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Effects of Developmental Nicotine Exposure on Frontal Cortical GABA-to-Non-GABA Neuron Ratio and Novelty-Seeking Behavior.

ABSTRACT: Cigarette smoking during pregnancy is a major public health concern, resulting in detrimental health effects in the mother and her offspring. The adverse behavioral consequences for children include increased risk for attention deficit hyperactivity disorder, working memory deficits, epilepsy, novelty-seeking, and risk-taking behaviors. Some of these behavioral conditions are consistent with an imbalance in frontal cortical excitatory (glutamate) and inhibitory (GABA) neurotransmitter signaling. We used a GAD67-GFP knock-in mouse model to examine if developmental nicotine exposure alters frontal cortical GABA neuron numbers, GABA-to-non-GABA neuron ratio and behavioral phenotypes. Female mice were exposed to nicotine (100 or 200 ?g/mL) in drinking water beginning 3 weeks prior to breeding and until 3 weeks postpartum. Male and female offspring were examined beginning at 60 days of age. The nicotine exposure produced dose-dependent decreases in GABA-to-non-GABA neuron ratios in the prefrontal and medial prefrontal cortices without perturbing the intrinsic differences in cortical thickness and laminar distribution of GABA or non-GABA neurons between these regions. A significant increase in exploratory behavior and a shift toward "approach" in the approach-avoidance paradigm were also observed. Thus, developmental nicotine exposure shifts the cortical excitation-inhibition balance toward excitation and produces behavioral changes consistent with novelty-seeking behavior.

SUBMITTER: Martin MM

PROVIDER: S-EPMC7305802 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Effects of Developmental Nicotine Exposure on Frontal Cortical GABA-to-Non-GABA Neuron Ratio and Novelty-Seeking Behavior.

Martin Melissa M MM McCarthy Deirdre M DM Schatschneider Chris C Trupiano Mia X MX Jones Sara K SK Kalluri Aishani A Bhide Pradeep G PG

Cerebral cortex (New York, N.Y. : 1991) 20200301 3

Cigarette smoking during pregnancy is a major public health concern, resulting in detrimental health effects in the mother and her offspring. The adverse behavioral consequences for children include increased risk for attention deficit hyperactivity disorder, working memory deficits, epilepsy, novelty-seeking, and risk-taking behaviors. Some of these behavioral conditions are consistent with an imbalance in frontal cortical excitatory (glutamate) and inhibitory (GABA) neurotransmitter signaling. ...[more]

PMID: 31599922

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Project description:BackgroundNovelty-seeking (NS) and impulsive personality traits have been proposed to reflect an interplay between fronto-cortical and limbic systems, including the limbic striatum (LS). Although neuroimaging studies have provided some evidence for this, most are comprised of small samples and many report surprisingly large effects given the challenges of trying to relate a snapshot of brain function or structure to an entity as complex as personality. The current work tested a priori hypotheses about associations between striatal dopamine (DA) release, cortical thickness (CT), and NS in a large sample of healthy adults.MethodsFifty-two healthy adults (45M/7F; age: 23.8±4.93) underwent two positron emission tomography scans with [11C]raclopride (specific for striatal DA D2/3 receptors) with or without amphetamine (0.3 mg/kg, p.o.). Structural magnetic resonance image scans were acquired, as were Tridimensional Personality Questionnaire data. Amphetamine-induced changes in [11C]raclopride binding potential values (ΔBPND) were examined in the limbic, sensorimotor (SMS) and associative (AST) striatum. CT measures, adjusted for whole brain volume, were extracted from the dorsolateral sensorimotor and ventromedial/limbic cortices.ResultsBPND values were lower in the amphetamine vs. no-drug sessions, with the largest effect in the LS. When comparing low vs. high LS ΔBPND groups (median split), higher NS2 (impulsiveness) scores were found in the high ΔBPND group. Partial correlations (age and gender as covariates) yielded a negative relation between ASTS ΔBPND and sensorimotor CT; trends for inverse associations existed between ΔBPND values in other striatal regions and frontal CT. In other words, the greater the amphetamine-induced striatal DA response, the thinner the frontal cortex.ConclusionsThese data expand upon previously reported associations between striatal DA release in the LS and both NS related impulsiveness and CT in the largest sample reported to date. The findings add to the plausibility of these associations while suggesting that the effects are likely weaker than has been previously proposed.

