Dean\u27s Significant Activities Report 07-31-2020

The Dean’s Weekly Significant Activities Report lists all activities conducted within the Departments, Centers & Staff. The Report is provided to the Dean and Directorate personnel for situational awareness.https://digitalcommons.usmalibrary.org/sigact/1030/thumbnail.jp

5α-reductase isoenzymes mediate stress-exacerbated Tourette-like responses in animal models

Tourette syndrome is a neurodevelopmental disorder characterized by purposeless, uncontrollable muscle movements known as tics. These tics are extremely sensitive to environmental factors, especially psychosocial stress. Stress has been demonstrated to increase neurosteroids in animal models, but the relationship of these neurosteroids to Tourette syndrome is unknown. The neurosteroid allopregnanolone is a key regulator of the stress cascade but has also been demonstrated to influence dopamine-mediated behaviors in animal models. Clinical results have shown that inhibiting the synthesis of allopregnanolone and other 3α, 5α steroids with the 5α-reductase inhibitor finasteride reduces tics in adult male patients with Tourette syndrome; however, the mechanism of action is largely unidentified. In this dissertation, the mechanism by which stress exacerbates Tourette syndrome symptoms and finasteride attenuates these behaviors was examined. We found that in various animal models of Tourette syndrome, stress exacerbated tic-like behaviors and deficits in prepulse inhibition (PPI), an operational measure of sensorimotor gating aimed at filtering salient information from the environment; this process is also disrupted in Tourette syndrome patients. These stress-induced tic-like behaviors and PPI deficits were ablated by finasteride treatment, which indicated a role for 3α, 5α steroids. We found that one of these steroids, allopregnanolone exacerbated tic-like behaviors and induced PPI deficits in our animal models. In addition, we determined that allopregnanolone is mediating these effects through several possible receptors; specifically we found evidence suggesting that the pregnane xenobiotic receptor and the purinergic P2X4 receptor are involved in these processes. Finally, we demonstrated that the isoenzymes 5α-reductase type 1 and type 2 exert different effects in regulating Tourette syndrome-like symptoms, and specifically that 5α-reductase type 1 may be the more beneficial and safe target for inhibition over 5α-reductase type 2

Animal models of tic disorders: A translational perspective

Tics are repetitive, sudden movements and/or vocalizations, typically enacted as maladaptive responses to intrusive premonitory urges. The most severe tic disorder, Tourette syndrome (TS), is a childhood-onset condition featuring multiple motor and at least one phonic tic for a duration longer than 1 year. The pharmacological treatment of TS is mainly based on antipsychotic agents; while these drugs are often effective in reducing tic severity and frequency, their therapeutic compliance is limited by serious motor and cognitive side effects. The identification of novel therapeutic targets and development of better treatments for tic disorders is conditional on the development of animal models with high translational validity. In addition, these experimental tools can prove extremely useful to test hypotheses on the etiology and neurobiological bases of TS and related conditions. In recent years, the translational value of these animal models has been enhanced, thanks to a significant re-organization of our conceptual framework of neuropsychiatric disorders, with a greater focus on endophenotypes and quantitative indices, rather than qualitative descriptors. Given the complex and multifactorial nature of TS and other tic disorders, the selection of animal models that can appropriately capture specific symptomatic aspects of these conditions can pose significant theoretical and methodological challenges. In this article, we will review the state of the art on the available animal models of tic disorders, based on genetic mutations, environmental interventions as well as pharmacological manipulations. Furthermore, we will outline emerging lines of translational research showing how some of these experimental preparations have led to significant progress in the identification of novel therapeutic targets for tic disorders

The implication of neuroactive steroids in Tourette syndrome pathogenesis: a role for 5α-reductase?

This is the peer reviewed version of the following article: Bortolato, M., Frau, R., Godar, S. C., Mosher, L. J., Paba, S., Marrosu, F. and Devoto, P. (2013), The Implication of Neuroactive Steroids in Tourette's Syndrome Pathogenesis: A Role for 5α-Reductase?. J Neuroendocrinol, 25: 1196–1208. doi:10.1111/jne.12066, which has been published in final form at http://doi.org/10.1111/jne.12066. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Tourette syndrome (TS) is a neurodevelopmental disorder characterized by recurring motor and phonic tics. The pathogenesis of TS is thought to reflect dysregulations in the signaling of dopamine (DA) and other neurotransmitters, which lead to excitation/inhibition imbalances in cortico-striato-thalamocortical circuits. The causes of these deficits may reflect complex gene × environment × sex (G×E×S) interactions; indeed, the disorder is markedly predominant in males, with a male-to-female prevalence ratio of ~4:1. Converging lines of evidence point to neuroactive steroids as likely molecular candidates to account for GxExS interactions in TS. Building on these premises, our group has begun examining the possibility that alterations in the steroid biosynthetic process may be directly implicated in TS pathophysiology; in particular, our research has focused on 5α-reductase (5αR), the enzyme catalyzing the key rate-limiting step in the synthesis of pregnane and androstane neurosteroids. In clinical and preclinical studies, we found that 5αR inhibitors exerted marked anti-DAergic and tic-suppressing properties, suggesting a central role for this enzyme in TS pathogenesis. Based on these data, we hypothesize that enhancements in 5αR activity in early developmental stages may lead to an inappropriate activation of the “backdoor” pathway for androgen synthesis from adrenarche until the end of puberty. We predict that the ensuing imbalances in steroid homeostasis may impair the signaling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioral abnormalities in TS

