Biology subjects

Trifilieff, P.

Publications and source records attributed to Trifilieff, P..

10 recordsLinked to original sources

bioRxiv2025

A role for prefrontal dopamine signaling in control of goal-directed actions

Impairments in behavioral flexibility commonly found across psychiatric disorders have often been attributed to a dysfunction of the medial prefrontal cortex (mPFC), notably in relation with altered dopamine transmission. However, how dopamine transmission shapes neuronal activity in the mPFC to allow adapting to a changing situation remains largely elusive. Here, we show that dopamine dynamics in the mPFC encode the value of instrumental actions, in particular during reversal learning. Such signal shapes the activity of mPFC dopaminoceptive neurons during reversal learning through the recruitment of heteromers formed by dopamine D1 and D2 receptors with NMDA receptors. In accordance, blockade of either D1/NMDA or D2/NMDA heteromers in the mPFC selectively impairs reversal of outcome identities but not learning and expression of initial action-outcome associations. Our findings provide mechanistic evidence for a central role of dopamine in the mPFC to allow updating goal-directed actions.

neuroscience↗

bioRxiv2025

Developmental vitamin A deficiency induces sex-specific reward processing alterations through a dysregulation of the mesolimbic dopamine transmission in mice

Neurodevelopmental psychiatric diseases such as schizophrenia or affective disorders share common symptomatic dimensions, in particular reward processing dysfunctions, associated with dysregulation of dopamine (DA) transmission. Retinoic acid (RA) homeostasis is altered across psychiatric disorders but whether impaired developmental RA signaling impacts the functionality of DA-related reward processing at adulthood remains poorly explored. Herein, we explored in male and female mice how developmental vitamin A deficiency (VAD), as a model of blunted RA signaling, could impact motivational processes through a modulation of mesolimbic DA transmission. Behavioral performances were evaluated using operant conditioning tasks, parallel with investigations of the integrity of DA transmission through biochemical analyses of markers of DA transmission and measures of DA dynamics using DA biosensor coupled with fiber photometry. Finally, chemogenetic manipulation of the mesolimbic DA pathway was used to normalize DA transmission and assess the effect on motivational performance in VAD offspring. Developmental VAD induced sex-specific alterations of reward-related processes at adulthood. Indeed, while female behavioral performances were spared, VAD males exhibited elevated instrumental performance and impulsivity. These behavioral alterations were coherent with reduced DA transporter (DAT) expression and increased DA dynamic in the mesolimbic pathway. Strikingly, chemogenetic inhibition of the mesolimbic DA pathway normalized motivational performance in VAD males. Our results show that developmental RA hyposignaling induces sex-specific reward processing alterations in adulthood through hyperactivity of the mesolimbic DA pathway. Our data support that developmental impairment in RA signaling might be at the core of reward-related symptoms across psychiatric disorders.

neuroscience↗

bioRxiv2025

Obesogenic diet impairs memory consolidation via the hippocampal endocannabinoid system

Although obesogenic high-fat/high-sugar diets impair memory function in humans and rodents, the underlying mechanisms remain elusive. Given that the brain endocannabinoid system and type-1 cannabinoid receptors (CB1R) control memory processes and are overactive under obesogenic conditions, we studied whether the effects of obesogenic diet consumption on memory function are dependent on this system. Using an object recognition memory (ORM) task in male mice, we showed that CB1R activity is required for obesogenic diet-induced impairment of long-term memory performance. This impairment was prevented by post-training systemic blockade of CB1R, which also normalized training-induced hippocampal cellular and synaptic overactivation. Consistently, obesogenic diet potentiated the increase of hippocampal endocannabinoid levels and enhanced CB1R expression induced by ORM, and genetic CB1R deletion from hippocampal glutamatergic neurons abolished diet-induced memory deficits. Strikingly, obesogenic diet enhanced the hippocampal mTOR pathway in a CB1R-dependent manner, and pharmacological mTOR inhibition after training rescued diet-induced ORM consolidation deficits. Together, these results establish how an obesogenic environment can lead to hippocampal overactivation of the endocannabinoid system and of the mTOR pathway to eventually impair memory consolidation. Thus, these results shed light on the mechanisms of diet-induced cognitive alterations and may pave the way to novel therapeutic strategies. HighlightsO_LIObesogenic diet induces long-term memory deficits, which are rescued by CB1R blockade C_LIO_LICB1R blockade rescues diet-induced aberrant hippocampal activity/plasticity after training C_LIO_LIObesogenic diet enhances hippocampal endocannabinoid levels and CB1R after training C_LIO_LIDeletion of hippocampal CB1R rescues diet-induced long-term memory deficits C_LIO_LIObesogenic diet enhances hippocampal mTOR phosphorylation after training C_LIO_LImTOR inhibition rescues diet-induced memory consolidation deficits C_LI

