Connectomics signatures of prenatal cocaine exposure affected adolescent brains.
Ontology highlight
ABSTRACT:
SUBMITTER: Li K
PROVIDER: S-EPMC3954601 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The associations between prenatal cocaine exposure (PCE) and adolescent behavior, cognitive development, and physical growth were examined in 219 15-year-olds who have participated in a longitudinal study since their fourth gestational month. During the first trimester, 42% of the women used cocaine, with use declining across pregnancy. At the 15-year follow-up, the caregivers were, on average, 43 years old, had 13 years of education, and 50% were African American. First trimester PCE was not associated with global cognitive development or with measures of learning and memory. First trimester PCE was significantly related to adolescent-reported delinquent behavior, poorer problem solving and abstract reasoning, and reduced weight, height, and head circumference at 15 years. These results were significant after other factors that affect these domains were controlled in regression analyses. In addition, exposure to violence partially mediated the effect of PCE on delinquent behavior. These adolescent domains are important because they are predictors of poorer adult functioning.
| S-EPMC4458454 | biostudies-literature
Project description:Preclinical research has demonstrated the effects of prenatal cocaine exposure (PCE) on brain regions involved in emotional regulation, motivational control, and addiction vulnerability-eg, the ventral striatum (VS), anterior cingulate (ACC), and prefrontal cortex (PFC). However, little is known about the function of these regions in human adolescents with PCE. Twenty-two adolescents with PCE and 22 age-, gender-, and IQ-matched non-cocaine exposed (NCE) adolescents underwent functional magnetic resonance imaging (fMRI) during exposure to individually personalized neutral/relaxing, stressful, and favorite-food cues. fMRI data were compared using group-level two-tailed t-tests in the BioImage Suite. In comparison with NCE adolescents, PCE adolescents had reduced activity within cortical and subcortical brain regions, including the VS, ACC, and medial and dorslolateral PFC during exposure to favorite-food cues but did not differ in neural responses to stress cues. Subjective food craving was inversely related to dorsolateral PFC activation among PCE adolescents. Among PCE adolescents, subjective anxiety ratings correlated inversely with activations in the orbitofrontal cortex and brainstem during the stress condition and with ACC, dorsolateral PFC, and hippocampus activity during the neutral-relaxing condition. Thus adolescents with PCE display hypoactivation of brain regions involved in appetitive processing, with subjective intensities of craving and anxiety correlating inversely with extent of activation. These findings suggest possible mechanisms by which PCE might predispose to the development of addictions and related disorders, eg, substance-use disorders and binge-eating.
| S-EPMC4200493 | biostudies-literature
Project description:Prenatal cocaine exposure (PCE) can cause persistent neuropsychological and motor abnormalities in affected children, but the physiological consequences of PCE remain unclear. Conclusions drawn from clinical studies can sometimes be confounded by polysubstance abuse and nutritional deprivation. However, existing observations suggest that cocaine exposure in utero, as in adults, increases synaptic dopamine and promotes enduring dopamine-dependent plasticity at striatal synapses, altering behaviors and basal ganglia function.We used a combination of behavioral measures, electrophysiology, optical imaging, and biochemical and electrochemical recordings to examine corticostriatal activity in adolescent mice exposed to cocaine in utero.We show that PCE caused abnormal dopamine-dependent behaviors, including heightened excitation following stress and blunted locomotor augmentation after repeated treatment with amphetamine. These abnormal behaviors were consistent with abnormal ?-aminobutyric acid (GABA) interneuron function, which promoted a reversible depression in corticostriatal activity. PCE hyperpolarized and reduced tonic GABA currents in both fast-spiking and persistent low-threshold spiking type GABA interneurons to increase tonic inhibition at GABAB receptors on presynaptic corticostriatal terminals. Although D2 receptors paradoxically increased glutamate release following PCE, normal corticostriatal modulation by dopamine was reestablished with a GABAA receptor antagonist.The dynamic alterations at corticostriatal synapses that occur in response to PCE parallel the reported effects of repeated psychostimulants in mature animals, but differ in being specifically generated through GABAergic mechanisms. Our results indicate approaches that normalize GABA and D2 receptor-dependent synaptic plasticity may be useful for treating the behavioral effects of PCE and other developmental disorders that are generated through abnormal GABAergic signaling.
