Gut microbiota changes require vagus nerve integrity to promote depressive-like behaviors in mice.

Chronic stress constitutes a major risk factor for depression that can disrupt various aspects of homeostasis, including the gut microbiome (GM). We have recently shown that GM imbalance affects adult hippocampal (HPC) neurogenesis and induces depression-like behaviors, with the exact mechanisms being under active investigation. Here we hypothesized that the vagus nerve (VN), a key bidirectional route of communication between the gut and the brain, could relay the effects of stress-induced GM changes on HPC plasticity and behavior. We used fecal samples derived from mice that sustained unpredictable chronic mild stress (UCMS) to inoculate healthy mice and assess standard behavioral readouts for anxiety- and depressive-like behavior, conduct histological and molecular analyses for adult HPC neurogenesis and evaluate neurotransmission pathways and neuroinflammation. To study the potential role of the VN in mediating the effects of GM changes on brain functions and behavior, we used mice that sustained subdiaphragmatic vagotomy (Vx) prior the GM transfer. We found that inoculation of healthy mice with GM from UCMS mice activates the VN and induces early and sustained changes in both serotonin and dopamine neurotransmission pathways in the brainstem and HPC. These changes are associated with prompt and persistent deficits in adult HPC neurogenesis and induce early and sustained neuroinflammatory responses in the HPC. Remarkably, Vx abrogates adult HPC neurogenesis deficits, neuroinflammation and depressive-like behavior, suggesting that vagal afferent pathways are necessary to drive GM-mediated effects on the brain.

Assessing positive and negative valence systems to refine animal models of bipolar disorders: the example of GBR 12909-induced manic phenotype.

Bipolar disorders are defined by recurrences of depressive and manic episodes. The pathophysiology is still unknown, and translating clinical symptoms into behaviors explorable in animal models is challenging. Animal models of bipolar disorder do not exist because cyclicity of the disease is impossible to mimic, and it is therefore necessary to study mania and depression models separately. Beyond mood, emotional biases differentiate bipolar states in humans. Mania is associated with positive biases, e.g. emotional stimuli become more rewarding and less aversive, and the opposite for depression. We propose to assess behavioral hedonic responses to innately appetitive and aversive olfactory and gustatory cues in mice as proxies for the assigned emotional valence. A mania model is therefore supposed to exhibit positive hedonic bias. Using the GBR 12909 mania model, we observed the classical hyperactivity phenotype, along with low depressive-like but high anxiety-like behaviors. Unexpectedly, GBR 12909-treated mice exhibited strong negative hedonic biases. Consequently, the GBR 12909 model of mania might not be appropriate for studying emotional disturbances associated with mania states. We propose olfactory and gustatory preference tests as crucial assessment for positive and negative valence biases, necessary for precisely characterizing animal models of bipolar disorders.

An emotional-response model of bipolar disorders integrating recent findings on amygdala circuits.

Because of our classification system limitations for defining psychiatric disorders and understanding their physiopathology, a new research area based on dimensions has emerged. It consists of exploring domains derived from fundamental behavioral components linked to neurobiological systems. Emotional processing is among the most affected dimensions in bipolar disorders (BD), but is excluded from the definition criteria. The purpose of this review is to synthesize the emotional responses disruption during the different phases of BD, using intensity and valence as the two key characteristics of emotions. We integrate those emotional disruptions into an original, emotion-based model contrasting with the current diagnostic frame built on mood. Emotional processing is underpinned by cortico-limbic circuits involving the amygdala. Recent publications showed the crucial role of the amygdala in emotional processes triggered by stimuli of negative, but also positive valence. We show how these neuroscience data can provide physiological basis for emotional disturbances observed in BD. We conclude with translational perspectives to improve the current knowledge about neural substrates underlying altered emotional responses characterizing BD.

Changes in Gut Microbiota by Chronic Stress Impair the Efficacy of Fluoxetine.

