Adolescent cannabinoid exposure permanently suppresses cortical oscillations in adult mice.
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ABSTRACT:
SUBMITTER: Raver SM
PROVIDER: S-EPMC3799078 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Marijuana is the most widely used illicit drug among adolescents and young adults. Unique cognitive, emotional, and social changes occur during this critical period of development from childhood into adulthood. The adolescent brain is in a state of transition and differs from the adult brain with respect to both anatomy (e.g., neuronal connections and morphology) and neurochemistry (e.g., dopamine, GABA, and glutamate). These changes are thought to support the emergence of adult cerebral processes and behaviors. The endocannabinoid system plays an important role in development by acting on synaptic plasticity, neuronal cell proliferation, migration, and differentiation. Delta-9-tetrahydrocanabinol (THC), the principal psychoactive component in marijuana, acts as a partial agonist of the cannabinoid type 1 receptor (CB1R). Thus, over-activation of the endocannabinoid system by chronic exposure to CB1R agonists (e.g., THC, CP-55,940, and WIN55,212-2) during adolescence can dramatically alter brain maturation and cause long-lasting neurobiological changes that ultimately affect the function and behavior of the adult brain. Indeed, emerging evidence from both human and animal studies demonstrates that early-onset marijuana use has long-lasting consequences on cognition; moreover, in humans, this use is associated with a two-fold increase in the risk of developing a psychotic disorder. Here, we review the relationship between cannabinoid exposure during adolescence and the increased risk of neuropsychiatric disorders, focusing on both clinical and animal studies.
| S-EPMC4226229 | biostudies-literature
Project description:Maternal immune activation (MIA) is strongly associated with an increased risk of developing mental illness in adulthood, which often co-occurs with alcohol misuse. The current study aimed to begin to determine whether MIA, combined with adolescent alcohol exposure (AE), could be used as a model with which we could study the neurobiological mechanisms behind such co-occurring disorders. Pregnant Sprague-Dawley rats were treated with polyI:C or saline on gestational day 15. Half of the offspring were given continuous access to alcohol during adolescence, leading to four experimental groups: controls, MIA, AE, and Dual (MIA + AE). We then evaluated whether MIA and/or AE alter: (1) alcohol consumption; (2) locomotor behavior; and (3) cortical-striatal-hippocampal local field potentials (LFPs) in adult offspring. Dual rats, particularly females, drank significantly more alcohol in adulthood compared to all other groups. MIA led to reduced locomotor behavior in males only. Using machine learning to build predictive models from LFPs, we were able to differentiate Dual rats from control rats and AE rats in both sexes, and Dual rats from MIA rats in females. These data suggest that Dual "hits" (MIA + AE) increases substance use behavior and disrupts activity in reward-related circuits, and that this may be a valuable heuristic model we can use to study the neurobiological underpinnings of co-occurring disorders. Our future work aims to extend these findings to other addictive substances to enhance the translational relevance of this model, as well as determine whether amelioration of these circuit disruptions can reduce substance use behavior.
| S-EPMC9300672 | biostudies-literature
Project description:IntroductionDuring adolescence, exposure to nicotine or cannabis independently induces effects on neuromaturation and later cognitive function. However, the potential effect of both drugs under co-use conditions has become of increasing concern given the prevalence of e-cigarettes, legalization of cannabis, and availability of synthetic "spice" cannabinoid agonists.Aims and methodsThe current studies investigated the effects of exposure to a cannabinoid receptor agonist (WIN55,212-2) and/or nicotine over a discrete time period in mid-adolescence on later intravenous nicotine self-administration in adult male and female mice. We further examined whether cannabinoid agonist administration in adulthood would alter nicotine reinforcement, with either acute or chronic pairing across 7 days.ResultsWe found that adult males exhibited increased nicotine self-administration at a lower, rewarding nicotine dose following adolescent cannabinoid exposure, either alone or with nicotine coadministration. In contrast, adult females demonstrated an opposing effect in which adolescent cannabinoid and nicotine coexposure resulted in decreased nicotine intake compared with the nicotine only and control groups. Furthermore, after maintaining nicotine self-administration across sessions, pretreatment with a low dose of the cannabinoid agonist decreased nicotine intake in both male and female control mice, and this lowering effect was evidenced after both acute and chronic treatment. However, the cannabinoid agonist was ineffective in altering nicotine intake in mice previously exposed to nicotine, cannabinoid agonist, or both during adolescence.ConclusionsThese data provide evidence that adolescent drug exposure can alter later nicotine reinforcement in a sex-specific manner and can further modulate the effectiveness of interventions in reducing nicotine intake during adulthood.ImplicationsThese studies demonstrate a significant impact of nicotine, cannabinoids, or coexposure on developmental processes during adolescence. Differential effects were observed within each sex, with opposing results found for cannabinoid exposure on nicotine intake in males and females. Intriguingly, we also evidenced resistance to the lowering effects of a cannabinoid agonist on nicotine intake in adulthood based on adolescent drug exposure. Thus, these findings have important implications for our understanding of the impact of nicotine and cannabinoids (eg, Δ9-tetrahydrocannabinol (THC) and synthetic "spice" cannabinoids) during development, with further implications for the effectiveness of therapeutic interventions based on prior drug exposure in youth.
