Stress

SNS is stimulated by

"emergency" situations

Four main types of adrenergic receptors

(α1, α2, β1, β2, β3)

Amygdala

- processing/regulation of emotion; mediating affectively influenced memories detects threats, mounts physiological and behavioral responses to avoid threats (with its direct and indirect connections to the PVN), establishes memories to predict and respond appropriately to future threats

Cells in the paraventricular nucleus (PVN) of the hypothalamus regulate this system

ANS response

Adrenal Gland

Adrenal cortex •80% of mass of adrenal gland •Stimulated by ACTH, produces adrenocorticoids - Glucocorticoids (e.g., cortisol): glucose metabolism, anti-inflammatory, stress response, synthetic glucocorticoids - Mineralocorticoids (e.g., aldosterone): controls ion concentrations (e.g. Na and K) in body, controls urine production - Sex steroids: androstenedione, secondary sexual characteristics

why does prolonged stress play a role in other inflammatory diseases

Because inflammation plays a role in progression of multiple diseases, this model not only provides an explanation for the increased risk for [upper respiratory infections] under stress, but might provide a more general explanation

List of tropic hormones released by pituitary

CRH -> ACTH*** GnRH ->FSH/LH TRH->TSH, prolactin, GH

how do organs and built-in reflexes maintain homeostasis

Can regulate themselves without higher levels of control required

Chronic stress has also been associated with various physical conditions

Cardiovascular disease, diabetes, autoimmune diseases, upper respiratory infections, poorer wound healing

how does the brain stem maintain homeostasis

Helps regulate organs via automatic outputs & reflex centers

Role of Hypothalamus in Homeostasis

Hypothalamic bi-directional (and a couple of efferent-only) connections with limbic system structures and brainstem help to maintain homeostasis via control of the autonomic nervous system (ANS) and endocrine system (HPA) •Control of blood pressure and electrolyte system •Regulate body temperature •Regulate metabolic rate and energy metabolism •Controls reproductive processes •Drives physiological and behavioral aspects of stress response

The PFC can also regulate the

LC activity (therefore regulating its own NE inputs)

working memory processes are related to

NE in an inverted-U form

how do higher brain centers maintain homeostasis

Obtain information from our external world that can be used to alter hypothalamic brain stem activity

Combination therapy

Pharmacological agents can produce "windows of plasticity" that then facilitate behavioral interventions (McEwen et al., 2015)

____________ are activated, and responses are produced to manage physical and psychological challenges

Physiological resources

how do autonomic nervous system and endocrine system maintain homeostasis

Provide communication from the CNS to individual organs

how do hypothalamus maintain homeostasis

Regulates ANS & endocrine messaging Coordinates actions of brain stem autonomic nuclei

other CNS structures are involved with ANS activity

SNS & PSN

Homeostasis

Tendency to maintain a stable internal environment

____________ contains the most prominent group of noradrenergic neurons (although groups of NE neurons can be found in other areas of the Pons and Medulla)

The Locus Coeruleus

General Adaptation Syndrome

Three stages of physiological reactions to noxious events: alarm, resistance, and exhaustion (depletion of physical defenses against stress leading to high blood pressure, heart disease, etc.)

Primarily excitatory/stimulatory receptor s

a1 & b1

primarily inhibitory receptors

a2, b2, b3

Prolonged anxiety/anticipation can raise

allostatic load

The stress response is meant to serve as

an adaptive process

Pituitary

anterior pituitary - Relatively slower and more prolonged response to a stressor Releasing hormones from hypothalamus Secretion into capillaries Stimulation of pituitary cells - Release their hormones into bloodstream

β3 receptors

associated with body weight regulation

β2 receptors

associated with smooth muscle relaxation in lungs, uterus, bladder, GI tract, breaking down glycogen into glucose in liver

