Integration of sensory and molecular inputs from the environment shapes animal behaviour. A major site of exposure to environmental molecules is the gastrointestinal tract, in which dietary ...components are chemically transformed by the microbiota
and gut-derived metabolites are disseminated to all organs, including the brain
. In mice, the gut microbiota impacts behaviour
, modulates neurotransmitter production in the gut and brain
, and influences brain development and myelination patterns
. The mechanisms that mediate the gut-brain interactions remain poorly defined, although they broadly involve humoral or neuronal connections. We previously reported that the levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were increased in a mouse model of atypical neurodevelopment
. Here we identified biosynthetic genes from the gut microbiome that mediate the conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice and decreased oligodendrocyte-neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioural outcomes
. Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.
The gut microbiome contributes to the development and function of the immune, metabolic, and nervous systems. Furthermore, commensal bacteria modulate symptoms and pathology in mouse models of ...neuropsychiatric and neurodevelopmental diseases. Uncovering mechanisms that are utilized by the microbiome to mediate gut-brain connections may provide novel opportunities to target therapies to the gut in order to treat neurologic disorders.
Gene therapy offers great promise in addressing neuropathologies associated with the central and peripheral nervous systems (CNS and PNS). However, genetic access remains difficult, reflecting the ...critical need for the development of effective and non-invasive gene delivery vectors across species. To that end, we evolved adeno-associated virus serotype 9 (AAV9) capsid in mice and validated two capsids, AAV-MaCPNS1 and AAV-MaCPNS2, across rodent species (mice and rats) and non-human primate (NHP) species (marmosets and rhesus macaques). Intravenous administration of either AAV efficiently transduced the PNS in rodents and both the PNS and CNS in NHPs. Furthermore, we used AAV-MaCPNS1 in mice to systemically deliver the following: (1) the neuronal sensor jGCaMP8s to record calcium signal dynamics in nodose ganglia and (2) the neuronal actuator DREADD to dorsal root ganglia to mediate pain. This conclusively demonstrates the translatability of these two systemic AAVs across four species and their functional utility through proof-of-concept studies in mice.
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•Directed evolution in rodents identified AAV vectors targeting the PNS•Systemically administered MaCPNS1 and MaCPNS2 efficiently target the PNS in rodents•Systemic MaCPNS1 is used for functional readout and non-invasive modulation of the PNS•Systemic MaCPNS1 and MaCPNS2 transduce both the PNS and CNS in macaque and marmoset
Chen et al. evolved a family of AAV capsid variants, including MaCPNS1 and MaCPNS2, that efficiently transduced the PNS in rodents following systemic administration, enabling functional readout and non-invasive modulation of PNS. Both vectors could also enable efficient gene delivery to both PNS and CNS in macaque and marmoset.
The gastrointestinal (GI) tract is innervated by intrinsic neurons of the enteric nervous system (ENS) and extrinsic neurons of the central nervous system and peripheral ganglia. The GI tract also ...harbors a diverse microbiome, but interactions between the ENS and the microbiome remain poorly understood. Here, we activate choline acetyltransferase (ChAT)-expressing or tyrosine hydroxylase (TH)-expressing gut-associated neurons in mice to determine effects on intestinal microbial communities and their metabolites as well as on host physiology. The resulting multi-omics datasets support broad roles for discrete peripheral neuronal subtypes in shaping microbiome structure, including modulating bile acid profiles and fungal colonization. Physiologically, activation of either ChAT+ or TH+ neurons increases fecal output, while only ChAT+ activation results in increased colonic contractility and diarrhea-like fluid secretion. These findings suggest that specific subsets of peripherally activated neurons differentially regulate the gut microbiome and GI physiology in mice without involvement of signals from the brain.
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•ChAT+ and TH+ neurons show distinct spatial organization within the ENS of mice•ChAT+ and TH+ neurons differentially shape the composition of the gut microbiome•Gut-associated TH+ neurons regulate fungal colonization of the gut•Gut-associated ChAT+ neuron activation promotes fluid secretion and colonic motility
Griffiths et al. examine how activating ChAT+ or TH+ gut-associated neurons shapes the gut microbiome and physiology in mice. They uncover unique alterations in the metagenome, transcriptome, metabolome, and proteome, as well as GI motility, suggesting that subpopulations of peripherally activated neurons differentially regulate the gut microbiome and GI function with no involvement of signals from the brain.
