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Syracuse and, NY, United States

Glendinning J.I.,Barnard College | Simons Y.M.,Barnard College | Youngentob L.,SUNY Upstate Medical University | Youngentob L.,Developmental Exposure Alcohol Research Center | And 2 more authors.
Experimental Biology and Medicine | Year: 2012

In humans, fetal ethanol exposure is highly predictive of adolescent ethanol use and abuse. Prior work in our labs indicated that fetal ethanol exposure results in stimulus-induced chemosensory plasticity in the taste and olfactory systems of adolescent rats. In particular, we found that increased ethanol acceptability could be attributed, in part, to an attenuated aversion to ethanol's aversive odor and quinine-like bitter taste quality. Here, we asked whether fetal ethanol exposure also alters the oral trigeminal response of adolescent rats to ethanol. We focused on two excitatory ligand-gated ion channels, TrpV1 and TrpA1, which are expressed in oral trigeminal neurons and mediate the aversive orosensory response to many chemical irritants. To target TrpV1, we used capsaicin, and to target TrpA1, we used allyl isothiocyanate (or mustard oil). We assessed the aversive oral effects of ethanol, together with capsaicin and mustard oil, by measuring short-term licking responses to a range of concentrations of each chemical. Experimental rats were exposed in utero by administering ethanol to dams through a liquid diet. Control rats had ad libitum access to an iso-caloric iso-nutritive liquid diet. We found that fetal ethanol exposure attenuated the oral aversiveness of ethanol and capsaicin, but not mustard oil, in adolescent rats. Moreover, the increased acceptability of ethanol was directly related to the reduced aversiveness of the TrpV1-mediated orosensory input. We propose that fetal ethanol exposure increases ethanol avidity not only by making ethanol smell and taste better, but also by attenuating ethanol's capsaicin-like burning sensations. © 2012 by the Society for Experimental Biology and Medicine.

Wellmann K.A.,University of Maryland, Baltimore | Varlinskaya E.I.,Binghamton University State University of New York | Varlinskaya E.I.,Developmental Exposure Alcohol Research Center | Mooney S.M.,University of Maryland, Baltimore | Mooney S.M.,Developmental Exposure Alcohol Research Center
Brain Research Bulletin | Year: 2014

Prenatal exposure to valproic acid (VPA) alters rodent social interactions in a dose-dependent way: exposure to a high dose of VPA (>500. mg/kg) mid-gestation decreases social interactions whereas a moderate dose of VPA (350. mg/kg) increases peer-directed social behavior. The moderate dose also decreases expression of the mRNA for serine in amygdala and orbitofrontal cortex. In this study, we examined whether d-cycloserine could ameliorate VPA-induced alterations in ultrasonic vocalizations (USVs), social interactions, and locomotor activity. Pregnant Sprague Dawley rats were given intraperintoneal injections of VPA (200. mg/kg each) on gestational days 12, 12.5 and 13; controls were injected with saline. Offspring received a subcutaneous injection of saline or d-cycloserine (32 or 64. mg/kg) either acutely (1. h prior to testing) or repeatedly (once per day for four days). Social interactions were assessed during late adolescence, and USVs were recorded concomitantly. Male and female rats that were exposed to VPA demonstrated more locomotor activity than control animals during habituation to the testing chamber. VPA-exposed males showed increased play fighting. d-Cycloserine normalized the VPA-induced increase in play fighting in males and also increased social motivation in females. When the pair contained a VPA-exposed rat, significantly fewer USVs were emitted and 16% of the vocalizations were of a novel waveform. These effects were not seen in pairs containing VPA-exposed animals that were treated with d-cycloserine. Overall, these findings are consistent with data from other laboratories suggesting that d-cycloserine may be a promising pharmacotherapeutic compound for improving social behavior disorders. © 2014 Elsevier Inc.

