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1.
Neuropsychopharmacology ; 44(9): 1579-1588, 2019 08.
Article in English | MEDLINE | ID: mdl-30737481

ABSTRACT

Growing evidence has shown that developmental alcohol exposure induces central nervous system inflammation and microglia activation, which may contribute to long-term health conditions, such as fetal alcohol spectrum disorders. These studies sought to investigate whether neonatal alcohol exposure during postnatal days (PND) 2-6 in rats (third trimester human equivalent) leads to long-term disruption of the neuroimmune response by microglia. Exposure to neonatal alcohol resulted in acute increases in activation and inflammatory gene expression in hypothalamic microglia including tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). Adults with neonatal alcohol pre-exposure (alcohol fed; AF) animals showed an exaggerated peripheral stress hormonal response to an immune challenge (lipopolysaccharides; LPS). In addition, there were significantly more microglia present in the hypothalamus of adult AF animals, and their hypothalamic microglia showed more cluster of differentiation molecule 11b (Cd11b) activation, TNF-α expression, and IL-6 expression in response to LPS. Interestingly, blocking microglia activation with minocycline treatment during PND 2-6 alcohol exposure ameliorated the hormonal and microglial hypersensitivity to LPS in AF adult animals. Investigation of possible epigenetic programming mechanisms by alcohol revealed neonatal alcohol decreased several repressive regulators of transcription in hypothalamic microglia, while concomitantly increasing histone H3 acetyl lysine 9 (H3K9ac) enrichment at TNF-α and IL-6 promoter regions. Importantly, adult hypothalamic microglia from AF animals showed enduring increases in H3K9ac enrichment of TNF-α and IL-6 promoters both at baseline and after LPS exposure, suggesting a possible epigenetic mechanism for the long-term immune disruption due to hypothalamic microglial priming.


Subject(s)
Central Nervous System Depressants/pharmacology , Ethanol/pharmacology , Gene Expression/drug effects , Hypothalamus/drug effects , Microglia/drug effects , Tumor Necrosis Factor-alpha/drug effects , Animals , Animals, Newborn , Epigenesis, Genetic , Gene Expression/immunology , Histone Code/drug effects , Hypothalamus/cytology , Hypothalamus/immunology , Inflammation/immunology , Interleukin-6/immunology , Lipopolysaccharides/pharmacology , Microglia/immunology , Rats , Tumor Necrosis Factor-alpha/immunology
2.
Alcohol ; 60: 53-66, 2017 05.
Article in English | MEDLINE | ID: mdl-28431793

ABSTRACT

Excessive alcohol exposure has severe health consequences, and clinical and animal studies have demonstrated that disruptions in the epigenome of somatic cells, such as those in brain, are an important factor in the development of alcohol-related pathologies, such as alcohol-use disorders (AUDs) and fetal alcohol spectrum disorders (FASDs). It is also well known that alcohol-related health problems are passed down across generations in human populations, but the complete mechanisms for this phenomenon are currently unknown. Recent studies in animal models have suggested that epigenetic factors are also responsible for the transmission of alcohol-related pathologies across generations. Alcohol exposure has been shown to induce changes in the epigenome of sperm of exposed male animals, and these epimutations are inherited in the offspring. This paper reviews evidence for multigenerational and transgenerational epigenetic inheritance of alcohol-related pathology through the germline. We also review the literature on the epigenetic effects of alcohol exposure on somatic cells in brain, and its contribution to AUDs and FASDs. We note gaps in knowledge in this field, such as the lack of clinical studies in human populations and the lack of data on epigenetic inheritance via the female germline, and we suggest future research directions.


Subject(s)
Alcohol Drinking/genetics , Alcoholism/genetics , Brain/drug effects , Epigenesis, Genetic/drug effects , Ethanol/adverse effects , Germ-Line Mutation , Inheritance Patterns , Spermatozoa/drug effects , Alcohol Drinking/adverse effects , Alcohol Drinking/metabolism , Alcohol Drinking/pathology , Alcoholism/metabolism , Alcoholism/pathology , Animals , Brain/metabolism , Brain/pathology , Chromatin Assembly and Disassembly/drug effects , DNA Methylation/drug effects , Disease Models, Animal , Gene-Environment Interaction , Genetic Predisposition to Disease , Heredity , Humans , Male , Pedigree , Risk Factors , Spermatozoa/metabolism , Spermatozoa/pathology
3.
J Neuroinflammation ; 14(1): 83, 2017 04 14.
Article in English | MEDLINE | ID: mdl-28407740

