Stress and Stress related disorders

• Early life stress....


  Predicts mental illness later in life, e.g., developmental stress in 1st/ 2nd trimester has profound effects in the developing nervous system
• Seyle 


  Stress underpins non-specific signs and symptoms of illness. Later discovered chronic stress leads to a triad of symptoms (enlargement of adrenal glands, atrophy of lymphatic system, and peptic ulcers.
• Allostasis: 


  Dynamically changing 'set point' in anticipation of changing demands.
• 3 stages of the Pituitary adrenal axis:

  1. Alarm phase
  2. Resistance phase
  3. Exhaustion phase
• Alarm phase: 


  Exposure to acute stress causes adrenaline and noradrenaline to be released into bloodstream from Adrenal Medulla. Adrenaline raises the pulse, and noradrenaline increases blood pressure, both increase breathing and inhibit digestion.
• Resistance Phase: 


  Activation of the pituitary-adrenal axis triggers the release of corticotrophin-releasing hormone (CRH), particularly in the amygdala and hypothalamic paraventricular nucleus (PVN), influencing stress responses.

  CRH increases adrenocorticotropic hormone (ACTH) secretion from the pituitary, which then prompts the adrenal cortex to release cortisol and other corticosteroids, preparing the body for 'fight or flight,' while also providing feedback to regulate further hormone release.
• Exhaustion phase: 


  When stress is chronic, HPA system doesn't go back to baseline causing a pathological state of exhaustion.

  Exhaustion can cause tissue inflammation, increased susceptibility to infection, and impaired cognitive performance.
• Finsterwald and Alberini (2014)

  Animal study showing that exposure to chronic stress or interference with glucocorticoid receptors impairs learning and memory.

  Moderate stress has a positive effect on memory (specifically in the long-term formation of memories) which enables the organism to face similar stressors again.
• Coping responses: 


  Perceiving threat triggers coping responses, including attempts to escape, sympathetic activation, and adrenal activity, leading to changes in central nervous system activity.

  These responses aim to maintain homeostasis, they can exacerbate stress and eventually cause exhaustion if stress persists.

  Neural mechanisms of coping responses in humans involves various systems such as the prefrontal cortex for behavioral control, the amygdala and hypothalamus for emotional regulation, and the mesolimbic dopamine system for reward sensitivity- but not fully understood
• Neurotransmitter arousal systems: 


  Brain stem, pons and medullary regions are characterised with noradrenergic, serotonergic and dopaminergic components.

  Cholinergic systems originate in the basal forebrain and brainstem, and its function could be for thalamo-cortical arousal.
• Central noradrenergic systems and arousal:

  Arrises from the pontine locus coeruleus (LC) as well as neurocortex, hippocampus, and hypothalamus. Organisation features suggest its likely has functions of bifurcating axons which supply hippocampus with nerves, also responds to the sleep-wake cycle, changes in cortical EEG, and stressors first elevate NA release causing moderate to severe depletion, if stress is chronic and inescapable.
• What are the consequences of noradrenergic locus coeruleus?


  Noradrenaline enhances the signal-to-noise ratio, as well as modifying/ modulating responses of neurotransmitters from other inputs in a conditional way. Generally happens in one of two ways:

  1. Noradrenaline is inhibitory, and enhances signal-to-noise ratio in sensory regions of neocortex.
  2. Concurrent Noradrenaline, enhances inhibitory response and so when paired with a stimulus becomes salient, meaning excitatory responses in hippocampus were exaggerated, amplifying effect of CS (Segal and Bloom).
• Dopamine neuromodulatory system: 


  Mainly supplies nerves to anterior cortex and is associated with working memory, in basal ganglia it's associated with motor initiation, habit-based learning, and incentive motivation.
• Cohen et al (1993)

  Suggest that dopamine, like noradrenaline, increases signal-to-noise ratios but in own regions- e.g., basal ganglia.
• Arnesten: 


  Beneficial effects from stress probably come from: improved attentional selection, alertness, and enhanced prefrontal cortical functioning.
• Rodrigues et al (2009)


  When stress is prologued and intense, prefrontal networks are supressed causing bottom-up amygdala based processes which exacerbate the stress response.
• Dalley et al (2001) 


  Noradrenaline has a specified role in detection of 'unexpected uncertainty'. So when alarm phase of stress occurs, noradrenaline signals volatility in world, causing inhibition of slow to act prefrontal cortex functions for fast acting amygdala functions. Usually noradrenaline neurones are tuned to specific predictive environment of the world around you.
• Clark et al 


  Chronic, uncontrollable stress dramatically depletes serotonin, noradrenaline, and dopamine from many forebrain regions -> which could be the underlying mechanism for depression. Also interesting because it could explain rigid coping mechanisms to stress including impulsive aggression and cognitive inflexibility.

  X Lee and Han (2019)
• Lee and Han (2019)

  Effects of stress causing NA, 5-HT and DA depletion are not uniform across the brain, with an up-regulation in amygdala and other regions associated with stress.
• How does cortisol work?

  Cortisol binds to glucocorticoid receptors which is very common in Hippocampus and hypothalamus.

  Glucocorticoid receptors are ligand activated transcription factors which when bound with cortisol moves to nucleus when're is affects transcription and function of many different genes.

  Cortisol-Glucocorticoid receptor complex can also bind to glucocorticoid response elements which affect gene transcription and translation causing epigenetic modifications.
• Glucocorticoids how do they work?

  Mainly cause changes in DNA methylation, as well as inducing histone modifications, promoting dynamic remodelling of the chromatin which alters the avalibility of glucocorticoid binding sites to gene transcriptional processes.

