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Interactions of early-life stress and prenatal alcohol exposure on executive control
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Abstracts / Alcohol 60 (2017) 203e243
Symposium XIV
interventions. Understanding the core areas of susceptibility to prenatal alcohol effects with and without comorbid maternal depression as they manifest in early life is key to developing strategies for early focused identification and interventions. Using multimodal imaging techniques in neonates prenatally exposed to alcohol, a group co-morbidly exposed to antenatal maternal depression and unexposed control infants in a South African birth cohort we describe alterations in both structural volumes and white matter microstructural in the brains of these infants. Alterations demonstrable at this age indicate that prenatal alcohol and maternal mental health affects multiple biological processes that result in physical growth of the brain, quality and maturation of the connecting circuitry in the first weeks of life. We expect that the identification of alcohol effects on key midline structures in the infant brain may be an early marker for later functional cognitive and behavioral deficits in prenatal alcohol exposure. However, the role of comorbid maternal mental health conditions on the developing brain is not well defined in this high risk group. This highly sensitive approach may prove to be valuable in identifying affected children early as well as monitoring the effectiveness of interventions.
Role of early life environment, co-morbid depression, neurochemical regulation and epigenetic reprogramming in stress abnormalities in fetal alcohol spectrum disorders. Chair: Dipak Sarkar, Ph.D.
S58 PRENATAL ALCOHOL EXPOSURE: FETAL PROGRAMMING, ALCOHOLSTRESS INTERACTIONS, AND SEX DIFFERENCES IN OUTCOME
S56 INTERACTIONS OF EARLY-LIFE STRESS AND PRENATAL ALCOHOL EXPOSURE ON EXECUTIVE CONTROL
Joanne Weinberg, Charlis Raineki, Tamara Bodnar, Ni Lan, Kristina Uban, Vivian Lam, Kim Hellemans. University of British Columbia, Vancouver, BC, Canada
Rebecca Castillo, K. Caldwell, J.L. Brigman. University of New Mexico, Albuquerque, NM, USA
Fetal alcohol spectrum disorder (FASD) is an umbrella term encompassing the range of adverse effects resulting from prenatal alcohol exposure (PAE). Alcohol not only has direct effects on the developing fetal brain and organ systems, but also indirect effects through changes in maternal endocrine function and altered maternal-fetal hormonal interactions, with significant impacts on fetal neurobiological, metabolic, physiological and behavioral functions. The hypothalamic-pituitary-adrenal (HPA) axis, a key component of the stress system, is highly sensitive to programming during fetal and neonatal development. Data demonstrate that alcohol exposure in utero programs the fetal HPA axis such that HPA tone is increased throughout life. Importantly, although alterations in HPA responsiveness and regulation are robust phenomena, occurring in both male and female offspring, sexually dimorphic effects of alcohol are frequently observed. In this symposium, I will discuss data from our animal model of PAE suggesting possible mechanisms underlying differential effects of alcohol on male and female offspring, with special emphasis on fetal programming, modulatory influences of the hypothalamicepituitaryegonadal hormones, and changes in gene expression. The long-term implications of PAE for later life health and disease, including immune function and substance use disorders, will also be discussed in the context of the “developmental origins of health and disease” (DOHaD) concept and the 3-hit hypothesis of vulnerability. Research supported by grants from NIH/NIAAA R37 AA007789 and RO1AA022460, CIFASD U24AA014811, and NeuroDevNet (Canadian Networks of Centres of Excellence, UBC 20R64153).
studied brain glucose uptake in a DSM-based animal model of alcohol addiction under rest and following alcohol exposure. Acute alcohol administration significantly reduced the whole-brain glucose metabolism in rats. This effect was most pronounced in the parietal cortex and in the cerebellum. The decreases in regional brain [18F]-FDG uptake were less intense in non-addicted and absent in alcohol addicted rats. The latter finding indicates the occurrence of long-lasting tolerance to the intoxicating effects of alcohol in long-term drinking individuals. In contrary, some regions like the ventral striatum and entorhinal cortex showed enhanced metabolic uptake e an effect that did not undergo tolerance with long-term alcohol consumption. In comparison we studied brain glucose uptake in a DSM-based animal model of cocaine addiction under rest and following cocaine challenge. Patterns of glucose uptake did not match those seen in alcohol addicted rats neither under rest nor following cocaine challenge and many of the changes were present only in one hemisphere, suggesting a role for lateralization in development of addiction-like behavior.
