scholarly journals Impact of adolescent intermittent ethanol exposure on interneurons and their surrounding perineuronal nets in adulthood.

2022 ◽  
Author(s):  
Carol A. Dannenhoffer ◽  
Alex Gómez-A ◽  
Victoria Macht ◽  
Rayyanoor Jawad ◽  
E. Blake Sutherland ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Behavioral Flexibility ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Male Rats ◽  
Perineuronal Nets ◽  
Cholinergic Interneurons ◽  
Medial Pfc ◽  
Behavioral Impairments ◽  
Brain And Behavior

Background: Binge alcohol exposure during adolescence results in long-lasting alterations in brain and behavior. For example, adolescent intermittent ethanol (AIE) exposure in rodents results in long-term loss of functional connectivity among prefrontal cortex (PFC) and striatal regions as well as a variety of neurochemical, molecular, and epigenetic alterations. Interneurons in the PFC and striatum play critical roles in behavioral flexibility and functional connectivity. For example, parvalbumin (PV) interneurons are known to contribute to neural synchrony, and cholinergic interneurons contribute to strategy selection. Furthermore, extracellular perineuronal nets (PNNs) surround some interneurons, particularly PV+ interneurons, to further regulate cellular plasticity. The effect of AIE exposure on expression of these markers within the PFC is not well understood. Methods: The present study tested the hypothesis that AIE exposure reduces expression of PV+ and ChAT+ interneurons in the adult PFC and striatum and increases related expression of PNNs (marked by binding of Wisteria Floribunda agglutinin lectin; WFA) in adulthood. Male rats were exposed to AIE (5 g/kg/day, 2-days-on/2-days-off, i.g., P25-P54) or water (CON), and brain tissue was harvested in adulthood (> P80). Immunohistochemistry and co-immunofluorescence were used to assess expression of ChAT, PV, and WFA labeling within the adult PFC and striatum following AIE exposure. Results: ChAT and PV interneuron numbers in the striatum and PFC were unchanged after AIE exposure. However, WFA labeling in the PFC of AIE-exposed rats was increased compared to CON rats. Moreover, significantly more PV neurons were surrounded by WFA labeling in AIE-exposed subjects relative to controls in both PFC subregions assessed: the orbitofrontal cortex (CON = 34%; AIE = 40%) and the medial PFC (CON = 10%; AIE = 14%). Conclusions: These findings indicate that while PV interneuron expression in the adult PFC and striatum is unaltered following AIE exposure, PNNs surrounding these neurons (indicated by extracellular WFA binding) are increased. This increase in PNNs may restrict plasticity of the ensheathed neurons, thus contributing to impaired microcircuitry in frontostriatal connectivity and related behavioral impairments.

scholarly journals Altered cortico-subcortical network after adolescent alcohol exposure mediates behavioral deficits in flexible decision-making

2021 ◽  
Author(s):  
Alexander Gómez-A ◽  
Carol A. Dannenhoffer ◽  
Amanda Elton ◽  
SungHo Lee ◽  
Woomi Ban ◽  
...  
Keyword(s):  
Decision Making ◽  
Functional Connectivity ◽  
Behavioral Flexibility ◽  
Alcohol Exposure ◽  
Brain Structures ◽  
Brain Regions ◽  
Resting State Functional Connectivity ◽  
Mediation Analyses ◽  
Adolescent Alcohol ◽  
Subcortical Regions

AbstractBehavioral flexibility, the ability to modify behavior according to changing conditions, is essential to optimize decision-making. Deficits in behavioral flexibility that persist into adulthood are one consequence of adolescent alcohol exposure, and another is decreased functional connectivity in brain structures involved in decision-making; however, a link between these two outcomes has not been established. We assessed effects of adolescent alcohol and sex on both Pavlovian and instrumental behaviors and functional connectivity in adult animals to determine associations between behavioral flexibility and resting-state functional connectivity. Alcohol exposure impaired attentional set reversals and decreased functional connectivity among cortical and subcortical regions-of-interest that underlie flexible behavior. Moreover, mediation analyses indicated that adolescent alcohol-induced reductions in functional connectivity within a subnetwork of affected brain regions mediated errors committed during reversal learning. These results provide a novel link between persistent reductions in brain functional connectivity and deficits in behavioral flexibility resulting from adolescent alcohol exposure.