Norovirus Epidemiology and Duration of Shedding in Michigan, 2007-2008

Background: In the United States, an estimated 23 million cases of norovirus (NoV) are reported each year, and although mortality is low, the morbidity and economic impact are substantial. Methods: RT-PCR and sequencing were used for identification of NoV genotypes obtained from outbreak and sporadic cases. RT Quant PCR was used to determine the viral load in fecal specimens. In order to rule out bacterial infection as the cause for acute gastroenteritis (AGE), bacterial culture for Salmonella, E.coli O157, Shigella, Campylobacter and Clostridium difficile was performed by standard laboratory procedures. The duration of NV shedding was investigated with longitudinal sampling in the sporadic cases and an evaluation of the association between viral load and days since clinical onset in the outbreak-associated cases. Results: We describe the epidemiology and strain identification for NoV circulating in Michigan during 2007-8 in concurrent sporadic and outbreak-associated cases. In 2007- 8, 138 norovirus outbreaks (3,437 cases) were reported to the MDCH. Among the 47 outbreak specimens sequenced, GI was identified in 14 (29.8%) and GII in 33 (70.2%). The predominant type was GII.4, found in 23 of the 33 (69.6%) GII specimens. The statistical analysis of outbreak-associated cases showed that neither NoV type nor number of days post-onset were associated with NoV log concentration. Among the sporadic cases, the repeated measures analysis of variance showed that NoV type (I or II) was not associated with log titer (P = 0.90), but that the number of weeks post-onset was statistically associated with declining log titer at p = 0.0005. Conclusion: We found no predominant strain difference between concurrent sporadic and outbreak-associated cases. Prevalent strains of NoV were shed in high concentration for at least two weeks past disease onset, suggesting that current public health recommendations for 2-3 days home isolation following clinical recovery may need to be lengthened

Comparative responsiveness and minimally important difference of Fatigue Symptom Inventory (FSI) scales and the FSI-3 in trials with cancer survivors

Background Fatigue is a highly prevalent and disabling symptom in cancer survivors. Although many measures have been developed to assess survivors’ fatigue, their ability to accurately capture change following intervention has rarely been assessed in post-treatment survivors. Ultra-brief fatigue measures are preferable in clinical practice but have limited evidence supporting their use with cancer survivors. We examined the psychometric properties of four Fatigue Symptom Inventory (FSI) measures, including the new FSI-3, in cancer survivors. Examined properties included responsiveness to change and minimally important differences (MIDs). Methods We analyzed data from three randomized controlled trials with post-treatment cancer survivors (N = 328). Responsiveness to change was evaluated by comparing standardized response means for survivors who reported their fatigue as being better, the same, or worse at 2–3 months. Responsiveness to intervention was assessed via effect sizes, and MIDs were estimated by using several methods. We also computed area under the curve (AUC) values to assess FSI measures’ discriminative accuracy compared to an established cut-point. Results All FSI measures differentiated survivors who reported improvement at 2–3 months from those with stable fatigue, but did not uniformly differentiate worsening fatigue from stable fatigue. Measures showed similar levels of responsiveness to intervention, and MIDs ranged from 0.29 to 2.20 across FSI measures. AUC analyses supported the measures’ ability to detect significant fatigue. Conclusions Four FSI scales show similar responsiveness to change, and estimated MIDs can inform assessment of meaningful change in fatigue. The FSI-3 shows promise as an ultra-brief fatigue measure for survivors

The Steroidogenesis Inhibitor Finasteride Reduces the Response to Both Stressful and Rewarding Stimuli

This work is licensed under a Creative Commons Attribution 4.0 International License.Finasteride (FIN) is the prototypical inhibitor of steroid 5α-reductase (5αR), the enzyme that catalyzes the rate-limiting step of the conversion of progesterone and testosterone into their main neuroactive metabolites. FIN is clinically approved for the treatment of benign prostatic hyperplasia and male baldness; while often well-tolerated, FIN has also been shown to cause or exacerbate psychological problems in vulnerable subjects. Evidence on the psychological effects of FIN, however, remains controversial, in view of inconsistent clinical reports. Here, we tested the effects of FIN in a battery of tests aimed at capturing complementary aspects of mood regulation and stress reactivity in rats. FIN reduced exploratory, incentive, prosocial, and risk-taking behavior; furthermore, it decreased stress coping, as revealed by increased immobility in the forced-swim test (FST). This last effect was also observed in female and orchiectomized male rats, suggesting that the mechanism of action of FIN does not primarily reflect changes in gonadal steroids. The effects of FIN on FST responses were associated with a dramatic decrease in corticotropin release hormone (CRH) mRNA and adrenocorticotropic hormone (ACTH) levels. These results suggest that FIN impairs stress reactivity and reduces behavioral activation and impulsive behavior by altering the function of the hypothalamus–pituitary–adrenal (HPA) axis

Human Mycobacterium bovis Infection and Bovine Tuberculosis Outbreak, Michigan, 1994–2007

Mycobacterium bovis is endemic in Michigan’s white-tailed deer and has been circulating since 1994. The strain circulating in deer has remained genotypically consistent and was recently detected in 2 humans. We summarize the investigation of these cases and confirm that recreational exposure to deer is a risk for infection in humans

Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery

Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and threematernally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins.We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such asmRNAexport, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in human

2018 Scholars at Work Conference Program

Program for the 2018 Scholars at Work Conference at Minnesota State University, Mankato on March 30, 2018