There is growing consensus that moderate alcohol intake during pregnancy can lead to lasting cognitive impairments. These impairments, categorized as Fetal Alcohol Spectrum Disorder (FASD) are characterized by deficits in working memory, response inhibition, and behavioral flexibility. However, the clinical course is influenced by multiple factors, including early life environments. A communal nest, in which multiple dams are housed together prior to parturition and share a nest with subsequent litters, increases multiple measures of pup-care. Communal nests also rescue hippocampal-dependent learning and memory impairments after prenatal alcohol exposure (PAE). Recently we investigated the effects of moderate PAE using a standard nest, a dam solo-housed prior to parturition and isolated with her offspring, on a behavior often affected in FASD, control over reward seeking. PAE offspring showed similar rates of acquisition and extinction of a reward-associated operant response, but significantly increased reinstatement of responding to the stimulus after a brief post-extinction burst of reward. In order to investigate how early-life stress interacts with PAE to alter executive control we tested male and female PAE and control offspring reared in a standard or communal nest were on a simple touchscreen-based instrumental response. After acquisition, all rewards were removed to extinguish the behavior. The reward was then briefly reinstated to observe reward seeking patterns. Results showed that communal nest rearing does not alter acquisition but has significant effects on reinstatement of reward-cue responding. Preclinical modeling of PAE and early-life stress provides a framework for identifying interventions that may alter the outcomes of FASD. This work was supported by the National Institute on NIAAA Grant 1P50AA022534.
S59 CHOLINE SUPPLEMENTATION ATTENUATES SEVERITY OF HIPPOCAMPAL BDNF REDUCTIONS CAUSED BY DEVELOPMENTAL ALCOHOL EXPOSURE J.D. Thomas, K. Potter. San Diego State University, San Diego, CA, USA
S57 CO-OCCURRING MATERNAL DEPRESSION AND PRENATAL ALCOHOL EXPOSURE: MULTIMODAL MRI FINDINGS IN THE INFANT BRAIN Kirsty Donald Ph.D. University of Cape Town, Rondebosch, Cape Town, South Africa Alcohol use and alcohol use disorders contribute a significant proportion of the burden of disease in low, middle, and high-income countries. Maternal mental health disorders are common co-occurring problems in these populations. For neurodevelopmental disorders, studies have consistently shown that early intervention leads to better long-term outcomes. But early intervention is predicated on early detection and targeted
Prenatal alcohol exposure alters physical and neurological development, adversely affecting long-term behavior and health. Early nutritional variables are among the factors that can modify ethanol’s teratogenic effects. We have shown that supplementation with the nutrient choline can attenuate ethanol’s adverse effects on behaviors that depend on the functional integrity of the hippocampus, even when administered after alcohol exposure has ceased. However, it is not fully understood how choline reduces the severity of ethanol’s effects on hippocampal development. Brain-derived neurotrophic factor (BDNF) is known to enhance hippocampal plasticity and developmental alcohol exposure has been shown to reduce BDNF and other neurotrophic factors, which may contribute ongoing impairments in hippocampal function. To determine if
Abstracts / Alcohol 60 (2017) 203e243
Symposium XIV
interventions. Understanding the core areas of susceptibility to prenatal alcohol effects with and without comorbid maternal depression as they manifest in early life is key to developing strategies for early focused identification and interventions. Using multimodal imaging techniques in neonates prenatally exposed to alcohol, a group co-morbidly exposed to antenatal maternal depression and unexposed control infants in a South African birth cohort we describe alterations in both structural volumes and white matter microstructural in the brains of these infants. Alterations demonstrable at this age indicate that prenatal alcohol and maternal mental health affects multiple biological processes that result in physical growth of the brain, quality and maturation of the connecting circuitry in the first weeks of life. We expect that the identification of alcohol effects on key midline structures in the infant brain may be an early marker for later functional cognitive and behavioral deficits in prenatal alcohol exposure. However, the role of comorbid maternal mental health conditions on the developing brain is not well defined in this high risk group. This highly sensitive approach may prove to be valuable in identifying affected children early as well as monitoring the effectiveness of interventions.
Role of early life environment, co-morbid depression, neurochemical regulation and epigenetic reprogramming in stress abnormalities in fetal alcohol spectrum disorders. Chair: Dipak Sarkar, Ph.D.
S58 PRENATAL ALCOHOL EXPOSURE: FETAL PROGRAMMING, ALCOHOLSTRESS INTERACTIONS, AND SEX DIFFERENCES IN OUTCOME
S56 INTERACTIONS OF EARLY-LIFE STRESS AND PRENATAL ALCOHOL EXPOSURE ON EXECUTIVE CONTROL
Joanne Weinberg, Charlis Raineki, Tamara Bodnar, Ni Lan, Kristina Uban, Vivian Lam, Kim Hellemans. University of British Columbia, Vancouver, BC, Canada
Rebecca Castillo, K. Caldwell, J.L. Brigman. University of New Mexico, Albuquerque, NM, USA
Fetal alcohol spectrum disorder (FASD) is an umbrella term encompassing the range of adverse effects resulting from prenatal alcohol exposure (PAE). Alcohol not only has direct effects on the developing fetal brain and organ systems, but also indirect effects through changes in maternal endocrine function and altered maternal-fetal hormonal interactions, with significant impacts on fetal neurobiological, metabolic, physiological and behavioral functions. The hypothalamic-pituitary-adrenal (HPA) axis, a key component of the stress system, is highly sensitive to programming during fetal and neonatal development. Data demonstrate that alcohol exposure in utero programs the fetal HPA axis such that HPA tone is increased throughout life. Importantly, although alterations in HPA responsiveness and regulation are robust phenomena, occurring in both male and female offspring, sexually dimorphic effects of alcohol are frequently observed. In this symposium, I will discuss data from our animal model of PAE suggesting possible mechanisms underlying differential effects of alcohol on male and female offspring, with special emphasis on fetal programming, modulatory influences of the hypothalamicepituitaryegonadal hormones, and changes in gene expression. The long-term implications of PAE for later life health and disease, including immune function and substance use disorders, will also be discussed in the context of the “developmental origins of health and disease” (DOHaD) concept and the 3-hit hypothesis of vulnerability. Research supported by grants from NIH/NIAAA R37 AA007789 and RO1AA022460, CIFASD U24AA014811, and NeuroDevNet (Canadian Networks of Centres of Excellence, UBC 20R64153).