Major depressive disorders (MDDs) constitute a leading cause of disability worldwide and current pharmacological treatments are partially effective. The gut microbiota (GM) has recently emerged as a target of therapeutic interest for MDDs. In this study, we transfer GM from mice that sustained unpredictable chronic mild stress (UCMS) to healthy recipient mice. The fecal transfer induces despair-like behavior, decreases neurogenesis in the hippocampus (HpC), and impairs the antidepressant and neurogenic effects of a standard selective serotonin (5-HT) reuptake inhibitor, fluoxetine (FLX). These effects are paralleled by deficits in 5-HT bioavailability, biosynthesis, and reuptake in the HpC. Treatment with 5-hydroxytryptophan restores the levels of 5-HT and its precursors in the HpC, improves HpC neurogenesis, and alleviates despair-like symptoms. Our results reveal that stress-induced changes in GM are involved in the pathogenesis of depressive disorders and minimize FLX efficacy via alterations in the serotonergic pathway of Trp metabolism.

Can olfactory dysfunction be a marker of trait or states of bipolar disorders? A comprehensive review.

BACKGROUND: Olfactory deficits (OD) are reported as markers for a large spectrum of neuro-psychiatric disorders. Alterations can concern perception, identification, discrimination and assignment of odour's valence of olfaction process. We propose a comprehensive review to summarize which kind of OD were reported in bipolar disorders (BD) and in which phase of the disease, to know if they could be a marker of state or trait. METHODS: A Systematic Literature Review was conducted using PRISMA guidelines to include all studies assessing olfaction with objective measures in BD. RESULTS: 9 studies were identified. All of them have assessed odour identification and 3 reported deficits mainly in patients with psychotic features or elements of illness severity in comparison to healthy subjects. There is no difference in threshold of perception between BD patients and controls and it is no possible to conclude for discrimination because only one study has assessed this dimension in comparison to control. We cannot conclude for hedonic value of odours regarding these studies. LIMITATIONS: These studies are very incomplete because only one has evaluated all the processes involved in olfaction process. CONCLUSIONS: In light of this review, evidence is still missing to unveil potential disturbances of olfactory process as a marker of BD. These new avenues of research could help to clarify the links between OD and BD and provide information on the pathophysiology of the disorder according to the impaired dimension.

Modulation of Coordinated Activity across Cortical Layers by Plasticity of Inhibitory Synapses.

In the neocortex, synaptic inhibition shapes all forms of spontaneous and sensory evoked activity. Importantly, inhibitory transmission is highly plastic, but the functional role of inhibitory synaptic plasticity is unknown. In the mouse barrel cortex, activation of layer (L) 2/3 pyramidal neurons (PNs) elicits strong feedforward inhibition (FFI) onto L5 PNs. We find that FFI involving parvalbumin (PV)-expressing cells is strongly potentiated by postsynaptic PN burst firing. FFI plasticity modifies the PN excitation-to-inhibition (E/I) ratio, strongly modulates PN gain, and alters information transfer across cortical layers. Moreover, our LTPi-inducing protocol modifies firing of L5 PNs and alters the temporal association of PN spikes to γ-oscillations both in vitro and in vivo. All of these effects are captured by unbalancing the E/I ratio in a feedforward inhibition circuit model. Altogether, our results indicate that activity-dependent modulation of perisomatic inhibitory strength effectively influences the participation of single principal cortical neurons to cognition-relevant network activity.

The apparent mechanical effect of isolated amyloid-ß and α-synuclein aggregates revealed by multi-frequency MRE.

