Environmental factors profoundly affect the addictive potential of drugs of abuse and may also modulate the neuro-anatomical/neuro-chemical impacts of uncontrolled drug use and relapse propensity. This study examined the impact of environmental enrichment on heroin self-administration, addiction-related behaviors, and molecular processes proposed to underlie these behaviors. Male Sprague-Dawley rats in standard and enriched housing conditions intravenously self-administered similar amounts of heroin over 14 days. However, environmental enrichment attenuated progressive ratio, extinction, and reinstatement session responding after 14 days of enforced abstinence. Molecular mechanisms, namely DNA methylation and gene expression, are proposed to underlie abstinence-persistent behaviors. A global reduction in methylation is reported to coincide with addiction, but no differences in total genomic methylation or repeat element methylation were observed in CpG or non-CpG (CH) contexts across the mesolimbic circuitry as assessed by multiple methods including whole genome bisulfite sequencing. Immediate early gene expression associated with drug seeking, taking, and abstinence also were examined. EGR1 and EGR2 were suppressed in mesolimbic regions with heroin-taking and environmental enrichment. Site-specific methylation analysis of EGR1 and EGR2 promoter regions using bisulfite amplicon sequencing (BSAS) revealed hypo-methylation in the EGR2 promoter region and EGR1 intragenic CpG sites with heroin-taking and environmental enrichment that was associated with decreased mRNA expression. Taken together, these findings illuminate the impact of drug taking and environment on the epigenome in a locus and gene-specific manner and highlight the need for positive, alternative rewards in the treatment and prevention of drug addiction.

Heroin addiction is a disease of chronic relapse that harms the individual through devaluation of personal responsibilities in favor of finding and using drugs. Only some recreational heroin users devolve into addiction but the basis of these individual differences is not known. We have shown in rats that avoidance of a heroin-paired taste cue reliably identifies individual animals with greater addiction-like behavior for heroin. Here rats received 5 min access to a 0.15% saccharin solution followed by the opportunity to self-administer either saline or heroin for 6 hours. Large Suppressors of the heroin-paired taste cue displayed increased drug escalation, motivation for drug, and drug loading behavior compared with Small Suppressors. Little is known about the molecular mechanisms of these individual differences in addiction-like behavior. We examined the individual differences in mRNA expression in the nucleus accumbens (NAc) of rats that were behaviorally stratified by addiction-like behavior using next-generation sequencing. We hypothesized that based on the avoidance of the drug-paired cue there will be a unique mRNA profile in the NAc. Analysis of strand-specific whole genome RNA-Seq data revealed a number of genes differentially regulated in NAc based on the suppression of the natural saccharine reward. Large Suppressors exhibited a unique mRNA prolife compared to Saline controls and Small Suppressors. Genes related to immunity, neuronal activity, and behavior were differentially expressed among the 3 groups. In total, individual differences in avoidance of a heroin-paired taste cue are associated with addiction-like behavior along with differential NAc gene expression.

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SUMMARY Aims: To investigate regional and gender differences in prevalence rates and the pattern of cognitive and behavioral impairment in amyotrophic lateral sclerosis. Materials & methods: One hundred and ten subjects (55 male) from 14 amyotrophic lateral sclerosis clinics were cross-sectionally evaluated with the Penn State Brief Exam of frontal and temporal dysfunction syndromes. Results: Prevalence rates of cognitive impairment and behavioral impairment were statistically equivalent among rural, suburban and urban subgroups. Females evidenced significant strengths in fluency and limitations in configurational processing. Patterns of regional findings suggested greater frontal cortical involvement in the rural sample. Females demonstrated more bihemispheric involvement in comparison to more left hemispheric involvement for males. Conclusions: Regional prevalence differences in frontotemporal disease prodrome appear insignificant and multifactorial, while being consistent with the toxicity model implicating pesticides in frontal lobe change. Female gender potentially masks the frontotemporal disease prodrome due to a bilateral distribution of language processing, which requires an assessment of right hemisphere-mediated capacities to detect.

Phenylketonuria (PKU) is one of the first characterised metabolic diseases. PKU is an autosomal recessive metabolic disorder resulting in increased phenylalanine concentrations. Without intervention, such as pharmaceutical or dietary restriction of phenylalanine, most children with PKU develop a profound and irreversible intellectual disability. In fact, this treatable condition is one of the leading causes of mental retardation. PKU can occur via two main mechanisms: classical and nonclassical. Classical PKU results from impaired activity of the liver enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine. In nonclassical PKU, there is an absence or deficiency of dihydropteridine reductase which impairs the regeneration of tetrahydrobiopterin, a necessary cofactor in the conversion of phenylalanine to tyrosine. The advent of neonatal screening for PKU has enabled the start of a low‐phenylalanine diet early in life and thus, the prevention of intellectual retardation associated with the disease. The mainstay of treatment is a phenylalanine‐restricted diet, but its application varies both internationally and nationally. Key Concepts Phenylketonuria (PKU) is a rare metabolic disorder, characterised by an impaired ability to metabolise the amino acid phenylalanine and resultant high circulating levels of phenylalanine. Classical PKU (the most common form) is caused by mutations in the gene for phenylalanine hydroxylase (PAH). Nonclassical PKU can be caused by defects in the synthesis or function of the cofactor for PAH (BH 4 ). If not treated shortly after birth, PKU can be destructive to the nervous system, causing intellectual disability. The identification of PKU during routine newborn screening and management with a diet low in phenylalanine became standard practice in the early 1960s. PKU is a disorder that has an unequal geographic and ethnic distribution. Individuals on well‐controlled phenylalanine‐free diet may still develop cognitive symptoms. Several new therapies have recently emerged that provide alternatives to the strict low‐phenylalanine diet. A description of these treatments (medical foods, BH 4 administration, large neutral amino acid supplementation and enzymatic therapy) is covered herein.

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Researchers trained in pharmacology and physiology must possess not only a comprehensive knowledge of chemistry and the nature of compounds but also a deep understanding of physiology and predict how these compounds function in a system or organism. However, graduate programs in pharmacology and physiology have increasingly begun to focus on more reductionist approaches to basic science, neglecting training in integrative/systems physiology. In response to a decline in the competency of recent pharmacology and physiology graduates, a biennial meeting, National Directors of Graduate Studies (NDOGS) in pharmacology and physiology, was conceived to address these concerns and improve the quality of graduate education. NDOGS functions as a forum for directors of pharmacology and physiology programs to exchange ideas and tackle the challenges facing graduate education. The 2015 meeting was held on the campus of the University of Cincinnati, and each day of the meeting was allocated for discussion of a broad topic. On Friday, talks were aimed at “enhancing the professional pipeline.” On Saturday, the theme of “fitting training to emerging needs” tackled ways that universities can respond to the emerging needs of a changing society. Sunday morning updated graduate program directors about changes to National Institutes of Health T32 Training Grant applications and provided a forum for program directors to share their experiences and concerns. Throughout the meeting, presentations and discussions highlighted challenges and opportunities that apply broadly to PhD training in the biomedical sciences and revealed best practices to improve training and career preparation of PhD trainees.