studied brain glucose uptake in a DSM-based animal model of alcohol addiction under rest and following alcohol exposure. Acute alcohol administration significantly reduced the whole-brain glucose metabolism in rats. This effect was most pronounced in the parietal cortex and in the cerebellum. The decreases in regional brain [18F]-FDG uptake were less intense in non-addicted and absent in alcohol addicted rats. The latter finding indicates the occurrence of long-lasting tolerance to the intoxicating effects of alcohol in long-term drinking individuals. In contrary, some regions like the ventral striatum and entorhinal cortex showed enhanced metabolic uptake e an effect that did not undergo tolerance with long-term alcohol consumption. In comparison we studied brain glucose uptake in a DSM-based animal model of cocaine addiction under rest and following cocaine challenge. Patterns of glucose uptake did not match those seen in alcohol addicted rats neither under rest nor following cocaine challenge and many of the changes were present only in one hemisphere, suggesting a role for lateralization in development of addiction-like behavior.
There is growing consensus that moderate alcohol intake during pregnancy can lead to lasting cognitive impairments. These impairments, categorized as Fetal Alcohol Spectrum Disorder (FASD) are characterized by deficits in working memory, response inhibition, and behavioral flexibility. However, the clinical course is influenced by multiple factors, including early life environments. A communal nest, in which multiple dams are housed together prior to parturition and share a nest with subsequent litters, increases multiple measures of pup-care. Communal nests also rescue hippocampal-dependent learning and memory impairments after prenatal alcohol exposure (PAE). Recently we investigated the effects of moderate PAE using a standard nest, a dam solo-housed prior to parturition and isolated with her offspring, on a behavior often affected in FASD, control over reward seeking. PAE offspring showed similar rates of acquisition and extinction of a reward-associated operant response, but significantly increased reinstatement of responding to the stimulus after a brief post-extinction burst of reward. In order to investigate how early-life stress interacts with PAE to alter executive control we tested male and female PAE and control offspring reared in a standard or communal nest were on a simple touchscreen-based instrumental response. After acquisition, all rewards were removed to extinguish the behavior. The reward was then briefly reinstated to observe reward seeking patterns. Results showed that communal nest rearing does not alter acquisition but has significant effects on reinstatement of reward-cue responding. Preclinical modeling of PAE and early-life stress provides a framework for identifying interventions that may alter the outcomes of FASD. This work was supported by the National Institute on NIAAA Grant 1P50AA022534.
S59 CHOLINE SUPPLEMENTATION ATTENUATES SEVERITY OF HIPPOCAMPAL BDNF REDUCTIONS CAUSED BY DEVELOPMENTAL ALCOHOL EXPOSURE J.D. Thomas, K. Potter. San Diego State University, San Diego, CA, USA
S57 CO-OCCURRING MATERNAL DEPRESSION AND PRENATAL ALCOHOL EXPOSURE: MULTIMODAL MRI FINDINGS IN THE INFANT BRAIN Kirsty Donald Ph.D. University of Cape Town, Rondebosch, Cape Town, South Africa Alcohol use and alcohol use disorders contribute a significant proportion of the burden of disease in low, middle, and high-income countries. Maternal mental health disorders are common co-occurring problems in these populations. For neurodevelopmental disorders, studies have consistently shown that early intervention leads to better long-term outcomes. But early intervention is predicated on early detection and targeted
Prenatal alcohol exposure alters physical and neurological development, adversely affecting long-term behavior and health. Early nutritional variables are among the factors that can modify ethanol’s teratogenic effects. We have shown that supplementation with the nutrient choline can attenuate ethanol’s adverse effects on behaviors that depend on the functional integrity of the hippocampus, even when administered after alcohol exposure has ceased. However, it is not fully understood how choline reduces the severity of ethanol’s effects on hippocampal development. Brain-derived neurotrophic factor (BDNF) is known to enhance hippocampal plasticity and developmental alcohol exposure has been shown to reduce BDNF and other neurotrophic factors, which may contribute ongoing impairments in hippocampal function. To determine if