Lecture 21 Stress

Lecture Summary: Stress and the Brain

Goals

  • Explore the stress response and its dual nature (adaptive vs. maladaptive).
  • Understand the Hypothalamus-Pituitary-Adrenal (HPA) axis and its neural control.
  • Investigate the roles of glucocorticoid and mineralocorticoid receptors in stress responses.
  • Examine the effects of chronic stress on the hippocampus, amygdala, and medial prefrontal cortex (mPFC).
  • Discuss epigenetics and its influence on stress and neurogenesis.

What is Stress?

Stress is a physiological and psychological response to perceived threats or challenges. The body engages in the fight-or-flight response, mediated by the HPA axis and the autonomic nervous system.

Adaptive vs. Maladaptive Stress

  • Short-Term (Acute Stress):
    • Mobilizes energy (e.g., increased glucose in blood).
    • Enhances attention and memory for critical events.
    • Supports survival by activating fight-or-flight systems.
  • Long-Term (Chronic Stress):
    • Prolonged activation of stress pathways leads to wear and tear (allostatic load).
    • Contributes to cardiovascular disease, diabetes, neurodegeneration, and emotional dysregulation.

Hypothalamus-Pituitary-Adrenal (HPA) Axis

Sequence of Activation

  1. Hypothalamus (PVN):
    • Releases corticotropin-releasing factor (CRF).
  2. Anterior Pituitary:
    • CRF stimulates the release of adrenocorticotropic hormone (ACTH) into the bloodstream.
  3. Adrenal Gland:
    • ACTH triggers the adrenal cortex to release glucocorticoids (e.g., cortisol) and the adrenal medulla to release epinephrine.

Brain Control of the HPA Axis

  • Amygdala: Activates the HPA axis, initiating stress responses.
  • Hippocampus: Detects rising cortisol levels and provides negative feedback to inhibit the HPA axis.
  • Medial Prefrontal Cortex (mPFC): Modulates the amygdala and hippocampus to help regulate stress responses.

Glucocorticoid and Mineralocorticoid Receptors

Overview

Cortisol binds to two main receptor types in the brain, enabling a broad range of responses to stress.

  1. Mineralocorticoid Receptors (MRs):
    • High Affinity: Activated at low cortisol concentrations, such as during non-stressful conditions.
    • Found predominantly in the hippocampus.
    • Regulate baseline activity of the HPA axis and maintain homeostasis.
  2. Glucocorticoid Receptors (GRs):
    • Low Affinity: Activated only at high cortisol concentrations, such as during acute or chronic stress.
    • Widely distributed in the brain, including the hippocampus, amygdala, and mPFC.
    • Mediate the stress response and adapt physiology to cope with high-demand situations.

Functional Mechanisms

  • Genomic Pathway (Cytosolic Receptors):
    • Both MRs and GRs are located in the cytosol of neurons and translocate to the nucleus upon activation.
    • Inside the nucleus, they regulate gene expression by acting on DNA, leading to the production of stress-related proteins.
    • Genomic effects are slow, taking hours to days to manifest.
  • Non-Genomic Pathway (Membrane Receptors):
    • Rapid effects occur through membrane-bound receptors.
    • These receptors initiate intracellular signaling cascades, influencing neuronal activity and synaptic plasticity in seconds to minutes.

Temporal Dynamics

  • MRs operate continuously under low cortisol levels, maintaining stability and supporting memory.
  • GRs are activated during stress, enhancing memory for critical events and adapting physiology for immediate survival needs.

Effects of Chronic Stress on the Brain

Hippocampus

  • Role: Memory formation and HPA axis regulation.
  • Effects:
    • Chronic stress suppresses neurogenesis and leads to dendritic retraction, reducing hippocampal volume.
    • High cortisol disrupts glucose metabolism, increasing vulnerability to metabolic challenges and excitotoxicity.
    • Hippocampal damage impairs memory and diminishes inhibitory control over the HPA axis.

Amygdala

  • Role: Emotional processing and HPA axis activation.
  • Effects:
    • Chronic stress increases dendritic branching and synaptic connectivity in the basolateral amygdala.
    • Heightened amygdala activity contributes to hypervigilance and emotional dysregulation.
    • Stress-induced amygdala overactivity is implicated in anxiety disorders and PTSD.

Medial Prefrontal Cortex (mPFC)

  • Role: Executive control and emotional regulation.
  • Effects:
    • Chronic stress reduces dendritic complexity and synaptic plasticity in the mPFC.
    • Impaired mPFC function weakens inhibitory control over the amygdala and HPA axis, exacerbating stress reactivity.

Epigenetics and Stress

  • Definition: Modifications to gene expression caused by environmental factors without altering DNA sequences.
  • Mechanisms:
    • DNA Methylation: Silences specific genes.
    • Histone Modification: Alters chromatin accessibility.
    • MicroRNAs: Regulate gene expression post-transcription.
  • Notable Studies:
    • Rat Pup Study:
      • High maternal care increases hippocampal glucocorticoid receptor expression, leading to better stress regulation in offspring.
    • Human Suicide Study:
      • Childhood abuse is linked to reduced glucocorticoid receptor expression in the hippocampus, showing long-term epigenetic effects.

Stress and Memory

  • Glucocorticoid Effects:
    • Enhance memory for stressful events by strengthening synaptic connections (short-term, non-genomic effects).
    • Suppress new memory formation post-stress to prevent interference with the consolidation of critical events.
  • Attention and Learning:
    • Cortisol increases attentional focus during stress, prioritizing critical information.
    • Chronic stress impairs memory flexibility and reduces the ability to adapt to new learning.

Applications and Ethical Considerations

  • Therapeutic Strategies:
    • Targeting GRs and MRs to regulate stress responses.
    • Combining mindfulness, therapy, and pharmacological interventions.
  • Ethical Concerns:
    • Manipulating stress pathways for clinical purposes requires caution to avoid long-term adverse effects on neuroplasticity and emotional health.

Key Terms

  • HPA Axis: Central stress response system involving the hypothalamus, pituitary, and adrenal glands.
  • Mineralocorticoid Receptors (MRs): High-affinity cortisol receptors active at baseline conditions.
  • Glucocorticoid Receptors (GRs): Low-affinity receptors activated during stress.
  • Neurogenesis: Formation of new neurons, particularly in the hippocampus.
  • Epigenetics: Environmental regulation of gene expression.

This lecture detailed the physiological, molecular, and neurobiological mechanisms of stress, emphasizing both adaptive and maladaptive outcomes. The discussion on glucocorticoid and mineralocorticoid receptors provided insights into how cortisol mediates its effects on the brain and body.

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