Biology subjects

Onimus, O.

Publications and source records attributed to Onimus, O..

5 recordsLinked to original sources

bioRxiv2025

Peripheral CB1R inhibition modulates food intake and metabolic efficiency in obesity independently of the gut-brain vagal axis

Background and PurposeObesity involves profound disruptions in neuronal circuits, neuroendocrine communication and the endocannabinoid system (ECS). While global cannabinoid type-1 receptor (CB1R) blockade improves metabolism, its clinical use is limited by neuropsychiatric side effects. Peripherally restricted CB1R antagonists offer a safer alternative, yet the neural pathways, specifically the role of the gut-brain vagal axis, mediating their effects remain unclear. Experimental ApproachWe investigated the metabolic and neural effects of peripheral inhibition of CB1R (JD5037 and AM6545) in lean and diet-induced obese (DIO). Metabolic parameters were assessed using indirect calorimetry, and neuronal activation was mapped by cFos immunoreactivity. The requirement for vagal signaling was examined using subdiaphragmatic vagotomy (SDV) and pharmacological blockade of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) receptors. Key ResultsPeripheral CB1R inhibition suppressed food intake and shifted nutrient partitioning toward fatty acid oxidation in DIO, but not lean, mice. Obesity upregulated CB1R expression in the nodose ganglia. In DIO mice, peripheral CB1R inhibition robustly activated satiety-related brainstem (NTS, AP, PBN) and hypothalamic (ARC, PVN) nuclei. SDV abolished brainstem activation but failed to blunt hypothalamic recruitment or the anorexigenic and metabolic benefits. Furthermore, antagonism of CCK or GLP-1 receptors did not prevent the feeding-suppressive effects of JD5037. Conclusions and ImplicationsOur findings reveal a dual-mechanism model: vagal pathways mediate brainstem engagement, while hypothalamic recruitment and metabolic improvements occur via vagal-independent signaling. These results demonstrate that peripherally restricted CB1R antagonists indirectly engage central homeostatic circuits, supporting their therapeutic potential for obesity even in conditions with impaired vagal signaling. Bullet point summaryO_ST_ABS What is already knownC_ST_ABSO_LIObesity is associated with elevated circulating endocannabinoids, reflecting chronic overactivation of the peripheral endocannabinoid system. C_LIO_LIClinical and preclinical studies indicate that peripheral CB1R inhibition ameliorates obesity-related dysfunctions. C_LI What this study addsO_LIPeripheral CB1R inhibition suppresses food intake and promotes fatty acid oxidation in obese but not lean conditions. C_LIO_LIPeripheral CB1R inhibition engages brainstem nuclei via vagal signaling and hypothalamic nuclei via vagal-independent mechanisms. C_LI Clinical significanceO_LIMetabolic state-dependent CB1R responsiveness must be considered when designing endocannabinoids-targeted obesity therapies. C_LIO_LIPeripheral CB1R antagonists engage central homeostatic circuits via body-brain pathways, warranting surveillance of CNS outcomes. C_LI

neuroscience↗

bioRxiv2025

The gut-brain vagal axis governs mesolimbic dopamine dynamics and reward events

Reward-related processes have traditionally been ascribed to neural circuits centered on the dopamine (DA) system. While exteroceptive stimuli, such as food and drugs of abuse, are well-established activators of DA-neuron activity, growing evidence indicates that interoceptive signals also play a critical role in modulating reward. Among these, the gut-brain vagal axis has emerged as a key pathway, yet its precise contribution to mesolimbic DA-dependent signaling, dynamics and behaviors remains poorly defined. Here, we combine complementary ex vivo and in vivo approaches across multiple scales to investigate how the gut-brain vagal axis regulates DA dynamics and reward-related behaviors. We show that gut-brain vagal tone is essential for gating mesolimbic DA system activity and functions, modulating DA-dependent molecular and cellular processes, and scaling both food- and drugs-induced reinforcement. These findings challenge the traditional brain-centric view of reward processing, supporting a more unified and integrated model in which gut-derived and vagus-mediated interoceptive signals are pivotal in intrinsically shaping motivation and reinforcement. By uncovering the influence of gut-brain vagal communication on mesolimbic DA functions, this work offers new insights into the neurobiological mechanisms underlying both adaptive and maladaptive reward processes, with broad implications for eating disorders and addiction.

