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Marsicano, G.

Publications and source records attributed to Marsicano, G..

At least 19 recordsLinked to original sources

A Female-Specific Microglial Redox Program Gates Susceptibility to Obesity

Chronic consumption of energy-dense, high-fat foods persistently exposes hypothalamic circuits that govern body weight to nutrient excess, progressively altering their activity and thereby promoting obesity. Microglia, the brain resident immune cells, sense circulating lipids, but how their intracellular metabolic programs adapt to chronic dietary excess, and how this contributes to obesity risk, is unclear. Here, we reveal a sex-dependent control of calorie overload by hypothalamic microglial cells. In females, but not males, microglia engage a protective metabolic program with increased antioxidant capacity and mitochondrial network remodeling, conferring resistance to early weight gain. Over time, activation of mTORC1 signaling in microglia disrupts mitochondrial functions and dismantles this transient resilience, culminating in weight gain. These findings identify microglial mTORC1 as a sex-specific switch between resilience and vulnerability to obesity and position microglial metabolism as a tractable target for sex-informed weight control.

neuroscience↗

Endocannabinoid-dopamine interactions mediate incidental associations in the hippocampus

Reinforced conditioning allows individuals predicting future events with high confidence. However, many daily behaviours rely on unreinforced connections of neutral stimuli, called Incidental Associations (IAs), which enhance predictive capacity in unstable environments and are observed across species. IAs can be studied through sensory preconditioning paradigms, where two neutral stimuli (S1/S2) are presented together in a preconditioning phase, followed by classical conditioning of S1 with a potent reinforcer. As a result, subjects present a direct response to the S1 stimulus, but also display mediated responses to the S2 stimulus never explicitly reinforced, indicating IA formation during preconditioning. Our previous work demonstrated that type-1 cannabinoid receptors (CB1 receptors) in the hippocampus are essential for this IA formation. As dopamine signaling is also important for this process, we investigate the role of interactions between these dopamine-cannabinoid systems in IA memory formation in the hippocampus. Extending our previous work on odor-taste association, using light-sound association we showed that global CB1 receptor knock-out or specific hippocampal CB1 receptor deletion also blocked mediated responses to sound (S2) while direct response to light (S1) was unaltered. Focusing on dopamine, we then found hippocampal dopaminergic activity is enhanced during paired presentations of S1 and S2 and that blockade of dopamine D1 receptor during preconditioning S1-S2 associations abolished mediated response to S2. Interestingly, mice lacking CB1 receptors specifically in D1-receptor-expressing cells (D1-CB1-KO) failed to show mediated responses for either light-sound or odor-taste associations, identifying this CB1 receptor population as critical for IA formation. Enhanced activation of CB1 receptors, through either increase of endocannabinoids (using degradation enzyme inhibition) or exogenous stimulation by cannabis-derived Delta-9-tetrahydrocannabinol (THC), was able to promote the formation of IAs under insufficient conditions. The effect of endogenous CB1 activation, but not THC, was blocked in D1-CB1-KO mice indicating that IA-facilitation by endogenous and exogenous receptor activation rely on different mechanisms. Overall, these data uncover new mechanisms underlying unreinforced associative learning.

neuroscience↗

Selective Shank3 Deletion in Glutamatergic Neurons of the Anterior Insular Cortex Induces Autism-Related Behavior and Circuit Dysfunction

Mutations in the synaptic scaffold protein SHANK3 represent one of the most frequent genetic causes of autism spectrum disorder (ASD), yet the circuit mechanisms through which SHANK3 dysfunction leads to behavioral alterations remain incompletely understood. The anterior insular cortex (aINS) is a key integrative hub involved in socio-emotional processing, anxiety regulation, and social cognition, a group of behaviors frequently disrupted in ASD. Here, we investigated whether selective deletion of SHANK3 signaling in glutamatergic neurons of the aINS is sufficient to produce ASD-relevant behavioral and circuit phenotypes. Using conditional Shank3flox4-22 mice combined with stereotaxic viral delivery of Cre recombinase under the CaMKII promoter, we selectively deleted Shank3 in glutamatergic neurons of the aINS. Behavioral phenotyping revealed increased anxiety-like behavior, enhanced repetitive behavior, and impaired social memory, while sociability and locomotor activity were largely preserved. These behavioral alterations were accompanied by genotype-dependent differences in neuronal activity revealed by calcium imaging, indicating disrupted activity dynamics in insular glutamatergic neurons following Shank3 deletion. To assess the broader relevance of these findings, we evaluated the behavioral profile of BTBR T+ Itpr3tf/J mice, a model of idiopathic ASD, in the same battery of behavioral tests. Several behavioral alterations observed following insular Shank3 deletion partially overlapped with those present in BTBR mice, supporting the relevance of aINS Shank3 in ASD-related phenotypes. Together, these findings identify glutamatergic neurons of the aINS as a critical locus through which Shank3 dysfunction can disrupt socio-emotional, cognitive, and repetitive behaviors. Our results highlight the aINS as a key circuit node contributing to ASD-related behavioral alterations and provide mechanistic insight into how synaptic scaffold disruption leads to circuit dysfunction and produces behavioral alterations.

