Exposure of a fetus to ethanol can lead to the development of fetal alcohol syndrome, which is characterized by various morphological and behavioral deficits in fetal alcohol-exposed (FAE) offspring. These offspring often show clinical sleep-wake disturbances and abnormalities in the functions of the neuroendocrine system. Recent studies have identified the possibility that the sleep-wake disturbances and neuroendocrine function abnormalities in the FAE offspring are related to long-term changes in circadian clock mechanisms. Employing the rat animal model, this proposal determines whether fetal exposure to ethanol causes long- lasting changes in the circadian output of beta-endorphin neurons located in the arcuate nucleus of the hypothalamus and their regulation of plasma gonadotropin release. It tests the hypothesis that fetal exposure to ethanol causes an abnormality in the adult expression of the central clock mechanisms in the suprachaismatic nucleus of the hypothalamus leading to alteration in the internal clock mechanisms and the phasic hormonal output of beta-endorphin neurons. It also identifies whether fetal exposure to ethanol alters the molecular mechanism governing the photic responses of the central and internal clocks. The proposed research uses laser-captured microscopy, immunohistochemistry, Western blot, radioimmunoassay, and real-time RT-PCR techniques to identify gene and protein expressions that are critically involved in the regulation of central and internal clock mechanisms and the phasic hormonal outputs from beta-endorphin neurons. The proposed studies should provide a better understanding of the long-term consequences of fetal exposure to ethanol in the circadian clock functions. This information should help to develop therapeutic strategies in managing sleep-wake disturbances and the resultant health consequences in FAE offspring.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA015718-05
Application #
7799663
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Grandison, Lindsey
Project Start
2006-04-10
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$261,987
Indirect Cost
Name
Rutgers University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Agapito, Maria A; Zhang, Changqing; Murugan, Sengottuvelan et al. (2014) Fetal alcohol exposure disrupts metabolic signaling in hypothalamic proopiomelanocortin neurons via a circadian mechanism in male mice. Endocrinology 155:2578-88
Murugan, Sengottuvelan; Boyadjieva, Nadka; Sarkar, Dipak K (2014) Protective effects of hypothalamic beta-endorphin neurons against alcohol-induced liver injuries and liver cancers in rat animal models. Alcohol Clin Exp Res 38:2988-97
Cermakian, Nicolas; Lange, Tanja; Golombek, Diego et al. (2013) Crosstalk between the circadian clock circuitry and the immune system. Chronobiol Int 30:870-88
Logan, Ryan W; Sarkar, Dipak K (2012) Circadian nature of immune function. Mol Cell Endocrinol 349:82-90
Agapito, Maria; Mian, Nadia; Boyadjieva, Nadka I et al. (2010) Period 2 gene deletion abolishes beta-endorphin neuronal response to ethanol. Alcohol Clin Exp Res 34:1613-8
Boyadjieva, Nadka I; Ortigüela, María; Arjona, Alvaro et al. (2009) Beta-endorphin neuronal cell transplant reduces corticotropin releasing hormone hyperresponse to lipopolysaccharide and eliminates natural killer cell functional deficiencies in fetal alcohol exposed rats. Alcohol Clin Exp Res 33:931-7
Sarkar, Dipak K; Boyadjieva, Nadka I; Chen, Cui Ping et al. (2008) Cyclic adenosine monophosphate differentiated beta-endorphin neurons promote immune function and prevent prostate cancer growth. Proc Natl Acad Sci U S A 105:9105-10