Bidirectional regulation of distinct memory domains by α5-subunit-containing GABAA receptors in CA1 pyramidal neurons.

Reduction in the expression or function of α5-subunit-containing GABAA receptors (α5GABAARs) leads to improvement in several hippocampus-dependent memory domains. However, studies thus far mostly lack anatomical specificity in terms of neuronal circuits and populations. We demonstrate that mice with a selective knockdown of α5GABAARs in CA1 pyramidal neurons (α5CA1KO mice) show improved spatial and trace fear-conditioning memory. Unexpectedly, α5CA1KO mice were comparable to controls in contextual fear-conditioning but showed an impairment in context discrimination, suggesting fine-tuning of activity in CA1 pyramidal cell dendrites through α5-mediated inhibition might be necessary for distinguishing highly similar contexts.

Tonic Inhibitory Control of Dentate Gyrus Granule Cells by α5-Containing GABAA Receptors Reduces Memory Interference.

Interference between similar or overlapping memories formed at different times poses an important challenge on the hippocampal declarative memory system. Difficulties in managing interference are at the core of disabling cognitive deficits in neuropsychiatric disorders. Computational models have suggested that, in the normal brain, the sparse activation of the dentate gyrus granule cells maintained by tonic inhibitory control enables pattern separation, an orthogonalization process that allows distinct representations of memories despite interference. To test this mechanistic hypothesis, we generated mice with significantly reduced expression of the α5-containing GABAA (α5-GABAARs) receptors selectively in the granule cells of the dentate gyrus (α5DGKO mice). α5DGKO mice had reduced tonic inhibition of the granule cells without any change in fast phasic inhibition and showed increased activation in the dentate gyrus when presented with novel stimuli. α5DGKO mice showed impairments in cognitive tasks characterized by high interference, without any deficiencies in low-interference tasks, suggesting specific impairment of pattern separation. Reduction of fast phasic inhibition in the dentate gyrus through granule cell-selective knock-out of α2-GABAARs or the knock-out of the α5-GABAARs in the downstream CA3 area did not detract from pattern separation abilities, which confirms the anatomical and molecular specificity of the findings. In addition to lending empirical support to computational hypotheses, our findings have implications for the treatment of interference-related cognitive symptoms in neuropsychiatric disorders, particularly considering the availability of pharmacological agents selectively targeting α5-GABAARs. SIGNIFICANCE STATEMENT: Interference between similar memories poses a significant limitation on the hippocampal declarative memory system, and impaired interference management is a cognitive symptom in many disorders. Thus, understanding mechanisms of successful interference management or processes that can lead to interference-related memory problems has high theoretical and translational importance. This study provides empirical evidence that tonic inhibition in the dentate gyrus (DG), which maintains sparseness of neuronal activation in the DG, is essential for management of interference. The specificity of findings to tonic, but not faster, more transient types of neuronal inhibition and to the DG, but not the neighboring brain areas, is presented through control experiments. Thus, the findings link interference management to a specific mechanism, proposed previously by computational models.

Training Health Center Staff in the Provision of Culturally Responsive Care for Sexual and Gender Minority Patients: Results of a Randomized Controlled Trial.

Purpose: The study was designed to evaluate whether an educational intervention to train the health center (HC) staff to optimize care for sexual and gender minority (SGM) patients could improve documentation of sexual orientation and gender identity (SOGI) and increase preventive screenings. Methods: Twelve HCs were matched and randomized to either receive a tailored, multicomponent educational intervention or a 1-hour prerecorded webinar. Documentation of SGM status and clinical testing was measured through analysis of data that HCs report annually. Nonparametric statistics were used to assess associations between baseline HC characteristics and outcome measures. Results: The HCs were geographically, racially, and ethnically diverse. In all but one HC, <10% of the patients were identified as SGM. Intervention HCs underwent between 3 and 10 trainings, which were highly acceptable. In 2018, 9 of 12 HCs documented SO and 11 of 12 documented GI for at least 50% of their patients. Five of 6 intervention HCs increased SO documentation by 2020, compared to 3 of 6 control HCs (nonsignificant, NS). Five intervention HCs increased GI documentation, although generally by less than 10%, compared to 2 of the controls (NS). Intervention HCs tended to increase documentation of preventive services more than control HCs, but the changes were NS. Conclusions: An educational intervention designed to train the HC staff to provide culturally responsive services for SGM patients was found to be acceptable, with favorable, but nonsignificant changes. Further refinement of the intervention using a larger sample of HCs might demonstrate the effectiveness of this approach. Clinical trial registration #: NCT03554785.

Health Center Leadership Perspectives Regarding Barriers to and Facilitators of Providing Culturally Responsive Care for Sexual and Gender Minority Patients.

Purpose: This study identified barriers and facilitators associated with providing culturally responsive care for sexual and gender minority (SGM) patients at federally qualified health centers (FQHCs) in the United States, from the perspective of clinical leadership. Methods: Between July and December 2018, 23 semistructured, in-depth qualitative interviews were held with clinical leaders representing six FQHCs residing in rural and urban settings. Stakeholders included Chief Executive Officer, Executive Director, Chief Medical Officer, Medical Director, Clinic Site Director, and Nurse Manager positions. Interview transcripts were analyzed using inductive thematic analysis. Results: Barriers included personnel factors related to lack of training and fear, competing priorities, and environments that focused on treating all patients similarly. Facilitators included established partnerships with external organizations, staff with prior SGM training and knowledge, and active initiatives in clinic settings targeting SGM care. Conclusions: Clinical leadership expressed strong support for evolving their FQHCs into organizations that provide culturally responsive care for their SGM patients. FQHC staff across all levels of clinical care would benefit from regularly occurring training sessions on culturally responsive care for SGM patients. To ensure sustainability, improve staff buy-in, and mitigate the impact of staff turnover, improving culturally competent care for SGM patients should be a shared goal and responsibility for leadership, medical providers, and administrative staff. CTN Registration: NCT03554785.

Wide Variability in Documentation of Sexual Orientation, Gender Identity, and Preventive Health Screenings in a Diverse Sample of U.S. Community Health Centers.

Purpose: This study was conducted to characterize documentation of sexual orientation and gender identity (SOGI) and provision of screening and preventive services in a diverse sample of community health centers (CHCs). Methods: Twelve CHCs provided data submitted to the Health Resources and Services Administration (HRSA) in 2018 from their Uniform Data System (UDS) reports. Prevalence of SOGI documentation, screenings, and preventive services were calculated. Sociodemographic correlates of documentation were analyzed using Fisher's exact test and Wilcoxon rank sum/Mann-Whitney U test. Results: Patient data recording sexual orientation (SO) were missing in 2%-93% of UDS reports from the 12 CHCs, and gender identity (GI) data were missing from 0% to 96% of UDS reports. CHCs were most likely to report body mass index and tobacco screening and least likely to report hepatitis A or B vaccination, independent of SO or GI. Transgender females were less likely to have mammography documented than cisgender females. Transgender males were less likely to have anal Pap tests, be vaccinated for hepatitis B, or be referred for risky alcohol use compared to cisgender males. Patients who identified as "another gender" were less likely to be referred for risky alcohol use, undergo mammography or anal Pap testing, or receive hepatitis A vaccination than cisgender people. Individuals who did not disclose their GI were less likely to be vaccinated for hepatitis A or B than cisgender people. Conclusion: SOGI status was often not documented by a diverse array of CHCs. However, when SOGI status was documented, we saw evidence of disparities in preventive interventions and referrals, particularly for transgender patients. Clinical trial registration number: NCT03554785.