| S-EPMC3766752 | biostudies-literature
Project description:The dense expression of glucocorticoid receptors (GR) within the amygdala, medial prefrontal cortex (mPFC) and paraventricular nucleus of hypothalamus (PVN) mediates many aspects of emotional and stress regulation. Importantly, both prenatal alcohol exposure (PAE) and adolescent stress are known to induce emotional and stress dysregulation. Little is known, however, about how PAE and/or adolescent stress may alter the expression of GR in the amygdala, mPFC, and PVN. To fill this gap, we exposed PAE and control adolescent male and female rats to chronic mild stress (CMS) and assessed GR mRNA expression in the amygdala, mPFC, and PVN immediately following stress or in adulthood. We found that the effects of PAE on GR expression were more prevalent in the amygdala, while effects of adolescent stress on GR expression were more prevalent in the mPFC. Moreover, PAE effects in the amygdala were more pronounced during adolescence and adolescent stress effects in the mPFC were more pronounced in adulthood. GR expression in the PVN was affected by both PAE and adolescent stress. Finally, PAE and/or adolescent stress effects were distinct between males and females. Together, these results suggest that PAE and adolescent CMS induce dynamic alterations in GR expression in the amygdala, mPFC, and PVN, which manifest differently depending on the brain area, age, and sex of the animal. Additionally, these data indicate that PAE-induced hyperresponsiveness to stress and increased vulnerability to mental health problems may be mediated by different neural mechanisms depending on the sex and age of the animal.
| S-EPMC6579044 | biostudies-literature
Project description:Epidemiological studies have shown a clear association of adverse intrauterine environment and an increased risk of cardiovascular diseases and hypertension in adult life. The present study tested the hypothesis that prenatal cocaine exposure causes reprogramming of vascular reactivity, leading to an increased risk of hypertension in adult offspring. Pregnant rats received cocaine (30 mg kg(-1) day(-1)) or saline from days 15 to 21 of gestational age, and experiments were conducted in 3-month-old offspring. Cocaine had no effect on the baseline blood pressure but significantly increased norepinephrine-stimulated blood pressure and decreased the baroreflex sensitivity in male but not female offspring. The cocaine treatment significantly increased norepinephrine-induced contractions in pressurized resistance-sized mesenteric arteries but not in aortas, which was primarily because of a loss of endothelial NO synthase-mediated inhibition and an enhanced Ca(2+) sensitivity in mesenteric arteries. In addition, the cocaine treatment significantly attenuated the endothelium-dependent relaxation in mesenteric arteries in male but not female offspring. Endothelial NO synthase protein levels in aortas but not mesenteric arteries were significantly increased in the cocaine-treated animals. However, cocaine significantly decreased phosphorylation levels of endothelial NO synthase in both aortas and mesenteric arteries. The results suggest that prenatal cocaine exposure programs vascular contractility via changes in endothelial NO synthase-regulated Ca(2+) sensitivity of myofilaments in the sex- and tissue-dependent manners in resistance arteries leading to an increased risk of hypertension in male offspring.
| S-EPMC2698595 | biostudies-literature
Project description:With the rise of e-cigarette use, teen nicotine exposure is becoming more widespread. Findings from clinical and preclinical studies show that the adolescent brain is particularly sensitive to nicotine. Animal studies have demonstrated that adolescent nicotine exposure increases reinforcement for cocaine and other drugs. However, the mechanisms that underlie these behaviors are poorly understood. Here, we report reactive microglia are critical regulators of nicotine-induced increases in adolescent cocaine self-administration. Nicotine has dichotomous, age-dependent effects on microglial morphology and immune transcript profiles. A multistep signaling mechanism involving D2 receptors and CX3CL1 mediates nicotine-induced increases in cocaine self-administration and microglial activation. Moreover, nicotine depletes presynaptic markers in a manner that is microglia-, D2- and CX3CL1-dependent. Taken together, we demonstrate that adolescent microglia are uniquely susceptible to perturbations by nicotine, necessary for nicotine-induced increases in cocaine-seeking, and that D2 receptors and CX3CL1 play a mechanistic role in these phenomena.
| S-EPMC6965638 | biostudies-literature
Project description:Prenatal cocaine exposure (PCE) affects neurobehavioral development, however, disentangling direct drug-related mechanisms from contextual effects (e.g., socioeconomic status) has proven challenging in humans. The effects of environmental confounds are minimal immediately after birth thus we aimed to delineate neurobehavioral correlates of PCE in a large cohort of neonates (2-6weeks of age, N=152) with and without drug exposure using resting state functional magnetic resonance imaging (rsfMRI) and developmental assessments at 3months with the Bayley Scales of Infant & Toddler Development, 3rd edition. The cohort included healthy controls and neonates with similar poly-drug exposure±cocaine. We focused on the thalamus given its critical importance in early brain development and its unique positioning in the dopamine system. Our results revealed PCE-related hyper-connectivity between the thalamus and frontal regions and a drug-common hypo-connective signature between the thalamus and motor-related regions. PCE-specific neonatal thalamo-frontal connectivity was inversely related to cognitive and fine motor scores and thalamo-motor connectivity showed a positive relationship with composite (gross plus fine) motor scores. Finally, cocaine by selective-serotonin-reuptake-inhibitor (SSRI) interactions were detected, suggesting the combined use of these drugs during pregnancy could have additional consequences on fetal development. Overall, our findings provide the first delineation of PCE-related disruptions of thalamocortical functional connectivity, neurobehavioral correlations, and drug-drug interactions during infancy.
