Acute Alcohol and Cognition: Remembering What It Causes Us to Forget

Addiction has been conceptualized as a specific form of memory that appropriates typically adaptive neural mechanisms of learning to produce the progressive spiral of drug-seeking and drug-taking behavior, perpetuating the path to addiction through aberrant processes of drug-related learning and memory. From that perspective, to understand the development of alcohol use disorders it is critical to identify how a single exposure to alcohol enters into or alters the processes of learning and memory, so that involvement of and changes in neuroplasticity processes responsible for learning and memory can be identified early on. This review characterizes the effects produced by acute alcohol intoxication as a function of brain region and memory neurocircuitry. In general, exposure to ethanol doses that produce intoxicating effects causes consistent impairments in learning and memory processes mediated by specific brain circuitry, whereas lower doses either have no effect or produce a facilitation of memory under certain task conditions. Therefore, acute ethanol does not produce a global impairment of learning and memory, and can actually facilitate particular types of memory, perhaps particular types of memory that facilitate the development of excessive alcohol use. In addition, the effects on cognition are dependent on brain region, task demands, dose received, pharmacokinetics, and tolerance. Additionally, we explore the underlying alterations in neurophysiology produced by acute alcohol exposure that help to explain these changes in cognition and highlight future directions for research. Through understanding the impact acute alcohol intoxication has on cognition, the preliminary changes potentially causing a problematic addiction memory can better be identified

PKCγ expression in adolescent and adult rats : evidence for a cerebellar mechanism underlying age-dependent motor impairments produced by acute ethanol.

Adolescents are less sensitive to ethanol-induced motor impairments compared to adults; however, a definitive mechanism underlying this difference has not been identified. Compared to wild-type littermates, PKCγ knock-out mice exhibit reduced motor sensitivity to ethanol; it is plausible that adolescent rats also have reduced PKCγ expression in brain regions responsible for motor function, specifically the cerebellum and cortex. Reduced PKCγ expression in these regions may govern the age-dependent motor impairments produced by ethanol. The current study analyzed membrane-bound PKCγ expression in adolescent and adult rats 40 minutes after an acute ethanol or saline injection. Western blot analysis indicates adolescent rats have reduced PKCγ expression in the cerebellum and cortex compared to adults. It is concluded that PKCγ expression may be part of a larger mechanism regulating the age-dependent motor impairments produced by acute ethanol administration.by Candice E. Van Skike.M.A

Chronic intermittent ethanol treatment yields persistent increases in anxiety and receptor subunit changes in adolescent and adult rats.

GABAA and NMDA receptors are involved in the behavioral effects of ethanol; however, the age-dependent molecular mechanisms associated with the effects of chronic ethanol have yet to be fully elucidated. Adolescence is marked by unique sensitivity to certain effects of ethanol, including distinct consumption patterns, increased prevalence of consumption during young adulthood compared to that of abstaining adolescents, and increased risk for development of future alcohol use disorders. In the adult, tolerance and dependence are marked by attenuated function of GABAA receptors and increased function of NMDA receptors, but the receptor subunit expression profiles for adolescents following binge-like ethanol exposure are not yet completely known. Since tolerance and withdrawal appear to be age dependent, it is likely that receptor subunit expression is differentially altered following chronic ethanol exposure in adolescence compared to adulthood. Additionally, chronic ethanol exposure and its withdrawal can alter behavior. Especially relevant to the maintenance and persistence of consumption behaviors are alterations in anxiety. Anxiety levels can often be used to predict relapse in detoxified alcohol-dependent patients long after ethanol cessation, therefore it is important to determine the persistence of the anxiogenic effects of ethanol withdrawal and how alterations in receptor subunits may interact with withdrawal-induced anxiogenesis. Given that very little research has focused on age dependent anxiogenesis and subunit alterations following chronic ethanol consumption, this project will investigate multiple withdrawal induced changes in anxiety and its persistence in adolescent and adult rats. Additionally, the persistence of any changes in receptor subunit expression will be assessed using the same animals from the anxiety data. This multimodal, within-subjects design allows for the direct exploration of the relationship between behavioral and molecular alterations due to chronic ethanol exposure.Ph.D

Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection

Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. We show that DBR1 expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all DBR1 mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of DBR1-mutated patients contain higher RNA lariat levels than control cells, this difference becoming even more marked during HSV1 infection. Finally, we show that the patients\ue2\u80\u99 fibroblasts are highly susceptible to HSV1. RNA lariat accumulation and viral susceptibility are rescued by wild-type DBR1. Autosomal recessive, partial DBR1 deficiency underlies viral infection of the brainstem in humans through the disruption of tissue-specific and cell-intrinsic immunity to viruses. Autosomal recessive DBR1 deficiency underlies a cellular accumulation of RNA lariats, resulting in patient susceptibility to severe viral infections of the brainstem