scholarly journals Altered Cortico-Subcortical Network After Adolescent Alcohol Exposure Mediates Behavioral Deficits in Flexible Decision-Making

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexander Gómez-A ◽  
Carol A. Dannenhoffer ◽  
Amanda Elton ◽  
Sung-Ho Lee ◽  
Woomi Ban ◽  
...  
Keyword(s):  
Decision Making ◽  
Functional Connectivity ◽  
Resting State ◽  
Behavioral Flexibility ◽  
Alcohol Exposure ◽  
Brain Structures ◽  
Brain Regions ◽  
Resting State Functional Connectivity ◽  
Mediation Analyses ◽  
Adolescent Alcohol

Behavioral flexibility, the ability to modify behavior according to changing conditions, is essential to optimize decision-making. Deficits in behavioral flexibility that persist into adulthood are one consequence of adolescent alcohol exposure, and another is decreased functional connectivity in brain structures involved in decision-making; however, a link between these two outcomes has not been established. We assessed effects of adolescent alcohol and sex on both Pavlovian and instrumental behaviors and resting-state functional connectivity MRI in adult animals to determine associations between behavioral flexibility and resting-state functional connectivity. Alcohol exposure impaired attentional set reversals and decreased functional connectivity among cortical and subcortical regions-of-interest that underlie flexible behavior. Moreover, mediation analyses indicated that adolescent alcohol-induced reductions in functional connectivity within a subnetwork of affected brain regions statistically mediated errors committed during reversal learning. These results provide a novel link between persistent reductions in brain functional connectivity and deficits in behavioral flexibility resulting from adolescent alcohol exposure.

scholarly journals Functional Activation of Newborn Neurons Following Alcohol-Induced Reactive Neurogenesis

2021 ◽  
Vol 11 (4) ◽  
pp. 499
Author(s):  
Natalie N. Nawarawong ◽  
Chelsea G. Nickell ◽  
Deann M. Hopkins ◽  
James R. Pauly ◽  
Kimberly Nixon
Keyword(s):  
Alcohol Dependence ◽  
Training Session ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Male Rats ◽  
Neuronal Nuclei ◽  
Structural Recovery ◽  
Dividing Cells ◽  
Newborn Neurons ◽  
Fluorescent Immunohistochemistry

Abstinence after alcohol dependence leads to structural and functional recovery in many regions of the brain, especially the hippocampus. Significant increases in neural stem cell (NSC) proliferation and subsequent “reactive neurogenesis” coincides with structural recovery in hippocampal dentate gyrus (DG). However, whether these reactively born neurons are integrated appropriately into neural circuits remains unknown. Therefore, adult male rats were exposed to a binge model of alcohol dependence. On day 7 of abstinence, the peak of reactive NSC proliferation, rats were injected with bromodeoxyuridine (BrdU) to label dividing cells. After six weeks, rats underwent Morris Water Maze (MWM) training then were sacrificed ninety minutes after the final training session. Using fluorescent immunohistochemistry for c-Fos (neuronal activation), BrdU, and Neuronal Nuclei (NeuN), we investigated whether neurons born during reactive neurogenesis were incorporated into a newly learned MWM neuronal ensemble. Prior alcohol exposure increased the number of BrdU+ cells and newborn neurons (BrdU+/NeuN+ cells) in the DG versus controls. However, prior ethanol exposure had no significant impact on MWM-induced c-Fos expression. Despite increased BrdU+ neurons, no difference in the number of activated newborn neurons (BrdU+/c-Fos+/NeuN+) was observed. These data suggest that neurons born during alcohol-induced reactive neurogenesis are functionally integrated into hippocampal circuitry.

scholarly journals Moderate prenatal alcohol exposure impairs performance by adult male rats in an object-place paired-associate task

2019 ◽  
Vol 360 ◽  
pp. 228-234 ◽  
Author(s):  
Lilliana M. Sanchez ◽  
Jonathan Goss ◽  
Jennifer Wagner ◽  
Suzy Davies ◽  
Daniel D. Savage ◽  
...  
Keyword(s):  
Adult Male ◽  
Paired Associate ◽  
Prenatal Alcohol Exposure ◽  
Alcohol Exposure ◽  
Male Rats ◽  
Prenatal Alcohol

scholarly journals Galantamine prevents and reverses neuroimmune induction and loss of adult hippocampal neurogenesis following adolescent alcohol exposure