neuroscience↗

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↗

Oscillatory and aperiodic neural dynamics shape temporal perception and weighting of perceptual priors in ADHD profiles

Attention-deficit/hyperactivity disorder (ADHD) is characterized by an atypically compressed sense of time, yet the neural mechanisms underlying this atypical temporal perception remain poorly understood. Temporal perception depends on the brains ability to organize sensory input into coherent experiences, ensuring perceptual stability despite uncertainty. Oscillations in the alpha band (8-13 Hz) and aperiodic 1/f dynamics have been proposed as key neural mechanisms through which the visual system orchestrates sensory information over time. Individuals with ADHD show atypicalities in these neural dynamics, but how these features relate to ADHD differences in temporal processing remains unexplored. Here, we combined a sustained visual temporal integration task with resting-state EEG to test whether oscillatory and aperiodic neural dynamics jointly account for temporal processing performance across neurotypical participants with self-reported ADHD traits (n = 83). Higher ADHD features in both inattentive and hyperactive-impulsive domains were associated with narrower temporal binding windows and reduced serial dependence on prior perception, indicating sharper temporal resolution but diminished perceptual stability. Resting-state EEG revealed systematically faster individual alpha frequency (IAF) and flatter aperiodic spectra in individuals with higher ADHD traits. Mediation analyses showed that faster IAF explained ADHD-related reductions in temporal integration thresholds and serial dependence, whereas increased neural noise selectively amplified perceptual history-dependent biases. These findings reveal distinct oscillatory and aperiodic neural pathways through which ADHD features shape temporal perception, suggesting a multidimensional neural architecture underlying atypical temporal processing in ADHD.

neuroscience↗

Alpha oscillations and aperiodic neural dynamics jointly predict visual temporal resolution, confidence, and dependence on prior experience

Perception requires integrating sensory input over time to construct coherent experiences. Alpha oscillations have been proposed to define the temporal resolution of perception, yet empirical evidence remains inconsistent. Here we combined a sustained visual integration paradigm with resting-state EEG to investigate how oscillatory and aperiodic neural dynamics jointly shape temporal perception. Participants (n=83) viewed alternating gratings that varied in alternation speed, producing the perception of either a fused plaid (integration) or two interchanging gratings (segregation). Faster individual alpha rhythms were associated with narrower temporal integration windows, and a steeper aperiodic spectrum predicted greater perceptual precision. Moreover, individuals with slower alpha frequencies and flatter spectra showed stronger reliance on prior judgments, suggesting reduced sensory precision and increased weighting of recent experience. Subjective confidence increased with faster alpha rhythms, reflecting the clarity of sensory evidence and its consistency with prior responses. Together, these findings show that the perceptual interpretation, confidence and previous experience effects in temporal integration reflect the joint influence of alpha rhythms and aperiodic neural activity. Mechanistically, faster alpha rhythms and lower neural noise may enhance perceptual resolution by generating more precise sampling frames per time unit, leading to finer temporal perception, reduced reliance on prior experience, and greater confidence.

neuroscience↗

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

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Astrocyte CB1 receptors drive blood-brain barrier disruption in CNS inflammatory disease

