Lecture 14: Chronic Stress and Depression Flashcards
What is stress?
- Stress is defined as the psychological and physiological responses generated in the face of, or in anticipation of, a perceived threat
- The body produces a very robust, non-specific response to each and every stressor
- Stress response can be considered an automatic (i.e. ANS) reaction to actively maintain physiological homeostasis.
What are stressors?
- Something that causes an organism to be stressed is called a stressor.
- Stressors:
- Stimulus that threatens an animal’s physiological homeostasis (e.g. exercise);
- Physical vs. psychological; bear vs exam stress
- Environmental vs. internal; bullied vs chronic illness
- Real vs. perceived;
- Predictability matters; unpredictable stressors are more potent than predictable ones
What is the fast response to stress?
– Sympathetic division of ANS produces “fight or flight” response;
– In the fight or flight response, the hypothalamus sends a neural message through the spinal cord
– the sympathetic division of the autonomic nervous system is activated to stimulate the adrenal medulla
– the adrenal medulla and locus coeruleus releases epinephrine into the circulatory system
– epinephrine activates the body’s cells, endocrine glands, and the brain (increased heart rate/breathing for burst of energy)
– Catecholamines, CRH, neurosteroids all released;
Increases vigilance, alertness, arousal and attention;
Facilitates spontaneous (automatic) behaviors related to fight or flight.
What is the slow response to stress?
- Mediated by glucocorticoids
- Controls “slow” changes throughout, and following, a stress response:
- Hypothalamic-Pituitary-Adrenal Axis (HPA axis);
- the hypothalamus (paraventricular nucleus) releases corticotropic releasing hormone (CRH) into the pituitary gland
- the anterior pituitary gland releases adrenocorticotropic hormone (ACTH) into the adrenal cortex to release cortisol
- cortisol activates the body’s cells, endocrine glands, and the brain
- Cortisol turns off insulin secretion to increase energy supply, promotes gluconeogenesis in the liver, turns off reproductive function, inhibits production of growth hormone, shuts off immune function, changes gene expression, increases blood pressure, decreases sensitivity to pain, consolidation of memories (related to stressor), preparation for future responses.
What is the POM-C gene?
–POM-C gene are turned on by the fast stress response (epinephrine released causes this gene to be transcribed). One of the things produced is ACTH which is needed in the slow response to stimulate cortisol
a-MSH (anorectic peptide) -makes you stop eating
B-endorphin -opioid, mutes afferent sensory information so you don’t feel pain
What are glucocorticoids?
– Glucocorticoids (GCs) are a form of steroid hormone that belong to the corticosteroid family.
– Gluco = glucose
– Cort = cortex
As the name implies, GCs regulate circulating glucose levels, and are synthesized in the adrenal cortex.
- Cortisol > humans
- Corticosterone > rodents
GCs bind to corticosteroid receptors which are expressed in many tissues
What are the two main types of corticosteroid receptors?
- Mineralocorticoid Receptor (MR)
- - Appraisal, initial (fast) stress response;
- - Important in gene transcription;
- - More sensitive to corticosteroids (~10X) - Glucocorticoid Receptor
- - Terminates stress response;
- - Increased sensitivity to corticosteroids during stress;
- - High density in the paraventricular nucleus of the hypothalamus (PVN)-where slow stress response is initiated- and hippocampus;
- - Promotes stressor-related memory storage.
- - Lower affinity for cortisol than the MR. This means that GR is preferentially activated by elevated cortisol levels
How do you terminate the stress response?
– Negative Feedback Loop turns off HPA axis
> cortisol stops secretion of CRH in paraventricular nucleus of the hypothalamus (PVN)
> cortisol travels back and binds to anterior pituitary to stop the release of ACTH
> Cortisol binding to and stimulating GR receptors in hippocampus inhibits hypothalamus (hippocampus has inhibitory effect on hypothalamus)
What is the maladaptive stress response?
Chronic stress can lead to a dysfunctional HPA axis and leads to detrimental changes. All of a sudden the stress response is working against us, rather than for us.
– Continuous mobilization of energy results in muscle wasting and fatigue;
– Growth hormone inhibition prevents body from growing/repairing itself;
– GI tract is shut off, therefore reduced food intake and processing of nutrients to replace spend resources;
– Reproductive functions are inhibited;
– Immune system is suppressed, therefore organism is vulnerable to infection/disease;
– Hypertension, Type-II diabetes, ulcers, etc.
The negative feedback loop becomes desensitized and therefore creates a vicious cycle.
What is chronic stress and how does it damage neurons
The hippocampus contains a high density of GRs
> Projects directly to the hypothalamus;
> Exerts control over HPA axis activity
Elevated cortisol stimulate GRs, and activates inhibitory projections to CRH neurons of the hypothalamus.
Chronically elevated cortisol levels overstimulate GRs and damage hippocampal neurons.
> Hippocampal cells eventually display atrophy (wasting away)
> Over time, damaged hippocampus loses control over the HPA axis;
> Hippocampal atrophy is closely related to depressive symptoms.
positive correlation between magnitude of hippocampal atrophy and the severity of depression symptoms
How is chronic stress related to depression?
Depression is associated with damaged hippocampal neurons
- GR and MR downregulation; hippocampus gets rid of these receptors from membrane because of overstimulation from chronic stress so they become less responsive to cortisol
- Reduced cell proliferation in the dentate gyrus of the hippocampus; one of the places involved in production of new neurons. You make new neurons when you learn and make memories, so this affects long-term potentiation
- Reduced 5-HT (serotonin) receptor function;
- Reduced long-term potentiation (learning, memory)
Serotonin appears to play a role in this process.
> Lack of serotonin is associated with hippocampal atrophy;
Anti-depressants increase growth factors in the hippocampus, correct the atrophy and alleviate depressive symptoms.
How do antidepressants work?
Antidepressants come in many different forms.
- Selective Serotonin Reuptake Inhibitors (SSRI) are commonly used to treat depressed patients with hypo-serotonergic function.
- Inhibit reuptake of serotonin;
- Increases serotonin availability in the synaptic cleft;
- Increases serotonin binding and neurotransmission.
SSRI’s have been effective at ameliorating depressive symptoms.
– Reduces depressive symptoms;
Takes weeks-to-months to have an effect, but why?
The hippocampus contains an abundance of serotonin receptors.
– Specifically, the 5-HT1A sub-type;
– 5-HT neurotransmission activates PKA (protein kinase A) signaling cascade which causes upregulation of brain derived neurotrophic factor (BDNF);
– thus, shriveled up neurons become nourished with serotonin. This takes time which is why depressive symptoms don’t go away immediately
Fluoxetine, and other SSRI’s, have been shown to increase hippocampal volume in patients who respond (symptomatically) to treatment.
