Stress doesn’t just feel bad—it speeds up aging. At the heart of this process lies the CRH/ACTH/glucocorticoids axis, a feedback loop that keeps stress hormones in check. The brain triggers glucocorticoid release indirectly through CRH (from the hypothalamus) and ACTH (from the pituitary). To decide whether to keep pumping out CRH, the brain monitors circulating glucocorticoid levels against a set point. If levels dip low, CRH secretion continues; once they hit the set point, negative feedback kicks in, halting CRH. The hippocampus plays a starring role in this inhibition, sensing glucocorticoid levels to dial things back.
Psychological factors can tweak this stress response. Humans handle stress better with outlets for frustration—we’re cerebral enough to even imagine them for relief. Social support is key: a lone primate in a tough spot mounts a stress response, but with strangers, it worsens; with friends, it shrinks. Having a shoulder to cry on, a hand to hold, or someone to say “it’ll be okay” builds resilience through social networks.
Predictability and control matter too. Repeated stressors lead to habituation—a familiar one triggers a milder response, even if it still disrupts balance. Lack of control ramps up stress, often more than the stressor itself; earning rewards through control feels better than getting them for free. These elements intertwine: losing predictability or control, lacking outlets or support, or sensing things worsening can ignite or amplify stress on their own.
Everyday “blues” pass quickly, but major depression is different—chronic (lasting two weeks or more) and marked by anhedonia, the inability to feel pleasure (dysphoria’s opposite of hedonism’s pleasure chase). It collapses positive emotions while flooding with negatives like grief and guilt. Worldwide, it drives 800,000 suicides yearly. Psychomotor retardation slows movement and speech, demanding huge effort for basics—severely depressed people rarely suicide because they lack energy to even get out of bed.
Vegetative symptoms hit hard: reduced diet, less sleep, disrupted patterns. Some subtypes cycle rhythmically, like manic-depressive swings—manic for days, deeply depressed for a week, then symptom-free, repeating.
Neurochemistry and Treatments
Depression disrupts norepinephrine, serotonin, and dopamine. After signaling, neurotransmitters face reuptake (recycling into axons) or synaptic degradation (flushed via cerebrospinal fluid to blood to urea).
Tricyclic antidepressants block reuptake, prolonging these chemicals’ effects. MAO inhibitors stop degradation by blocking monoamine oxidase, hitting all three systems—making it tricky to pinpoint depression’s main culprit.
All major antidepressants—SSRIs, tricyclics, MAOIs—target these neurotransmitters. ECT (electroconvulsive therapy) helps by reducing norepinephrine autoreceptors. Substance P, a pain-related neurotransmitter activating spinal pathways, shows promise; blockers act as antidepressants in some.
The locus coeruleus (“blue spot”) synthesizes norepinephrine, projecting diffusely via the reticular activating system to alert the brain. Stress or panic revs it up; shortages cause psychomotor retardation.
Brain Regions and Hormonal Links
Core regions like the hypothalamus manage breathing, heart rate, and stress responses (e.g., blood pressure drops trigger it with midbrain/hindbrain). The limbic system layers on emotion.
Depression can stem from the cortex’s abstract negative thoughts convincing the brain they’re as real as physical threats. Surgeries like cingulotomy sever the cingulum bundle, disconnecting the anterior cingulate cortex (ACC)—a hub for negative emotions and pain of all kinds.
Left prefrontal cortex activation links to positive moods; right to negative. Women face risks from hormonal shifts (e.g., birth control pills altering estrogen/progesterone), which tweak neurotransmitter metabolism like epinephrine, norepinephrine, and serotonin.
In depression, glucocorticoid feedback fails—the brain doesn’t sense high levels to stop CRH, letting stress hormones rage.
Everyday stressors mimic depression’s neurochemical shifts and symptoms, but we rebound with built-in recovery. Severe, unrelenting stress overwhelms these mechanisms, plunging anyone into despair.
Source : Why Zebras Don’t Get Ulcers by Robert M. Sapolsky
Goodreads : https://www.goodreads.com/book/show/327.Why_Zebras_Don_t_Get_Ulcers
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Thinking Beyond Science 
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