Biology subjects

Cannich, A.

Publications and source records attributed to Cannich, A..

8 recordsLinked to original sources

bioRxiv2026

Ventromedial striatal GABAergic interneurons sex-dependently gate cost-benefit choices between food and exercise

Healthy energy balance relies on an equilibrated trade-off between the respective drives for food and exercise. However, the motivation circuitry underlying the choice between these two rewards remains unknown. Here, we developed a neuroeconomic model wherein mice living in operant chambers needed to choose between standard food and wheel running under increasing effort demands. Reward seeking resistance to increasing costs was then quantified using feeding and exercise essential values (EVs). Through conditional genetics and viral approaches, we show that cannabinoid type-1 receptors (CB1Rs) located on GABAergic neurons gate in necessary and sufficient manners exercise EV, exercise preference over feeding and exercise duration per rewarded sequence. Further, we report that these GABAergic neurons are located in the ventromedial striatum in males, but not females. CB1R deletion from medium spiny neurons did not impact exercise motivation, revealing an unforeseen role for ventromedial striatal GABAergic interneurons in effort-based decision-making between food and exercise.

neuroscience↗

bioRxiv2025

Pregnenolone and AEF0117 block cannabinoid-induced hyperlocomotion through GSK3β signaling at striatopallidal neurons

Administration of {Delta}9-tetrahydrocannabinol (THC), the main psychoactive component of the plant Cannabis sativa, can induce psychotic symptomatology in humans and a large spectrum of acute psychotic-like behaviors in mice, including hyperlocomotion observed at low dose of THC (0.3 mg/kg). The cellular and molecular substrates of this effect have not been fully identified yet. Here we demonstrate that THC-induced hyperlocomotion depends on plasma membrane CB1R, which regulate the {beta}-arrestin 1/Akt/GSK3{beta} signaling pathway in D2R-positive neurons of the dorsal striatum forming the striatopallidal pathway of the basal ganglia. Pregnenolone (PREG) and its clinically developed analog, AEF0117, which are signaling specific inhibitors of CB1R (CB1-SSi), prevented GSK3{beta}-dependent psychomotor stimulation induced by THC. Overall, this work highlights a novel intracellular mechanism of CB1R, thereby revealing a neuronal pathway underlying an important but still underexplored effect of THC and cannabis consumption, which could help the development of innovative therapeutic concepts against psychotic conditions.

neuroscience↗

bioRxiv2023

A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes

Control of brain energy metabolism and regulation of synaptic activity through gliotransmission are two important ways, through which astrocytes contribute to mental functions. However, the potential functional and molecular links between these two astrocyte-dependent processes have been scantly explored. Here we show that a lactate-dependent shift of glycolysis underlies the production of the gliotransmitter D-serine by acute activation of astrocyte type-1 cannabinoid (CB1) receptors, thereby gating synaptic and cognitive processes. Acute cannabinoid application causes a CB1 receptor-dependent rapid and reversible increase of lactate production and release in primary astrocyte cultures. As shown before, mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) were impaired in a novel object recognition (NOR) memory task. This phenotype was rescued not only by the gliotransmitter D-serine, but also by its precursor L-serine. Surprisingly, the administration of lactate and of an agonist of the lactate receptor HCAR1 also reverted the memory impairment of GFAP-CB1-KO mice. This rescue effect was abolished by in vivo blockade of the astrocyte-specific phosphorylated pathway (PP), which diverts glycolysis towards L-serine synthesis, suggesting that lactate signaling might promote the accumulation of this amino acid. Consistent with this idea, lactate and HCAR1 agonism increased the co-agonist occupancy of CA1 post-synaptic hippocampal NMDA receptors. This effect of lactate was abolished by blockade of PP. By establishing a mechanistic link between lactate production and signaling, serine availability, synaptic activity and behavior, these results reveal an unforeseen functional connection between energy metabolism and gliotransmission to control cognitive processes.

neuroscience↗

bioRxiv2022

Cannabinoids regulate an insula circuit controlling water intake

The insular cortex, or insula, is a large brain region involved in the detection of thirst and the control of water intake. However our understanding of the topographical, circuit and molecular mechanisms the controlling water intake within the insula remains parcellated. We found that type-1 cannabinoid receptors (CB1) within the insular cortex participate to the regulation of water intake, and deconstructed circuit mechanisms of this control. Topographically, we revealed that the activity of excitatory neurons in both anterior (aIC) and posterior (pIC) insula increases in response to water intake, yet removal of CB1 receptors only in the pIC decreases water intake. Interestingly, we found that CB1 receptors are highly expressed in insula projections to the basolateral amygdala (BLA), while undetectable in the neighboring central part of the amygdala. Thus, we imaged the neurons of the anterior or posterior insula targeting the BLA (aIC-BLA and pIC-BLA), and found they oppositely respond to water intake, respectively decreasing and increasing their activity upon water drinking. Consistently, chemogenetic activation of pIC-BLA neurons decreased water intake. Finally, we uncovered CB1-dependent short term synaptic plasticity (depolarization-induced suppression of excitation, DSE) selectively in pIC-BLA, compared to aIC-BLA synapses. Altogether, our results support a model where CB1 signaling in the pIC-BLA pathway exerts a positive control on water intake.

