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Abstract Background Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson’s disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain. Methods aSYN PFFs were stereotaxically injected into the SNc or PPN of mice. Twelve weeks later, mice were studied using a combination of approaches, including immunocytochemical analysis, cell-type specific transcriptomic profiling, electron microscopy, electrophysiology and two-photon-laser-scanning microscopy of genetically encoded sensors for bioenergetic and redox status. Results In addition to inducing a significant neuronal loss, SNc injection of PFFs induced the formation of intracellular, phosphorylated aSYN aggregates selectively in dopaminergic neurons. In these neurons, PFF-exposure decreased mitochondrial gene expression, reduced the number of mitochondria, increased oxidant stress, and profoundly disrupted mitochondrial adenosine triphosphate production. Consistent with an aSYN-induced bioenergetic deficit, the autonomous spiking of dopaminergic neurons slowed or stopped. PFFs also up-regulated lysosomal gene expression and increased lysosomal abundance, leading to the formation of Lewy-like inclusions. Similar changes were observed in PPN cholinergic neurons following aSYN PFF exposure. Conclusions Taken together, our findings suggest that disruption of mitochondrial function, and the subsequent bioenergetic deficit, is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD.

Abstract In the primary visual cortex area V1 activation of inhibitory interneurons, which provide negative feedback for excitatory pyramidal neurons, can improve visual response reliability and orientation selectivity. Moreover, optogenetic activation of one class of interneurons, parvalbumin (PV) positive cells, reduces the receptive field (RF) width. These data suggest that in V1 the negative feedback improves visual information processing. However, according to information theory, noise can limit information content in a signal, and to the best of our knowledge, in V1 signal-to-noise ratio (SNR) has never been estimated following either pyramidal or inhibitory neuron activation. Therefore, we optogenetically activated pyramidal or PV neurons in the deep layers of cortical area V1 and measured the SNR and RF area in nearby pyramidal neurons. Activation of pyramidal or PV neurons increased the SNR by 267% and 318%, respectively, and reduced the RF area to 60.1% and 77.5%, respectively, of that of the control. A simple integrate-and-fire neuron model demonstrated that an improved SNR and a reduced RF area can increase the amount of information encoded by neurons. We conclude that in V1 activation of pyramidal neurons improves visual information processing since the location of the visual stimulus can be pinpointed more accurately (via a reduced RF area), and more information is encoded by neurons (due to increased SNR).

Hikitia te Ora (Certificate in Health Sciences) is a 1 year Indigenous bridging foundation programme at the University of Auckland, Aotearoa New Zealand. The programme aims to increase Maori and Pacific health workforce representation. This qualitative study applied a Kaupapa Maori positioning to elucidate the strengths, challenges, and opportunities of the programme. Data were collected through two workshops and seven focus groups with a total of 67 participants who were students of Hikitia te Ora from past and present cohorts, or their family members. Using a general inductive thematic analysis, the primary themes identified were that programme successes encompassed whanaungatanga (process of establishing relationships), academic and pastoral support, programme structure and the teaching content. Challenges included social cliques and divisive social groupings, timetabling of courses and high workloads. The three areas that emerged for further development include extending Pacific content, increasing the number of students in the programme, and maintaining a programme-specific study space for students. Implementing the findings from this study into Hikitia te Ora is expected to improve educational outcomes for Maori and Pacific students and may have the potential to benefit other bridging foundation courses aiming to promote Indigenous health workforce development.