ABSTRACT

BACKGROUND: Opioid receptors are known to control neurotransmission of various peptidergic neurons, but their potential role in regulation of microglia and neuronal cell communications is unknown. We investigated the role of mu-opioid receptors (MOR) and delta-opioid receptors (DOR) on microglia in the regulation of apoptosis in proopiomelanocortin (POMC) neurons induced by neonatal ethanol in the hypothalamus. METHODS: Neonatal rat pups were fed a milk formula containing ethanol or control diets between postnatal days 2-6. Some of the alcohol-fed rats additionally received pretreatment of a microglia activation blocker minocycline. Two hours after the last feeding, some of the pups were sacrificed and processed for histochemical detection of microglial cell functions or confocal microscopy for detection of cellular physical interaction or used for gene and protein expression analysis. The rest of the pups were dissected for microglia separation by differential gradient centrifugation and characterization by measuring production of various activation markers and cytokines. In addition, primary cultures of microglial cells were prepared using hypothalamic tissues of neonatal rats and used for determination of cytokine production/secretion and apoptotic activity of neurons. RESULTS: In the hypothalamus, neonatal alcohol feeding elevated cytokine receptor levels, increased the number of microglial cells with amoeboid-type circularity, enhanced POMC and microglial cell physical interaction, and decreased POMC cell numbers. Minocycline reversed these cellular effects of alcohol. Alcohol feeding also increased levels of microglia MOR protein and pro-inflammatory signaling molecules in the hypothalamus, and MOR receptor antagonist naltrexone prevented these effects of alcohol. In primary cultures of hypothalamic microglia, both MOR agonist [D-Ala 2, N-MePhe 4, Gly-ol]-enkephalin (DAMGO) and ethanol increased microglial cellular levels and secretion of pro-inflammatory cell signaling proteins. However, a DOR agonist [D-Pen2,5]enkephalin (DPDPE) increased microglial secretion of anti-inflammatory cytokines and suppressed ethanol's ability to increase microglial production of inflammatory signaling proteins and secretion of pro-inflammatory cytokines. In addition, MOR-activated inflammation promoted while DOR-suppressed inflammation inhibited the apoptotic effect of ethanol on POMC neurons. CONCLUSIONS: These results suggest that ethanol's neurotoxic action on POMC neurons results from MOR-activated neuroinflammatory signaling. Additionally, these results identify a protective effect of a DOR agonist against the pro-inflammatory and neurotoxic action of ethanol.


Subject(s)
Ethanol/toxicity , Microglia/metabolism , Neurons/metabolism , Pro-Opiomelanocortin/metabolism , Receptors, Opioid, delta/physiology , Receptors, Opioid, mu/physiology , Animals , Animals, Newborn , Apoptosis/drug effects , Apoptosis/physiology , Cells, Cultured , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Female , Hypothalamus/drug effects , Hypothalamus/metabolism , Hypothalamus/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microglia/drug effects , Microglia/pathology , Neurons/drug effects , Neurons/pathology , Rats , Rats, Sprague-Dawley , Receptors, Opioid, delta/agonists , Receptors, Opioid, mu/agonists
4.
Neuropsychopharmacology ; 41(11): 2782-93, 2016 10.
Article in English | MEDLINE | ID: mdl-27296153

ABSTRACT

The effect of preconception drinking by the mother on the life-long health outcomes of her children is not known, and therefore, in this study using an animal model, we determined the impact of preconception alcohol drinking of the mother on offspring stress response during adulthood. In our preconception alcohol exposure model, adult female rats were fed with 6.7% alcohol in their diet for 4 weeks, went without alcohol for 3 weeks and were bred to generate male and female offspring. Preconception alcohol-exposed offsprings' birth weight, body growth, stress response, anxiety-like behaviors, and changes in stress regulatory gene and protein hormone levels were evaluated. In addition, roles of epigenetic mechanisms in preconception alcohol effects were determined. Alcohol feeding three weeks prior to conception significantly affected pregnancy outcomes of female rats, with respect to delivery period and birth weight of offspring, without affecting maternal care behaviors. Preconception alcohol negatively affected offspring adult health, producing an increased stress hormone response to an immune challenge. In addition, preconception alcohol was associated with changes in expression and methylation profiles of stress regulatory genes in various brain areas. These changes in stress regulatory genes were normalized following treatment with a DNA methylation blocker during the postnatal period. These data highlight the novel possibility that preconception alcohol affects the inheritance of stress-related diseases possibly by epigenetic mechanisms.


