Graduate Research Assistant , Florida State University
Developmental nicotine exposure and it's effects on GABA neuron development
Cigarette smoking during pregnancy is a major public health concern because it can have detrimental effects on both the mother and her child. For example, developmental nicotine exposure (DNE) is associated with increased risk for ADHD, conduct disorder, learning disabilities, anxiety, epilepsy, and depression. The GABA neurotransmitter system is known to be altered in many of these developmental disorders raising the possibility that DNE may target the GABA system in the developing brain. During embryonic development, the majority of the GABA neurons originate in the basal forebrain and migrate to regions of the dorsal forebrain and these GABA neurons have been shown to express nicotinic acetylcholine receptors (nAChRs). Thus, it is possible that DNE alters the GABAergic system during the embryonic period via activation of the nAChRs on migrating GABA neurons.
Abstract: This paper reviews results from published, in press, and conference proceedings from 2007 and 2008 that link in-utero tobacco exposure to neurodevelopmental outcomes in exposed offspring.Prenatal tobacco exposure (PTE) affected speech processing, levels of irritability and hypertonicity, attention levels, ability to self-regulate, need to be handled, and response to novelty preference in infants. In early childhood, PTE effects were mostly behavioral outcomes including activity and inattention and externalizing behaviors, including conduct disorder and antisocial behavior. In adolescents, PTE predicted increased attention deficit hyperactivity disorder, modulation of the cerebral cortex and white matter structure, and nicotine addiction. Several studies found moderating effects with PTE and genetic susceptibilities including dopamine transporter, serotonergic synaptic function, and monomine oxidase pathways. Other studies suggested that environmental and genetic factors might be more important than the direct teratological effects of PTE.The majority of studies reviewed were prospective and tobacco exposure was quantified biologically. Most demonstrated a direct association between PTE and neurodevelopmental outcomes. More work is needed to examine multifactorial influences. Effects of PTE on the offspring appear to be moderated by genetic variability, neurobehavioral disinhibition, and sex.
Pub.: 18 Jun '09, Pinned: 21 Jul '17
Abstract: Cigarette smoking during pregnancy is associated with various disabilities in the offspring such as attention deficit/hyperactivity disorder, learning disabilities, and persistent anxiety. We have reported that nicotine exposure in female mice during pregnancy, in particular from embryonic day 14 (E14) to postnatal day 0 (P0), induces long-lasting behavioral deficits in offspring. However, the mechanism by which prenatal nicotine exposure (PNE) affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that PNE disrupted the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and subventricular zones. In addition, using a cumulative 5-bromo-2'-deoxyuridine labeling assay, we evaluated the rate of cell cycle progression causing the impairment of neuronal progenitor proliferation, and uncovered anomalous cell cycle kinetics in mice with PNE. Accordingly, the density of glutamatergic neurons in the medial prefrontal cortex (medial PFC) was reduced, implying glutamatergic dysregulation. Mice with PNE exhibited behavioral impairments in attentional function and behavioral flexibility in adulthood, and the deficits were ameliorated by microinjection of D-cycloserine into the PFC. Collectively, our findings suggest that PNE affects the proliferation and maturation of progenitor cells to glutamatergic neuron during neurodevelopment in the medial PFC, which may be associated with cognitive deficits in the offspring.
Pub.: 25 Jun '15, Pinned: 21 Jul '17
Abstract: Based on emerging preclinical findings suggesting that paternal smoking at conception may be a risk for ADHD in the offspring, we investigated whether a similar effect can be observed in humans.We analyzed data from an opportunistic dataset of girl probands with ( N = 140) and without ( N = 122) ADHD with available information on paternal smoking at conception. Data were analyzed using Pearson's chi-square tests and multiple logistic regression.ADHD probands had a significantly higher rate of paternal smoking at conception than controls (35% vs. 23%, χ(2) = 3.82, p = .05) with a significant odds ratio of 1.5. However, the association lost significance after controlling for paternal ADHD, most likely due to limited statistical power.While preliminary, findings suggest that paternal smoking at conception may be a risk factor for ADHD in the offspring.
