart rate increase in blood pressure shunting of blood away from the digestive tract and toward the heart, skeletal muscle and nervous system in addition, vasopressin is released from axon terminals in the posterior pituitary and acts to stimulate water reabsorption in the kidney; this increase in blood volume also serves to increase blood pressure Stress-Response

14. Acute Stress Response: Analgesia Purpose: to decrease the perception of pain Two forms of stress-induced analgesia (SIA): opiate-dependent SIA: endogenous opiates (enkephalins and -endorphin) are released within the brain to inhibit the processing of sensory information associated with pain opiate-independent SIA: other neurotransmitters (e.g., glutamate) can also act to inhibit the processing of painful information; endogenous opiates are not involved in this process both forms of SIA would occur during a normal stress encounter Adaptive nature of SIA: the zebra and the lion a lion attacks but does not kill a zebra; the zebra’s stomach is ripped open (stress response), yet for the next few hours, it has enough strength to evade the lion; a part of this response is the occurrence of SIA; if the zebra stopped to attend to it’s wound, it would most likely be killed by the lion; the decrease in perception of pain allows the zebra to continue to flee from the lion Stress-Response

15. Acute Stress Response: Alterations in behavior CRH released within the brain causes a shift in behavior from nonstressful responses (e.g., feeding, mating) to responses geared toward dealing with threatening stimuli--increased attention, caution, and fight or flight responses Stress-Response activates behaviors associated with increased state of fear (anxiety) CRH release in brain increased vigilance (attention) increased freezing inhibition of mating inhibits behaviors not associated with stress increased behavioral reactivity inhibition of feeding

16. Acute Stress Response: Gastrointestinal Tract at times of rest or feeding (low stress), see high parasympathetic tone of ANS associated with digestive processes: secretion of saliva in the mouth secretion of digestive enzymes, hormones and mucus in the stomach and intestines stimulation of stomach churning and gut motility under stress conditions, see high sympathetic tone of ANS: all of the digestive processes are inhibited one obvious sign of stress: our mouths become dry when we are nervous because we stop secreting saliva decreased blood flow to the GI tract increased defecation (imbalance between parasympathetic and sympathetic control) Stress-Response

18. Acute Stress Response: Nonspecific & Specific Defense Mechanisms stress inhibits inflammation associated with injury or infection inflammation occurs during an infection or injury; it is a recuperative process--influx of WBCs and proteins into infected region that destroy the pathogen, remove cellular debris, and repair damage inflammatory response means “setting on fire”; infected or damaged region will appear red and hot, with an increase in swelling; the infected region will be painful, and if located near joints, it will also be stiff (limited movement) elevations in glucocorticoids inhibit inflammation stress-induced inhibition of inflammation is adaptive by limiting a process that is painful and could limit mobility (important for fight or flight responses)--similar to stress-induced analgesia this recuperative process will take place when the level of stress is reduced (e.g., stressor is gone) Stress-Response

19. Acute Stress Response: Nonspecific & Specific Defense Mechanisms stress hormones also limit activation of the immune system that occurs during an infection an infection which activates the immune system will also activate the HPA axis (secretion of glucocorticoids) glucocorticoids, act in part, to inhibit the synthesis and release of various interleukin molecules as well as the synthesis of their receptors effect: limited proliferation of nonspecific defense mechanisms--NK cells and macrophages, and limited proliferation of specific defense mechanisms--humoral- and cell-mediated immunity immune system activates the HPA axis which acts to inhibit the immune system why? adaptive significance: may protect the body from becoming too active and possibly attacking self (autoimmune disease) Stress-Response

20. Background--Defense against pathogens The body has two systems to defend against pathogens, or infectious agents: nonspecific defense system this system nonspecifically attacks all types of pathogens--viruses, viral-infected cells, bacteria, and other foreign agents this system is also mediates inflammatory response that occurs in response to an infection or an injury this system includes: skin, mucous membranes (pH and enzymes), white blood cells, complement (serum proteins) WBCs: neutrophils and macrophages phagocytose pathogen and dead or dying cells WBCs: natural killer cells (NK cells) kill virus-infected cells and tumors (damage to cell membranes leading to cell lysis) Stress-Response

21. Background--Defense against pathogens The body has two systems to defend against pathogens, or infectious agents: specific defense system--immune system this system attacks substances detected as “foreign” by proliferating cells that either attack the invader directly or produce specific defensive proteins called antibodies that lead to the destruction of the pathogen B cells and T cells are lymphocytes that originate in bone marrow; B cells also mature in bone marrow--hence B designation; T cells migrate to, and mature within, the thymus--hence the T designation; the maturation process involves development of immunocompetence--specific cells in both groups can detect unique antigenic regions of bacteria and viruses--capacity for selective destruction of viruses and bacteria several types of T cells: helper T cell, cytotoxic T cell, suppressor T cell; one main type of B cell; however, there are a multitude of T and B cells that respond to different antigenic sequences of different pathogens Stress-Response