neuroscience↗

bioRxiv2023

Membrane lipid poly-unsaturation selectively affects ligand induced dopamine D2 receptor internalization

The brain is highly enriched in poly-unsaturated fatty acids (PUFAs) and their deficiency has been associated with several neuropsychiatric disorders. Here, we demonstrate that the Dopamine receptor D2 (D2R), a class A G protein coupled receptor (GPCR) which is a main target of antipsychotics, displays unique sensitivity to membrane PUFA composition. We found that membrane enrichment with either of two distinct PUFAs significantly impairs agonist-induced D2R endocytosis in HEK-293 cells and cortical neurons. This treatment does not affect clathrin-mediated endocytosis or the internalization of several other GPCRs. Moreover, we show that D2R clustering at endocytic pits is not affected, but that recruitment of {beta}-arrestin2 is strongly impaired and endocytic vesicle formation is slowed down. Finally, mutation of key residues in intracellular loop 2 abolishes the sensitivity of D2R endocytosis to PUFA enrichment. We conclude that D2R trafficking is uniquely dependent on membrane PUFAs, which could influence its role in the control of brain function and behavior.

cell biology↗

bioRxiv2023

Dual role of striatal astrocytes in behavioral flexibility and metabolism in the context of obesity

Brain circuits involved in metabolic control and reward-associated behaviors are potent drivers of feeding behavior and are both dramatically altered in obesity, a multifactorial disease resulting from genetic and environmental factors. In both mice and human, exposure to calorie-dense food has been associated with increased astrocyte reactivity and pro-inflammatory response in the brain. Although our understanding of how astrocytes regulate brain circuits has recently flourish, whether and how striatal astrocytes contribute in regulating food-related behaviors and whole-body metabolism is still unknown. In this study, we show that exposure to enriched food leads to profound changes in neuronal activity and synchrony. Chemogenetic manipulation of astrocytes activity in the dorsal striatum was sufficient to restore the cognitive defect in flexible behaviors induced by obesity, while manipulation of astrocyte in the nucleus accumbens led to acute change in whole-body substrate utilization and energy expenditure. Altogether, this work reveals a yet unappreciated role for striatal astrocyte as a direct operator of reward-driven behavior and metabolic control.

physiology↗

bioRxiv2022

Obesogenic diet induces circuit-specific memory deficits in mice

Obesity is associated with neurocognitive dysfunction, including memory deficits. This is particularly worrisome during adolescence, which represents a crucial period for maturation of brain structures, such as the hippocampus which are crucial for cognition. In rodent models, we recently reported that memory impairments induced by obesogenic high-fat diet (HFD) intake during the periadolescent period can be reversed by chemogenetic manipulation of the ventral hippocampus (vHPC). Here, we used an intersectional viral approach in HFD-fed male mice to chemogenetically inactivate specific vHPC efferent pathways to nucleus accumbens or medial prefrontal cortex during memory tasks. We first demonstrated that HFD enhanced activation of both pathways after training and that our chemogenetic approach was effective in normalising this activation. Inactivation of the vHPC-nucleus accumbens pathway rescued HFD-induced deficits in recognition but not location memory. Conversely, inactivation of the vHPC-medial prefrontal cortex pathway restored location but not recognition memory impairments produced by HFD. Either pathway manipulation did not affect exploration, locomotion or anxiety-like behaviour. These findings suggest that HFD intake throughout adolescence impairs different types of memory through overactivation of specific hippocampal efferent pathways and that targeting these overactive pathways has therapeutic potential.

