Total gene expression analysis (TOGA) was used to identify genes that are differentially expressed in brain regions between the alcohol-naïve, inbred alcohol-preferring (iP), and -nonpreferring (iNP) rats. ␣-Synuclein, expressed at >2-fold higher levels in the hippocampus of the iP than the iNP rat, was prioritized for further study. In situ hybridization was used to determine specific brain regions and cells expressing ␣-synuclein in the iP and iNP rats. Similar to ␣-synuclein mRNA levels, protein levels in the hippocampus were higher in iP rats than iNP rats. Higher protein levels were also observed in the caudate putamen of iP rats compared with iNP rats. Sequence analysis identified two single nucleotide polymorphisms in the 3 UTR of the cDNA. The polymorphism was used to map the gene, by using recombination-based methods, to chromosome 4, within a quantitative trait locus for alcohol consumption that was identified in the iP and iNP rats. A nucleotide exchange in the iNP 3 UTR reduced expression of the luciferase reporter gene in SK-N-SH neuroblastoma cells. These results suggest that differential expression of the ␣-synuclein gene may contribute to alcohol preference in the iP rats.

Children with Neurofibromatosis type 1 (NF1) are increasingly recognized to have high prevalence of social difficulties and autism spectrum disorders (ASD). We demonstrated selective social learning deficit in mice with deletion of a single Nf1 gene (Nf1+/−), along with greater activation of mitogen activated protein kinase pathway in neurons from amygdala and frontal cortex, structures relevant to social behaviors. The Nf1+/− mice showed aberrant amygdala glutamate/GABA neurotransmission; deficits in long-term potentiation; and specific disruptions in expression of two proteins associated with glutamate and GABA neurotransmission: a disintegrin and metalloprotease domain 22 (ADAM22) and heat shock protein 70 (HSP70), respectively. All of these amygdala disruptions were normalized by co-deletion of p21 protein-activated kinase (Pak1) gene. We also rescued the social behavior deficits in Nf1+/− mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide novel insights and therapeutic targets for NF1 and ASD patients.

Results from this study suggest that ALDH1A1*2 may be associated with protection from the development of alcohol and other substance use disorders.

BackgroundIn the highly competitive environment of academic medicine, junior faculty investigators face high attrition rates due to challenges in finding effective mentorship, securing grant funding, and obtaining resources to support their career development and research productivity. The purpose of this study was to describe the centralized, cost-sharing design of the Independent Investigator Incubator (I3) program as a novel approach to junior faculty mentoring and to evaluate quantitative outcomes for program improvement.MethodsIn September 2014, the I3 pilot program, a comprehensive mentorship program targeting junior faculty pursuing research careers, was launched. Participants included junior faculty during the crucial first three years of their research careers or during their transition from career development awards to more independent research. Following initial screening, the I3 mentees were paired with a senior faculty “super-mentor” with expertise in either basic science or clinical research. Mentees were provided with robust traditional one-on-one mentoring, targeted feedback from a super-mentor review committee, as well as biostatistician and grant writing support. To assess the effectiveness of the I3 program, we tracked outcome measures via baseline and 12-month mentee surveys. Data collected assessed program diversity, mentee self-assessments, evaluation of the mentoring relationship, scholarship and productivity metrics. Raw data were analyzed using a paired t-test in Excel (P < 0.05).ResultsResults of the baseline mentee self-assessment survey found that the I3 mentees indicated common “perceive deficits” including navigating the organizational and institutional culture, clear direction in achieving promotion and tenure, among others. When baseline mentee survey responses were compared to 12-month responses, we identified strong “perceived growth” in categories, such as Research and Interpersonal Skills and Career Development Skills. Further, productivity metrics at 12-months revealed that roughly 80% of I3 mentees successfully published a manuscript(s). The I3 program has helped generate roughly $12.1 million dollars in investigator-initiated funding after two years in the program.ConclusionThe I3 program allows for shared costs between institutions and increased availability of successful subject matter experts. Study results imply that the I3 mentoring program provides transformative mentorship for junior faculty. Using our findings, we developed courses and an annual “snapshot” of mentee performance for mentors.Electronic supplementary materialThe online version of this article (10.1186/s12909-018-1290-3) contains supplementary material, which is available to authorized users.