neuroscience↗

bioRxiv2020

Astroglial calcium transfer from endoplasmic reticulum to mitochondria determines synaptic integration

Intracellular calcium signaling underlies the astroglial control of synaptic transmission and plasticity. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is currently unexplored. We found that the activation of astrocyte mitochondrial-associated CB1 receptors (mtCB1) determines MERCs-dependent intracellular calcium signaling and synaptic integration. The stimulation of mtCB1 receptors promotes calcium transfer from the endoplasmic reticulum to mitochondria through specific mechanisms regulating the activity of the mitochondrial calcium uniporter (MCU) channel. Physiologically, mtCB1-dependent mitochondrial calcium uptake determines the precise dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization. Accordingly, electrophysiological recordings in hippocampal slices showed that genetic exclusion of mtCB1 receptors or specific astroglial MCU inhibition blocks lateral synaptic potentiation, a key example of astrocyte-dependent integration of distant synapses activity. Altogether, these data reveal an unforeseen link between astroglial MERCs and the regulation of brain network functions.

neuroscience↗

bioRxiv2020

POMC neurons functional heterogeneity relies on mTORC1 signaling

Hypothalamic Pro-opiomelanocortin (POMC) neurons are classically known to trigger satiety. However, they encompass heterogeneous subpopulations whose functions are unknown. Here we show that POMC neurons releasing GABA, glutamate or both neurotransmitters possess distinct spatial distribution, molecular signatures and functions. Functional specificity of these subpopulations relies on the energy sensor mechanistic Target of Rapamycin Complex 1 (mTORC1), since pharmacological blockade of mTORC1, by mimicking a cellular negative energy state, simultaneously inhibited POMC/glutamatergic and activated POMC/GABAergic neurons. Chemogenetics and conditional deletion of mTORC1 then demonstrated that mTORC1 blockade in POMC neurons causes hyperphagia. This is due to decreased POMC-derived anorexigenic -melanocyte-stimulating hormone and the recruitment of POMC/GABAergic neurotransmission, which is restrained by cannabinoid type 1 receptor signaling. Genetic inhibition of glutamate release from POMC neurons also produced hyperphagia, recapitulating the phenotype caused by mTORC1 blockade. Altogether, these findings pinpoint the molecular mechanisms engaged by POMC neurons to oppositely control feeding, thereby challenging conventional views about their functions.

neuroscience↗

bioRxiv2019

Specific hippocampal interneurons shape consolidation of recognition memory

A complex array of different inhibitory interneurons tightly controls hippocampal activity, but how such diversity specifically impacts on memory processes is scantly known. We found that a small subclass of type-1 cannabinoid receptor (CB1)-expressing hippocampal interneurons determines episodic-like memory consolidation by linking dopamine D1 receptor signaling to GABAergic transmission. Mice lacking CB1 in D1-positive cells (D1-CB1-KO) displayed impaired long-term, but not short-term, object recognition memory. Re-expression of CB1 in hippocampal, but not striatal, D1-positive cells rescued this memory impairment. Learning induced a facilitation of in vivo hippocampal long-term potentiation (LTP), which was abolished in mutant mice. Chemogenetic and pharmacological experiments revealed that both CB1-mediated memory and associated LTP facilitation involves the local control of GABAergic inhibition in a D1-dependent manner. This study reveals that CB1-/D1-expressing interneurons shape hippocampal circuits to sustain recognition memory, thereby identifying a mechanism linking the diversity of hippocampal interneurons to specific behavioral and cognitive outcomes.

neuroscience↗

bioRxiv2019

Top-down control of water intake by the endocannabinoid system

Water intake is regulated by neocortical top-down circuits, but their identity and the cellular mechanisms involved are scantly known. Here, we show that endogenous activation of type-1 cannabinoid receptors (CB1) promotes water intake and that endocannabinoid modulation of excitatory projections from the anterior cingulate cortex to the basolateral amygdala is sufficient to guarantee physiological drinking. These data reveal a new circuit involved in the homeostatic control of water intake.

neuroscience↗