Brain Insulin Action Regulates Hypothalamic Glucose Sensing and the Counterregulatory Response to Hypoglycemia

The brain is the primary organ that senses blood glucose levels and initiates a stress response when blood glucose levels are too low: hypoglycemia). Insulin-dependent people with Type 1 diabetes: T1DM) have an impaired ability to sense hypoglycemia and an impaired ability to activate this counterregulatory response: CRR) to hypoglycemia. As a result, T1DM are at a greater risk of experiencing insulin induced severe hypoglycemic episodes, which can result in seizures, brain damage, or even death. Since hypoglycemia is a major barrier that limits intensive blood glucose control, important research initiatives are needed to prevent or reduce the burden of hypoglycemia for people with Type 1 diabetes, specifically by defining the mechanisms and modulators of brain glucose sensing. The experiments in this thesis were designed to investigate the role and mechanism by which insulin may regulate brain glucose sensing. Recent evidence suggests that insulin acts in the brain to regulate glucose homeostasis, central nervous system: CNS) glucose sensing, and the CRR to hypoglycemia, but the site and method of CNS insulin action are still unknown. This study 1) investigated whether insulin acts on hypothalamic neurons to regulate brain glucose sensing and 2) ascertained how insulin regulates glucose sensing by evaluating its effects on key glucose sensors and CNS glucose uptake. Taking advantage of a genetic mouse model that chronically lacks CNS insulin action: the neuronal insulin receptor knockout NIRKO mouse), this report assessed whether CNS insulin signaling regulates the brain\u27s ability to detect and respond to hypoglycemia by analyzing glucose counterregulation and neuronal activation in response to hypoglycemia. Further, to clarify a mechanism of CNS insulin action, this study assessed whether insulin regulates key glucose sensors and/or CNS glucose uptake by examining the expression patterns of key glucose sensing proteins, including glucose transporters: GLUTs) and glucokinase: GK), and measuring regional brain glucose utilization. Understanding how the brain regulates the counterregulatory response to hypoglycemia is critical to devise therapies to combat severe hypoglycemia in diabetic patients. Overall, this thesis provides new insights into insulin\u27s role in the brain to regulate CNS glucose sensing and the counterregulatory response to hypoglycemia

Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma-induced retinal pathology

Children with neurofibromatosis type 1 (NF1) develop low-grade brain tumors throughout the optic pathway. Nearly 50% of children with optic pathway gliomas (OPGs) experience visual impairment, and few regain their vision after chemotherapy. Recent studies have revealed that girls with optic nerve gliomas are five times more likely to lose vision and require treatment than boys. To determine the mechanism underlying this sexually dimorphic difference in clinical outcome, we leveraged Nf1 optic glioma (Nf1-OPG) mice. We demonstrate that female Nf1-OPG mice exhibit greater retinal ganglion cell (RGC) loss and only females have retinal nerve fiber layer (RNFL) thinning, despite mice of both sexes harboring tumors of identical volumes and proliferation. Female gonadal sex hormones are responsible for this sexual dimorphism, as ovariectomy, but not castration, of Nf1-OPG mice normalizes RGC survival and RNFL thickness. In addition, female Nf1-OPG mice have threefold more microglia than their male counterparts, and minocycline inhibition of microglia corrects the retinal pathology. Moreover, pharmacologic inhibition of microglial estrogen receptor-β (ERβ) function corrects the retinal abnormalities in female Nf1-OPG mice. Collectively, these studies establish that female gonadal sex hormones underlie the sexual dimorphic differences in Nf1 optic glioma–induced retinal dysfunction by operating at the level of tumor-associated microglial activation

Comparing the Outcomes of Face-to-Face and Synchronous Online Research Mentor Training Using Propensity Score Matching

In this study, propensity score matching (PSM) was conducted to examine differences in the effectiveness of research mentor training (RMT) implemented using two modes-face-to-face or synchronous online training. This study investigated each training mode and assessed participants\u27 perceived gains in mentoring skills, ability to meet mentees\u27 expectations, and overall quality of mentoring, as well as intention to make changes to their mentoring practices. Additional factors that may contribute to participant outcomes were also examined. In total, 152 mentors trained using a synchronous online platform and 655 mentors trained in in-person workshops were analyzed using the PSM method. Mentors were matched based on similar characteristics, including mentee\u27s career stage, mentor\u27s title, mentor\u27s prior mentoring experience, mentor\u27s race/ethnicity and sex, and mentor\u27s years of experience; results show that both face-to-face and synchronous online modes of RMT are effective. Findings indicated that the training mode did not significantly impact the mentors\u27 perceived training outcomes. Factors associated with the reported training outcomes included dosage (hours of training), facilitator effectiveness, race/ethnicity, and previous mentoring experience. The results of this study demonstrate that mentors\u27 perceived training outcomes are comparable regardless of the training modality used-online versus face-to-face

Sex bias in autism spectrum disorder in neurofibromatosis type 1

BACKGROUND: Despite extensive literature, little is known about the mechanisms underlying sex bias in autism spectrum disorder (ASD). This study investigates the sex differences in ASD associated with neurofibromatosis type 1, a single-gene model of syndromic autism. METHODS: We analysed data from n = 194 children aged 4–16 years with neurofibromatosis type 1. Sex differences were evaluated across the Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS), verbal IQ, Social Responsiveness Scale (SRS) and Conners questionnaires. RESULTS: There was 2.68:1 male:female ratio in children meeting ASD criteria on the deep phenotyping measures. On symptom profile, males with neurofibromatosis type 1 (NF1) + ASD were more impaired on reciprocal social interaction and communication domains of the ADI-R but we found no differences on the restricted, repetitive behaviours (RRBs) domain of the ADI-R and no differences on the social on the ADOS. NF1 ASD males and females were comparable on verbal IQ, and the inattention/hyperactivity domains of the Conners questionnaire. CONCLUSIONS: There is a significant male bias in the prevalence of ASD in NF1. The phenotypic profile of NF1 + ASD cases includes greater social communication impairment in males. We discuss the implications of our findings and the rationale for using NF1 as a model for investigating sex bias in idiopathic ASD

Insulin in the nervous system and the mind: Functions in metabolism, memory, and mood

Background: Insulin, a pleotrophic hormone, has diverse effects in the body. Recent work has highlighted the important role of insulin's action in the nervous system on glucose and energy homeostasis, memory, and mood. Scope of review: Here we review experimental and clinical work that has broadened the understanding of insulin's diverse functions in the central and peripheral nervous systems, including glucose and body weight homeostasis, memory and mood, with particular emphasis on intranasal insulin. Major conclusions: Implications for the treatment of obesity, type 2 diabetes, dementia, and mood disorders are discussed in the context of brain insulin action. Intranasal insulin may have potential in the treatment of central nervous system-related metabolic disorders. Keywords: Insulin, Intranasal insulin, Memory, Metabolism, Moo