Reactive astrocytes shape central nervous system (CNS) inflammation and participate in myelin damage and repair mechanisms in multiple sclerosis (MS). Through the activation of cannabinoid CB1 receptors (CB1R) expressed by neurons and oligodendrocyte lineage cells, endocannabinoid signaling restricts neurodegeneration and promote remyelination in preclinical MS models. However, despite accumulating evidence that supports a crucial role for these receptor populations in brain physiology and pathology, the implications of astrocyte CB1R signaling in MS initiation and progression remain uncertain. Using complementary in vivo disease models, here we investigated the effects of targeted genetic deletion of astrocytes CB1R on the expression of MS-like pathology in mice. Interestingly, astrocyte-specific deletion of CB1R reduced demyelinating neuropathology, attenuated astrocyte reactivity and improved clinical deficits during the time-course of experimental autoimmune encephalomyelitis (EAE). Mice with astrocyte CB1R inactivation displayed unaltered oligodendrocyte populations both in EAE lesions and in lysolecithin-induced remyelinating spinal cord lesions, likely excluding that astrocyte CB1R modulate myelin repair processes. Conversely, inactivation of CB1R in astroglial cells restricted humoral and leukocyte parenchymal infiltration and reduced the expression of vascular effectors in EAE lesions. Finally, loss of blood-brain barrier (BBB) function induced by cortical microinjection of VEGF-A was less severe in GFAP-CB1R-KO mice. These results show that astrocyte CB1R signaling constitutes a significant pro-inflammatory mechanism in MS and bring to light a deleterious role for endocannabinoid-mediated modulation of astroglial cells with potential implications in the etiopathology and therapy of neuroinflammatory disorders.

neuroscience↗

Atypical weighting of sensory evidence and priors in causality perception along the autism-schizotypy continuum

The brain constructs a perceptual interpretation of the world by integrating sensory input with prior knowledge and expectations. Causality perception, a core example of this inferential process, enables observers to infer cause-effect relationships, such as whether a moving object causes another to move. Traditionally considered a low-level visual computation, causality perception is increasingly recognized as shaped by top-down dynamics, perceptual history, and individual predictive processing styles. Here, we examined how prior experience and cognitive-perceptual traits shape causal inference in 150 neurotypical individuals, using data-driven clustering to stratify participants along the autism-schizotypy (ASD-SSD) spectrum. Participants viewed dynamic collision events in which a moving circle contacted a stationary one, followed by variable temporal lags before the second objects motion, and judged whether the interaction appeared causal or non-causal. Causality judgments were influenced by both physical timing (sensory-driven) and serial dependence on previous perceptual decisions (prior-driven). Hierarchical drift diffusion modeling (HDDM) revealed that SSD-like individuals showed a strong prior bias toward causality, greater serial dependence, and lower decision thresholds, reflecting a prior-dominated perceptual style. Conversely, ASD-like individuals exhibited reduced influence of perceptual history and higher decision thresholds, reflecting a conservative, data-driven style. Crucially, prior bias, serial dependence, and decision-making dynamics were strongly interrelated, revealing a hierarchical structure to perceptual inference across neurocognitive profiles. These findings demonstrate that causality perception emerges from predictive processes operating at multiple timescales and shaped by individual differences in neurocognitive style and perceptual flexibility. Significance StatementAccurate causality perception is a fundamental building block of cognition, supporting our ability to parse the sensory world, guide action, and construct coherent models of the environment. It provides a key example of perceptual inference, and thus how the brain integrates sensory input, prior expectations, and recent experience to shape subjective perception. Here, we show that causality perception is not fixed, but varies systematically across individuals, mirroring broader variability in how different neurocognitive architectures balance sensory evidence and prior expectations along the autism-schizotypy (ASD-SSD) spectrum within the general population. By combining psychophysical data with hierarchical computational modeling, we reveal distinct perceptual inference styles along the autism-schizotypy continuum, ranging from sensory-driven to prior-driven processing. These findings advance predictive processing accounts of individual variability and offer new insights into the mechanisms supporting flexible and adaptive perception in neurodiverse populations.

neuroscience↗

NEUROGLIAL CB1 RECEPTORS CONTROL NAVIGATION STRATEGIES

Navigation and memory functions are essential for survival and are regulated by the hippocampus. These processes are tightly controlled, and one of the key modulators involved is the endocannabinoid system, particularly through the cannabinoid receptor type-1 (CB1). CB1 is widely expressed in various hippocampal cell types. While it is known that CB1 participates in memory processes, its specific roles in different cell types and how these roles may differ between sexes remain unclear. This study investigates how CB1 signaling in the hippocampus, in both, cell-type-specific and sex-dependent manner, contributes to navigation and memory. To this end, we selectively deleted CB1 receptors from neurons, CAMKII-expressing neurons, and astrocytes from the hippocampus of adult male and female mice. We then assessed its effect on a broad range of behaviors, including innate emotional responses, memory, navigation, and other hippocampus-related functions such as nesting. Deletion of CB1 in CAMKII-expressing neurons produced a pronounced effect in males, leading to increased anxiety and impairments in both reference and spatial memory. These mice also showed altered performance in the Barnes maze, relying less on spatial strategies. By contrast, females were less affected by this specific deletion. Interestingly, only deletion of CB1 from astrocytes led to spatial memory impairments in females, which also showed reduced LTP and a decreased reliance on spatial strategies in the Barnes maze. In conclusion, our findings show that neuronal CB1 receptors are critical for the spatial navigation strategy in males, while astrocytic CB1 receptors play a key role in memory processes both in males and females.