Chronic stress exposure produces _________________ in amygdala

branching of dendrites

other hormones secreted during stress response- ENDORPHINS

by anterior pituitary help regulate pain perception and reproductive physiology

other hormones secreted during stress response- GLUCAGON

by pancreas regulates carbohydrate dispersion

other hormones secreted during stress response- VASOPRESSIN

by posterior pituitary regulates kidney function and water volume

other hormones secreted during stress response- THYROXINE

by thyroid gland regulates cell metabolism (how much oxygen cells use and transforming glucose and oxygen into energy) and enhances the body's sensitivity to the catecholamines

In humans, these responses are complex and incorporate many neural circuits in the

cortex, midbrain, and brainstem

under chronic stress conditions

deleterious physiological and psychological consequences can arise

Hypothalamus and these other structures are interconnected via

different pathways

•DMPFC is associated with

error monitoring and reality testing

Hippocampus and PFC important in

fear extinction ex_ •People with PTSD who show deficits in extinction show reduced activity of the hippocampus and VM PFC

•Cortisol helps to ready the body for action in

fight-or-flight response. Receptors for cortisol are found throughout the brain and body

Individuals with low anxiety exhibit greater ________ _________ between mPFC and amygdala

functional connectivity

_____ drive the function of stress-modulating molecules

genes ex) •A gene encoding a serotonin transporter is related to trait anxiety in humans (Caspi et al., 2010) •A single-nucleotide polymorphism in a gene linked to an enzyme that regulates anandamide (FAAH) is associated with enhanced fear extinction and lower scores on PTSD-risk traits in healthy participants (this phenotype is associated to rapid habituation to threat in the amygdala) (Dincheva, 2015; Gunduz-Cinar, et al., 20130; Hariri, et al., 2009) •No definitive genetic markers that can predict whether someone will develop a stress-related disorder have been identified yet

•rIPFC inhibits

inappropriate motor responses

anxiety is associated with _______________________ from PFC to amygdala, possibly due to reduced ability to evaluate emotional meaning of stressors

ineffective top-down inhibition

Hippocampus

learning, memory encoding/consolidation, spatial navigation encodes complex contextual environmental information that is associated with threat; serves as a source of negative feedback to the HPA axis via glucocorticoid receptors

Locus Coeruleus

many functions, including arousal, vigilance, and attention LC plays important role in PFC function

Holmes and Rahe (1967; Social Readjustment Rating Scale) major life events were followed by

medical visits and hospitalizations •Too many events could leave someone vulnerable to infection, disease, illness, disability, death Correlations between number of events and poor health outcomes were not of great magnitude (.10 to .35)

Hyperactivity of amygdala predicts

mood and anxiety responses to stressors (e.g., new job, moving) up to 4 years later

•Glucocorticoid receptor (GR) resistance may be a result of chronic stress, thus GR resistance may lead to

poor control over inflammatory responses and greater expression of disease symptoms

Direct connections between PFC regions and amygdala as well as pathways that include other limbic structures have been associated with

reappraisal of stressful stimuli, with weaker connections in those with trait anxiety

Under normal conditions, cortisol released as a result of HPA activation serves to

reduce immune response and related inflammation; chronic stress conditions impair this response

other hormones secreted during stress response- PROLACTIN

released by anterior pituitary regulates reproductive physiology; role in stress response not well understood - perhaps regulates/fine-tunes stress response or buffers immunosuppression of stress response

•Prolonged anxiety/anticipation can lead to

risky health behaviors (e.g., overeating, substance use) or health-promoting behaviors (e.g., physical exercise) that can alter allostatic load

NE neurons

silent or produce very low tonic firing during sleep increase in tonic and phasic firing during stimulus exposure in non-stress awake conditions and high tonic and dysregulated phasic firing during stress exposure (fire to relevant stimuli during alert waking but will fire to irrelevant stimuli during stress)

Smaller amygdala gray matter volume may predispose

soldiers to PTSD

Chronic stress exposure will lead to _________ changes in the hippocampus

structural

Chronic stress produces ___________ _______ in PFC neurons (as early as one week of stress exposure); reduction in dendrite length, branching and density of spines

structural changes

•VMPFC has extensive connections with

subcortical structures (e.g., hypothalamus. amygdala) and regulates emotional responses

learned fear responses is associated with

the amygdala

allostatic load

the prolonged effects ("wear and tear") of chronic stress due to sustained elevated glucocorticoid levels

