Motor Function Deficits Following Chronic Prenatal Ethanol Exposure are Linked to Impairments in Insulin/IGF, Notch and Wnt Signaling in the Cerebellum

Tong, Ming; Ziplow, Jason; Chen, William Cy; Nguyen, Quynh-Giao; Kim, Charles

doi:10.4172/2155-6156.1000238

Cited by 18 publications

(17 citation statements)

References 80 publications

(106 reference statements)

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“…Therefore, the early reductions in relative area of the molecular layer suggest that ethanol exposure causes loss of nerve terminals destined to synapse on Purkinje cells which drive motor output from the cerebellum. These adverse effects could account for alcohol-related cerebellar dysfunction, manifested by poor performance on tasks such as the rotarod [ 40 , 72 , 73 ]. The relative decline in granule cells late in the time course (Week 8), corresponds with granule cell loss that is characteristic of alcohol-related cerebellar degeneration in humans and experimental models [ 8 , 37 , 74 ].…”

Section: Discussionmentioning

confidence: 99%

Ethanol-Induced White Matter Atrophy Is Associated with Impaired Expression of Aspartyl-Asparaginyl-β-Hydroxylase (ASPH) and Notch Signaling in an Experimental Rat Model

Tong¹,

Gonzalez-Navarrete²,

Kirchberg³

et al. 2017

J Drug Alcohol Res

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Alcohol-induced white matter (WM) degeneration is linked to cognitive-motor deficits and impairs insulin/insulin-like growth factor (IGF) and Notch networks regulating oligodendrocyte function. Ethanol downregulates Aspartyl-Asparaginyl-β-Hydroxylase (ASPH) which drives Notch. These experiments determined if alcohol-related WM degeneration was linked to inhibition of ASPH and Notch. Adult Long Evans rats were fed for 3, 6 or 8 weeks with liquid diets containing 26% ethanol (caloric) and in the last two weeks prior to each endpoint they were binged with 2 g/kg ethanol, 3×/week. Controls were studied in parallel. Histological sections of the frontal lobe and cerebellar vermis were used for image analysis. Frontal WM proteins were used for Western blotting and duplex ELISAs. The ethanol exposures caused progressive reductions in frontal and cerebellar WM. Ethanol-mediated frontal WM atrophy was associated with reduced expression of ASPH, Jagged 1, HES-1, and HIF-1α. These findings link ethanol-induced WM atrophy to inhibition of ASPH expression and signaling through Notch networks, including HIF-1α.

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Section: Discussionmentioning

confidence: 99%

Ethanol-Induced White Matter Atrophy Is Associated with Impaired Expression of Aspartyl-Asparaginyl-β-Hydroxylase (ASPH) and Notch Signaling in an Experimental Rat Model

Tong¹,

Gonzalez-Navarrete²,

Kirchberg³

et al. 2017

J Drug Alcohol Res

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“…Our findings are consistent with other studies of fetal alcohol exposure, although a few discrepancies regarding this issue do exist in the literature. Motor deficits were found following continuous prenatal access to 24% v/v alcohol in rats (Tong et al, 2013) and also in mice prenatally exposed to 18% v/v alcohol (Cebolla et al, 2009). However, the prenatal DID test did not alter rotarod performance either in adolescent or adult mice offspring (Boehm et al, 2008) and after chronic intragastric administration of 6 g EtOH/kg/day throughout gestation, no rotarod impairments were found in adult rat offspring (Dursun et al, 2006), although higher maternal BACs were reached in those studies (124-180 mg/dl and 334.45±18 mg/dl, respectively).…”

Section: Animal Model and Behavioral Effects Induced By Prenatal And mentioning

confidence: 98%

Maternal alcohol binge drinking induces persistent neuroinflammation associated with myelin damage and behavioural dysfunctions in offspring mice