Several biological processes are involved in dementia, and fibrillar aggregation of misshaped endogenous proteins appears to be an early hallmark of neurodegenerative disease. A recently developed means of studying neurodegenerative diseases is magnetic resonance elastography (MRE), an imaging technique investigating the mechanical properties of tissues. Although mechanical changes associated with these diseases have been detected, the specific signal of fibrils has not yet been isolated in clinical or preclinical studies. The current study aims to exploit the fractal-like properties of fibrils to separate them from nonaggregated proteins using a multi-frequency MRE power law exponent in a phantom study. Two types of fibril, α-synuclein (α-Syn) and amyloid-ß (Aß), and a nonaggregated protein, bovine serum albumin, used as control, were incorporated in a dedicated nondispersive agarose phantom. Elastography was performed at multiple frequencies between 400 and 1200 Hz. After 3D-direct inversion, storage modulus (G'), phase angle (ϕ), wave speed and the power law exponent (y) were computed. No significant changes in G' and ϕ were detected. Both α-Syn and Aß inclusions showed significantly higher y values than control inclusions (P = 0.005) but did not differ between each other. The current phantom study highlighted a specific biomechanical effect of α-Syn and Aß aggregates, which was better captured with the power law exponent derived from multi-frequency MRE than with single frequency-derived parameters.

5-HT2A receptor-dependent phosphorylation of mGlu2 receptor at Serine 843 promotes mGlu2 receptor-operated Gi/o signaling.

The serotonin 5-HT2A and glutamate mGlu2 receptors continue to attract particular attention, given their implication in psychosis associated with schizophrenia and the mechanism of action of atypical antipsychotics and a new class of antipsychotics, respectively. A large body of evidence indicates a functional crosstalk between both receptors in the brain, but the underlying mechanisms are not entirely elucidated. Here, we have explored the influence of 5-HT2A receptor upon the phosphorylation pattern of mGlu2 receptor in light of the importance of specific phosphorylation events in regulating G protein-coupled receptor signaling and physiological outcomes. Among the five mGlu2 receptor-phosphorylated residues identified in HEK-293 cells, the phosphorylation of Ser843 was enhanced upon mGlu2 receptor stimulation by the orthosteric agonist LY379268 only in cells co-expressing the 5-HT2A receptor. Likewise, administration of LY379268 increased mGlu2 receptor phosphorylation at Ser843 in prefrontal cortex of wild-type mice but not 5-HT2A-/- mice. Exposure of HEK-293 cells co-expressing mGlu2 and 5-HT2A receptors to 5-HT also increased Ser843 phosphorylation state to a magnitude similar to that measured in LY379268-treated cells. In both HEK-293 cells and prefrontal cortex, Ser843 phosphorylation elicited by 5-HT2A receptor stimulation was prevented by the mGlu2 receptor antagonist LY341495, while the LY379268-induced effect was abolished by the 5-HT2A receptor antagonist M100907. Mutation of Ser843 into alanine strongly reduced Gi/o signaling elicited by mGlu2 or 5-HT2A receptor stimulation in cells co-expressing both receptors. Collectively, these findings identify mGlu2 receptor phosphorylation at Ser843 as a key molecular event that underlies the functional crosstalk between both receptors.

Magnetic Resonance Elastography of Rodent Brain.

Magnetic resonance elastography (MRE) is a non-invasive imaging technique, using the propagation of mechanical waves as a probe to palpate biological tissues. It consists in three main steps: production of shear waves within the tissue; encoding subsequent tissue displacement in magnetic resonance images; and extraction of mechanical parameters based on dedicated reconstruction methods. These three steps require an acoustic-frequency mechanical actuator, magnetic resonance imaging acquisition, and a post-processing tool for which no turnkey technology is available. The aim of the present review is to outline the state of the art of reported set-ups to investigate rodent brain mechanical properties. The impact of experimental conditions in dimensioning the set-up (wavelength and amplitude of the propagated wave, spatial resolution, and signal-to-noise ratio of the acquisition) on the accuracy and precision of the extracted parameters is discussed, as well as the influence of different imaging sequences, scanners, electromagnetic coils, and reconstruction algorithms. Finally, the performance of MRE in demonstrating viscoelastic differences between structures constituting the physiological rodent brain, and the changes in brain parameters under pathological conditions, are summarized. The recently established link between biomechanical properties of the brain as obtained on MRE and structural factors assessed by histology is also studied. This review intends to give an accessible outline on how to conduct an elastography experiment, and on the potential of the technique in providing valuable information for neuroscientists.