NE release increases in the PFC during exposure

to acute stress

•Both SNS and PNS pathways consist of

two nerve sequences •Presynaptic nerves begin in CNS, travel down spinal cord, transmit information to postsynaptic nerves •Generally postsynaptic nerves convey information to effector tissue/organs

•DLPFC connects extensively with sensory and motor cortices; regulates attention, thought and action

with sensory and motor cortices; regulates attention, thought and action

Rates of psychological and physical problems are disproportionately higher among

women, Blacks, Hispanics, lower SES groups

Optimal amount of NE (alert, non-stressed) enhances

working memory

Excess NE (or too little) impairs

working memory (partially mediated by binding to lower affinity alpha1 and beta1 receptors)

what serves as buffers to the effects of stress on health

•A sense of control/mastery, high self-esteem, and social support

Social relationships/networking/support interventions

•Allostatic load (as defined by a summary measure of physiological activity) negatively correlated with social integration and social support •Experience Corps improves prefrontal cortex blood flow, enhances executive function and overall health (Carlson et al., 2009) •Effects of social buffering in early life and beyond are associated with better regulation of HPA activity, neural activity in areas such as amygdala and PFC, and volumetric size of areas such as the hippocampus (Hostinar & Gunnar, 2015) •Social support/social integration are negatively correlated with inflammatory biomarkers (Uchino et al., 2018) •Perceived social support has been identified as an important factor in anxiety and depression across many different medical and psychiatric groups

Physical activity interventions

•Animal models show physical activity can increase expression of neurotrophic growth factors in cortex/hippocampus, improves memory, reduces behavioral manifestations of depression (Phillips, 2017) •Humans show increases in hippocampal volume after one year of aerobic exercise training (Erickson et al., 2011); gray matter volume in prefrontal cortex and temporal cortex and increased blood volume in middle-aged adults is associated with physical activity (Erickson et al., 2014) •Increased physical activity reduces proinflammatory biomarkers (e.g., CRP, inflammatory cytokines) and is associated with reduced risk of diabetes, cardiovascular diseases, cancer, dementia and depression (Gleeson et al., 2011) •Physical activity can be an effective intervention in the treatment of anxiety and anxiety disorders with various physiological/psychological mechanisms of action serving as proposed ways in which exercise is effective (Kandola et al., 2018)

tx for anxiety disorders

•Benzodiazepines - target the GABA receptors found in the amygdala •Not appropriate for long-term treatment of anxiety •SSRIs and CBT (e.g., fluvoxamine for panic disorder) •D-cycloserine (DCS, a partial agonist for glutamate) has been found to augment effects of psychological interventions for anxiety disorders (Moskow et al. 2020) •Low and isolated dosing (timed before exposure session); it works not because of anxiolytic effects but because it enhances the consolidation of learning that takes place during early treatment sessions •May enhance reconsolidation of fear memory if session ends with high levels of fear

Stress is ubiquitous and the stress response is necessary why?

•Cluster of physiological changes associated with real or perceived threat •All organisms face adversity, unpredictability and hostile environments •To survive, all organisms must find ways to manage and adapt to these challenges in order to maintain homeostasis •The stress response is a universal biological response

Communications To/From Hypothalamus - neuroendocrine system

•Control of endocrine functions via neural activation and the bloodstream

prolonged effects of stress response

•Cortisol, vasopressin, thyroxine, etc. (minutes, hours, days...even weeks) •HPA axis, hypothalamus/posterior pituitary, hypothalamus/thyroid gland)

SNS has several components that allow for response changes directed from the CNS

•Descending autonomic nerve fibers from hypothalamus and brainstem exit at specific levels of spinal column and travel to autonomic ganglia outside of the spinal cord (aka preganglionic fibers) •Primary neurotransmitter released by preganglionic fibers is acetylcholine . •Postganglionic fibers travel from autonomic ganglia to target tissue/organs. •The primary neurotransmitter released by postganglionic fibers is norepinephrine. - Neuroeffector junctions are located at points where postganglionic fibers communicate with organs or tissue where NE is released (therefore neuron communicating with smooth muscle cell, cardiac muscle cell or endocrine cell).