Project description:Innate differences in human temperament strongly influence how individuals cope with stress and predispose for specific types of psychopathology. The present study examines the developing brain in an animal model of temperamental differences to understand how altered neurodevelopment may engender differences in emotional reactivity that are stable throughout the animal’s life. We utilize selectively-bred High Responder (bHR) and Low Responder (bLR) rats that exhibit dramatic emotional behavior differences, with bHRs exhibiting exaggerated novelty-exploration, aggression, impulsivity and drug self-administration, and bLRs showing marked behavioral inhibition, exaggerated anxiety- and depressive-like behavior. Using Affymetrix microarrays, we assessed bLR/bHR gene expression in the developing brain on postnatal days (P)7, 14, and 21, focusing on the hippocampus and nucleus accumbens, two regions related to emotionality and known to differ in adult bLR/bHR rats. We found dramatic bLR/bHR gene expression differences in the P7 and P14 hippocampus, with minimal differences in the nucleus accumbens. Some of the most profound differences involved genes critical for neurodevelopment and synaptogenesis. Stereological studies evaluated hippocampal structure in developing bHR/bLR pups, revealing enhanced hippocampal volume and cell proliferation in bLR animals. Finally, behavioral studies showed that the bHR/bLR behavioral phenotypes emerge very early in life, with exploratory differences apparent at P16 and anxiety differences present by P25. Together these data point to specific brain regions and critical periods when the bHR/bLR phenotypes begin to diverge, which may eventually allow us to test possible therapeutic interventions to normalize extreme phenotypes (e.g. the anxiety-prone nature of bLRs or drug addiction proclivity of bHRs). 2x2x3 factorial design with N=6 per group. Factors as follows: 1) Two selectively bred strains of rats (derived from an original Sprague Dawley population) termed High Responders (HR) and Low Responders (LR), 2) Two brain regions, Hippocampus (HPC) and Nucleus Accumbens (N.Acc), 3) Three developmental timepoints, specifically postnatal days 7 (P7), 14 (P14) and 21 (P21).

Project description:IntroductionClinical studies suggest that HIV-1-infected patients are more likely to use or abuse addictive drugs than is the general population. We hypothesized that HIV-1 proteins impact novelty-seeking behavior and enhance the transcriptional response to nicotine in genes implicated in both novelty-seeking behavior and drug addiction.MethodsWe assessed the effects of HIV-1 proteins on novelty-seeking behavior by comparing baseline activity differences of HIV-1Tg and F344 control rats in the open-field test. One day after behavioral testing, all rats began daily subcutaneous injections of either nicotine (0.4 mg/kg, base) or saline (the same for each rat) for 27 days. At the end of treatment, the prefrontal cortex, nucleus accumbens, and ventral tegmental area were collected for RNA expression analysis of genes in the receptor families for dopamine, GABA, glutamate, and serotonin.ResultsSignificant strain difference was detected in the distance moved in the center, such that HIV-1Tg rats traveled greater distance in the center of the arena than did F344 rats. Quantitative RT-PCR analysis showed that mRNA from Drd3 and Grm2 in the prefrontal cortex and Drd5 and Gabra6 in the ventral tegmental area was significantly upregulated, whereas that of Drd5 in the nucleus accumbens was downregulated in HIV-1Tg rats compared with F344 rats. Further, more addiction-related genes were significantly modulated by nicotine in each brain region in the HIV-1Tg rats than in the control animals.ConclusionsHIV-1 proteins may affect novelty-seeking behavior and modulate the expression of genes related to drug addiction and novelty-seeking behavior.ImplicationsHIV-1 viral proteins and chronic nicotine treatment impact the expression of genes involved in novelty-seeking behavior and addiction in three brain regions of the HIV-1 transgenic rat. These findings implicate that HIV-1 proteins may be involved in novelty-seeking behavior and in modulating the expression of genes related to drug addiction and novelty seeking.

Dataset Information

Effects of Developmental Nicotine Exposure on Frontal Cortical GABA-to-Non-GABA Neuron Ratio and Novelty-Seeking Behavior.

Publications

Effects of Developmental Nicotine Exposure on Frontal Cortical GABA-to-Non-GABA Neuron Ratio and Novelty-Seeking Behavior.

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