In the early stages of Alzheimer's disease (AD), the accumulation of the peptide amyloid-β (Aβ) damages synapses and disrupts neuronal activity, leading to the disruption of neuronal oscillations ...associated with cognition. This is thought to be largely due to impairments in CNS synaptic inhibition, particularly via parvalbumin (PV)-expressing interneurons that are essential for generating several key oscillations. Research in this field has largely been conducted in mouse models that over-express humanised, mutated forms of AD-associated genes that produce exaggerated pathology. This has prompted the development and use of knock-in mouse lines that express these genes at an endogenous level, such as the AppNL-G-F/NL-G-F mouse model used in the present study. These mice appear to model the early stages of Aβ-induced network impairments, yet an in-depth characterisation of these impairments in currently lacking. Therefore, using 16 month-old AppNL-G-F/NL-G-F mice, we analysed neuronal oscillations found in the hippocampus and medial prefrontal cortex (mPFC) during awake behaviour, rapid eye movement (REM) and non-REM (NREM) sleep to assess the extent of network dysfunction. No alterations to gamma oscillations were found to occur in the hippocampus or mPFC during either awake behaviour, REM or NREM sleep. However, during NREM sleep an increase in the power of mPFC spindles and decrease in the power of hippocampal sharp-wave ripples was identified. The latter was accompanied by an increase in the synchronisation of PV-expressing interneuron activity, as measured using two-photon Ca2+ imaging, as well as a decrease in PV-expressing interneuron density. Furthermore, although changes were detected in local network function of mPFC and hippocampus, long-range communication between these regions appeared intact. Altogether, our results suggest that these NREM sleep-specific impairments represent the early stages of circuit breakdown in response to amyloidopathy.
•NREM sleep-associated neuronal oscillation deficits found in AppNL-G-F/NL-G-F mice.•Cortical spindle and hippocampal sharp-wave ripple alterations precede gamma oscillation breakdown.•Long-range neuronal oscillation communication in the medial prefrontal cortex – hippocampal circuit is spared.•A reduction in hippocampal CA1 parvalbumin-expressing interneuron density in AppNL-G-F/NL-G-F mice.•Increased synchrony between hippocampal CA1 parvalbumin-expressing interneurons in AppNL-G-F/NL-G-F mice.
Mother and baby units (MBUs) are an inpatient mental health service where women experiencing acute severe postpartum psychiatric difficulties can be admitted with their babies. They are currently ...viewed as best practice in the UK and elsewhere. However, as service provision is fragmented, some women residing in areas without MBUs are admitted to acute general psychiatric wards without their infants. This study aimed to compare qualitatively experiences of these two service types from the perspectives of women and clinicians.
Semi-structured interviews were conducted with fifteen women who received treatment for perinatal mental health problems on a general psychiatric ward and/or MBU in England. Two focus groups were also conducted, one with MBU staff (n = 11) and one with acute ward staff (n = 6). Data were analysed thematically.
Women generally preferred being co-admitted with their baby to an MBU over lone admission to a general psychiatric ward. Women and clinicians felt that MBUs provided more perinatally-focused, family-centred care, and were better-equipped to meet women's needs. General wards were reported by women and staff to lack the necessary facilities and expertise to support perinatal women adequately, while separation of mothers and babies was often experienced by women as traumatic and detrimental to recovery. However, some areas for improvement were also identified across both service types, particularly relating to difficulties transitioning home post-discharge, inadequate support for family members, staffing issues and access problems (with MBUs).
Findings suggest that specialist perinatal inpatient care is considered preferable to generic care in the perinatal period from both service user and staff perspectives. Increased collaboration between perinatal and non-perinatal services could help improve perinatal expertise on general psychiatric wards, while further expansion of perinatal services (e.g. to cater for women currently considered too high risk for MBUs and for those discharged from inpatient settings) could tackle other shortfalls in care.
Experiences of trauma in childhood and adulthood are highly prevalent among service users accessing acute, crisis, emergency, and residential mental health services. These settings, and restraint and ...seclusion practices used, can be extremely traumatic, leading to a growing awareness for the need for trauma informed care (TIC). The aim of TIC is to acknowledge the prevalence and impact of trauma and create a safe environment to prevent re-traumatisation. This scoping review maps the TIC approaches delivered in these settings and reports related service user and staff experiences and attitudes, staff wellbeing, and service use outcomes.We searched seven databases (EMBASE; PsycINFO; MEDLINE; Web of Science; Social Policy and Practice; Maternity and Infant Care Database; Cochrane Library Trials Register) between 24/02/2022-10/03/2022, used backwards and forwards citation tracking, and consulted academic and lived experience experts, identifying 4244 potentially relevant studies. Thirty-one studies were included.Most studies (n = 23) were conducted in the USA and were based in acute mental health services (n = 16). We identified few trials, limiting inferences that can be drawn from the findings. The Six Core Strategies (n = 7) and the Sanctuary Model (n = 6) were the most commonly reported approaches. Rates of restraint and seclusion reportedly decreased. Some service users reported feeling trusted and cared for, while staff reported feeling empathy for service users and having a greater understanding of trauma. Staff reported needing training to deliver TIC effectively.TIC principles should be at the core of all mental health service delivery. Implementing TIC approaches may integrate best practice into mental health care, although significant time and financial resources are required to implement organisational change at scale. Most evidence is preliminary in nature, and confined to acute and residential services, with little evidence on community crisis or emergency services. Clinical and research developments should prioritise lived experience expertise in addressing these gaps.