Adapting indigenous qualitative research methods to an online platform was essential for indigenous qualitative research to continue during the COVID-19 pandemic. Online qualitative data collection is a new method supporting health and other research. During the pandemic, shifting to online qualitative data collection was largely driven by impacts of COVID-19 restrictions where in-person data collection could not be undertaken. Recent research has evaluated online focus groups compared to the in-person focus group approach. However, less is understood about how Māori, Pacific and other Indigenous cultural protocols translate to an online approach. This article is based on a study that undertook an Indigenous approach to online data collection during a period of COVID-19 restrictions in 2022. The study was based in Auckland, Aotearoa New Zealand, focused on gaining Māori, Samoan, Tongan and Cook Island Māori perspectives of streptococcus isolate use for rheumatic fever surveillance and research. In Aotearoa New Zealand, rheumatic fever inequitably affects Māori and Pacific children aged 5–15 years. The project used Kaupapa Māori and Pacific centred research methodologies that included online wānanga and fono methods to collect qualitative data from Māori, Tongan, Samoan and Cook Island Māori participants. This article critically reflects on the strengths and challenges of using these methodologies and Māori and Pacific cultural practices in an online health research. The article demonstrates how Indigenous methodologies can effectively be undertaken in online contexts and still maintain cultural integrity and provide rich qualitative data compared to in-person and western informed online qualitative data collection methods.

ABSTRACTThere is strong evidence demonstrating cold housing prevalence in Aotearoa New Zealand. Whānau (families) were recruited from a healthy homes programme based in South Auckland. Forty whānau consented to participate in a temperature-based study that assessed the ability of homes to protect against outdoor temperatures. In this observational study, temperature sensors measured night-time indoor temperature every 15 min from May 2020 to October 2020. Whānau were provided with healthy homes education and practical suggestions to help make homes warmer and dryer. Notably, each device (and house) spent 85% or more of the time below the World Health Organization Housing and Health Guidelines recommended minimum indoor temperature of 20°C for vulnerable groups. The lower standard of 18°C for more general populations referenced in the Healthy Homes Standards was not met over 60% of the time. Over a quarter of the time temperatures measured inside homes were below 12°C. If Māori and Pacific whānau continue to live in substandard housing due to residential inequities, they will continue to experience inequitable health outcomes related to cold housing. Solutions include the anticipated Residential Tenancies (Healthy Homes Standards) Regulations, supports for tenants and support with housing-related costs.

Summary: Long-term synaptic plasticity at glutamatergic synapses on striatal spiny projection neurons (SPNs) is central to learning goal-directed behaviors and habits. Our studies reveal that SPNs manifest a heterosynaptic, nitric oxide (NO)-dependent form of long-term postsynaptic depression of glutamatergic SPN synapses (NO-LTD) that is preferentially engaged at quiescent synapses. Plasticity is gated by Ca2+ entry through CaV1.3 Ca2+ channels and phosphodiesterase 1 (PDE1) activation, which blunts intracellular cyclic guanosine monophosphate (cGMP) and NO signaling. Both experimental and simulation studies suggest that this Ca2+-dependent regulation of PDE1 activity allows for local regulation of dendritic cGMP signaling. In a mouse model of Parkinson disease (PD), NO-LTD is absent because of impaired interneuronal NO release; re-balancing intrastriatal neuromodulatory signaling restores NO release and NO-LTD. Taken together, these studies provide important insights into the mechanisms governing NO-LTD in SPNs and its role in psychomotor disorders such as PD.

[This corrects the article DOI: 10.1371/journal.pbio.3002483.].

Synaptic transmission mediated by GABAA receptors (GABAARs) in adult, principal striatal spiny projection neurons (SPNs) can suppress ongoing spiking, but its effect on synaptic integration at subthreshold membrane potentials is less well characterized, particularly those near the resting down-state. To fill this gap, a combination of molecular, optogenetic, optical, and electrophysiological approaches were used to study SPNs in mouse ex vivo brain slices, and computational tools were used to model somatodendritic synaptic integration. In perforated patch recordings, activation of GABAARs, either by uncaging of GABA or by optogenetic stimulation of GABAergic synapses, evoked currents with a reversal potential near -60 mV in both juvenile and adult SPNs. Transcriptomic analysis and pharmacological work suggested that this relatively positive GABAAR reversal potential was not attributable to NKCC1 expression, but rather to HCO3- permeability. Regardless, from down-state potentials, optogenetic activation of dendritic GABAergic synapses depolarized SPNs. This GABAAR-mediated depolarization summed with trailing ionotropic glutamate receptor (iGluR) stimulation, promoting dendritic spikes and increasing somatic depolarization. Simulations revealed that a diffuse dendritic GABAergic input to SPNs effectively enhanced the response to dendritic iGluR signaling and promoted dendritic spikes. Taken together, our results demonstrate that GABAARs can work in concert with iGluRs to excite adult SPNs when they are in the resting down-state, suggesting that their inhibitory role is limited to brief periods near spike threshold. This state-dependence calls for a reformulation for the role of intrastriatal GABAergic circuits.

