Orexin 2 receptor regulation of the hypothalamic–pituitary–adrenal (HPA) response to acute and repeated stress

Orexins are hypothalamic neuropeptides that have a documented role in mediating the acute stress response. However, their role in habituation to repeated stress, and the role of orexin receptors (OX1R and OX2R) in the stress response, has yet to be defined. Orexin neuronal activation and levels in the cerebrospinal fluid were found to be stimulated with acute restraint, but were significantly reduced by day five of repeated restraint. As certain disease states such as panic disorder are associated with increased central orexin levels and failure to habituate to repeated stress, the effect of activating orexin signaling via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on the hypothalamic-pituitary-adrenal (HPA) response was evaluated after repeated restraint. While vehicle-treated rats displayed habituation of Adrenocorticotropic Hormone (ACTH) from day 1 to day 5 of restraint, stimulating orexins did not further increase ACTH beyond vehicle levels for either acute or repeated restraint. We delineated the roles of orexin receptors in acute and repeated stress by using a selective OX2R antagonist (MK-1064). Pretreatment with MK-1064 reduced day 1 ACTH levels, but did not allow further habituation on day 5 compared with vehicle-treated rats, indicating that endogenous OX2R activity plays a role in acute stress, but not in habituation to repeated stress. However, in restrained rats with further stimulated orexins by DREADDs, MK-1064 decreased ACTH levels on day 5. Collectively, these results indicate that the OX2R plays a role in acute stress, and can prevent habituation to repeated stress under conditions of high orexin release

Orexin 2 receptor regulation of the hypothalamic–pituitary–adrenal (HPA) response to acute and repeated stress

Orexins are hypothalamic neuropeptides that have a documented role in mediating the acute stress response. However, their role in habituation to repeated stress, and the role of orexin receptors (OX1R and OX2R) in the stress response, has yet to be defined. Orexin neuronal activation and levels in the cerebrospinal fluid were found to be stimulated with acute restraint, but were significantly reduced by day five of repeated restraint. As certain disease states such as panic disorder are associated with increased central orexin levels and failure to habituate to repeated stress, the effect of activating orexin signaling via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on the hypothalamic-pituitary-adrenal (HPA) response was evaluated after repeated restraint. While vehicle-treated rats displayed habituation of Adrenocorticotropic Hormone (ACTH) from day 1 to day 5 of restraint, stimulating orexins did not further increase ACTH beyond vehicle levels for either acute or repeated restraint. We delineated the roles of orexin receptors in acute and repeated stress by using a selective OX2R antagonist (MK-1064). Pretreatment with MK-1064 reduced day 1 ACTH levels, but did not allow further habituation on day 5 compared with vehicle-treated rats, indicating that endogenous OX2R activity plays a role in acute stress, but not in habituation to repeated stress. However, in restrained rats with further stimulated orexins by DREADDs, MK-1064 decreased ACTH levels on day 5. Collectively, these results indicate that the OX2R plays a role in acute stress, and can prevent habituation to repeated stress under conditions of high orexin release

The Development of Videoconference-Based Support for People Living With Rare Dementias and Their Carers: Protocol for a 3-Phase Support Group Evaluation

BACKGROUND: People living with rarer dementias face considerable difficulty accessing tailored information, advice, and peer and professional support. Web-based meeting platforms offer a critical opportunity to connect with others through shared lived experiences, even if they are geographically dispersed, particularly during the COVID-19 pandemic. OBJECTIVE: We aim to develop facilitated videoconferencing support groups (VSGs) tailored to people living with or caring for someone with familial or sporadic frontotemporal dementia or young-onset Alzheimer disease, primary progressive aphasia, posterior cortical atrophy, or Lewy body dementia. This paper describes the development, coproduction, field testing, and evaluation plan for these groups. METHODS: We describe a 3-phase approach to development. First, information and knowledge were gathered as part of a coproduction process with members of the Rare Dementia Support service. This information, together with literature searches and consultation with experts by experience, clinicians, and academics, shaped the design of the VSGs and session themes. Second, field testing involved 154 Rare Dementia Support members (people living with dementia and carers) participating in 2 rounds of facilitated sessions across 7 themes (health and social care professionals, advance care planning, independence and identity, grief and loss, empowering your identity, couples, and hope and dementia). Third, a detailed evaluation plan for future rounds of VSGs was developed. RESULTS: The development of the small groups program yielded content and structure for 9 themed VSGs (the 7 piloted themes plus a later stages program and creativity club for implementation in rounds 3 and beyond) to be delivered over 4 to 8 sessions. The evaluation plan incorporated a range of quantitative (attendance, demographics, and geography; pre-post well-being ratings and surveys; psycholinguistic analysis of conversation; facial emotion recognition; facilitator ratings; and economic analysis of program delivery) and qualitative (content and thematic analysis) approaches. Pilot data from round 2 groups on the pre-post 3-word surveys indicated an increase in the emotional valence of words selected after the sessions. CONCLUSIONS: The involvement of people with lived experience of a rare dementia was critical to the design, development, and delivery of the small virtual support group program, and evaluation of this program will yield convergent data about the impact of tailored support delivered to geographically dispersed communities. This is the first study to design and plan an evaluation of VSGs specifically for people affected by rare dementias, including both people living with a rare dementia and their carers, and the outcome of the evaluation will be hugely beneficial in shaping specific and targeted support, which is often lacking in this population