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Stress is a valuable evolutionary-conserved physiological response to threatening or adverse environments. Chronic stress is a pathological state that is caused by prolonged upregulation of the normal acute stress response. Anxiety disorders, such as phobias and post-traumatic stress disorder, are due to fear conditioning to a neutral stimulus and involve many of the same brain regions as stress.
The brain is the key organ in the response to stress. The hypothalamus and brainstem regions are essential for the autonomic and neuroendocrine stress response, and stress hormones produce both adaptive and maladaptive structural changes in these areas throughout life. The hippocampus, amygdala and prefrontal cortex (PFC) are also involved in stress and anxiety. They represent highly interconnected circuits that influence one another through direct and indirect neural activity.
There are numerous factors that predispose a person to chronic stress and anxiety. Early life experiences have a prolonged effect on human physiology and behavior. Genetic differences play an important role and different alleles of commonly occurring genes determine how individuals respond to stressful life experiences. For example, the short form of the serotonin receptor is associated with the development of chronic stress and predisposes to development of a subsequent depressive illness. The Val66Met allele of brain-derived neurotropic factor (BDNF) has an effect on hippocampal volume, memory and mood disorders. This allele produces reduced dendritic branching in the hippocampus, impaired fear conditioning and increased anxiety. Alleles in the glucocorticoid receptor alter the sensitivity to this 'stress' hormone and is linked to maladaptation to acute stress.
Activation of the autonomic nervous system and hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of the stress response. This is a normal physiological process that is essential for everyday life events, including simple things such as walking, and is termed allostasis. Chemical mediators include catecholamines, cortisol and proinflammatory cytokines. However, chronic elevation of these same mediators can cause pathological changes, referred to as allostatic load. Allosteric load induced by chronic stress or anxiety causes atrophy of neurons in the hippocampus and PFC, areas associated with memory and executive function, and hypertrophy of neurons in the amygdala, a region associated with fear. Levels of neural cytokines, oxidative stress markers and brain glycogen levels are also altered by chronic stress.
Chronic stress or anxiety cause functional and structural changes in certain brain regions. These can be reversed, but many are long lasting, especially if stress occurred during the pre or peripubertal period. Neuron replacement and neurogenesis is suppressed by chronic stress and NMDA receptors play a role in this process. Dendrite remodeling occurs in the hippocampus, PFC and amygdala, and glutamate is involved in mediating these changes. Hippocampal neuronal plasticity in response to repeated stress is mediated by adrenal steroids, which interact with many neurochemical systems including serotonin, endogenous opioids, calcium currents, GABA-BDZ receptors and excitatory amino acids. Microtubule acetylation is also altered.
Anxiety, although closely linked to stress and has similar etiology, is a separate phenomenon involving aberrant fear conditioning and acquisition. The amygdala, PFC, thalamus and hippocampus are the most relevant brain areas. The amygdala is responsible for acquisition and expression of fear conditioning and involves long term potentiation (LTP) in the basal, lateral and central nuclei. NMDA receptors and voltage-gated calcium channels are involved in this process. Reconsolidation is the repeated activation of a memory and can produce the symptoms seen in anxiety. It requires input from β-adrenoceptors and NMDA receptors, with induction of cAMP response element binding protein (CREB). Alleviation of anxiety involves disruption of consolidation of emotional or traumatic memories and extinguishing adverse stimuli.
Pharmacological interventions for chronic stress and anxiety disorders include anxiolytics, beta-blockers and antidepressants. In addition, drugs that counteract the metabolic and neurological consequences of chronic stress, such as agents that reduce oxidative stress, inflammation or cholesterol synthesis, can be employed.