Cohen O.S.,SUNY Upstate Medical University | Varlinskaya E.I.,Binghamton University State University of New York | Varlinskaya E.I.,Developmental Exposure Alcohol Research Center | Wilson C.A.,SUNY Upstate Medical University | And 3 more authors.
International Journal of Developmental Neuroscience | Year: 2013

Prenatal exposure to moderate doses of valproic acid (VPA) produces brainstem abnormalities, while higher doses of this teratogen elicit social deficits in the rat. In this pilot study, we examined effects of prenatal exposure to a moderate dose of VPA on behavior and on transcriptomic expression in three brain regions that mediate social behavior. Pregnant Long Evans rats were injected with 350. mg/kg VPA or saline on gestational day 13. A modified social interaction test was used to assess social behavior and social preference/avoidance during early and late adolescence and in adulthood. VPA-exposed animals demonstrated more social investigation and play fighting than control animals. Social investigation, play fighting, and contact behavior also differed as a function of age; the frequency of these behaviors increased in late adolescence. Social preference and locomotor activity under social circumstances were unaffected by treatment or age. Thus, a moderate prenatal dose of VPA produces behavioral alterations that are substantially different from the outcomes that occur following exposure to a higher dose. At adulthood, VPA-exposed subjects exhibited transcriptomic abnormalities in three brain regions: anterior amygdala, cerebellar vermis, and orbitofrontal cortex. A common feature among the proteins encoded by the dysregulated genes was their ability to be modulated by acetylation. Analysis of the expression of individual exons also revealed that genes involved in post-translational modification and epigenetic regulation had particular isoforms that were ubiquitously dysregulated across brain regions. The vulnerability of these genes to the epigenetic effects of VPA may highlight potential mechanisms by which prenatal VPA exposure alters the development of social behavior. © 2013 ISDN.

Hicks S.D.,New York University | Hicks S.D.,Developmental Exposure Alcohol Research Center | Middleton F.A.,New York University | Middleton F.A.,Developmental Exposure Alcohol Research Center | And 3 more authors.
Journal of Neurochemistry | Year: 2010

Ethanol inhibits the proliferation of neural precursors by altering mitogenic and anti-mitogenic growth factor signaling and can affect global methylation activity in the fetus. We tested the hypothesis that epigenetic modification of specific cell cycle genes underlies the ethanol-induced inhibition of growth factor-regulated cell cycle progression. Monolayer cultures of neural stem cells (NSCs) were treated with fibroblast growth factor 2 or transforming growth factor (TGF) β1 in the absence or presence of ethanol. Ethanol increased the total length of the cell cycle by elongating the amount of time spent in the gap 1 (G1) and synthesis (S) phases of the cell cycle. Ethanol induced the hypermethylation of multiple cell cycle genes associated with the G1/S and gap 2/mitotic phase (G2/M) checkpoints and increased the expression and activity of DNA methyltransferases. These changes were most pronounced in the presence of TGFβ1. Epigenetic alterations paralleled the down-regulation of associated transcripts and other checkpoint-related mRNAs both in vitro (NS-5 cell culture) and in vivo (fetal mouse cortex). Ethanol-induced hypermethylation was accompanied by decreases in the proportion of NSCs expressing associated cell cycle proteins. Thus, ethanol disrupts growth factor-related cell cycle progression by inducing checkpoint restriction at the G1/S transition through a feed-forward system involving the methylation of G2/M regulators. © 2010 International Society for Neurochemistry.

Lindke A.L.,New York University | Middleton F.A.,New York University | Middleton F.A.,Developmental Exposure Alcohol Research Center | Miller M.W.,New York University | And 2 more authors.
Experimental Neurology | Year: 2010

Transforming growth factor (TGF) β1 is a key player in early brain development, hence, its availability (i.e., synthesis and release) affects neuronogenesis. TGFβ1 moves proliferating cells out of the cell cycle and promotes their subsequent migration. The present study tested the hypothesis that neural progenitors self-regulate TGFβ1. B104 neuroblastoma cells which can grow in the absence of serum or growth factors were used in systematic studies of transcription, translation, release, and activation. These studies relied on quantitative enzyme-linked immunosorbent assays and real-time polymerase chain reactions. TGFβ1 positively upregulated its own intracellular expression and promoted increased release of TGFβ1 from cells. The induction of TGFβ1 was independent of a change in transcription, but it depended on cycloheximide-inhibited translation. Signaling mediated by downstream Smad2/3 through the TGF receptors and intracellular protein transport were also required for release of TGFβ1 from B104 cells. Thus, TGFβ1 production and release were mediated through a feed-forward mechanism and were pivotally regulated at the level of translation. These activities appear to be key for the role of TGFβ1 in the proliferation and migration of young neurons. © 2010.

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