Biology subjects

Melis, M.

Publications and source records attributed to Melis, M..

7 recordsLinked to original sources

bioRxiv2026

An endocannabinoid-nitric oxide signaling switch triggers reciprocal inhibitory-excitatory plasticity at dopamine neuron inputs following prenatal cannabinoid exposure

Dynamic regulation of midbrain dopamine neuron activity is necessary for diverse processes including motivation, novelty detection, reinforcement learning, and cognitive flexibility. By setting the strength of synaptic inputs to dopaminergic neurons, endocannabinoid signaling is essential for regulating dopaminergic activity. Prenatal exposure to {Delta}9-tetrahydrocannabinol (THC), the main psychoactive substance in cannabis, is known to induce abnormal dopaminergic activity and increased susceptibility to psychopathology. However, how prenatal cannabinoid exposure (PCE) affects endocannabinoid-mediated synaptic plasticity of dopamine neurons remains largely unknown. Here, we use a rat model of PCE to directly determine this. We found that endocannabinoid-mediated synaptic plasticity at excitatory synapses on dopamine neurons of the ventral tegmental area (VTA) was absent in PCE male rat offspring, where the presynaptic nanoscale architecture of excitatory afferents onto VTA dopamine neurons was reorganized to impair the control of type-1 cannabinoid receptors on glutamate release. We demonstrate that, in response to postsynaptic depolarization, PCE dopamine cells switch to nitric oxide (NO) rather than endocannabinoid signaling to induce opposing forms of synaptic plasticity at inhibitory and excitatory inputs. We disclosed a NO-dependent long-term potentiation of GABAA-receptor-mediated synaptic transmission, and a long-term depression of glutamatergic synapses requiring presynaptic activation of GABAB-receptors. These PCE-induced reciprocal forms of synaptic plasticity reshape the balance of excitatory and inhibitory control over dopamine neurons, potentially contributing to increased vulnerability to psychiatric disorders.

neuroscience↗

bioRxiv2026

Sex-specific effects of prenatal delta-9-tetrahydrocannabinol exposure on repetitive behavior and prefrontal cortex neuronal excitability in preadolescent rats

Cannabis is the most common illicit drug abused worldwide, and its consumption has substantially increased among pregnant women. We previously demonstrated that male preadolescent offspring prenatally exposed to {Delta}9-tetrahydrocannabinol (THC), a model of prenatal cannabinoid exposure (PCE), exhibit a mesolimbic dopamine (DA) neuron dysfunction contributing to at-risk psychotic-like (endo)phenotypes that are unmasked by acute THC exposure at preadolescence. Dysregulation of mesocortical DA signaling along with prefrontal cortex (PFC) function is also a central feature of psychotic disorders. Furthermore, studies investigating the impact of PCE on PFC in the offspring at preadolescence, a window of heightened plasticity and vulnerability, are limited. To fill this gap, we applied a multiscale analysis of mesocortical DA transmission and PFC function in PCE preadolescent offspring by integrating behavioral, neurochemical, electrophysiological, and molecular approaches. PCE enhanced spontaneous repetitive behaviors in a male-specific manner. PCE also abolished sex differences in the intrinsic excitability of PFC pyramidal neurons and Netrin-1 expression. In addition, PCE altered the expression of genes associated with endocannabinoid signaling without changing basal and THC-induced extracellular levels of DA in the PFC. Collectively, these findings demonstrate that prenatal THC exposure disrupts both proper maturation and sexual differentiation of PFC circuitry, thus extending the impact of PCE from previously described mesolimbic abnormalities to mesocortical pathway. Finally, our data identify early cortical molecular and cellular alterations that may contribute to neuropsychiatric vulnerability later in life. Highlights* Preadolescent male rats exposed in utero to THC display repetitive behavior * Prenatal cannabinoid exposure (PCE) does not alter dopamine transmission in the PFC * PCE potentiates AMPA-mediated transmission in male pyramidal cells * PCE abolishes sex differences in Netrin-1 expression levels in the PFC

neuroscience↗

bioRxiv2026

Sleep deprivation impairs information processing via dysregulation of chloride homeostasis in the prefrontal cortex

Sleep deprivation (SD) impairs information processing through alterations of prefrontal cortex (PFC) function, yet the molecular underpinnings of this process remain poorly understood. We previously showed that SD disrupts sensorimotor gating by elevating prefrontal levels of the neurosteroid allopregnanolone (AP), a positive allosteric modulator of GABA-A receptors. Here we identify a complementary, mechanistically independent process whereby SD alters GABA-A currents in the PFC of mice and rats. SD reduced membrane expression of the chloride exporter KCC2, leading to intracellular chloride accumulation and a depolarizing shift in GABA-A receptor reversal potential that weakened GABAergic inhibition. Pharmacological normalization of chloride homeostasis with bumetanide fully rescued SD-induced deficits in sensorimotor gating and information encoding. SD also upregulated BDNF, and intra-PFC antagonism of its receptor TrkB restored KCC2 expression and normalized information processing, identifying BDNF-TrkB signaling as an upstream driver of chloride dysregulation. Notably, blocking AP synthesis rescued behavioral deficits without correcting chloride imbalance, confirming mechanistic independence. Finally, combined administration of AP and a KCC2 blocker produced information-processing deficits akin to those induced by SD. These findings identify TrkB-dependent disruption of prefrontal chloride homeostasis as a druggable mechanism underlying sleep loss-induced cognitive dysfunction.

