Patterns of social-experience-related c-fos and Arc expression in the frontal cortices of rats exposed to saccharin or moderate levels of ethanol during prenatal brain development.

Recent findings from our laboratory indicate that alterations in frontal cortex function, structural plasticity, and related social behaviors are persistent consequences of exposure to moderate levels of ethanol during prenatal brain development [24]. Fetal-ethanol-related reductions in the expression of the immediate early genes (IEGs) c-fos and Arc and alterations in dendritic spine density in ventrolateral and medial aspects of frontal cortex suggest a dissociation reminiscent of that described by Kolb et al. [38] in which these aspects of frontal cortex undergo reciprocal experience-dependent changes. In addition to providing a brief review of the available data on social behavior and frontal cortex function in fetal-ethanol-exposed rats, the present paper presents novel data on social-experience-related IEG expression in four regions of frontal cortex (Zilles LO, VLO, Fr1, Fr2) that are evaluated alongside our prior data from AID and Cg3. Social experience in normal rats was related to a distinct pattern of IEG expression in ventrolateral and medial aspects of frontal cortex, with generally greater expression observed in ventrolateral frontal cortex. In contrast, weaker expression was observed in all aspects of frontal cortex in ethanol-exposed rats, with the exception of an experience-related increase in the medial agranular cortex. Behaviors related to social investigation and wrestling/boxing were differentially correlated with patterns of activity-related IEG expression in the regions under investigation for saccharin- and ethanol-exposed rats. These observations suggest that recruitment and expression of IEGs in frontal cortex following social experience are potentially important for understanding the long-term consequences of moderate prenatal ethanol exposure on frontal cortex function, synaptic plasticity, and related behaviors.

Prenatal exposure to moderate levels of ethanol alters social behavior in adult rats: relationship to structural plasticity and immediate early gene expression in frontal cortex.

The goals of the present study were to characterize the effects of prenatal exposure to moderate levels of ethanol on adult social behavior, and to evaluate fetal-ethanol-related effects on dendritic morphology, structural plasticity and activity-related immediate early gene (IEG) expression in the agranular insular (AID) and prelimbic (Cg3) regions of frontal cortex. Baseline fetal-ethanol-related alterations in social behavior were limited to reductions in social investigation in males. Repeated experience with novel cage-mates resulted in comparable increases in wrestling and social investigation among saccharin- and ethanol-exposed females, whereas social behavioral effects among males were more evident in ethanol-exposed animals. Male ethanol-exposed rats also displayed profound increases in wrestling when social interaction was motivated by 24h of isolation. Baseline decreases in dendritic length and spine density in AID were observed in ethanol-exposed rats that were always housed with the same cage-mate. Modest experience-related decreases in dendritic length and spine density in AID were observed in saccharin-exposed rats housed with various cage-mates. In contrast, fetal-ethanol-exposed rats displayed experience-related increases in dendritic length in AID, and no experience-related changes in spine density. The only effect observed in Cg3 was a baseline increase in basilar dendritic length among male ethanol-exposed rats. Robust increases in activity-related IEG expression in AID (c-fos and Arc) and Cg3 (c-fos) were observed following social interaction in saccharin-exposed rats, however, activity-related increases in IEG expression were not observed in fetal-ethanol-exposed rats in either region. The results indicate that deficits in social behavior are among the long-lasting behavioral consequences of moderate ethanol exposure during brain development, and implicate AID, and to a lesser degree Cg3, in fetal-ethanol-related social behavior abnormalities.

Recent behavioral history modifies coupling between cell activity and Arc gene transcription in hippocampal CA1 neurons.

The ability of neurons to alter their transcriptional programs in response to synaptic input is of fundamental importance to the neuroplastic mechanisms underlying learning and memory. Because of technical limitations of conventional gene detection methods, the current view of activity-dependent neural transcription derives from experiments in which neurons are assumed quiescent until a signaling stimulus is given. The present study was designed to move beyond this static model by examining how earlier episodes of neural activity influence transcription of the immediate-early gene Arc. Using a sensitive FISH method that detects primary transcript at genomic alleles, the proportion of hippocampal CA1 neurons that activate transcription of Arc RNA was constant at approximately 40% in response to both a single novel exploration session and daily sessions repeated over 9 days. This proportion is similar to the percentage of active neurons defined electrophysiologically. However, this close correspondence was disrupted in rats exposed briefly, but repeatedly, to the same environment within a single day. Arc transcription in CA1 neurons declined dramatically after as few as four 5-min sessions, despite stable electrophysiological activity during all sessions. Additional experiments indicate that the decrement in Arc transcription occurred at the cellular, rather than synaptic level, and was not simply linked to habituation to novelty. Thus, the neural genomic response is governed by recent, but not remote, cell firing history in the behaving animal. This state-dependence of neuronal transcriptional coupling provides a mechanism of metaplasticity and may regulate capacity for synaptic modification in neural networks.