| S-EPMC7364841 | biostudies-literature
Project description:BackgroundAdolescence and early-adulthood are vulnerable developmental periods during which binge drinking can have long-lasting effects on brain function. However, little is known about the effects of binge drinking on the pyramidal cells of the prelimbic cortex (PrL) during early and protracted withdrawal periods.MethodsIn the present study, we performed whole-cell patch clamp recordings and dendritic spine staining to examine the intrinsic excitability, spontaneous excitatory post-synaptic currents (sEPSCs), and spine morphology of pyramidal cells in the PrL from rats exposed to chronic intermittent ethanol (CIE) during adolescence or early-adulthood.ResultsCompared to chronic intermittent water (CIW)-treated controls, the excitability of PrL-L5 pyramidal neurons was significantly increased 21 days after adolescent CIE but decreased 21 days after early-adult CIE. No changes of excitability in PrL Layer (L) 5 were detected 2 days after either adolescent or early-adulthood CIE. Interestingly, decreases in sEPSC amplitude and increases in thin spines ratio were detected 2 days after adolescent CIE. Furthermore, decreased frequency and amplitude of sEPSCs, accompanied by a decrease in the density of total spines and non-thin spines were observed 21 days after adolescent CIE. In contrast, increased frequency and amplitude of sEPSCs, accompanied by increased densities of total spines and non-thin spines were found 21 days after early adult CIE.ConclusionCIE produced prolonged neuronal and synaptic alterations in PrL-L5, and the developmental stage, i.e., adolescence vs. early-adulthood when subjects receive CIE, is a key factor in determining the direction of these changes.
| S-EPMC7814343 | biostudies-literature
Project description:BACKGROUND:Adolescent intermittent ethanol (AIE) exposure is an emerging risk factor for adult psychopathology, such as anxiety disorders. Enhancer RNAs (eRNAs) are short noncoding RNAs transcribed from enhancer regions that regulate synaptic plasticity-associated gene expression, including Arc, but their role in AIE-induced susceptibility to anxiety in adulthood is unknown. METHODS:Rats were exposed to AIE (ethanol exposure 2 days on/off) or intermittent normal saline during postnatal days 28 to 41 and allowed to grow to adulthood for analysis of behavior and biochemical measures. Some AIE rats and rats with intermittent normal saline exposure were exposed to an acute challenge with ethanol in adulthood. Cohorts of alcohol-naïve adult rats were cannulated in the central nucleus of amygdala and infused with either Kdm6b small interfering RNA or an antisense locked nucleic acid oligonucleotide specific to Arc eRNA before behavioral and biochemical analysis. RESULTS:AIE adult rats displayed heightened anxiety and decreased Arc eRNA expression, which is regulated epigenetically through decreased Kdm6b expression. This triggered condensed chromatin at the synaptic activity response element site and promoter of the Arc gene, facilitating increased negative elongation factor binding to the Arc promoter and decreasing Arc expression in the amygdala. Knockdown of Kdm6b or Arc eRNA expression in the central nucleus of amygdala provoked anxiety in alcohol-naïve adult rats and recapitulated the molecular and epigenetic phenotypes of AIE. CONCLUSIONS:These data suggest that eRNA regulation via epigenetic reprogramming in the amygdala, particularly at the Arc synaptic activity response element site, contributes to adult anxiety after adolescent alcohol exposure.
| S-EPMC6684056 | biostudies-literature
Project description:During adolescence, the integration of specialized functional brain networks related to cognitive control continues to increase. Slow frequency oscillations (4-10 Hz) have been shown to support cognitive control processes, especially within prefrontal regions. However, it is unclear how neural oscillations contribute to functional brain network development and improvements in cognitive control during adolescence. To bridge this gap, we employed magnetoencephalography (MEG) to explore changes in oscillatory power and phase coupling across cortical networks in a sample of 68 adolescents and young adults. We found a redistribution of power from lower to higher frequencies throughout adolescence, such that delta band (1-3 Hz) power decreased, whereas beta band power (14-16 and 22-26 Hz) increased. Delta band power decreased with age most strongly in association networks within the frontal lobe and operculum. Conversely, beta band power increased throughout development, most strongly in processing networks and the posterior cingulate cortex, a hub of the default mode (DM) network. In terms of phase, theta band (5-9 Hz) phase-locking robustly decreased with development, following an anterior-to-posterior gradient, with the greatest decoupling occurring between association networks. Additionally, decreased slow frequency phase-locking between frontolimbic regions was related to decreased impulsivity with age. Thus, greater decoupling of slow frequency oscillations may afford functional networks greater flexibility during the resting state to instantiate control when required.