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Victoria Macht ◽  
Ryan Vetreno ◽  
Natalie Elchert ◽  
Fulton Crews
Keyword(s):  
Cell Death ◽  
High Mobility ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Hmgb1 Protein ◽  
Immature Neurons ◽  
Environmental Milieu ◽  
Binge Ethanol Exposure

Abstract Background Binge ethanol exposure during adolescence reduces hippocampal neurogenesis, a reduction which persists throughout adulthood despite abstinence. This loss of neurogenesis, indicated by reduced doublecortin+ immunoreactivity (DCX+IR), is paralleled by an increase in hippocampal proinflammatory signaling cascades. As galantamine, a cholinesterase inhibitor, has anti-inflammatory actions, we tested the hypothesis that galantamine would prevent (study 1) or restore (study 2) AIE induction of proinflammatory signals within the hippocampus as well as AIE-induced loss of hippocampal neurogenesis. Methods Galantamine (4 mg/kg) or vehicle (saline) was administered to Wistar rats during adolescent intermittent ethanol (AIE; 5.0 g/kg ethanol, 2 days on/2 days off, postnatal day [P] 25-54) (study 1, prevention) or after AIE during abstinent maturation to adulthood (study 2, restoration). Results Results indicate AIE reduced DCX+IR and induced cleaved caspase3 (Casp3) in DCX-expressing immature neurons. Excitingly, AIE induction of activated Casp3 in DCX-expressing neurons is both prevented and reversed by galantamine treatment, which also resulted in prevention and restoration of neurogenesis (DCX+IR). Similarly, galantamine prevented and/or reversed AIE induction of proinflammatory markers, including the chemokine (C-C motif) ligand 2 (CCL2), cyclooxygenase-2 (COX-2), and high mobility group box 1 (HMGB1) protein, suggesting that AIE induction of proinflammatory signaling mediates both cell death cascades and hippocampal neurogenesis. Interestingly, galantamine treatment increased Ki67+IR generally as well as increased pan-Trk expression specifically in AIE-treated rats but failed to reverse AIE induction of NADPH-oxidase (gp91phox). Conclusions Collectively, our studies suggest that (1) loss of neurogenesis after AIE is mediated by persistent induction of proinflammatory cascades which drive activation of cell death machinery in immature neurons, and (2) galantamine can prevent and restore AIE disruptions in the hippocampal environmental milieu to then prevent and restore AIE-mediated loss of neurogenesis.

scholarly journals The NKCC1 antagonist bumetanide mitigates interneuronopathy associated with ethanol exposure in utero

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Alexander GJ Skorput ◽  
Stephanie M Lee ◽  
Pamela WL Yeh ◽  
Hermes H Yeh
Keyword(s):  
Prefrontal Cortex ◽  
Cortical Neurons ◽  
Fetal Alcohol Spectrum Disorders ◽  
Behavioral Flexibility ◽  
Ethanol Exposure ◽  
Embryonic Mouse ◽  
Form And Function ◽  
Tangential Migration ◽  
And Function

Prenatal exposure to ethanol induces aberrant tangential migration of corticopetal GABAergic interneurons, and long-term alterations in the form and function of the prefrontal cortex. We have hypothesized that interneuronopathy contributes significantly to the pathoetiology of fetal alcohol spectrum disorders (FASD). Activity-dependent tangential migration of GABAergic cortical neurons is driven by depolarizing responses to ambient GABA present in the cortical enclave. We found that ethanol exposure potentiates the depolarizing action of GABA in GABAergic cortical interneurons of the embryonic mouse brain. Pharmacological antagonism of the cotransporter NKCC1 mitigated ethanol-induced potentiation of GABA depolarization and prevented aberrant patterns of tangential migration induced by ethanol in vitro. In a model of FASD, maternal bumetanide treatment prevented interneuronopathy in the prefrontal cortex of ethanol exposed offspring, including deficits in behavioral flexibility. These findings position interneuronopathy as a mechanism of FASD symptomatology, and posit NKCC1 as a pharmacological target for the management of FASD.

