Gordon Holmes Syndrome Model Mice Exhibit Alterations in Microglia, Age, and Sex-Specific Disruptions in Cognitive and Proprioceptive Function.

Gordon Holmes syndrome (GHS) is a neurological disorder associated with neuroendocrine, cognitive, and motor impairments with corresponding neurodegeneration. Mutations in the E3 ubiquitin ligase RNF216 are strongly linked to GHS. Previous studies show that deletion of Rnf216 in mice led to sex-specific neuroendocrine dysfunction due to disruptions in the hypothalamic-pituitary-gonadal axis. To address RNF216 action in cognitive and motor functions, we tested Rnf216 knock-out (KO) mice in a battery of motor and learning tasks for a duration of 1 year. Although male and female KO mice did not demonstrate prominent motor phenotypes, KO females displayed abnormal limb clasping. KO mice also showed age-dependent strategy and associative learning impairments with sex-dependent alterations of microglia in the hippocampus and cortex. Additionally, KO males but not females had more negative resting membrane potentials in the CA1 hippocampus without any changes in miniature excitatory postsynaptic current (mEPSC) frequencies or amplitudes. Our findings show that constitutive deletion of Rnf216 alters microglia and neuronal excitability, which may provide insights into the etiology of sex-specific impairments in GHS.

Increased LPS-Induced Fever and Sickness Behavior in Adult Male and Female Rats Perinatally Exposed to Morphine.

As a result of the current opioid crisis, the rate of children born exposed to opioids has skyrocketed. Later in life, these children have an increased risk for hospitalization and infection, raising concerns about potential immunocompromise, as is common with chronic opioid use. Opioids can act directly on immune cells or indirectly via the central nervous system to decrease immune system activity, leading to increased susceptibility, morbidity, and mortality to infection. However, it is currently unknown how perinatal opioid exposure (POE) alters immune function. Using a clinically relevant and translatable model of POE, we have investigated how baseline immune function and the reaction to an immune stimulator, lipopolysaccharide, is influenced by in utero opioid exposure in adult male and female rats. We report here that POE potentiates the febrile and neuroinflammatory response to lipopolysaccharide, likely as a consequence of suppressed immune function at baseline (including reduced antibody production). This suggests that POE increases susceptibility to infection by manipulating immune system development, consistent with the clinical literature. Investigation of the mechanisms whereby POE increases susceptibility to pathogens is critical for the development of potential interventions for immunosuppressed children exposed to opioids in utero.

Erratum: The E3 ubiquitin ligase RNF216/TRIAD3 is a key coordinator of the hypothalamic-pituitary-gonadal axis.

[This corrects the article DOI: 10.1016/j.isci.2022.104386.].

The E3 ubiquitin ligase RNF216/TRIAD3 is a key coordinator of the hypothalamic-pituitary-gonadal axis.

Recessive mutations in RNF216/TRIAD3 cause Gordon Holmes syndrome (GHS), in which dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis and neurodegeneration are thought to be core phenotypes. We knocked out Rnf216/Triad3 in a gonadotropin-releasing hormone (GnRH) hypothalamic cell line. Rnf216/Triad3 knockout (KO) cells had decreased steady-state GnRH and calcium transients. Rnf216/Triad3 KO adult mice had reductions in GnRH neuron soma size and GnRH production without changes in neuron densities. In addition, KO male mice had smaller testicular volumes that were accompanied by an abnormal release of inhibin B and follicle-stimulating hormone, whereas KO females exhibited irregular estrous cycling. KO males, but not females, had reactive microglia in the hypothalamus. Conditional deletion of Rnf216/Triad3 in neural stem cells caused abnormal microglia expression in males, but reproductive function remained unaffected. Our findings show that dysfunction of RNF216/TRIAD3 affects the HPG axis and microglia in a region- and sex-dependent manner, implicating sex-specific therapeutic interventions for GHS.

Video-Based Remote Administration of Cognitive Assessments and Interventions: a Comparison with In-Lab Administration.

While remote data collection is not a new concept, the quality and psychometric properties of data collected remotely often remain unclear. Most remote data collection is done via online survey tools or web-conferencing applications (i.e., Skype or Zoom) and largely involves questionnaires, interviews, or other self-report data. Little research has been done on the collection of cognitive assessments and interventions via web-conferencing that requires multiple sessions with or without the assistance of an experimenter. The present paper discusses limitations and challenges of studies administered remotely, and outlines methods used to overcome such challenges while effectively collecting cognitive performance data remotely via Zoom. We further discuss relative recruitment, retention rates, compliance, and performance findings between in-lab and remotely administered cognitive assessment and intervention studies, as well as limitations to remote data collection. We found that while it was necessary to recruit more participants in remote studies to reach enrollment goals, compliance and performance were largely comparable between in-lab and remotely administered studies, illustrating the opportunities of conducting this type of experimental research remotely with adequate fidelity.