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

Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling

The heterogenous and dynamic constitution of the membrane fine-tunes signal transduction. In particular, the polyunsaturated fatty acid (PUFA) tails of phospholipids influence the biophysical properties of the membrane, production of second messengers, or membrane partitioning. Few evidence mostly originating from studies of rhodopsin suggest that PUFAs directly modulate the conformational dynamic of transmembrane proteins. However, whether such properties translate to other G protein-coupled receptors remains unclear. We focused on the dopamine D2 receptor (D2R), a main target of antipsychotics. Membrane enrichment in n-3, but not n-6, PUFAs potentiates ligand binding. Molecular dynamics simulations show that the D2R preferentially interacts with n-3 over n-6 PUFAs. Furthermore, even though this mildly affects signalling in heterologous systems, in vivo n-3 PUFA deficiency blunts the effects of D2R ligands. These results suggest that n-3 PUFAs act as allosteric modulators of the D2R and provide a putative mechanism for their potentiating effect on antipsychotic efficacy.

cell biology↗

bioRxiv2020

Synaptic and supra-synaptic organisation of the dopaminergic projection to the striatum.

Dopamine is a monoamine involved in reward processing and motor control. Volume transmission is thought to be the mechanism by which monoamines modulate effector systems at glutamate and GABA synapses. Hence, dopamine synapses are scarcely described. We applied fluorescence activated synaptosome sorting to explore the features of the dopaminergic synaptome. We provide the proteome of striatal dopaminergic synapses with 57 proteins specifically enriched. Beyond canonical markers of dopamine neurotransmission (Th, Slc6a3/DAT, Slc18a2/VMAT2), we validated 6 proteins belonging to pre- and postsynaptic sides (Cpne7, Apba1/Mint1, Cadps2, Cadm2/SynCAM 2, Stx4 and Mgll). Moreover, dopaminergic varicosities adhere to both a post-synapse with cognate receptors and glutamatergic, GABAergic or cholinergic synapses in structures we named dopaminergic "hub synapses". Markers of presynaptic vesicles and active zone, post-synaptic density and spine apparatus, are significantly increased upon association with dopamine inputs in hubs. Thus neuromodulation frequently operates from hub synapses affecting associated synapses and is not solely dependent on volume transmission. Finally, FASS provides a new framework for the exploration of dopaminergic synapses and more generally for discrete synapse populations ex-vivo. HighlightsO_LIA first proteome of dopaminergic synapses in the striatum C_LIO_LIStriatal dopaminergic synaptosomes display post-synaptic cognate receptors C_LIO_LIDopaminergic projections build hub synapses with excitatory, inhibitory, and cholinergic projections. C_LIO_LICortico-striatal synaptic scaffolds are strengthened upon association in hub synapses. C_LI

neuroscience↗

bioRxiv2019

Detecting GPCR Complexes in Postmortem Human Brain with Proximity Ligation Assay and a Bayesian Classifier

Despite the general controversy regarding the existence and physiological relevance of Class A GPCR dimerization, there is substantial evidence for functional interactions between dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AR). A2AR-D2R complexes have been detected in rodent brains by proximity ligation assay (PLA), but their existence in the human brain is yet to be demonstrated. In this study, we used brightfield PLA, combined with a systematic sampling and a parameter-free naive Bayesian classifier, and demonstrated proximity between D2R and A2AR in the adult human ventral striatum, consistent with their colocalization within complexes and the possible existence of D2R-A2AR heteromers. These methods are applicable to the quantitative analysis of proximity of two proteins and the expression of individual proteins.\n\nMethod SummaryBrightfield proximity ligation assay (PLA) was used to assess the expression of G protein-coupled receptors and their proximity in postmortem adult human brains. A novel automated machine learning method (Bayesian Optimized PLA Signal Sorting) was developed to automatically quantify brightfield PLA data.

neuroscience↗