22. The Basic Immune Response: the activation of an immune response involves the activation and proliferation of numerous cell types, a process that requires the synthesis and release of interleukins and the synthesis of receptors that can respond to the various interleukins (see attached pages illustrating basic concept) Stress-Response

23. Acute Stress Response: considered adaptive--it allows us to deal with an emergency situation (short-lived) metabolic: to increase levels of glucose within the bloodstream cardiovascular/respiratory: to increase cardiovascular tone to speed delivery of mobilized glucose and oxygen to tissues that need it--heart, skeletal muscle and the nervous system analgesia: to decrease the perception of pain inhibition of behaviors and processes that might threaten the survival of the individual: inhibition of mating behavior inhibition of feeding inhibition of gastrointestinal processes inhibition of inflammation and the immune system Stress-Response

24. Chronic Stress Response: considered maladaptive--detrimental affects on the body chronic stress can lead to physical disease: metabolic changes, increased risk for coronary heart disease, formation of gastric ulcers, inhibition of growth, immunosuppression chronic stress can also affect behavior: inhibition of reproduction, development of a state of learned helplessness, drug-seeking behavior, increased anxiety, impairment in learning and memory in addition, chronic stress has been linked to psychiatric illness in humans depression anxiety Stress-Response

25. Chronic Stress Response: Metabolic “stress-induced diabetes” decreased ability to utilize elevated blood glucose levels--hyperglycemia (elevated levels of blood glucose) and insulin resistance result: fatigue result: muscle weakness (loss of protein--atrophy of muscle fibers) “stress-induced obesity” increasing accumulation of fat as adipose tissue within the intra-abdominal area in adipose tissue, glucocorticoids inhibit the fat-releasing effect of insulin and promote the storage of fat as triglycerides Stress-Response

26. Chronic Stress Response: Cardiovascular increased risk of coronary heart disease chronic hypertension (elevated blood pressure) damage to heart muscle weakened blood vessels (increased likelihood of stroke) deposition of cholesteral and the formation of atherosclerotic plaques Stress-Response

27. Chronic Stress Response: Gastrointestinal Tract formation of gastric ulcers stomach expends considerable energy in building and thickening stomach walls and secreting mucus--effects that protect the stomach walls from the ulcerative effects of gastric acids prolonged exposure to stress can result in a reduction in the thickening of stomach walls and in secreting mucus (in addition to the secretion of digestive enzymes)--when stressor abates, acid secretion may damage the stomach walls before the walls can thicken and mucus levels can increase also, prostaglandins aid in repairing stomach ulcers; glucocorticoids inhibit prostaglandin synthesis and this may increse the likelihood that gastric ulcers will form Stress-Response

28. Chronic Stress Response: Reproduction chronic stress can inhibit sex behavior, sexual desire and reproductive physiology Ex. stress of social subordination a high-ranking female monkey can ensure that she is the only member of her group to reproduce by physically harassing subordinates into anovulation in males, exposure to multiple defeat experiences in social interactions can suppress testosterone secretion mechanism? HYPOTHALAMUS: CRH and B-endorphin (released within the brain during stress) can inhibit release of GnRH PITUITARY: glucocorticoids act at the pituitary to decrease responsiveness to GnRH (fewer receptors); as a result, less LH and FSH will be secreted GONAD: glucocorticoids act at the level of the gonad to decrease responsiveness to LH and FSH (fewer receptors); as a result, lower levels of gonadal steroids will be secreted Stress-Response

29. Chronic Stress Response: Growth & Repair HYPOTHALAMUS: neurons within the hypothalamus secretegrowth hormone releasing factor (GHRH) and other neurons that secrete somatostatin PITUITARY: GHRH stimulates release of growth hormone (GH) from the anterior pituitary; in contrast, somatostatin acts to inhibit release of growth hormone LIVER: growth hormone stimulates the release of somatomedins from the liver somatomedins are growth factors that directly stimulate bone and cartilage growth chronic stress inhibits secretion of growth hormone due to increased release of somatostatin in children, stress-induced inhibition of GH can impair physical growth: “psychosocial dwarfism”--children are half the expected height for their age and secrete very little GH; this condition is associated with severe emotional stress Stress-Response

30. Chronic Stress Response: Growth & Repair removal of children from stressful environment is associated with increased secretion of GH and increased rate of growth in adults, chronic elevations in glucocorticoids are associated with a loss of bone density and an increase in the likelihood for bone fractures Stress-Response

31. Chronic Stress Response: Nonspecific & Specific Defense Systems chronic exposure to stress can lead to immunosuppression--decreased ability to defend the body against pathogens acutely, glucocorticoids act to inhibit inflammation and to limit proliferation of nonspecific and specific defense systems during an infection; an effect associated with decreased synthesis and release of interleukins and decreased synthesis of interleukin receptors chronically, the effects of glucocorticoids are more profound: decreased proliferation of nonspecific and specific defense systems in response to an infectious agent--decreases in NK cells, in cell-mediated immunity and humoral-mediated immunity decreased maturation of developing lymphocyte associated with involution of immune tissue during chronic stress (e.g., decrease in size of the thymus gland) Stress-Response

