Clinical studies demonstrate that exposure to ethanol early in life, particularly during gestation, increases the consumption of and preference for ethanol and the risk for alcoholism. The molecular and cellular mechanisms involved in this phenomenon have yet to be characterized. Our recent studies in rats, focusing on the hypothalamic orexigenic neuropeptides, melanin-concentrating hormone (MCH) and orexin (OX), that increase ethanol intake and related emotional behaviors, demonstrate a stimulatory effect of embryonic exposure to ethanol, at relatively low levels and only during peak hypothalamic neurogenesis, on the density and long-term expression of neurons that produce these peptides in the perifornical lateral hypothalamus (PF+LH). Building on evidence that the inflammatory agent lipopolysaccharide, like ethanol, increases peripheral chemokine levels, peptide expression, and drinking of ethanol, we investigated and demonstrated in our most recent study a close link between these orexigenic peptides and local chemokine system, CCL2, and its receptor, CCR2. Consistent with evidence that mutations of CCL2 or CCR2 genes markedly reduce ethanol intake, we found that prenatal ethanol exposure, at low doses from embryonic day 10 (E10) to E15, increases circulating CCL2 levels, density in pre-pubertal offspring of MCH neurons that contain CCR2 but not CCL2, and intake of and preference for ethanol during adolescence. This evidence, along with our extensive preliminary findings, provides the foundation for our hypothesis, to be tested in 4 aims, that: Activation of the CCL2/CCR2 signaling system in the embryo as well as dam contributes to the stimulatory effects of prenatal ethanol exposure, at low levels and for a brief period, on development and migration of orexigenic peptide neurons in the PF+LH, resulting in their increased density and expression after birth that subsequently promote ethanol intake and related behaviors during adolescence.
In Aim 1, we will examine in adolescent offspring whether prenatal exposure to CCL2 acts similarly to ethanol and mediates its stimulatory effects on neuronal development and behaviors induced by the peptides.
In Aim 2, we will directly compare in the embryo effects of prenatal exposure to ethanol and CCL2 and determine whether CCL2 mediates ethanol-induced proliferation, differentiation and migration of peptide neurons that co-express CCR2. Building on our preliminary finding that radial glia in the hypothalamic neuroepithelium (NEP) contain CCL2 and are highly responsive to ethanol, we propose in Aim 3 to test in the embryo, from E12 to E19, the effects of ethanol or CCL2 on development of these neuroprogenitor cells and peptide neurons in NEP and the role of these CCL2 cells in mediating ethanol's effects.
In Aim 4, we will test, with direct manipulations of the embryo involving third ventricular injections of CCL2 or CCL2 siRNA, whether neuroepithelial CCL2 is involved in ethanol's effects on neuronal development and adolescent drinking. This research should provide fundamentally new information on how gestational exposure to ethanol acts through the neuroimmune system to control the development of peptide neurons that contribute to substance abuse.
This project will investigate the mechanisms that mediate the stimulatory effect of ethanol exposure early in life, particularly during gestation, on later consumption of and preference for ethanol and the risk for alcohol abuse. Using our rat model, we will explore how exposure to ethanol in utero activates the maternal immune system and neuroimmune system of the embryo, which causes the stimulation of embryonic development of neuropeptide systems that become overactive after birth and increase the consumption of ethanol during adolescence. These studies have real potential of moving the field forward by providing new information for developing tools that can reduce the fetal brain's neuroimmune response to ethanol in utero and thus the impact of ethanol on brain development and propensity for alcohol abuse.
| Chang, Guo-Qing; Karatayev, Olga; Halkina, Viktoriya et al. (2018) Hypothalamic CCL2/CCR2 Chemokine System: Role in Sexually Dimorphic Effects of Maternal Ethanol Exposure on Melanin-Concentrating Hormone and Behavior in Adolescent Offspring. J Neurosci 38:9072-9090 |
| Barson, Jessica R; Poon, Kinning; Ho, Hui Tin et al. (2017) Substance P in the anterior thalamic paraventricular nucleus: promotion of ethanol drinking in response to orexin from the hypothalamus. Addict Biol 22:58-69 |
| Barson, Jessica R; Leibowitz, Sarah F (2017) Orexin/Hypocretin System: Role in Food and Drug Overconsumption. Int Rev Neurobiol 136:199-237 |
| Poon, Kinning; Barson, Jessica R; Shi, Huanzhi et al. (2017) Involvement of the CXCL12 System in the Stimulatory Effects of Prenatal Exposure to High-Fat Diet on Hypothalamic Orexigenic Peptides and Behavior in Offspring. Front Behav Neurosci 11:91 |
