Biology subjects

GIROS, B.

Publications and source records attributed to GIROS, B..

4 recordsLinked to original sources

bioRxiv2023

Behavioral and transcriptomic changes following brain-specific loss of noradrenergic transmission.

Noradrenaline (NE) plays an integral role in shaping behavioral outcomes including anxiety/depression, fear, learning and memory, attention and shifting behavior, sleep-wake state, pain, and addiction. However, it is unclear whether dysregulation of NE release is a cause or a consequence of maladaptive orientations of these behaviors, many of which associated with psychiatric disorders. To address this question, we used a unique genetic model in which the brain-specific Vesicular Monoamine Transporter-2 (VMAT2) gene expression was removed in NE-positive neurons disabling NE release in the entire brain. We engineered VMAT2 gene splicing and NE depletion by crossing floxed VMAT2 mice with mice expressing the Cre-recombinase under the DBH gene promotor. In this study, we performed a comprehensive behavioral and transcriptomic characterization of the VMAT2DBHcre KO mice to evaluate the role of central NE in behavioral modulations. We demonstrated that NE depletion induces anxiolytic and antidepressant-like effects, improves contextual fear memory, alters shifting behavior, decreases the locomotor response to amphetamine, and induces deeper sleep during the non-rapid eye movement (NREM) phase. In contrast, NE depletion did not affect spatial learning and memory, working memory, response to cocaine, and the architecture of the sleep-wake cycle. Finally, we used this model to identify genes that could be up- or down-regulated in the absence of NE release. We found an up-regulation of the Synaptic Vesicle Glycoprotein 2c (SV2c) gene expression in several brain regions, including the locus coeruleus (LC), and were able to validate this up-regulation as a marker of vulnerability to chronic social defeat.

neuroscience↗

bioRxiv2023

Persistent Extrasynaptic Hyperdopaminergia in the mouse Hippocampus Induces Plasticity and Recognition Memory Deficits Reversed by Antipsychotics

Evidence suggests that subcortical hyperdopaminergia alters cognitive function in schizophrenia and antipsychotic drugs (APD) fail at rescuing cognitive deficits in patients. In a previous study, we showed that blocking D2 dopamine receptors (D2R), a core action of APD, led to profound reshaping of mesohippocampal fibers, deficits in synaptic transmission and impairments in learning and memory in the mouse hippocampus (HP). However, it is currently unknown how excessive dopamine affects HP-related cognitive functions, and how APD would impact HP functions in such a state. After verifying the presence of DAT-positive neuronal projections in the ventral (temporal), but not in the dorsal (septal), part of the HP, GBR12935, a blocker of dopamine transporter (DAT), was infused in the CA1 of adult C57Bl/6 mice to produce local hyperdopaminergia. Chronic GBR12935 infusion in temporal CA1 induced a mild learning impairment in the Morris Water Maze and abolished long-term recognition memory in novel-object (NORT) and object-place recognition tasks (OPRT). Deficits were accompanied by a significant decrease in DAT+ mesohippocampal fibers. Intrahippocampal or systemic treatment with sulpiride during GBR infusions improved the NORT deficit but not that of OPRT. In vitro application of GBR on hippocampal slices abolished long-term depression (LTD) of fEPSP in temporal CA1. LTD was rescued by co-application with sulpiride. In conclusion, chronic DAT blockade in temporal CA1 profoundly altered mesohippocampal modulation of hippocampal functions. Contrary to previous observations in normodopaminergic mice, antagonising D2Rs was beneficial for cognitive functions in the context of hippocampal hyperdopaminergia.

neuroscience↗

bioRxiv2022

The ventral striatum contributes to energy balance

Accumulating evidence points to dysregulations of common brain systems in eating disorders (ED), the Nucleus Accumbens (NAc) in particular. However, to which extent alterations in NAc activity contribute to ED-like dimensions remains unclear. Using chemogenetic manipulations of dopamine D1 receptor-expressing and D2-expressing neuronal subpopulations of the NAc in male mice, we assessed their respective roles in incentive processes, food intake and the balance between feeding and exercise-mediated energy expenditure. We found that D1-neurons facilitate effort for a food reward but decreased food intake, while D2-neurons have opposite effects. The anorexigenic influence of D1-neurons was accompanied by increased voluntary exercise while the orexigenic effect of D2-neurons was concomitant with decreased running, congruent with D2-neurons being more active than D1-neurons during feeding while it is the opposite during running. Chronic manipulations of each subpopulations had limited effects on energy balance. However, repeated activation of D1-neurons combined with inhibition of D2-neurons biased behavior toward activity-related energy expenditure leading to weight/fat loss, whilst the opposite manipulations favored energy intake and hence weight/fat gain. Strikingly, concomitant activation of D1-neurons and inhibition of D2-neurons precipitated weight loss in anorexia models. These results suggest that dysregulations of NAc dopaminoceptive neurons might be at the core of EDs.

neuroscience↗

bioRxiv2022

Unexpected inhibition of motor function by dopamine activation of D1/D2 co-expressing striatal neurons.

The central function of the striatum and its dopaminergic (DA) afferents in motor control and the integration of cognitive and emotional processes is commonly explained by the two striatal efferent pathways characterized by striatal projection neurons (SPNs) expressing DA D1 receptors and D2 receptors (D1-SPNs and D2-SPNs), without regard to SPNs coexpressing both receptors (D1/D2-SPNs). We developed an approach that enables the targeting of these hybrid SPNs and demonstrated that although these SPNs are less abundant, they play a major role in guiding the motor function of the other two main populations. D1/D2-SPNs project exclusively to the external globus pallidus (GPe) and have specific electrophysiological features with distinctive integration of DA signals. Optogenetic stimulation and loss-of-function experiments indicated that D1/D2-SPNs potentiate the prokinetic and antikinetic functions of D1-SPNs and D2-SPNs, respectively, and restrain the integrated motor response to psychostimulants. Overall, our findings demonstrate the essential role of this third unacknowledged population of D1/D2 coexpressing neurons, which orchestrates the fine-tuning of DA regulation in the thalamo-cortico-striatal loops. One-Sentence SummaryD1/D2 SPNs modulate the motor function of both D1- and D2-SPNs

neuroscience↗