CHD7 and SOX2 act in a common gene regulatory network during mammalian semicircular canal and cochlear development.

Inner ear morphogenesis requires tightly regulated epigenetic and transcriptional control of gene expression. CHD7, an ATP-dependent chromodomain helicase DNA-binding protein, and SOX2, an SRY-related HMG box pioneer transcription factor, are known to contribute to vestibular and auditory system development, but their genetic interactions in the ear have not been explored. Here, we analyzed inner ear development and the transcriptional regulatory landscapes in mice with variable dosages of Chd7 and/or Sox2. We show that combined haploinsufficiency for Chd7 and Sox2 results in reduced otic cell proliferation, severe malformations of semicircular canals, and shortened cochleae with ectopic hair cells. Examination of mice with conditional, inducible Chd7 loss by Sox2CreER reveals a critical period (~E9.5) of susceptibility in the inner ear to combined Chd7 and Sox2 loss. Data from genome-wide RNA-sequencing and CUT&Tag studies in the otocyst show that CHD7 regulates Sox2 expression and acts early in a gene regulatory network to control expression of key otic patterning genes, including Pax2 and Otx2. CHD7 and SOX2 directly bind independently and cooperatively at transcription start sites and enhancers to regulate otic progenitor cell gene expression. Together, our findings reveal essential roles for Chd7 and Sox2 in early inner ear development and may be applicable for syndromic and other forms of hearing or balance disorders.

Co-production and adaptation of a prison-based problem-solving workbook to support the mental health of patients housed within a medium- and low-secure forensic service.

INTRODUCTION: Problem-solving skills (PSS) help to provide a systematic approach to dealing with and managing complex problems. The overall aim of this study was to assess the acceptability and feasibility of developing and adapting a prison-based PSS  workbook for adults within a medium- and low-secure hospital. METHOD: We used the Medical Research Council framework in our participatory mixed methods study incorporating an adapted survey (to identify what types of problems people experience in secure hospitals), a series of three interactive workshops (to co-produce two case study examples for a workbook) and we gathered feedback from patients and hospital staff on the acceptability and feasibility of the workbook. Data from the survey were used to inform the case study examples, and the feedback from patients and hospital staff was descriptively summarised and the results consolidated. RESULTS: In total, 82 (51%) patients took part in the survey; 22 patients and 49 hospital staff provided feedback on the workbook. The survey results indicated that patients regularly experience problems while in the hospital. Patients reported problems relating to restrictions of freedom and boredom. The workshops produced two case studies for the workbooks, with mainly positive patient and staff feedback. More work is required to improve the visual representation of the characters in the case studies, the amount and content of the language and the mechanism of the intervention delivery. CONCLUSION: The adaptation process proved acceptable and feasible to both patients and staff. The co-production methodology for the workbook and feedback from patients and staff was an effective way of iteratively refining the materials to ensure that they were both meaningful and acceptable to staff and patients. Subsequent work is required to develop the workbook and evaluate the feasibility of the intervention delivery, recruitment rates, uptake and adherence to the PSS using a randomised controlled trial. PATIENT OR PUBLIC CONTRIBUTION: At each stage of the project consultation with patients and/or hospital staff was involved.

An examination of the effects of nucleus accumbens core nociceptin on appetitive and consummatory motivation for food.

The nucleus accumbens (NAc) is a critical region for regulating the appetitive and consummatory aspects of motivated behavior. Previous work has shown differential effects of NAc µ-, δ-, and κ- receptor stimulation on food intake and for shifting motivation within an effort-based choice (EBC) task. However, the motivational role of the nociceptin opioid peptide (NOP) receptor, a fourth member of the opioid receptor family, is less well understood. These experiments therefore characterized the effect of NAc injections of nociceptin, the endogenous ligand for the NOP receptor, on consummatory and appetitive motivation. Three groups of male Sprague-Dawley rats received nociceptin injections into the NAc core prior to testing in a progressive ratio lever pressing task, an EBC task, or a palatable feeding assay. In the feeding experiment, 10 nmol of nociceptin increased consumption in the first 30 min, but this increase was not sustained through the end of the 2-hr session. Additionally, nociceptin injections did not alter breakpoint in the progressive ratio task. However, in the EBC task, nociceptin significantly decreased breakpoint for sugar pellets without affecting consumption of rat chow. These data suggest that NAc NOP receptor stimulation transiently increases consummatory motivation toward palatable diets and inhibits appetitive motivation when alternate food options are freely available. This pattern of effects contrasts with those obtained following NAc stimulation of other opioid receptors, suggesting that the four opioid receptor classes each serve unique roles in modulating food-directed motivation within the NAc core.