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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↗

Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism

Astrocytes are known to modulate neuronal activity by gliotransmission and through metabolic regulation. However, the connection between these two processes is still poorly defined. In this work we show that the p110 isoform of the phosphatidylinositol 3-kinase (PI3K) in astrocytes is required for long-term potentiation (LTP) and has an impact on learning and memory. Using a specific deletion of p110 from hippocampal astrocytes in adult mice, we found that LTP depends on astrocytic p110 to sustain D-serine levels for the activation of NMDA receptors during LTP induction. This requirement is based on the L-serine biosynthetic pathway of the astrocyte, which is defective in the absence of p110 because of a reduced glycolytic flux. Accordingly, the behavioral impairment in mice lacking p110 can be rescued by in vivo administration of L-serine. These results link for the first time the function of PI3K in astrocytes to cerebral metabolism and its influence in synaptic plasticity and cognition.

neuroscience↗

Mice-side bias: Deliberative decision making in a model of rule revision reveals 'myside' confirmation bias-like cognitive processes in mice.

Confirmation or myside bias--over-valuation of novel information which confirms previously internalized cognitive content (prior beliefs, rules of conduct, etc.) and corresponding under-valuation of disconfirming novel information--constitutes a serious obstacle to adaptive revision of our beliefs, especially in ambiguous or complex epistemic environments. Indeed, myside bias has become a particularly pernicious fact of societal cohesion, contributing to the propagation of fake news, to social polarization, and even to the replication crisis in experimental science. By contrast, relatively little is understood about either its neurocognitive underpinnings or its evolution, one reason for this being that the potential presence of myside bias-like tendencies in non-human animals has never been directly tested. Hence, in order to advance research in both of these directions, we designed a novel mouse model of everyday-like rule revision such that the dynamic model environment would be sufficient to call out myside bias-like behaviors providing that mice did indeed possess the particular kind of competing neurocognitive processes necessary for it to manifest. Here, we both validate that model and provide the first behavioral descriptions of myside confirmation bias-like deliberative profiles in a non-human animal. Notably, we observe that this bias does not manifest in a merely unreflective or heuristic/ system 1 manner but rather also emerges through and indeed increases deliberative behaviors, especially in contexts of low representational resolution. Several other parallels with findings from human studies of myside bias are also detailed in the discussion.

neuroscience↗

Cannabinoid type-1 (CB1) receptors in glial cells promote neuromuscular junction repair following nerve injury.

Cannabinoids are frequently used in the treatment of neuropathic pain related to nerve injury. However, despite evidence for their roles in the regulation of axonal guidance and synapse formation during development of the central nervous system (CNS), their possible involvement in response to peripheral nerve injury remains poorly defined and the knowledge of its role is mostly related to the peripheral sensory system. Following nerve injury, contemporary to axonal repair, massive morphological and functional changes reshape synaptic elements at neuromuscular junctions (NMJs) aiming to promote their reinnervation. This process is mediated in part by Perisynaptic Schwann cells (PSCs), glial cells at the NMJ essential for its maintenance and repair. Here we investigated the novel role of Cannabinoid type-1 receptor (CB1R) at NMJ, in particular on PSCs, during motor nerve recovery following nerve injury. Using morphological analysis, we studied the consequences of CB1R pharmacological and genetic blockade following denervation and reinnervation in adult NMJs. CB1R blockade caused an acceleration of the denervation process followed by a great delay in reinnervation as indicated by a significant percentage of denervated NMJs, accompanied by a decrease of mono- and poly-innervated NMJs. Remarkably, a similar phenomenon was observed when CB1R is selectively knocked-out in glia, indicating that the protective actions of these receptors are largely glia-dependent. These data highlight a novel role of the endocannabinoid system at NMJs, where the CB1Rs on PSCs can control NMJ denervation and reinnervation following nerve injury. A better understanding of the functional mechanisms underlying CB1R role in NMJ repair may contribute to finding a new pharmacological treatment having a dual role in improvements of motor recovery and in pain-related relief.