Background-Cytosolic aldehyde dehydrogenase, or ALDH1A1, functions in ethanol detoxification, metabolism of neurotransmitters, and synthesis of retinoic acid. Because the promoter region of a gene can influence gene expression, the ALDH1A1 promoter regions were studied to identify polymorphism, to assess their functional significance, and to determine whether they were associated with a risk for developing alcoholism.

Further evaluation of each of these QTL regions is ongoing in a sample of HAD2xLAD2 F2 progeny currently being generated that will be used to assess the evidence of linkage in each of these QTL regions.

Using animal models of alcoholism, previous studies suggest that neuropeptide Y (NPY) may be implicated in alcohol preference and consumption due to its role in the modulation of feeding and anxiety. Quantitative trait loci (QTL) analysis previously identified an interval on rat chromosome 4 that is highly associated with alcohol preference and consumption using an F2 population derived from inbred alcohol-preferring (iP) and -nonpreferring (iNP) rats. NPY mapped to the peak of this QTL region and was prioritized as a candidate gene for alcohol-seeking behavior in the iP and iNP rats. In order to identify a potential mechanism for reduced NPY protein levels documented in the iP rat, genetic and molecular components that influence NPY expression were analyzed between iP and iNP rats. Comparing the iP rat to the iNP rat, quantitative real-time polymerase chain reaction detected significantly decreased levels of NPY mRNA expression in the iP rat in the six brain regions tested: nucleus accumbens, frontal cortex, amygdala, hippocampus, caudate-putamen, and hypothalamus. In addition, the functional significance of three previously identified polymorphisms was assessed using in vitro expression analysis. The polymorphism defined by microsatellite marker D4Mit7 in iP rats reduced luciferase reporter gene expression in SK-N-SH neuroblastoma cells. These results suggest that differential expression of the NPY gene resulting from the D4mit7 marker polymorphism may contribute to reduced levels of NPY in discrete brain regions in the iP rats.Keywords neuropeptide Y; alcohol preference; selective breeding; mRNA expression; polymorphism; quantitative trait locus Alcoholism is a complex disorder influenced by the interaction between multiple genes and the environment, exhibiting a heritability that ranges from 50 to 60% in both men and women (Heath et al., 1997). Thus far, however, only the protective effects of the alcohol metabolizing enzymes have been consistently replicated (Foroud and Li, 1999;Thomasson et al., 1993). To identify genetic factors that influence alcoholism, the alcohol-preferring (P) and -nonpreferring (NP) lines were developed from a randomly bred closed colony of Wistar HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript rats through bidirectional selective breeding on the basis of alcohol consumption and preference (Li et al., 1991). In this model, P rats display the characteristics that are considered necessary for an animal model of alcoholism (Cicero, 1979). Subsequently, inbred P (iP) and NP (iNP) strains have been established that maintain highly discordant alcohol consumption scores.Previous studies suggest that neuropeptide Y (NPY) is implicated in the modulation of alcohol consumption in P and NP rats (Cowen et al., 2004;Thiele and Badia-Elder, 2003;Pandey et al., 2003). P rats display lower levels of NPY immunoreactivity in various regions of the brain, including the central nucleus of the amygdala, hippocampus and the frontal cortex and higher level...

A genome scan of the F2 generation from an inbred alcohol-preferring (iP) and inbred alcohol-nonpreferring (iNP) rat cross identified a significant quantitative trait locus (QTL) on chromosome 4 with a lod score of 9.2. To confirm this QTL and to create animals for fine mapping of the QTL region, chromosome 4 reciprocal congenic strains were developed by transferring the chromosome 4 QTL interval into the respective iP or iNP backgrounds. The iP strain was crossed with the iNP strain to create iPiNP F1 animals, which were backcrossed to either iNP or iP animals to produce the N2 generation. Using marker-assisted selection, 10 generations of backcrossing were performed. The selection was followed by an intercross between the N10 animals to produce homozygous animals (N10F1), resulting in the finished congenic strains. Congenic strains in which the iP chromosome 4 QTL interval was transferred to the iNP (NP.P) and the iNP chromosome 4 QTL was transferred to the iP (P.NP) exhibited the expected effect on alcohol consumption of the donor strain. Development of these congenic strains further indicates that the chromosome 4 QTL region is, in part, responsible for the disparate alcohol consumption observed between the iP and iNP rats. These congenic animals will be an invaluable resource for fine mapping the QTL region and for the identification of the gene(s) that influences the drinking behavior of the iP and iNP rats.