neuroscience↗

bioRxiv2024

The gut-brain vagal axis scales hippocampal memory processes and plasticity

The vagus nerve serves as an interoceptive relay between the body and the brain. Despite its well-established role in feeding behaviors, energy metabolism, and cognitive functions, the intricate functional processes linking the vagus nerve to the hippocampus and its contribution to learning and memory dynamics remain still elusive. Here, we investigated whether and how the gut-brain vagal axis contributes to hippocampal learning and memory processes at behavioral, functional, cellular, and molecular levels. Our results indicate that the integrity of the vagal axis is essential for long-term recognition memories, while sparing other forms of memory. In addition, by combing multi-scale approaches, our findings show that the gut-brain vagal tone exerts a permissive role in scaling intracellular signaling events, gene expressions, hippocampal dendritic spines density as well as functional long-term plasticities (LTD and LTP). These results highlight the critical role of the gut-brain vagal axis in maintaining the spontaneous and homeostatic functions of hippocampal ensembles and in regulating their learning and memory functions. In conclusion, our study provides comprehensive insights into the multifaceted involvement of the gut-brain vagal axis in shaping time-dependent hippocampal learning and memory dynamics. Understanding the mechanisms underlying this interoceptive body-brain neuronal communication may pave the way for novel therapeutic approaches in conditions associated with cognitive decline, including neurodegenerative disorders. HighlightsO_LIThe gut-brain vagal axis contributes to long-term recognition memories C_LIO_LIThe gut-brain vagal axis is dispensable for short-term memories C_LIO_LIThe vagal axis regulates molecular and signaling dynamics in the hippocampus C_LIO_LIThe gut-brain vagal tone shapes the structural density of hippocampal dendritic spines C_LIO_LIThe gut-brain vagal tone ensures physiological forms of synaptic plasticity C_LI

neuroscience↗

bioRxiv2023

NAPE-PLD in the ventral tegmental area regulates reward events, feeding and energy homeostasis

The N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) catalyzes the production of N-acylethanolamines (NAEs), a family of endogenous bioactive lipids, which are involved in various biological processes ranging from neuronal functions to energy homeostasis and feeding behaviors. Reward-dependent behaviors depend on the dopamine (DA) transmission between the ventral tegmental area (VTA) and the nucleus accumbens (NAc) which conveys reward-values and scales reinforced behaviors. However, whether and how NAPE-PLD may contribute to the regulation of feeding and reward-dependent behaviors has not been investigated yet. This biological question is of paramount importance since NAEs are altered in obesity and metabolic disorders. Here, we show that transcriptomic meta-analysis highlights a potential role for NAPE-PLD within the VTA[->]NAc circuit. Using brain-specific invalidation approaches, we report that the integrity of NAPE-PLD is required for the proper homeostasis of NAEs within the midbrain VTA and it affects food-reward behaviors. Moreover, region-specific knock-down of NAPE-PLD in the VTA resulted in enhanced food-reward seeking and reinforced behaviors which were associated with increased in vivo DA release dynamics in response to both food and non-food-related rewards together with heightened tropism towards food consumption. Furthermore, midbrain knock-down of NAPE-PLD, which led to increased energy expenditure and adapted nutrients partitioning, elicited a relative protection against high-fat diet-mediated body fat gain and obesity-associated metabolic features. In conclusion, these findings unravel a new key role of VTA NAPE-PLD in shaping DA-dependent events, feeding behaviors and energy homeostasis, thus providing new insights on the regulation of body metabolism. Highlights- NAPE-PLD and NAEs are enriched in the VTA and regulate food-reinforced behaviors and reward processes. - NAPE-PLD scales in vivo VTA[->]NAc dopamine dynamics. - NAPE-PLD in the VTA contributes to whole-body energy balance and metabolic efficiency. - Downregulation of VTA NAPE-PLD ameliorates obesity-associated metabolic features.

neuroscience↗

bioRxiv2022

Haloperidol-induced immediate early genes in striatopallidal neurons requires the converging activation of cAMP/PKA/DARPP-32 and mTOR pathways

Antipsychotics share the common pharmacological feature of antagonizing the dopamine 2 receptor (D2R) which is abundant in the striatum and involved in both the therapeutic and side effects of this drugs class. Pharmacological blockade of striatal D2R, by disinhibiting the D2R-containing medium-size spiny neurons (MSNs), leads to a plethora of molecular, cellular and behavioral adaptations which are central in the action of antipsychotics. Here, we focused on the cell type-specific (D2R-MSNs) regulation of some striatal immediate early genes (IEGs), such as cFos, Arc and Zif268. Taking advantage of transgenic mouse models, pharmacological approaches and immunofluorescence analyses, we found that haloperidol-induced IEGs in the striatum required the synergistic activation of A2a (adenosine) and NMDA (glutamate) receptors. At the intracellular signaling level, we found that the PKA/DARPP-32 and mTOR pathways synergistically cooperate to control the induction of IEGs by haloperidol. By confirming and further expanding previous observations, our results provide novel insights into the regulatory mechanisms underlying the molecular/cellular action of antipsychotics in the striatum.

neuroscience↗