Pub.: 06 Feb '17, Pinned: 11 Jul '17
Abstract: Epidemiological and animal studies have reported that prenatal nicotine exposure (PNE) leads to obesity and type-2 diabetes in offspring. Central leptin-melanocortin signaling via hypothalamic arcuate proopiomelanocortin (POMC) neurons is crucial for the regulation of energy and glucose balance. Furthermore, hypothalamic POMC neurons were recently found to mediate the anorectic effects of nicotine through activation of acetylcholine receptors. Here, we hypothesized that PNE impairs leptin-melanocortinergic regulation of energy balance in first-generation offspring by altering expression of long non-coding RNAs (lncRNAs) putatively regulating development and/or function of hypothalamic POMC neurons.C57BL/6J females were exposed ad libitum to nicotine through drinking water and crossed with C57BL/6J males. Nicotine exposure was sustained during pregnancy and discontinued at parturition. Offspring development was monitored from birth into adulthood. From the age of 8 weeks, central leptin-melanocortin signaling, diabetes, and obesity susceptibility were assessed in male offspring fed a low-fat or high-fat diet for 16 weeks. Nicotine-exposed and non-exposed C57BL/6J females were also crossed with C57BL/6J males expressing the enhanced green fluorescent protein specifically in POMC neurons. Transgenic male offspring were subjected to laser microdissections and RNA sequencing (RNA-seq) analysis of POMC neurons for determination of nicotine-induced gene expression changes and regulatory lncRNA/protein-coding gene interactions.Contrary to expectation based on previous studies, PNE did not impair but rather enhanced leptin-melanocortinergic regulation of energy and glucose balance via POMC neurons in offspring. RNA-seq of laser microdissected POMC neurons revealed only one consistent change, upregulation of Gm15851, a lncRNA of yet unidentified function, in nicotine-exposed offspring. RNA-seq further suggested 82 cis-regulatory lncRNA/protein-coding gene interactions, 19 of which involved coding genes regulating neural development and/or function, and revealed expression of several previously unidentified metabolic, neuroendocrine, and neurodevelopment pathways in POMC neurons.PNE does not result in obesity and type 2 diabetes but instead enhances leptin-melanocortinergic feeding and body weight regulation via POMC neurons in adult offspring. PNE leads to selective upregulation of Gm15851, a lncRNA, in adult offspring POMC neurons. POMC neurons express several lncRNAs and pathways possibly regulating POMC neuronal development and/or function.
Pub.: 10 Sep '16, Pinned: 05 Jul '17
Abstract: Prenatal nicotine exposure over an entire pregnancy has been associated with an increased prevalence of hyperactivity, anxiety-like behavior and depression-like behavior in mature rats. However, the effects of maternal nicotine exposure in late gestation and lactation on the psychology and behavior of adolescent rat offspring are unclear. Thus, we investigated the effect of nicotine exposure during late gestation and lactation on anxiety-like and impulsive decision-making behavior in adolescent offspring of rat. Female rats were orally exposed to nicotine which is within range of plasma level of human chronic smokers during the period of third last period of gestation and lactation. When the offspring were weaned, we observed alterations in the anxiety-like behavior and decision-making ability of adolescent rat offspring using light/dark box test and T-maze delay-based cost-benefit decision-making task. The maternal consumption of nicotine reduced both the time spent in the light compartment and the number of transitions compared to nicotine-free rats. Moreover, such nicotine exposed adolescent offspring rats showed impulsive decision making which chose the instant reward in a decision-making situation. We found that nicotine exposure during late gestation and lactation induces an increase in anxiety-like and impulsive decision-making behavior at this developmental stage. These findings suggest that maternal nicotine-exposed offspring are at an increased risk of developing anxious and impulsive behavior.
Pub.: 08 Nov '16, Pinned: 05 Jul '17
Abstract: The dopamine (DA) neurons found in the Ventral Tegmental Area (VTA) are widely involved in the addiction and natural reward circuitry of the brain. Their firing patterns were shown to be important modulators of dopamine release and repetitive burst-like firing activity was highlighted as a major firing pattern of DA neurons in the VTA. In the present study we use a state space model to characterize the DA neurons firing patterns, and trace transitions of neural activity through bursting and non-bursting states. The hidden semi-Markov model (HSMM) framework, which we use, offers a statistically principled inference of bursting states and considers VTA DA firing patterns to be generated according to a Gamma process. Additionally, the explicit Gamma-based modeling of state durations allows efficient decoding of underlying neural information. Consequently, we decode and segment our single unit recordings from DA neurons in VTA according to the sequence of statistically discriminated HSMM states. The segmentation is used to study bursting state characteristics in data recorded from rats prenatally exposed to nicotine (6 mg/kg/day starting with gestational day 3) and rats from saline treated dams. Our results indicate that prenatal nicotine exposure significantly alters burst firing patterns of a subset of DA neurons in adolescent rats, suggesting nicotine exposure during gestation may induce severe effects on the neural networks involved in addiction and reward.
Pub.: 14 Dec '16, Pinned: 05 Jul '17
Abstract: The brain is highly susceptible to adverse effects of drugs of abuse during early phases of life. Prenatal nicotine exposure (PNE), a preventable cause of gestational and infant mortality, can alter neuron wiring and induce sustained deficits in attention and learning. Here, a rat model of PNE (embryonic days 7-21) was used to examine the maturing hippocampus, which encodes new memories and processes emotional memory. Components of synaptic signaling were evaluated at postnatal day 14 (P14), a period of prolific synaptogenesis in rats, to determine if glutamatergic transmission-associated molecules are regulated in subregions of hippocampus as early as P14. PNE resulted in reduced expression of GluN2B, GluA2 and CaMKIIα, but elevated SNAP25 proteins specifically in the CA3 but not CA1. Only CaMKIIα was regulated in dentate gyrus at this age. These results suggest that glutamatergic and synaptic dysregulation of learning and memory may occur in hippocampus in a temporally and subregionally specific manner.
