Serotonergic Modulation in Neurobehavioral and Neurocognitive Disorders

Serotonin (5-hydroxytryptamine, 5-HT) is a pivotal neuromodulator that orchestrates a spectrum of behaviours and cognitive functions, spanning mood regulation, reward processing, memory consolidation and stress resilience. Dysregulation of serotonergic signalling underlies many neurobehavioral conditions such as depression, anxiety and obsessive–compulsive disorder, as well as neurocognitive disorders including Alzheimer’s disease and age-related cognitive decline. Serotonergic neurons, predominantly originating in the dorsal raphe nucleus, innervate widespread forebrain regions and engage a diverse array of receptor subtypes (e.g. 5-HT1A, 5-HT2A, 5-HT4) to fine-tune synaptic plasticity, network oscillations and neurotrophic support. Advances in circuit dissection techniques have revealed how 5-HT release is dynamically regulated by peripheral inputs, behavioural state and even physical exercise, offering new insights into how modulation of this system can restore neural circuit integrity. Clinically, selective serotonin reuptake inhibitors and emerging receptor-targeted compounds continue to be refined to achieve symptom relief with fewer off-target effects, while novel strategies aim to harness peripheral–central axes and cell-based therapies to bolster central serotonin tone. Together, these findings emphasise the global importance of serotonergic modulation in both the pathogenesis and treatment of a wide range of psychiatric and neurodegenerative disorders.

Research from Nature Portfolio

Recent studies have demonstrated that peripheral administration of mesenchymal stromal cells can activate a lung-to-brain vagal pathway, leading to targeted release of 5-HT in the dorsal raphe nucleus and alleviation of depressive and anxiety-like behaviours in animal models. This work highlights a novel peripherally accessible route for modulating central serotonergic circuits by exploiting brain-derived neurotrophic factor and TrkB signalling. In parallel, investigations into the native activity of dorsal raphe serotonergic neurons during natural rewards have revealed that these cells fire in both tonic and phasic modes throughout the anticipation and receipt of diverse positive stimuli. These experiments, employing in vivo recordings and fibre photometry, have established that 5-HT neurons encode reward value across multiple timescales and complement GABAergic signals during aversive events, refining our understanding of how serotonin contributes to adaptive behaviour.

Serotonergic Modulation in Neurobehavioral and Neurocognitive Disorders publication trend

The graph below shows the total number of articles in serotonergic modulation in neurobehavioral and neurocognitive disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Serotonin (5-HT): A monoamine neurotransmitter involved in the regulation of mood, cognition, appetite and sleep.

Dorsal raphe nucleus (DRN): A midbrain structure housing the majority of central serotonergic neurons, projecting broadly across the forebrain.

Synaptic plasticity: The ability of synapses to strengthen or weaken over time in response to activity, critical for learning and memory.

Chemogenetics: A technique that uses engineered receptors activated by designer drugs to modulate neuronal activity selectively.

Optogenetics: A method employing light-sensitive proteins to control the electrical activity of genetically defined neurons with high temporal precision.

Functional positron emission tomography (fPET): An imaging approach that quantifies neurotransmitter synthesis or receptor occupancy in vivo using radioligands.

References

1. Mesenchymal stromal cells alleviate depressive and anxiety-like behaviors via a lung vagal-to-brain axis in male mice. Nature Communications (2023).
2. Serotonergic neurons signal reward and punishment on multiple timescales. eLife (2015).
3. Dorsal raphe nucleus–hippocampus serotonergic circuit underlies the depressive and cognitive impairments in 5×FAD male mice. Translational Neurodegeneration (2024).
4. Dynamics of human serotonin synthesis differentially link to reward anticipation and feedback. Molecular Psychiatry (2024).
5. Exercise‐Activated mPFC Tri‐Synaptic Pathway Ameliorates Depression‐Like Behaviors in Mouse. Advanced Science (2024).