Stress-related disease

•Disease occurs when stress response is of a chronic nature and when not activated for a physiological reason •Selye's General Adaptation Syndrome: alarm, resistance, exhaustion •McEwen's concept of allostatic load

how does the amygdala activate the stress pathways

•Indirectly increases the amount of NE in the PFC thereby dysregulating PFC function (e.g., higher order functions such as attention regulation and working memory). This sensitizes further the amygdala to threatening stimuli. •"Attention switches from 'top-down' control by the PFC that is based on what is most relevant to the task at hand to 'bottom-up' control by the sensory cortices, whereby the salience of the stimulus captures our attention" During stress reduced and dysregulated PFC function limits the ability to respond slowly and thoughtfully. Instead, we have amygdala activity driving "rapid and reflexive emotional responses"

•But physical stressors are not only stressful to the extent they cause emotional arousal other pertinent factors include

•Lack of control •Unpredictability •Access to outlets for frustration •Level of intelligence •Dominance factor •Poverty Genetics

Mindfulness-based Stress Reduction

•MBSR is associated with increased gray matter density in the hippocampus and PFC, among other brain areas (Tang, Hozel, & Posner (2015) •In individuals with GAD, MBSR reduces amygdala activation in response to neutral faces and increases activation in VLPFC; amygdala-PFC connectivity shifted with enhanced/positive coupling of frontolimbic pathways (Hozel et al., 2013) •MBSR is associated with reductions in various inflammatory biomarkers (Meyer et al., 2019, Reive, 2019) •MBSR reduces anxiety and depression in non-clinical populations (Khoury et al., 2015) and clinical populations (Arch et al., 2013)

Immediate Effects of stress response

•Norepinephrine from the SNS (2-3 seconds) •Organs and muscles innervated by pons (LC), hypothalamus via SNS

intermediate effects of stress response

•Norepinephrine from the SNS (2-3 seconds) •Organs and muscles innervated by pons (LC), hypothalamus via SNS

Evidence suggests that differential exposure to chronic stress among these groups may explain the inequalities in health that exist

•Older Black adults exhibit higher levels of systemic inflammation and metabolic dysregulation as compared to Whites ("weathering") •Blacks experience more cumulative stress burden than Whites •Prospective support for stress linked to greater health risk •Stress exposure mediated differences in producing racial differences in CRP, and less so in metabolic risk •Discriminatory experiences contribute further to poor health •"Stress proliferation" cross sectionally, across the life span, and across generations •Factors that are considered stress buffers are generally found in lower levels in disadvantaged group members

Parasympathetic Nervous System

•PNS involved with maintenance functions (e.g., digestion, breathing, slow heart rate) •PNS sends fibers to target organs by way of cranial nerves arising form the brainstem and by way of the sacral segment of the spinal cord. •No chain of ganglia located near spinal cord. Instead, ganglia are located close to (or inside) target organs. These ganglia are isolated from one another. •Different to SNS in that these fibers do not work in concert as sympathetic fibers do •Preganglionic and postganglionic fibers release Ach.

Communications To/From Hypothalamus - limbic system

•Paths associated with control and expression of emotions (also learning and reproductive behaviors)

•Exceptions to this path:

•Preganglionic fibers go directly to the adrenal medulla (without first synapsing at a sympathetic ganglion). These fibers release Ach at adrenal medulla. Cholinergic stimulation causes adrenal medulla to secrete epinephrine and norepinephrine (the latter in much smaller quantities) into the bloodstream •Preganglionic fibers also go directly to sweat glands on feet and palms where Ach causes them to produce sweat.

