Neurobiological Mechanisms of Stress and Mood Regulation

Stress and mood regulation emerge from dynamic interactions between neuroendocrine systems, neural circuits and cellular processes that maintain emotional homeostasis. Activation of the hypothalamic–pituitary–adrenal (HPA) axis leads to corticosteroid release, which modulates neuronal excitability and gene expression across limbic regions. Key structures including the amygdala, hippocampus, prefrontal cortex and nucleus accumbens integrate hormonal, synaptic and immune signals to shape behavioural and affective responses. Synaptic plasticity mechanisms—such as long-term potentiation and depression—allow adaptation to acute challenges, while neurogenesis and dendritic remodelling contribute to longer-term resilience or vulnerability. Glial cells, notably microglia, engage in surveillance and structural remodelling of synapses, providing negative feedback after excessive excitation. Dysregulation of neurotransmitter systems (glutamate, GABA, monoamines) and impaired plasticity underlie mood disorders. Recent work highlights how precise circuit-specific alterations, from spine pruning to parvalbumin interneuron dysfunction, translate environmental stress into persistent changes in mood and behaviour, pointing towards novel therapeutic targets.

Research from Nature Portfolio

Recent studies reveal a cellular feedback mechanism in which microglia actively terminate anxiety-like states. Following acute stress, increased activity of GABAergic neurons in the central amygdala drives elevated chemokine signalling, triggering microglial activation. Engulfment of dendritic spines by microglia then suppresses neuronal hyperactivity and restores homeostasis, delineating a clearance-based pathway for anxiety extinction. In parallel, optogenetic dissection of the prefrontal-to-amygdala projection has identified cell-type specific dysregulation under chronic stress. A subset of basolateral amygdala neurons receiving monosynaptic input from the dorsomedial prefrontal cortex exhibit a shift toward excitation, correlating with heightened anxiety. Low-frequency stimulation of this pathway normalises glutamate release and attenuates stress-induced behavioural changes, demonstrating the potential of precise circuit modulation.

Neurobiological Mechanisms of Stress and Mood Regulation publication trend

The graph below shows the total number of articles in neurobiological mechanisms of stress and mood regulation across all publications each year (not limited to Nature Index journals).

Technical terms

Hypothalamic–pituitary–adrenal (HPA) axis: A neuroendocrine system coordinating hormonal responses to stress via sequential release of corticotrophin-releasing hormone, adrenocorticotrophic hormone and glucocorticoids.

Synaptic plasticity: Activity-dependent strengthening or weakening of synaptic connections, encompassing long-term potentiation and long-term depression.

Microglia: Resident immune cells of the central nervous system that monitor synaptic integrity and can remodel neural circuits through phagocytosis.

GABAergic neuron: An inhibitory neuron releasing γ-aminobutyric acid to regulate excitability within neural networks.

Dendritic spine: Small protrusion from a neuron's dendrite that forms the postsynaptic component of most excitatory synapses and is a substrate for plastic change.

Theta rhythm: A neural oscillation in the 4–8 Hz range, often associated with emotional processing and memory in limbic structures.

References

1. Microglia govern the extinction of acute stress-induced anxiety-like behaviors in male mice. Nature Communications (2024).
2. Identification of a prefrontal cortex-to-amygdala pathway for chronic stress-induced anxiety. Nature Communications (2020).
3. Microelectrode Arrays for Detection of Neural Activity in Depressed Rats: Enhanced Theta Activity in the Basolateral Amygdala. Cyborg and Bionic Systems (2024).
4. Menin Reduces Parvalbumin Expression and is Required for the Anti‐Depressant Function of Ketamine. Advanced Science (2023).
5. The chronic mild stress (CMS) model of depression: History, evaluation and usage. Neurobiology of Stress (2016).