Impact of Serotonin Deficiency on Circadian Dopaminergic Rhythms.

Physiology and behavior are structured temporally to anticipate daily cycles of light and dark, ensuring fitness and survival. Neuromodulatory systems in the brain-including those involving serotonin and dopamine-exhibit daily oscillations in neural activity and help shape circadian rhythms. Disrupted neuromodulation can cause circadian abnormalities that are thought to underlie several neuropsychiatric disorders, including bipolar mania and schizophrenia, for which a mechanistic understanding is still lacking.

Reversible Morphological Remodeling of Prefrontal and Hippocampal Serotonergic Fibers by Fluoxetine.

Serotonin-releasing fibers depart from the raphe nuclei to profusely innervate the entire central nervous system, displaying in some brain regions high structural plasticity in response to genetically induced abrogation of serotonin synthesis. Chronic fluoxetine treatment used as a tool to model peri-physiological, clinically relevant serotonin elevation is also able to cause structural rearrangements of the serotonergic fibers innervating the hippocampus. Whether this effect is limited to hippocampal-innervating fibers or extends to other populations of axons is not known.

Fluoxetine Induces Morphological Rearrangements of Serotonergic Fibers in the Hippocampus.

Serotonin (5-HT)-releasing fibers show substantial structural plasticity in response to genetically induced changes in 5-HT content. However, whether 5-HT fibers appear malleable also following clinically relevant variations in 5-HT levels that may occur throughout an individual's life has not been investigated. Here, using confocal imaging and 3D modeling analysis in knock-in mice, we show that chronic administration of the antidepressant fluoxetine dramatically affects the morphology of 5-HT fibers innervating the dorsal and ventral hippocampus resulting in a reduced density of fibers.

Serotonin depletion causes valproate-responsive manic-like condition and increased hippocampal neuroplasticity that are reversed by stress.

Abnormal hippocampal neural plasticity has been implicated in behavioural abnormalities and complex neuropsychiatric conditions, including bipolar disorder (BD). However, the determinants of this neural alteration remain unknown. This work tests the hypothesis that the neurotransmitter serotonin (5-HT) is a key determinant of hippocampal neuroplasticity, and its absence leads to maladaptive behaviour relevant for BD.