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Autoimmune inflammation triggers aberrant astrocytic calcium signaling to impair synaptic plasticity

Cortical pathology involving inflammatory and neurodegenerative mechanisms is a hallmark of multiple sclerosis (MS) and a correlate of disease progression and cognitive decline. Astrocytes play a pivotal role in MS initiation and progression but astrocyte-neuronal network alterations contributing to gray matter pathology remain undefined. Here we measured astrocytic calcium in the experimental autoimmune encephalomyelitis (EAE) model of MS using fiber photometry in freely behaving mice and two-photon imaging ex vivo. We identified the emergence of spontaneously hyperactive cortical astrocytes displaying calcium transients of increased duration as well as dysfunctional responses to cannabinoid, glutamate and purinoreceptor agonists during acute EAE disease. Deficits in astrocyte calcium responses are associated to abnormal signaling by Gi and Gq protein coupled receptors in the inflamed cortex and are partially mirrored in cells activated with pro-inflammatory factors both in vitro and ex vivo thus suggesting cell-autonomous effects of the cortical neuroinflammatory environment. Finally, we show that deregulated astrocyte calcium activity is associated to an enhancement of glutamatergic gliotransmission and a shift of astrocyte-mediated short-term and long-term plasticity mechanisms towards synaptic potentiation. Overall our data identities astrocyte-neuronal network dysfunction as key pathological feature of the inflammatory gray matter that may contribute to MS symptomatology and clinical progression.

neuroscience↗

Distinct endocannabinoids specifically signal to astrocytes and neurons

The endocannabinoid system is an essential intercellular signaling mechanism with a decisive role in many physiological functions of the brain. Endocannabinoids (eCBs), directly acting on presynaptic neuronal CB1 receptors (CB1Rs), can inhibit neurotransmitter release. In addition, they can potentiate adjacent synapses, inducing lateral regulation of synaptic transmission through astrocyte CB1Rs. In contrast to most, if not all, neurotransmitter systems, the eCB system involves two distinct ligands, Anandamide and 2-Arachidonoylglycerol (AEA and 2AG), and a single receptor (CB1R). The physiological meaning of this particularity remains unknown. Here we show that different eCBs are signaling both astrocytes and neurons, inducing distinct and contrasting synaptic regulation. Combining two-photon with a pharmacological and optogenetic approaches and transgenic mice for the synthesis enzyme of both eCBs, we have found that the absence of 2-AG synthesis abolished the inhibitory effect, which was mediated exclusively by neuronal mechanisms. However, the absence of AEA synthesis prevents the lateral potentiation mediated by astrocyte calcium mobilization. Together this indicates that 2-AG signals to neurons, decreasing neurotransmitter release, while AEA signals to astrocytes and induces lateral potentiation. Additionally, AEA synthesis is required for the synaptic potentiation induced by spike-timing-dependent plasticity, as well as astrocyte CB1R, indicating that distinct eCBs-signaling influences neuronal plasticity. We conclude that 2-AG and AEA induce distinct and contrasting synaptic regulation through CB1R in different cell types.

neuroscience↗

To deliberate, remember; to anticipate, forget: Cognitive deliberation profiles underpinning active forgetting-dependent everyday-like memory performance in young and aged mice.

Recalling a specific past episode that will enable us to decide which action is suited to a given present situation is a core element of everyday life. A wealth of research has demonstrated that such selective remembering is dependent upon a capacity to inhibit or provisionally forget related yet inappropriate memory episodes which could orient behavior in unwilled directions. Everyday-like memory (EdM) refers to this type of common organizational mnemonic capacity, known to deteriorate significantly with age, putatively as a result of decline in the cognitive capacity for selective inhibition or active forgetting. Moreover, this memory retrieval-concomitant active forgetting comes at the cost of genuine amnesic weakening of the inhibited episodes, a phenomenon referred to as retrieval-induced forgetting (RIF). In the present study, we introduce a novel characterization of our previously validated mouse model of EdM in terms of the existing active forgetting and RIF literature. We also introduce novel behavioral analyses of the deliberation processes elicited by EdM challenge and use detailed multi-factorial explorations to reveal how these processes are impacted by age, temporal retention demand, difficulty of EdM challenge, and anticipation of trial outcome. Our observations indicate that deliberation requires remembering while accurate anticipation--in which a critical age-related deficit is also observed--requires active forgetting. Our results represent a significant advance towards unifying our understanding of the neurocognitive processes underpinning everyday-like memory, RIF, mnemonic deliberation, anticipatory function, and how they all are impacted by the physiological ageing process. In parallel, we present preliminary results using a transgenic mouse model which point to a fundamental role for the endocannabinoid system (eCS) in active forgetting and EdM, thereby demonstrating that deeper investigation of previously characterized age-related decline of the eCS should be a pre-clinical priority with a view to developing treatments for age-related decline of EdM function.

animal behavior and cognition↗

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.

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