Serotonergic Mechanisms in Stress and Anxiety Disorders
Summary
Serotonergic pathways are central to the regulation of mood, cognition and the physiological response to stress. Serotonin (5-hydroxytryptamine, 5-HT) synthesised in the raphe nuclei projects broadly throughout the brain, modulating circuits that govern emotional regulation, threat appraisal and resilience to adversity. Under stress, alterations in 5-HT release influence the hypothalamic-pituitary-adrenal (HPA) axis, shaping cortisol dynamics and negative feedback. Functional changes in receptor subtypes, notably 5-HT1A, 5-HT2A and 5-HT2C, recalibrate neuronal excitability in limbic structures such as the amygdala and hippocampus, thereby affecting anxiety-like behaviours. Developmental perturbations of tryptophan hydroxylase-2 (TPH2) or early life stress can disrupt serotonergic tone, leading to enduring vulnerability or resilience phenotypes. At the cellular level, 5-HT modulates adult hippocampal neurogenesis and synaptic plasticity, mechanisms implicated in recovery from mood disturbance and the action of selective serotonin reuptake inhibitors. Emerging evidence also highlights bidirectional communication between the gut microbiome and central 5-HT metabolism, offering novel targets for intervention. Together, these findings underscore the global significance of serotonergic regulation in the aetiology and treatment of stress-related anxiety disorders.
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Serotonergic Mechanisms in Stress and Anxiety Disorders publication trend
The graph below shows the total number of articles in serotonergic mechanisms in stress and anxiety disorders across all publications each year (not limited to Nature Index journals).
Technical terms
Serotonin (5-HT): A monoamine neurotransmitter synthesised from tryptophan, essential for mood regulation, stress response and gut–brain signalling.
Tryptophan hydroxylase-2 (TPH2): Rate-limiting enzyme for neuronal 5-HT synthesis, mutations of which impact emotional behaviour and stress sensitivity.
Hypothalamic-pituitary-adrenal (HPA) axis: Neuroendocrine network controlling cortisol release in response to stress, modulated by serotonergic input.
Neurogenesis: Generation of new neurons in the adult hippocampus, influenced by 5-HT and implicated in recovery from anxiety and depressive states.
Synaptic plasticity: Activity-dependent strengthening or weakening of synapses, shaped by 5-HT receptors and underlying adaptation to stress.
References
- 5-HT attenuates chronic stress-induced cognitive impairment in mice through intestinal flora disruption. Journal of Neuroinflammation (2023).
- Molecular signature of excessive female aggression: study of stressed mice with genetic inactivation of neuronal serotonin synthesis. Journal of Neural Transmission (2023).
- Constitutive depletion of brain serotonin differentially affects rats’ social and cognitive abilities. iScience (2023).
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