scholarly journals Tumour Necrosis Factor in Neuroplasticity, Neurogenesis and Alcohol Use Disorder

2020 ◽  
Vol 6 (1) ◽  
pp. 47-66 ◽  
Author(s):  
Ignatius Alvarez Cooper ◽  
Kate Beecher ◽  
Fatemeh Chehrehasa ◽  
Arnauld Belmer ◽  
Selena E. Bartlett
Keyword(s):  
Alcohol Use ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Alcohol Use Disorder ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Neuroimmune System ◽  
Inflammatory Status ◽  
The Brain ◽  
Necrosis Factor

Alcohol use disorder is a pervasive and detrimental condition that involves changes in neuroplasticity and neurogenesis. Alcohol activates the neuroimmune system and alters the inflammatory status of the brain. Tumour necrosis factor (TNF) is a well characterised neuroimmune signal but its involvement in alcohol use disorder is unknown. In this review, we discuss the variable findings of TNF’s effect on neuroplasticity and neurogenesis. Acute ethanol exposure reduces TNF release while chronic alcohol intake generally increases TNF levels. Evidence suggests TNF potentiates excitatory transmission, promotes anxiety during alcohol withdrawal and is involved in drug use in rodents. An association between craving for alcohol and TNF is apparent during withdrawal in humans. While anti-inflammatory therapies show efficacy in reversing neurogenic deficit after alcohol exposure, there is no evidence for TNF’s essential involvement in alcohol’s effect on neurogenesis. Overall, defining TNF’s role in alcohol use disorder is complicated by poor understanding of its variable effects on synaptic transmission and neurogenesis. While TNF may be of relevance during withdrawal, the neuroimmune system likely acts through a larger group of inflammatory cytokines to alter neuroplasticity and neurogenesis. Understanding the individual relevance of TNF in alcohol use disorder awaits a more comprehensive understanding of TNF’s effects within the brain.

Altered hippocampal neurogenesis in adult male rats after prenatal ethanol exposure

2006 ◽  
Vol 27 (1) ◽  
pp. 100-101 ◽  
Author(s):  
Joanna H. Sliwowska ◽  
Jennifer M. Barker ◽  
Cindy Barha ◽  
Linda Ellis ◽  
Wayne Yu ◽  
...  
Keyword(s):  
Adult Male ◽  
Ethanol Exposure ◽  
Hippocampal Neurogenesis ◽  
Male Rats ◽  
Prenatal Ethanol Exposure

Vascular function in alcohol-treated pregnant and nonpregnant mice

2001 ◽  
Vol 281 (5) ◽  
pp. R1449-R1455 ◽  
Author(s):  
Jocelynn L. Cook ◽  
Yunlong Zhang ◽  
Sandra T. Davidge
Keyword(s):  
Nitric Oxide ◽  
Vascular Function ◽  
Vascular System ◽  
Prenatal Alcohol Exposure ◽  
Control Diet ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Vascular Response ◽  
Oxide Component ◽  
Pregnant Mice

The effect of alcohol on maternal vascular adaptations to pregnancy is unknown. This study was designed to determine the effect of alcohol consumption on nitric oxide-mediated vascular function in mice during pregnancy. Female pregnant or nonpregnant C57BL/6J mice were fed a control diet or a liquid diet of 25% ethanol-derived calories for 13 days (from gestational days 6–18). Phenylephrine vasoconstriction was blunted in pregnancy compared with the nonpregnant state due to enhanced nitric oxide modulation, which was impaired by ethanol exposure. Although the EC50 and maximal responses to methacholine were not different in nonpregnant vs. pregnant mice, the nitric oxide component to methacholine-induced vasorelaxation was greater in the pregnant mice. Interestingly, alcohol affected only the pregnant animals in their response to methacholine. These data indicate that alcohol reduced the nitric oxide modulation of vascular response, which was more pronounced during pregnancy. These studies provide novel information regarding the effects of alcohol on the maternal vascular system during pregnancy and thereby contribute to further understanding of the adverse effects associated with prenatal alcohol exposure.

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