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.

Serotonin drives striatal synaptic plasticity in a sex-related manner.

Introduction: Plasticity at corticostriatal synapses is a key substrate for a variety of brain functions - including motor control, learning and reward processing - and is often disrupted in disease conditions. Despite intense research pointing toward a dynamic interplay between glutamate, dopamine (DA), and serotonin (5-HT) neurotransmission, their precise circuit and synaptic mechanisms regulating their role in striatal plasticity are still unclear. Here, we analyze the role of serotonergic raphe-striatal innervation in the regulation of DA-dependent corticostriatal plasticity.

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.

Brain-wide Mapping of Endogenous Serotonergic Transmission via Chemogenetic fMRI.

Serotonin-producing neurons profusely innervate brain regions via long-range projections. However, it remains unclear whether and how endogenous serotonergic transmission specifically influences regional or global functional activity. We combined designed receptors exclusively activated by designed drugs (DREADD)-based chemogenetics and functional magnetic resonance imaging (fMRI), an approach we term "chemo-fMRI," to causally probe the brain-wide substrates modulated by endogenous serotonergic activity.

Development of Serotonergic Fibers in the Post-Natal Mouse Brain.

Serotonin (5-HT)-synthetizing neurons, which are confined in the nuclei of the rhombencephalon, provide a pervasive innervation of the central nervous system (CNS) and are involved in the modulation of a plethora of functions in both developing and adult brain. Classical studies have described the post-natal development of serotonergic axons as a linear process of terminal field innervation. However, technical limitations have hampered a fine morphological characterization.

A Tph2 Reporter Stem Cell Line To Model in Vitro and in Vivo Serotonergic Neuron Development and Function.

Modeling biological systems in vitro has contributed to clarification of complex mechanisms in simplified and controlled experimental conditions. Mouse embryonic stem (mES) cells can be successfully differentiated toward specific neuronal cell fates, thus representing an attractive tool to dissect, in vitro, mechanisms that underlie complex neuronal features. In this study, we generated and characterized a reporter mES cell line, called Tph2, in which the vital reporter GFP replaces the tryptophan hydroxylase 2 (Tph2) gene.

Age-Related Changes in D-Aspartate Oxidase Promoter Methylation Control Extracellular D-Aspartate Levels and Prevent Precocious Cell Death during Brain Aging.

The endogenous NMDA receptor (NMDAR) agonist D-aspartate occurs transiently in the mammalian brain because it is abundant during embryonic and perinatal phases before drastically decreasing during adulthood. It is well established that postnatal reduction of cerebral D-aspartate levels is due to the concomitant onset of D-aspartate oxidase (DDO) activity, a flavoenzyme that selectively degrades bicarboxylic D-amino acids. In the present work, we show that d-aspartate content in the mouse brain drastically decreases after birth, whereas Ddo mRNA levels concomitantly increase.

Rhes influences striatal cAMP/PKA-dependent signaling and synaptic plasticity in a gender-sensitive fashion.

Mechanisms of gender-specific synaptic plasticity in the striatum, a brain region that controls motor, cognitive and psychiatric functions, remain unclear. Here we report that Rhes, a GTPase enriched in medium spiny neurons (MSNs) of striatum, alters the striatal cAMP/PKA signaling cascade in a gender-specific manner. While Rhes knockout (KO) male mice, compared to wild-type (WT) mice, had a significant basal increase of cAMP/PKA signaling pathway, the Rhes KO females exhibited a much stronger response of this pathway, selectively under the conditions of dopamine/adenosine-related drug challenge.