et al. 2017

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Alcohol binge drinking is on the increase in the young adult population, and consumption during pregnancy can be deleterious for foetal development. Maternal alcohol consumption leads to a wide range of long-lasting morphological and behavioural deficiencies known as foetal alcohol spectrum disorders (FASD), associated with neurodevelopmental disabilities. We sought to test the effects of alcohol on neuroimmune system activation and its potential relation to alcohol-induced neurodevelopmental and persistent neurobehavioural effects in offspring after maternal alcohol binge drinking during the prenatal period or in combination with lactation. Pregnant C57BL/6 female mice underwent a procedure for alcohol binge drinking either during gestation or both the gestation and lactation periods. Adult male offspring were assessed for cognitive functions and motor coordination. Early alcohol exposure induced motor coordination impairments in the rotarod test. Object recognition memory was not affected by maternal alcohol binge drinking, but Y-maze performance was impaired in pre- and early postnatal alcohol-exposed mice. Behavioural effects were associated with an upregulation of pro-inflammatory signalling (Toll-like receptor 4, nuclear factor-kappa B p65, NOD-like receptor protein 3, caspase-1, and interleukin-1β), gliosis, neuronal cell death and a reduction in several structural myelin proteins (myelin-associated glycoprotein, myelin basic protein, myelin proteolipid protein and myelin regulatory factor) in both the prefrontal cortex and hippocampus of adult mice exposed to alcohol. Altogether, our results reveal that maternal binge-like alcohol consumption induces neuroinflammation and myelin damage in the brains of offspring and that such effects may underlie the persistent cognitive and behavioural impairments observed in FASD.

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“…The implication of IR and IR‐related indirect mechanisms was documented during various challenges in adulthood that include aging, neurodegeneration, stress, and exposure to toxins such as alcohol, and are related to the roles of IR in the neuroprotection …”

Section: Insulin Receptor–mediated Signaling and Cns Pathologiesmentioning

confidence: 99%

“…Fundamental roles of the IR‐mediated signaling in brain development are reflected by numerous associations reported between its deficiency and neurodevelopmental disorders, such as autism and schizophrenia, as well as cancer, including cerebellar neoplasms and other syndromes . Altered neuroprotective functions of IR are ascribed to the contribution of IR‐related signaling to the pathophysiology of neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, and Parkinson's disorder; major depression; and neurotoxicity …”

Section: Introductionmentioning

confidence: 99%

Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment

et al. 2018

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While the insulin receptor (IR) was found in the CNS decades ago, the brain was long considered to be an insulin-insensitive organ. This view is currently revisited, given emerging evidence of critical roles of IR-mediated signaling in development, neuroprotection, metabolism, and plasticity in the brain. These diverse cellular and physiological IR activities are distinct from metabolic IR functions in peripheral tissues, thus highlighting region specificity of IR properties. This particularly concerns the fact that two IR isoforms, A and B, are predominantly expressed in either the brain or peripheral tissues, respectively, and neurons express exclusively IR-A. Intriguingly, in comparison with IR-B, IR-A displays high binding affinity and is also activated by low concentrations of insulin-like growth factor-2 (IGF-2), a regulator of neuronal plasticity, whose dysregulation is associated with neuropathologic processes. Deficiencies in IR activation, insulin availability, and downstream IR-related mechanisms may result in aberrant IR-mediated functions and, subsequently, a broad range of brain disorders, including neurodevelopmental syndromes, neoplasms, neurodegenerative conditions, and depression. Here, we discuss findings on the brain-specific features of IR-mediated signaling with focus on mechanisms of primary receptor activation and their roles in the neuropathology. We aimed to uncover the remaining gaps in current knowledge on IR physiology and highlight new therapies targeting IR, such as IR sensitizers.

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Motor Function Deficits Following Chronic Prenatal Ethanol Exposure are Linked to Impairments in Insulin/IGF, Notch and Wnt Signaling in the Cerebellum

Abstract: Background-Fetal alcohol spectrum disorder (FASD) is associated with deficits in cerebellar function that can persist through adolescence. Previous studies demonstrated striking inhibition of insulin and insulin-like growth factor (IGF) signaling in ethanol-exposed cerebella.

Cited by 18 publications

References 80 publications

Ethanol-Induced White Matter Atrophy Is Associated with Impaired Expression of Aspartyl-Asparaginyl-β-Hydroxylase (ASPH) and Notch Signaling in an Experimental Rat Model

Ethanol-Induced White Matter Atrophy Is Associated with Impaired Expression of Aspartyl-Asparaginyl-β-Hydroxylase (ASPH) and Notch Signaling in an Experimental Rat Model

Maternal alcohol binge drinking induces persistent neuroinflammation associated with myelin damage and behavioural dysfunctions in offspring mice

Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment

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