The amygdala is a deep temporal nuclear complex central to threat detection, emotional valence assignment and fear learning; it is densely connected with sensory cortex, hippocampus, prefrontal cortex, hypothalamus and autonomic centers. Neuromodulators (cortisol, noradrenaline, dopamine) and sleep-dependent processes regulate amygdala plasticity, while peripheral and microglial inflammation remodel basolateral and central amygdala circuits via excitatory/inhibitory (E/I) imbalance, promoting hyperexcitability linked to anxiety and depression. Preclinical models (CFA, LPS, chronic stress, high-fat diet) and clinical data implicate cytokines (TNF-α, IL-1β, IL-6, IL-17), disrupted GABA/glutamate signaling and monoaminergic alterations as mechanistic mediators. Nonpharmacological neuromodulation (ECT, low-intensity transcranial focused ultrasound) modifies amygdala volume and reactivity and represents a promising translational avenue that requires randomized trials integrating neuroimaging and inflammatory biomarkers for precise subnuclear targeting.
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