The corticostriatal dysfunction underlying Huntington’s disease remains incompletely understood. Here, the authors find increased intratelencephalic connectivity resulting from deficient cholinergic transmission in a mouse model of Huntington’s disease.

Like a handful of other neuronal types in the brain, cholinergic neurons (CNs) in the pedunculopontine nucleus (PPN) are lost during Parkinson's disease (PD). Why this is the case is unknown. One neuronal trait implicated in PD selective neuronal vulnerability is the engagement of feed-forward stimulation of mitochondrial oxidative phosphorylation (OXPHOS) to meet high bioenergetic demand, leading to sustained oxidant stress and ultimately degeneration. The extent to which this trait is shared by PPN CNs is unresolved. To address this question, a combination of molecular and physiological approaches were used. These studies revealed that PPN CNs are autonomous pacemakers with modest spike-associated cytosolic Ca2+ transients. These Ca2+ transients were partly attributable to the opening of high-threshold Cav1.2 Ca2+ channels, but not Cav1.3 channels. Cav1.2 channel signaling through endoplasmic reticulum ryanodine receptors stimulated mitochondrial OXPHOS to help maintain cytosolic adenosine triphosphate (ATP) levels necessary for pacemaking. Inhibition of Cav1.2 channels led to the recruitment of ATP-sensitive K+ channels and the slowing of pacemaking. A ‘side-effect’ of Cav1.2 channel-mediated stimulation of mitochondria was increased oxidant stress. Thus, PPN CNs have a distinctive physiological phenotype that shares some, but not all, of the features of other neurons that are selectively vulnerable in PD.

Abstract Recombinant adeno—associated viruses (rAAV) are extensively used in both research and clinical applications. Despite significant advances, there is a lack of short promoters able to drive the expression of virus delivered genes in specific classes of neurons. We designed an efficient rAAV vector suitable for the rAAV-mediated gene expression in cortical interneurons, mainly in the parvalbumin expressing cells. The vector includes a short parvalbumin promoter and a specialized poly(A) sequence. The degree of conservation of the parvalbumin gene adjoining non-coding regions was used in both the promoter design and the selection of the poly(A) sequence. The specificity was established by co-localizing the fluorescence of the virus delivered eGFP and the antibody for a neuronal marker. rAAV particles were injected in the visual cortex area V1/V2 of adult rats (2–4 months old). Neurons expressing the virus delivered eGFP were mainly positive for interneuronal markers: 66.5 ± 2.8% for parvalbumin, 14.6 ± 2.4% for somatostatin, 7.1 ± 1.2% for vasoactive intestinal peptide, 2.8 ± 0.6% for cholecystokinin. Meanwhile, only 2.1 ± 0.5% were positive for CaMKII, a marker for principal cells in the cortex. The efficiency of the construct was verified by optogenetic experiments: the expression of the virus delivered ChR2 channels was sufficient to evoke by blue light laser high frequency bursts of action potentials in putative fast spiking neurons. We conclude that our promoter allows highly specific expression of the rAAV delivered cDNAs in cortical interneurons with a strong preference for the parvalbumin positive cells.