animal behavior and cognition↗

bioRxiv2024

Sex-specific maladaptive responses to acute stress upon in utero THC exposure are mediated by dopamine

Cannabis remains by far the most consumed illicit drug in Europe. The availability of more potent cannabis has raised concerns regarding the enhanced health risks associated with its use, particularly among pregnant women. Growing evidence shows that cannabis use during pregnancy increases the risks of child psychopathology. We have previously shown that male rat offspring prenatally exposed to {Delta}9-tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), display a hyperdopaminergic phenotype associated with a differential susceptibility to acute THC- and stress-mediated effects on sensorimotor gating functions. Here, we explore the contribution of the hypothalamic-pituitary-adrenal (HPA) axis, key regulator of body adaptive stress responses, to the detrimental effects of acute stress on ventral tegmental area (VTA) dopamine neurons and sensorimotor gating function of PCE rats. We report a sex-dependent compromised balance in mRNA levels of genes encoding mineralocorticoid and glucocorticoid receptors in the VTA, alongside with stress-induced pre-pulse inhibition (PPI) deficits. Notably, VTA dopamine neuronal activity is required for the manifestation of stress-dependent deterioration of PPI. Finally, pharmacological manipulations targeting glycogen-synthase-kinase-3-{beta} signaling during postnatal development correct these stress-induced, sex-specific and dopamine-dependent deficits of PPI. Collectively, these results highlight the critical sex-dependent interplay between HPA axis and dopamine system in the regulation of sensorimotor gating functions in rats.

neuroscience↗

bioRxiv2024

Dynamic Accumbal Overrepresentation of Reward Cues in Food- and Opioid-Seeking Rats after Prenatal THC Exposure

The increasing prevalence of cannabis use during pregnancy has raised significant medical concerns, primarily related to the presence of {Delta}9-tetrahydrocannabinol (THC), which readily crosses the placenta and impacts fetal brain development. Previous research has identified midbrain dopaminergic neuronal alterations related to maternal THC consumption. However, the enduring consequences that prenatal cannabis exposure (PCE) has on striatum-based processing during voluntary reward pursuit have not been specifically determined. Here, we characterize PCE rats during food (palatable pellets) or opioid (remifentanyl)-maintained reward seeking. We find that the supra motivational phenotype of PCE rats is independent of value-based processing and is instead related to augmented reinforcing efficiency of opioid rewards. Our findings reveal that in utero THC exposure leads to increased cue-evoked dopamine release responses and an overrepresentation of cue-aligned, effort-driven striatal patterns of encoding. Recapitulating findings in humans, drug-related neurobiological adaptations of PCE were more pronounced in males, who similarly showed increased vulnerability for relapse. Collectively, these findings indicate that prenatal THC exposure in male rats engenders a pronounced neurodevelopmental susceptibility to addiction-like disorders later in life.

neuroscience↗

bioRxiv2022

Endocannabinoid-dependent persistent decrease of GABAergic transmission on dopaminergic neurons underlies gene-environment interaction-induced susceptibility to cocaine sensitization

Vulnerability to develop cocaine use disorder depends upon an unpredictable combination of genetic and non-genetic risk factors. Early life adversity and adolescence are critical non-genetic risk factors, and haplotypes of the monoamine oxidase (MAO) genes are among genetic variations increasing the risk of drug-related problems. However, data on the interactions between inheritable risk factors and early life stress (ES) with respect to predisposition to cocaine abuse are limited. Here, we show that a mouse model containing both genetic (low-activity alleles of the MAO A gene; MAOANeo) and environmental (i.e., ES) variables displays a long lasting increased sensitivity to repeated in vivo cocaine psychomotor stimulant actions associated with a reduction of GABAA receptor-mediated inhibition of dopamine neurons of the ventral tegmental area (VTA). Depolarization-induced suppression of inhibition (DSI), a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, also becomes readily expressed by dopamine neurons from MAOANeoES mice treated repeatedly with cocaine. Activation of either dopamine D2 or CB1 receptors is required for cocaine-induced DSI expression, decreased GABA synaptic efficacy, and hyperlocomotion. Next, in vivo pharmacological enhancement of 2-AG signaling during repeated cocaine exposure occludes its actions both in vivo and ex vivo. This data extends our knowledge of the multifaceted sequelae imposed by this gene by environment interaction in VTA dopamine neurons of male pre-adolescent mice, contributing to our understanding of neural mechanisms of vulnerability for early onset cocaine use disorder.

neuroscience↗

bioRxiv2020

Prenatal THC does not affect female mesolimbic dopaminergic system in preadolescent rats

Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes towards it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to {Delta}9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase of dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related-behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure. HighlightsO_LIPCE female offspring do not manifest a disease-relevant phenotype C_LIO_LIPrenatal THC does not affect female dopaminergic neurons C_LIO_LIPCE female mesolimbic dopamine function is less responsive to acute THC C_LI

neuroscience↗