Pub.: 29 Dec '16, Pinned: 05 Jul '17
Abstract: Prenatal exposure to nicotine via cigarette smoke or other forms of tobacco use is a significant environmental risk factor for attention deficit hyperactivity disorder (ADHD). The neurobiological mechanisms underlying the link between prenatal nicotine exposure (PNE) and ADHD are not well understood. Animal models, especially rodent models, are beginning to bridge this gap in knowledge. Although ADHD is characterized by hyperactivity, inattention, impulsivity and working memory deficits, the majority of the animal models are based on only one or two ADHD associated phenotypes, in particular, hyperactivity or inattention. We report a PNE mouse model that displays the full range of ADHD associated behavioral phenotypes including working memory deficit, attention deficit and impulsive-like behavior. All of the ADHD-associated phenotypes respond to a single administration of a therapeutic equivalent dose of methylphenidate. In an earlier study, we showed that PNE produces hyperactivity, frontal cortical hypodopaminergic state and thinning of the cingulate cortex. Collectively, these data suggest that the PNE mouse model recapitulates key features of ADHD and may be a suitable preclinical model for ADHD research.
Pub.: 10 Feb '17, Pinned: 05 Jul '17
Abstract: Increased risk of attention-deficit/hyperactivity disorder (AD/HD) is partly associated with the early developmental exposure to nicotine in tobacco smoke. Emerging reports link tobacco smoke exposure or prenatal nicotine exposure (PNE) with AD/HD-like behaviors in rodent models. We have previously reported that PNE induces cognitive behavioral deficits in offspring and decreases the contents of dopamine (DA) and its turnover in the prefrontal cortex (PFC) of offspring It is well known that the dysfunction of DAergic system in the brain is one of the core factors in the pathophysiology of AD/HD. Therefore, we examined whether the effects of PNE on the DAergic system underlie the AD/HD-related behavioral changes in mouse offspring. PNE reduced the release of DA in the medial PFC (mPFC) in mouse offspring. PNE reduced the number of tyrosine hydroxylase (TH)-positive varicosities in the mPFC and in the core as well as the shell of nucleus accumbens, but not in the striatum. PNE also induced behavioral deficits in cliff avoidance, object-based attention, and sensorimotor gating in offspring. These behavioral deficits were attenuated by acute treatment with atomoxetine (3 mg/kg, s.c.) or partially attenuated by acute treatment with MPH (1 mg/kg, s.c.). Taken together, our findings support the notion that PNE induces neurobehavioral abnormalities in mouse offspring by disrupting the DAergic system and improve our understanding about the incidence of AD/HD in children whose mothers were exposed to nicotine during their pregnancy.
Pub.: 24 Mar '17, Pinned: 05 Jul '17
Abstract: The intrauterine programming of hypothalamic-pituitary-adrenal (HPA) axis hypersensitivity is associated with chronic adult diseases. Our previous studies demonstrated the HPA-axis hypersensitivity in offspring rats induced by prenatal nicotine exposure. The goal of the present study is to further investigate the intrauterine programming mechanism. Pregnant Wistar rats were subcutaneously administered with 2.0 mg/kg day of nicotine from gestational day (GD) 9-20. A group of the pregnant rats was euthanized at GD20, and the fetal rats were extracted. The remaining rats were left to come to term, and the adult offspring were exposed to chronic stress. For adult offspring rats, prenatal nicotine exposure induced HPA-axis hypersensitivity after chronic stress, accompanied by imbalanced glutamatergic/GABAergic afferent inputs. Moreover, prenatal nicotine exposure enhanced the expression of hippocampal glutamic acid decarboxylase 67 (GAD67), accompanied by a decreased methylation ratio within nt -1019 to -689 of the GAD67 promoter, decreased expression of Dnmt1, and an increased GABA content and density of GABAergic neurons. The fetal rats exhibited changes consistent with the adult rats. Similar effects were also observed by treating the fetal hippocampal cell line H19-7 with 1-100 μM nicotine, while dihydro-β-erythroidine hydrobromide (DHβE), the specific inhibitor of α4β2nAChR, can reverse the effects caused by nicotine. These results indicate that prenatal nicotine exposure can enhance the potential excitability of the hypothalamus via the intrauterine programming of up-regulation of hippocampal GAD67. All of these results contribute to the HPA-axis hypersensitivity in adult offspring.
Pub.: 31 May '17, Pinned: 05 Jul '17
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