Background: Older adults may be vulnerable to loneliness due to natural and age-related transitions. Lonely older adults are at an increased risk of adverse health outcomes due to their loneliness, including cognitive decline, cardiovascular disease, and mortality. Objective: The purpose of this study was to explore the experiences of vulnerable older adults in a web-based loneliness intervention. Methods: Older adult participants in a web-based loneliness intervention ( n = 24) participated in semi-structured interviews eliciting feedback about their experience in the program and perceived outcomes. Participants’ responses were analyzed using qualitative content analysis. Results: Participants reported fewer negative perceptions of their social skills and future social interactions, gaining new social skills, improved relationships, and increased confidence to initiate and maintain social contact. Conclusions: Findings suggest the efficacy of combining a web-based loneliness intervention with cognitive behavioral therapy, and provide implications for future web-based interventions for older adult populations.

Adapting indigenous qualitative research methods to an online platform was essential for indigenous qualitative research to continue during the COVID-19 pandemic. Online qualitative data collection is a new method supporting health and other research. During the pandemic, shifting to online qualitative data collection was largely driven by impacts of COVID-19 restrictions where in-person data collection could not be undertaken. Recent research has evaluated online focus groups compared to the in-person focus group approach. However, less is understood about how Māori, Pacific and other Indigenous cultural protocols translate to an online approach. This article is based on a study that undertook an Indigenous approach to online data collection during a period of COVID-19 restrictions in 2022. The study was based in Auckland, Aotearoa New Zealand, focused on gaining Māori, Samoan, Tongan and Cook Island Māori perspectives of streptococcus isolate use for rheumatic fever surveillance and research. In Aotearoa New Zealand, rheumatic fever inequitably affects Māori and Pacific children aged 5–15 years. The project used Kaupapa Māori and Pacific centred research methodologies that included online wānanga and fono methods to collect qualitative data from Māori, Tongan, Samoan and Cook Island Māori participants. This article critically reflects on the strengths and challenges of using these methodologies and Māori and Pacific cultural practices in an online health research. The article demonstrates how Indigenous methodologies can effectively be undertaken in online contexts and still maintain cultural integrity and provide rich qualitative data compared to in-person and western informed online qualitative data collection methods. [ABSTRACT FROM AUTHOR]

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease.sup.1. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear.sup.2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism--which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm.sup.3,4. Dysfunction of mitochondrial complex I in mice is sufficient to cause progressive parkinsonism in which the loss of nigral dopamine release critically contributes to motor dysfunction., Author(s): Patricia González-Rodríguez [sup.1] , Enrico Zampese [sup.1] , Kristen A. Stout [sup.1] , Jaime N. Guzman [sup.1] , Ema Ilijic [sup.1] , Ben Yang [sup.1] , Tatiana Tkatch [sup.1] [...]

This document is a correction notice for an article titled "GABAergic regulation of striatal spiny projection neurons depends upon their activity state." The correction addresses errors in Figures 3 and 4, specifically in panel E of both figures. The incorrect labeling of the inset cartoon in Figure 3E is acknowledged, and the correct labeling is provided. Additionally, in Figure 4E, the y-axis of the right panel is mislabeled and the correct labels are given. The document also provides the correct data availability statement for the paper. [Extracted from the article]

There is strong evidence demonstrating cold housing prevalence in Aotearoa New Zealand. Whānau (families) were recruited from a healthy homes programme based in South Auckland. Forty whānau consented to participate in a temperature-based study that assessed the ability of homes to protect against outdoor temperatures. In this observational study, temperature sensors measured night-time indoor temperature every 15 min from May 2020 to October 2020. Whānau were provided with healthy homes education and practical suggestions to help make homes warmer and dryer. Notably, each device (and house) spent 85% or more of the time below the World Health Organization Housing and Health Guidelines recommended minimum indoor temperature of 20°C for vulnerable groups. The lower standard of 18°C for more general populations referenced in the Healthy Homes Standards was not met over 60% of the time. Over a quarter of the time temperatures measured inside homes were below 12°C. If Māori and Pacific whānau continue to live in substandard housing due to residential inequities, they will continue to experience inequitable health outcomes related to cold housing. Solutions include the anticipated Residential Tenancies (Healthy Homes Standards) Regulations, supports for tenants and support with housing-related costs. [ABSTRACT FROM AUTHOR]

