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

Gene-environment interactions in antisocial behavior are mediated by early-life 5-HT2A_{\textrm{2A}} receptor activation

The ontogeny of antisocial behavior (ASB) is rooted in complex gene-environment (G×E) interactions. The best-characterized of these interplays occurs between: a) low-activity alleles of the gene encoding monoamine oxidase A (MAOA), the main serotonin-degrading enzyme; and b) child maltreatment. The purpose of this study was to develop the first animal model of this G×E interaction, to help understand the neurobiological mechanisms of ASB and identify novel targets for its therapy. Maoa hypomorphic transgenic mice were exposed to an early-life stress regimen consisting of maternal separation and daily intraperitoneal saline injections and were then compared with their wild-type and non-stressed controls for ASB-related neurobehavioral phenotypes. Maoa hypomorphic mice subjected to stress from postnatal day (PND) 1 through 7 – but not during the second postnatal week - developed overt aggression, social deficits and abnormal stress responses from the fourth week onwards. On PND 8, these mice exhibited low resting heart rate - a well-established premorbid sign of ASB – and a significant and selective up-regulation of serotonin 5-HT2A receptors in the prefrontal cortex. Notably, both aggression and neonatal bradycardia were rescued by the 5-HT2 receptor antagonist ketanserin (1–3 mg kg−1, IP), as well as the selective 5-HT2A receptor blocker MDL-100,907 (volinanserin, 0.1–0.3 mg kg−1, IP) throughout the first postnatal week. These findings provide the first evidence of a molecular basis of G×E interactions in ASB and point to early-life 5-HT2A receptor activation as a key mechanism for the ontogeny of this condition

Gene-environment interactions in antisocial behavior are mediated by early-life 5-HT2A receptor activation

The ontogeny of antisocial behavior (ASB) is rooted in complex gene-environment (G×E) interactions. The best-characterized of these interplays occurs between: a) low-activity alleles of the gene encoding monoamine oxidase A (MAOA), the main serotonin-degrading enzyme; and b) child maltreatment. The purpose of this study was to develop the first animal model of this G×E interaction, to help understand the neurobiological mechanisms of ASB and identify novel targets for its therapy. Maoa hypomorphic transgenic mice were exposed to an early-life stress regimen consisting of maternal separation and daily intraperitoneal saline injections and were then compared with their wild-type and non-stressed controls for ASB-related neurobehavioral phenotypes. Maoa hypomorphic mice subjected to stress from postnatal day (PND) 1 through 7 – but not during the second postnatal week - developed overt aggression, social deficits and abnormal stress responses from the fourth week onwards. On PND 8, these mice exhibited low resting heart rate - a well-established premorbid sign of ASB – and a significant and selective up-regulation of serotonin 5-HT2A receptors in the prefrontal cortex. Notably, both aggression and neonatal bradycardia were rescued by the 5-HT2 receptor antagonist ketanserin (1–3 mg kg−1, IP), as well as the selective 5-HT2A receptor blocker MDL-100,907 (volinanserin, 0.1–0.3 mg kg−1, IP) throughout the first postnatal week. These findings provide the first evidence of a molecular basis of G×E interactions in ASB and point to early-life 5-HT2A receptor activation as a key mechanism for the ontogeny of this condition

Using Multitrait-Multimethod (MTMM) Techniques to Examine the Convergent and Discriminant Validity of Social Disorder

Objectives: Disorder has been measured by various data sources; however, little attention has been given to comparing the construct validity of different measures obtained through various methods in capturing social disorder and related phenomena. Methods: The multitrait-multimethod approach was used to triangulate the consistency between social disorder, prostitution and drug activity across resident surveys, systematic social observations, and police calls for service data. Results: Prostitution and drug activity showed convergent validity, while there was little evidence that social disorder was consistently measured across the three methods. None of the three social problem measures showed high discriminant validity. Drug activity seems to have highest trait-specific discriminant validity across measures, and prostitution is the most identifiable measure across data sources. Social disorder was found to have low discriminant validity. However, the agreement between databases varies across the type of social problems. Conclusions: Social disorder appears to the most difficult concept to define and measure consistently. The lack of correspondence across data sources cautions against the use of a single source of information in studying disorder. Future studies should explore the factors that shape perceptions of disorder and how to best measure disorder to test the broken windows thesis and related concepts

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling

The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function

Obesity, inflammatory and thrombotic markers, and major clinical outcomes in critically ill patients with COVID‐19 in the US

Objective This study aimed to determine whether obesity is independently associated with major adverse clinical outcomes and inflammatory and thrombotic markers in critically ill patients with COVID‐19. Methods The primary outcome was in‐hospital mortality in adults with COVID‐19 admitted to intensive care units across the US. Secondary outcomes were acute respiratory distress syndrome (ARDS), acute kidney injury requiring renal replacement therapy (AKI‐RRT), thrombotic events, and seven blood markers of inflammation and thrombosis. Unadjusted and multivariable‐adjusted models were used. Results Among the 4,908 study patients, mean (SD) age was 60.9 (14.7) years, 3,095 (62.8%) were male, and 2,552 (52.0%) had obesity. In multivariable models, BMI was not associated with mortality. Higher BMI beginning at 25 kg/m2 was associated with a greater risk of ARDS and AKI‐RRT but not thrombosis. There was no clinically significant association between BMI and inflammatory or thrombotic markers. Conclusions In critically ill patients with COVID‐19, higher BMI was not associated with death or thrombotic events but was associated with a greater risk of ARDS and AKI‐RRT. The lack of an association between BMI and circulating biomarkers calls into question the paradigm that obesity contributes to poor outcomes in critically ill patients with COVID‐19 by upregulating systemic inflammatory and prothrombotic pathways