| S-EPMC6291169 | biostudies-literature
Project description:Cannabinoids can cross the placenta, thus may interfere with fetal endocannabinoid signaling during neurodevelopment, causing long-lasting deficits. Despite increasing reports of cannabis consumption during pregnancy, the protracted consequences of prenatal cannabinoid exposure (PCE) remain incompletely understood. Here, we report sex-specific differences in behavioral and neuronal deficits in the adult progeny of rat dams exposed to low doses of cannabinoids during gestation. In males, PCE reduced social interaction, ablated endocannabinoid long-term depression (LTD) and heightened excitability of prefrontal cortex pyramidal neurons, while females were spared. Group 1 mGluR and endocannabinoid signaling regulate emotional behavior and synaptic plasticity. Notably, sex-differences following PCE included levels of mGluR1/5 and TRPV1R mRNA. Finally, positive allosteric modulation of mGlu5 and enhancement of anandamide levels restored LTD and social interaction in PCE adult males. Together, these results highlight marked sexual differences in the effects of PCE and introduce strategies for reversing detrimental effects of PCE.
| S-EPMC6162091 | biostudies-literature
Project description:Early life trauma (ELT) exposure and posttraumatic stress disorder (PTSD) both affect neural structure, which predicts a variety of mental health concerns throughout the lifespan and may present differently between adolescents and adults. However, few studies have identified the relationship between ELT, PTSD, development, and brain structure using cortical thickness (CT). CT may reveal previously obscured alterations that are potentially clinically relevant and, furthermore, could identify specific structural correlates distinct to ELT from PTSD. Two hundred and fifty-three female adolescent and adult survivors of interpersonal violence and non-trauma-exposed demographically matched controls underwent structural MRI at two different sites. Images were processed and CT was estimated using FreeSurfer. Vertex-wise linear model tests were conducted across the cortical surface to investigate whether PTSD and ELT exposure uniquely affect CT, controlling for scanner site. Planned follow-up tests included second-level analyses of clinical symptoms for CT clusters that were significantly related to PTSD or ELT. CT in the middle cingulate cortex was inversely related to ELT in both age groups, such that individuals with more ELT demonstrated less CT in this region. Additionally, CT was significantly greater in the bilateral intraparietal sulcus and left angular gyrus in both adolescents and adults with PTSD. Furthermore, CT in these clusters was also significantly related to clinical symptom severity in the adult PTSD group. This study provides evidence for distinct CT correlates of ELT and PTSD that are present across adolescents and adults, suggesting consistent markers related to ELT and PTSD on gray matter structure in trauma-exposed individuals.
| S-EPMC8027669 | biostudies-literature
Project description:Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. Nonetheless, until now, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, has been unexplored. Here, we report that adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in the mouse model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings highlight the importance of microglial Cnr1 to produce the adverse effect of cannabis exposure in genetically vulnerable individuals.
2023-10-03 | GSE242892 | GEO
Project description:Binge drinking is a significant problem in adolescent populations, and because of the reciprocal interactions between ethanol (EtOH) consumption and the endocannabinoid (eCB) system, we sought to determine if adolescent EtOH intake altered the localization and function of the cannabinoid 1 (CB1) receptors in the adult brain. Adolescent mice were exposed to a 4-day-per week drinking in the dark (DID) procedure for a total of 4 weeks and then tested after a 2-week withdrawal period. Field excitatory postsynaptic potentials (fEPSPs), evoked by medial perforant path (MPP) stimulation in the dentate gyrus molecular layer (DGML), were significantly smaller. Furthermore, unlike control animals, CB1 receptor activation did not depress fEPSPs in the EtOH-exposed animals. We also examined a form of excitatory long-term depression that is dependent on CB1 receptors (eCB-eLTD) and found that it was completely lacking in the animals that consumed EtOH during adolescence. Histological analyses indicated that adolescent EtOH intake significantly reduced the CB1 receptor distribution and proportion of immunopositive excitatory synaptic terminals in the medial DGML. Furthermore, there was decreased binding of [35S]guanosine-5*-O-(3-thiotriphosphate) ([35S] GTP?S) and the guanine nucleotide-binding (G) protein G?i2 subunit in the EtOH-exposed animals. Associated with this, there was a significant increase in monoacylglycerol lipase (MAGL) mRNA and protein in the hippocampus of EtOH-exposed animals. Conversely, deficits in eCB-eLTD and recognition memory could be rescued by inhibiting MAGL with JZL184. These findings indicate that repeated exposure to EtOH during adolescence leads to long-term deficits in CB1 receptor expression, eCB-eLTD, and reduced recognition memory, but that these functional deficits can be restored by treatments that increase endogenous 2-arachidonoylglycerol.
| S-EPMC6901552 | biostudies-literature