Treatment for PTSD

•Prevention: Low glucocorticoid levels at the time of a trauma increase the probability of PTSD symptoms •Single dose within 6 hours of traumatic even can reduce acute stress and PTSD symptoms in humans and administration in rats after stressor produces changes in hippocampal dendrites, dendritic length and dendritic spine density (Zohar et al. 2011) •Provides additional negative feedback to the HPA axis to reduce its activity •Blocking catecholamine stress hormones and enhancing GABAergic activity immediately following a trauma was also found to be helpful •Psychotherapy can alter activation of amygdala, PFC, hippocampus •Pharmacotherapy can increase hippocampal volume •Transcranial magnetic stimulation of PFC can reduce PTSD symptoms •

PTSD has associated with brain abnormalities in the amygdala and a reduction in volume of the hippocampus

•Reduction in hippocampal volume may develop prior to stress exposure due to expression of various genes or psychosocial variables •Hippocampal damage observed in war veterans •Smaller hippocampus is associated with more severe PTSD •Poor contextual discrimination in smaller hippocampus •Greater activation of amygdala when seeing faces with fearful expressions and less activation of the PFC •*Remember individual differences; not all studies support these changes

how does the ANS drive the acute physiological responses to a stressor

•Sympathetic and parasympathetic branches of ANS exert opposing effects; they are "tonically" active -- each provide some degree of input at all times (neither system is ever fully "turned off"). Generally, SNS and PNS actions seen as opposing each other. •Brainstem nuclei coordinate activity in such a way so that increased activity in one branch inhibits activity in the other.

Under stress conditions

•The amygdala activates the stress pathways

Under non-stress conditions

•Various areas of the PRC regulate emotions, thoughts, and behaviors. These areas connect with other structures to regulate responses and behaviors and with connect with each other to regulate decision-making, planning and organizing.

α1 receptors

•Vascular smooth muscle contractions (increased blood pressure), constriction of muscle in bladder wall (reduced urinary flow), constriction of specialized muscles in iris (pupil dilation)

Communications To/From Hypothalamus - sensory, autonomic, & cortical circuits

•Visceral and somatosensory afferents provide sensory and pain information to different hypothalamic nuclei •Noradrenergic and serotonergic afferents from brainstem nuclei modulate neuroendocrine functions •Hypothalamic efferents to ANS control fight/flight response and parasympathetic functions •Efferents to areas of frontal cortex and insula associated with control of motivation

Bruce McEwen

•allostatic load •Effects of chronic stress on hippocampal neurons •Later in career, effects of the stress on communities and chronic stress' impact on marginalized people

α2 receptors

•as autoreceptors inhibit release of NE, as heteroreceptors they inhibit ACh release inhibit release of insulin from pancreatic cells

β1 receptors

•associated with increased rate and contractile force of heart, relaxation of GI tract, aggregation of platelets

Prefrontal Cortex

•complex "human behaviors"; executive functions (planning, decision-making, problem-solving, goal-directed behaviors, self-control)

Walter Cannon (1920s)

•homeostasis (physiological mechanisms constantly maintain the internal balance via feedback loops) •Went beyond physiological stress; psychological stress could threaten homeostasis also •Described "fight-or-flight" responses that engage the sympathoadrenal system to produce physiological changes that preserve the internal environment and enhance survival

Claude Bernard (1860s)

•milieu interieur (organisms maintain a constant environment) •This environment is carefully regulated •The organism compensates in ways to maintain that balance

Hans Selye (1970s)

•redefined stress as "the nonspecific response of the body to any demand upon it" •Identified the HPA axis •Recognized the potentially deleterious effects of chronic stress though his General Adaptation Syndrome model

anxiety disorders lead to overactivity of the amygdala (closely resembles the fear response) with concomitant decreased activation of PFC areas

•vmPFC typically provides an inhibitory response once the stimulus is no longer threatening •Hippocampus usually provides information about the context - dysfunction can result in poor contextual stimulus discrimination with subsequent overgeneralized fear responding