32. Chronic Stress Response: Nonspecific & Specific Defense Systems immunosuppression has been linked to in an increase in disease in animals, clear link between chronic stress and cancer; chronic stress can increase the likelihood that tumors will develop in animals and also speed the growth of tumors in humans, some limited evidence suggesting a relationship between life stressors and increased cancer risk: one episode of major depression can increase cancer risk for decades afterward (independent of age, diet, smoking and other risk factors) however, other studies have not shown a consistent relationship between stress in humans and the development of cancer; it has been suggested that not all tumors may respond favorably to stress, and that many of the human studies are limited by requiring either the sick individual or their families to recall the individual’s history of stressors (retrospective analyses) in humans, though, there is reasonably good evidence that chronic stress can increase the likelihood of developing the common cold Stress-Response

33. Chronic Stress Response: Central Nervous System Stress-Response increased levels of CRH present within the brain PVN dysregulation of HPA axis chronic stress other brain areas (e.g., amygdala) elevated levels of glucocorticoids basally (also see an increase in size of adrenal gland--hypertrophy)

34. Stress-Response chronic exposure to glucocorticoids HIPPOCAMPUS • Hippocampus possesses high levels of receptors for glucocorticoids • it is important for glucocorticoid negative feedback (limiting HPA axis) • lesioning the hippocampus will increase activity of HPA axis • chronic exposure to glucocorticoids leads to damage of neurons within hippocampus (even loss of neurons) and to decreased glucocorticoid negative feedback • decreased negative feedback leads to dysregulation of HPA axis and increased HPA axis activity damage to hippocampus decreased glucocorticoid negative feedback increased activity of HPA axis • increase in CRH in brain • increase in basal glucocorticoids • increase in adrenal gland size

35. Chronic Stress Response: Central Nervous System Stress-Response drug-seeking behavior impairment of memory dysregulation of HPA axis (damage to hippocampus) increased anxiety • increase in CRH in brain • increase in basal glucocorticoids • increase in adrenal gland size development of a state of learned helplessness (animal model of depression)

36. Chronic Stress Response: Central Nervous System chronic stress and HPA axis dysregulation most likely interacts with a number of neurotransmitter systems in the brain: serotonin and norepinephrine--neurotransmitters linked to depression; drugs that increase the levels of serotonin and/or norepinephrine are used to treat depression GABA/benzodiazepines--neurotransmitters linked to anxiety; drugs that increase GABAergic neurotransmission are used to treat anxiety (or panic attacks) most recently, research efforts have focused on developing antagonists to CRH receptors to treat depression and anxiety general idea is that if one can limit HPA axis dysregulation it may be possible to limit development of depression and anxiety Stress-Response

37. Chronic Stress Response: Who will develop stress-related diseases? Some individuals may be more prone than others! How we cope or react to stress may be critical variable!! genetic predisposition--brain chemistry, personalities previous experiences with stress--early in development or later as adults these factors likely interact to influence how we cope with stress or react to stress, and whether we will develop stress-related disease Stress-Response

38. Role of multiple factors on response to stress: Ex. relationship between dominant and subordinate monkeys in a stable environment (where rank doesn’t change), dominant males have lower resting levels of glucocorticoids than subordinate males; dominant males are less stressed however, in unstable environments, dominant males can have basal levels of glucocorticoids that are as high if not higher than the levels observed in subordinate males; dominant males are stress when they are actively fighting for their social rank in addition to social rank and stability of the environment, low glucocorticoid levels mirrored the personality of the dominant male even bettern than rank and stability of the social environment dominant males with specific personality traits have the lowest basal levels of glucocorticoids than dominant males without these traits Stress-Response

39. Role of multiple factors on response to stress: Good Personality Traits: (“good state of mind”) developed social support groups--formed nonsexual friendships with the opposite sex they could differentiate between neutral and threatening social situations, and initiated fights only when the situations were indeed threatening--predicability and taking control when they lost a fight they showed displacement behavior-->they showed aggression toward an innocent bystander; we might consider exercise (raquetball) as a way to release tension associated with stress Stress-Response

40. Role of multiple factors on response to stress: It is possible to see similar effects in humans. Ex. Parents of childrn dying of cancer have been shown to hypersecrete glucocorticoids (clearly a stressful situation). However, some parents secrete much higher levels of glucocorticoids than others. Why? It appears that parents with certain coping strategies had lower levels of glucocortocoids: 1) religious backgroun, 2) ability to ignore facts of the disease, and 3) an ability to lose themselves in the details of managing the disease. These responses can be viewed in terms of taking control--prayer, reaching out to others with similar experiences (social support network) and also learning what’s next--predictability. Stress-Response