  Glucocorticoids will wither activate genes involved in stress-induced immune and metabolic responses (transactivation). Or it will repress genes by inhibiting certain transcription factors (transrepression).
• When are the most sensitive periods of stress induced epigenetic modifications?

  Prenatally and in early childhood - but can occur in any point in life.
• Stress-induced epigenetic effects in prenatal period:

  Glucocorticoids cross the placenta where profound changes are made to DNA methylation and histone Acetylation.

  Also believed prenatal stress causes 'stress memories' which are cumulative and persist throughout adulthood.

  Epigenetic marks are not diluted by neurogenesis because the two regions which neurogenesis affects are not 'powerful' enough to counter stress-induced plasticity in PFC and limbic amygdala circuitry.
• Social isolation stress is characterised by:

  Associated with increased dopamine neurotransmission throughout the brain meaning that early life social isolation can cause susceptibility to brain dopamine systems.
• Virdee et al (2014)

  Rat pups born to mothers who were exposed to a low does of synthetic glucocorticoids during embryonic days 16-19, showed massive increases to the number and density of dopamine neurones in substantial nigra and ventral tegmental area.
• Stress early in embryonic stage....

  decreases novelty-stress induced hyperactivity in female rats, causing anhedonia and depression. Suggesting early embryonic exposure to stress causes sex differences in dopamine systems and has different impacts depending on the developmental stages.
• Repeated maternal separation stress:

  To model psychosocial stress, young rat pups (2-5 days old) are separated from their mothers, until the start of adolescence (~18 days old). Findings show that separation causes activation in peripheral and central immune systems causing depression-relevant phenotypes including apathy and fatigue.

  Cambridge researchers have found that there's amygdala expansion in rats exposed to social isolation using above method. Showing early adversity has plasticity effects on the brain and affects how later life stressors affect brain systems.
• Roth et al (2009)


  Exposing infant rats to 'stressed and abusive' mothers causes reduced methylation status in brain-derived neurotrophic factor (BDNF) compared to pups with caring mothers.

  Reduced BDNF in PFC was transmitted to the next generation, but could be reversed by a DNA methylation inhibitor.
• Van der Knapp et al (2015)

  Increased methylation of Glucocorticoid receptors is linked to prolongs stress-evoked cortisol responses in situations like public speaking.
• Klengel et al (2013) 


  FKBP5 is a protein which decreases cortisol affinity for glucocorticoid receptors. Polymorphisms of PKBP5 have been associated with more extensive de-methylation in people with a history of sexual and emotional abuse.
• Elliot et al

  Rats were segregated into 3 groups (control, stress susceptible group and stress-resilient group). Found stress-resilient group had reduced demethylation in Crf gene which controls a certain area of the hypothalamus which is crucial to the stress response.

  Animals with higher demethylation surrendered to social stress (aka spent less time in interaction zone interacting with other rats).
• Limbic system: what structures are included in it:

  Hypothalamus

  Hippocampus

  Cingulate cortex

  Limbic cortex

  Amygdala

  Striatum
• Limbic system 


  Previously believed to be an emotional 'system', but hippocampus is more associated with cognitive processes (e.g., learning and memory) and hypothalamus is and brainstem nuclei are important to mediate autonomic, endocrine, and reflective behavioural responses which characterise emotional behaviour.

  Striatum contains nucleus accumbent which is hypothesised to accumulate info and modulate it for the mesolimbic dopamine system.

  Amygdala is the only one associated with emotions.
• Gray's 3 major emotional systems:

  Approach -> conditioned stimuli for reward and non-punishment resulting in behaviour like approach learning and active avoidance.

  Behavioural inhibition -> Conditioned stimuli for punishment or non-reward resulting in passive avoidance and extinction.

  Fight/ Flight-> unconditioned punishment and non-reward resulting in unconditioned escape and defensive aggression.
• Gray's assertions on the emotional systems:

  1. There must be different systems for conditioned and unconditioned emotions because their responses to CSs are often different. Disinhibitory effects seen when extinction occurs is the behavioural inhibition system.
  2. Hope is relief, positive secondary reinforcers and removal of negative stimuli are equivalent.
  3. Anxiolytics e.g., Benzodiazepines impair the function of the behavioural inhibition system and release behaviour suppressed by anxiety or fear.
• How does Gray's system relate to the amygdala?

  Expression of anxiety, fear and panic depends on the perceived proximity of the threat. The more proximal the threat, the more amygdala involvement.

  Argued that the behavioural inhibitory system mediated between the Behavioural approach system and the fight/flight/freeze system under motivational conditions conflict and can be related to personality traits e.g., neuroticism.
• Barros-Loscertales et al (2006)

  Anxiety is related to increased perception of motivational conflict and threat causing bias to the behavioural inhibitory system and also seems to be correlated with increased hippocampus and amygdala volumes.
• Function of amygdala in fear and anxiety:

  Emotional learning, coordination of behavioural, endocrine and autonomic changes in emotional states, especially fear.

  In humans amygdala stimulation results in subjective feelings of fear and anxiety.
• Lesions to central nucleus or basolateral nuclei of amygdala causes: 


  Lesions to central nucleus or basolateral nuclei of amygdala prevents conditioned suppression, conditioned freezing and fear-potentiated startle and passive/ active avoidance behaviour via learning

  Lesions specific to central nucleus prevents conditioned changes to heart rate and other fear-related autonomic signs.
• LTP and the Amygdala: Miserendino et al (1990):

  Lateral amygdala undergoes long-term potentiation when frightening stimuli are learnt.

  And so NMDA antagonists impair LTP in amygdala in conditions which require fear conditioning.