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. Here, we show that genetically depleting serotonin in Tph2 knockout mice promotes manic-like behaviors and disrupts daily oscillations of the dopamine biosynthetic enzyme tyrosine hydroxylase (TH) in midbrain dopaminergic nuclei. Specifically, while TH mRNA and protein levels in the Substantia Nigra (SN) and Ventral Tegmental Area (VTA) of wild-type mice doubled between the light and dark phase, TH levels were high throughout the day in Tph2 knockout mice, suggesting a hyperdopaminergic state. Analysis of TH expression in striatal terminal fields also showed blunted rhythms. Additionally, we found low abundance and blunted rhythmicity of the neuropeptide cholecystokinin (Cck) in the VTA of knockout mice, a neuropeptide whose downregulation has been implicated in manic-like states in both rodents and humans. Altogether, our results point to a previously unappreciated serotonergic control of circadian dopamine signaling and propose serotonergic dysfunction as an upstream mechanism underlying dopaminergic deregulation and ultimately maladaptive behaviors.

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. Here, we used confocal imaging and three-dimensional (3-D) modeling analysis to expand our morphological investigation of fluoxetine-mediated effects on serotonergic circuitry. We found that chronic treatment with a behaviorally active dose of fluoxetine affects the morphology and reduces the density of serotonergic axons innervating the medial prefrontal cortex, a brain region strongly implicated in the regulation of depressive- and anxiety-like behavior. Axons innervating the somatosensory cortex were unaffected, suggesting differential susceptibility to serotonin changes across cortical areas. Importantly, a 1-month washout period was sufficient to reverse morphological changes in both the medial prefrontal cortex and in the previously characterized hippocampus, as well as to normalize behavior, highlighting an intriguing relationship between axon density and an antidepressant-like effect. Overall, these results further demonstrate the bidirectional plasticity of defined serotonergic axons and provide additional insights into fluoxetine effects on the serotonergic system.