Peer support for mental health is recommended across international policy guidance and provision. Our systematic umbrella review summarises evidence on the effectiveness, implementation, and ...experiences of paid peer support approaches for mental health.
We searched MEDLINE, EMBASE, PsycINFO, The Campbell Collaboration, and The Cochrane Database of Systematic Reviews (2012-2022) for reviews of paid peer support interventions for mental health. The AMSTAR2 assessed quality. Results were synthesised narratively, with implementation reported using the CFIR (Consolidated Framework for Implementation Research). The protocol was registered with PROSPERO (registration number: CRD42022362099).
We included 35 reviews (426 primary studies, n = 95-40,927 participants): systematic reviews with (n = 13) or without (n = 13) meta-analysis, or with qualitative synthesis (n = 3), scoping reviews (n = 6). Most reviews were low or critically low (97%) quality, one review was high quality. Effectiveness was investigated in 23 reviews. Results were mixed; there was some evidence from meta-analyses that peer support may improve depression symptoms (particularly perinatal depression), self-efficacy, and recovery. Factors promoting successful implementation, investigated in 9 reviews, included adequate training and supervision, a recovery-oriented workplace, strong leadership, and a supportive and trusting workplace culture with effective collaboration. Barriers included lack of time, resources and funding, and lack of recognised peer support worker (PSW) certification. Experiences of peer support were explored in 11 reviews, with 3 overarching themes: (i) what the PSW role can bring, including recovery and improved wellbeing for service users and PSWs; (ii) confusion over the PSW role, including role ambiguity and unclear boundaries; and (iii) organisational challenges and impact, including low pay, negative non-peer staff attitudes, and lack of support and training.
Peer support may be effective at improving some clinical outcomes, self-efficacy, and recovery. Certain populations, e.g. perinatal populations, may especially benefit from peer support. Potential strategies to successfully implement PSWs include co-production, clearly defined PSW roles, a receptive hierarchical structure and staff, appropriate PSW and staff training with clinical and/or peer supervision alongside safeguarding. Services could benefit from clear, coproduced, setting specific implementation guidelines for PSW. PSW roles tend to be poorly defined and associations between PSW intervention content and impacts need further investigation. Future research should reflect the priorities of providers/service users involved in peer support.
BackgroundThe urgency of the climate crisis requires attention from biomedical research, not least clinical trials which can involve significant greenhouse gas emissions. The Low Carbon Clinical ...Trials Working Group set out a strategy to reduce the emissions of clinical trials, starting with the development of a method to measure their carbon footprint (CO2e).MethodsAs a first step, we developed a process map defining clinical trial core activities. Corresponding emission factors were sourced to convert activity data into greenhouse gas emissions. The subsequent method was applied to two Cancer Research UK (CRUK)-funded trials (the international randomised sarcoma trial CASPS (ISRCTN63733470) and the UK cohort-based breast cancer trial PRIMETIME (ISRCTN41579286)). A guidance document defining the scope, method and assumptions was written to allow application to any publicly funded/investigator initiated clinical trial.ResultsTrial specific activities over and above routine care were grouped into 10 modules covering trial set up, conduct and closure. We identified emission factors for all trial activities within both trials and used them to estimate their total carbon footprint. The carbon footprint of CASPS, an international phase 2 trial of an investigational medicinal product with 47 participants, was 72 tonnes CO2e, largely attributable to clinical trials unit emissions and staff travel. PRIMETIME, a UK-based phase 3 non-investigational medicinal product trial with 1962 patients, produced 89 tonnes CO2e, largely attributable to trial-specific in-person participant assessments.ConclusionWe have developed a method and guidance that trialists can use to determine the carbon footprint of clinical trials. The guidance can be used to identify carbon hotspots where alternative approaches to trial design and conduct could reduce a trial footprint, and where methodology research is required to investigate the potential impact of interventions taken to reduce carbon emissions. We will continue to refine the guidance to increase the potential application and improve usability.
Partners in Recovery (PIR) was an Australian government initiative designed to provide support and service linkage for individuals with complex needs living with severe and persistent mental illness. ...This article reports the external evaluation process and approach that was undertaken of the Gold Coast Partners in Recovery initiative between September and December 2015 regarding the achievement of PIR outcomes. The evaluation of this consortia-based initiative was framed using principles of realistic evaluation and recovery-oriented practice. Numerous evaluations of similar initiatives have recently been undertaken, each adopting different approaches and methods in accordance with local needs and expectations. The incorporation of realistic evaluation with recovery-oriented principles in this mixed methods research design, however, offers a unique perspective. This can be used to inform future developments in evaluative practice particularly in the area of recovery-oriented services and/or partnership-focused, capacity-building initiatives.
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