Subject(s)
Anxiety/physiopathology , Central Nervous System Depressants/adverse effects , Ethanol/adverse effects , Maternal Behavior/physiology , Prenatal Exposure Delayed Effects/physiopathology , Stress, Psychological/etiology , Animals , Animals, Newborn , Anxiety/etiology , Central Nervous System Depressants/administration & dosage , Central Nervous System Depressants/pharmacology , Corticotropin-Releasing Hormone/genetics , Corticotropin-Releasing Hormone/metabolism , DNA Methylation/drug effects , DNA Methylation/genetics , Ethanol/administration & dosage , Female , Gene Expression Regulation/drug effects , Lipopolysaccharides/adverse effects , Male , Neuropeptide Y/genetics , Neuropeptide Y/metabolism , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/metabolism , Pregnancy , Pregnancy Outcome , Rats , Rats, Inbred F344 , Receptors, Mineralocorticoid/genetics , Receptors, Mineralocorticoid/metabolism , Ribosomal Proteins/genetics , Ribosomal Proteins/metabolism
5.
Behav Brain Res ; 280: 160-71, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25449842

ABSTRACT

Schizophrenia is thought to be caused, at least in part, by dysfunction in striatal dopamine neurotransmission. Both clinical studies and animal research have implicated the dopamine neuromodulator neurotensin (NT) in the pathophysiology of schizophrenia. Utilizing male mice lacking the NT gene (NT(-/-)), these studies examined the consequences of NT deficiency on dopaminergic tone and function, investigating (1) dopamine concentrations and dopamine receptor and transporter expression and binding in dopaminergic terminal regions, and (2) the behavioral effects of selective dopamine receptor agonists on locomotion and sensorimotor gating in adult NT(-/-) mice compared to wildtype (NT(+/+)) mice. NT(-/-) mice did not differ from NT(+/+) mice in concentrations of dopamine or its metabolite DOPAC in any brain region examined. However, NT(-/-) mice showed significantly increased D1 receptor, D2 receptor, and dopamine transporter (DAT) mRNA in the caudate putamen compared to NT(+/+) controls. NT(-/-) mice also showed elevated D2 receptor binding densities in both the caudate putamen and nucleus accumbens shell compared to NT(+/+) mice. In addition, some of the behavioral effects of the D1-type receptor agonist SKF-82958 and the D2-type receptor agonist quinpirole on locomotion, startle amplitude, and prepulse inhibition were dose-dependently altered in NT(-/-) mice, showing altered D1-type and D2-type receptor sensitivity to stimulation by agonists in the absence of NT. The results indicate that NT deficiency alters striatal dopamine receptor expression, binding, and function. This suggests a critical role for the NT system in the maintenance of striatal DA system homeostasis and implicates NT deficiency in the etiology of dopamine-associated disorders such as schizophrenia.


Subject(s)
Corpus Striatum/physiology , Dopamine Plasma Membrane Transport Proteins/metabolism , Neuronal Plasticity/physiology , Neurotensin/deficiency , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Benzazepines/pharmacology , Corpus Striatum/drug effects , Dopamine/metabolism , Dopamine Agonists/pharmacology , Male , Mice, Knockout , Motor Activity/drug effects , Motor Activity/physiology , Neuronal Plasticity/drug effects , Neurotensin/genetics , Quinpirole/pharmacology , RNA, Messenger/metabolism , Reflex, Startle/drug effects , Reflex, Startle/physiology , Sensory Gating/drug effects , Sensory Gating/physiology
6.
Int Rev Neurobiol ; 118: 81-103, 2014.
Article in English | MEDLINE | ID: mdl-25175862

ABSTRACT

Exposure to alcohol, during development or adulthood, may result in damage to the nervous system, which underlies neurological and cognitive disruptions observed in patients with alcohol-related disorders, including fetal alcohol spectrum disorders (FASDs) and alcohol-use disorders (AUDs). Both clinical and preclinical evidence suggest microglia, the immune cells of the central nervous system, play a key role in modulating alcohol-induced neurotoxicity. Particularly, microglia are implicated in alcohol-induced neuroinflammation and in alcohol-induced increases in oxidative stress, which can lead to neuronal apoptosis. Recent studies also suggest a regenerative role for microglia in reestablishing homeostasis after alcohol exposure. These studies are summarized and reviewed in this chapter with emphasis on relevance to FASD and AUD.


Subject(s)
Alcohol-Related Disorders , Central Nervous System/pathology , Encephalitis/complications , Ethanol/toxicity , Microglia/pathology , Alcohol-Related Disorders/complications , Alcohol-Related Disorders/etiology , Alcohol-Related Disorders/pathology , Animals , Apoptosis/drug effects , Humans , Microglia/metabolism , Neurons/pathology , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism
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