SUMMARY The usual clinical presentation of non-functioning pituitary adenoma (NFPA) consists of symptoms of mass effect and hypopituitarism. NFPA is a rare condition in young women and an uncommon complication during pregnancy. We present the outcome of three patients with NFPA during pregnancy. Case 1: a 38-year-old woman was referred at 32nd week of spontaneous pregnancy because of diagnosis of a pituitary macroadenoma discovered in the context of progressive visual loss. Hormonal deficiency and hypersecretion were ruled out. Prolactin levels were high as expected. She developed diplopia and severe headache despite the use of dopamine agonists and corticosteroids, so pregnancy was interrupted at 34th week. After an uncomplicated delivery of a healthy newborn, transsphenoidal surgery was performed. The pathology was consistent with a gonadotroph adenoma. She recovered visual field, and remained with normal pituitary function. Postsurgical tumor remnant increased in size during the follow-up. Case 2: a 34-year-old woman was referred due to secondary amenorrhea and galactorrhea. A macroadenoma with suprasellar extension was discovered. Transsphenoidal surgery confirmed a gonadotroph adenoma. Two years after surgery she had a normal pregnancy. Six years after surgery a small tumor recurrence occurred. Case 3: a 23-year-old woman was referred due to a microincidental pituitary adenoma. Laboratory testing was normal. No findings on physical examination. A wait and see approach was decided. Two years after diagnosis, the patient got pregnant without complications. Image remained stable. This article may contribute new cases and provides an extensive review of NFPA during pregnancy.

Population aging is one of the most important social trends of the 21st century and in the United States, the number of people aged ≥65 is projected to increase by nearly 50% in the next 15 years. Most biomedical and public health efforts have focused on reducing harmful risk factors when targeting chronic disease—an approach that has contributed greatly to prevention and treatment programs. However, evidence suggests that the number of years lost to disability is increasing and historic gains we have made in life expectancy are eroding, and even reversing in some groups. As our society ages and grapples with these issues, expanding the focus to include resilience, as well as psychosocial assets in our prevention and treatment programs might help inform the multidisciplinary response effort we need. Here we synthesize research evaluating associations between different dimensions of psychological well-being (e.g., purpose in life, optimism, life satisfaction) and social well-being (e.g., structural, functional, quality) with chronic conditions. We also evaluate evidence around three biopsychosocial pathways hypothesized to underlie these associations. These factors are meaningful, measurable, and potentially modifiable; thus, further pursuing this line of inquiry might unveil innovative paths to enhancing the health of our rapidly aging society.

Background. While today’s older adults experience longevity, they often manage several chronic conditions and increasingly serve as informal caregivers for aging parents, children with life-long disabilities, and spouses. Older adult caregivers managing personal chronic illness often experience significant psychosocial hardships. Objective. The primary purpose of this study was to explore the experiences of older adult caregivers in an online, interactive mindfulness intervention. Methods. Self-reported older caregivers who participated in an online-based mindfulness program (n = 20) were recruited for semi-structured interviews. Participants were asked to provide feedback about any previous experience with mindfulness and/or meditation, hopes or goals held prior to the start of the program, desired expectations, motivation for joining, impressions of sessions, most beneficial topics, potential application of content, and any perceived effects. Participants’ responses were analyzed using qualitative content analysis. Results. Five themes emerged from the analysis: Managing the Comprehensive Effects of Caregiving, Openness to Meditation and Mindfulness, Course Engagement and Incremental Growth, Building Rapport through Shared Experiences, and Ongoing Application and Opportunities for Refinement. Participants reported both short-term post-exercise benefits such as increased calm, relaxation, and stress relief, as well as long-term positive outcomes. Notably, participants found the program’s unique interactive feature to be particularly beneficial as a form of perceived social support. Conclusions. Caregivers for older adults may derive benefit and potentially experience reduced subjective caregiver burden as a result of participating in a Mindfulness-Based Stress Reduction (MBSR) program, particularly when the program is augmented with a self-compassion approach and perceived social support.