| S-EPMC4935611 | biostudies-literature
Project description:Development of drug addictive behaviors is modulated by both genetic and environmental risk factors. However, the molecular mechanisms remain unknown. To address the role of adolescent stress in the development of drug addiction, we combined a transgenic mouse model in which a putative dominant-negative form of DISC1 under expressional control of the prion protein promoter is used as a genetic risk factor and adolescent social isolation stress as a gene-environmental interaction (GXE). Repeated cocaine exposure induced greater locomotion in the GXE group than in the other groups. In a conditioned place preference (CPP) test, GXE mice exhibited a significant place preference to the cocaine-conditioned area compared with the other groups. In the nucleus accumbens (NAc) of GXE mice, we found increased enzyme activity of phosphodiesterase-4 (PDE4), predominantly located in NAc D2-receptor-expressing neurons, and enhanced effects of the PDE4 inhibitor rolipram, but not the D1 agonist SKF81297, on the phosphorylation of DARPP-32 and GluA1 at PKA sites. Rolipram injection before cocaine exposure completely inhibited cocaine-induced hyperlocomotion and CPP in the GXE group. These results indicate that GXE enhances sensitivity to repeated cocaine exposure via an increase in PDE4 activity in NAc D2-recptor-expressing neurons, leading to the development of cocaine addictive behaviors.
| S-EPMC6717686 | biostudies-literature
Project description:Adolescent cocaine abuse increases the risk for developing addiction in later life, but the underlying molecular mechanism remains poorly understood. Here, we establish adolescent cocaine-exposed (ACE) male mouse models. A subthreshold dose of cocaine (sdC) treatment, insufficient to produce conditioned place preference (CPP) in adolescent mice, induces CPP in ACE mice during adulthood, along with more activated CaMKII-positive neurons, higher dual specificity protein kinase phosphatase-1 (Dusp1) mRNA, lower DUSP1 activity, and lower DUSP1 expression in CaMKII-positive neurons in the medial prefrontal cortex (mPFC). Overexpressing DUSP1 in CaMKII-positive neurons suppresses neuron activity and blocks sdC-induced CPP in ACE mice during adulthood. On the contrary, depleting DUSP1 in CaMKII-positive neurons activates more neurons and further enhances sdC-induced behavior in ACE mice during adulthood. Also, ERK1/2 might be a downstream signal of DUSP1 in the process. Our findings reveal a role of mPFC DUSP1 in ACE-induced higher sensitivity to the drug in adult mice. DUSP1 might be a potential pharmacological target to predict or treat the susceptibility to addictive drugs caused by adolescent substance use.
2023-05-20 | GSE231074 | GEO
Project description:Adolescent cocaine abuse increases the risk for developing addiction in later life, but the underlying molecular mechanism remains poorly understood. Here, we establish adolescent cocaine-exposed (ACE) male mouse models. A subthreshold dose of cocaine (sdC) treatment, insufficient to produce conditioned place preference (CPP) in adolescent mice, induces CPP in ACE mice during adulthood, along with more activated CaMKII-positive neurons, higher dual specificity protein kinase-phosphatase-1 (Dusp1) mRNA, lower DUSP1 activity and lower DUSP1 expression in CaMKII-positive neurons in the medial prefrontal cortex (mPFC). Overexpressing DUSP1 in CaMKII-positive neurons suppresses neurons activity and blocks sdC-induced CPP in ACE mice during adulthood. On the other hand, depleting DUSP1 in CaMKII-positive neurons activates more neurons, and further enhances sdC-induced behavior in ACE mice during adulthood. Also, ERK1/2 might be a downstream signal of DUSP1 in the process. Our findings reveal a role of mPFC DUSP1 in ACE-induced higher sensitivity to the drug in adult mice. DUSP1 might be a potential pharmacological target to predict or treat the susceptibility to addictive drugs caused by adolescent substance use.
| S-SCDT-10_15252-EMBR_202356981 | biostudies-other