Correlates and trajectories of loneliness among community-dwelling older adults during the COVID-19 pandemic: A Canadian longitudinal study.

The COVID-19 pandemic provided a unique opportunity to examine the contributions of social interaction and other non-social factors to loneliness among older adults in the context of confinement measures constraining opportunities for in-person social interactions. This study aims to identify groups of individuals with heterogeneous trajectories of loneliness during the COVID-19 pandemic and to explore the sociodemographic, health, psychological and social interaction-related factors associated with these trajectories. In this 12-month longitudinal study, 614 community-dwelling individuals aged 60+ years completed telephone-based interviews on four occasions between May 2020 and May 2021. Loneliness was evaluated using the three-item version of the UCLA Loneliness Scale. Multilevel modelling assessed average changes in loneliness over time. Group-based trajectory modelling was performed to identify distinct trajectories of loneliness over time. Multinomial logistic regressions were conducted to explore the predictors of these trajectories. On average, there was a curvilinear change in loneliness that tracked the stringency of the COVID-19-related confinement measures. In this convenience sample, three heterogeneous trajectories were identified: a stable-low (17.2%), a fluctuating-moderate (48.8%) and a sustained-elevated (34.0%) trajectory. Participants in the sustained-elevated loneliness trajectory were more likely to live alone and experience elevated psychological distress and greater COVID-19 perceived health threat compared to those in the stable-low trajectory. Participants in the fluctuating-moderate loneliness group were more likely to have multimorbidity, experience greater psychological distress, and have less frequent in-person interactions than the stable-low loneliness group. Assessing the combination of sociodemographic, health, psychological and social factors may help identify individuals at higher risk for chronic loneliness.

The Experience of Parents of Children With Genetically Determined Leukoencephalopathies With the Health Care System: A Qualitative Study.

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. We sought to gain a better understanding of their experience with the public health care system in Quebec, Canada, to obtain suggestions for improving their services, and to identify modifiable factors to improve their quality of life. We conducted interviews with 13 parents. Data was analyzed thematically. Five themes were identified: challenges of the diagnostic odyssey, limited access to services, excessive parental responsibilities, positive relationships with health care professionals as a facilitator of care, and benefits of a specialized leukodystrophy clinic. Parents felt like waiting for the diagnosis was extremely stressful, and they expressed their need for transparency during this period. They identified multiple gaps and barriers in the health care system, which burdened them with many responsibilities. Parents emphasized the importance of a positive relationship with their child's health care professionals. They also felt grateful for being followed at a specialized clinic as it improved the quality of care received.

Trajectories of psychological distress during the COVID-19 pandemic among community-dwelling older adults in Quebec: A longitudinal study.

OBJECTIVE: The COVID-19 pandemic and its associated public health measures may increase the risk for psychological distress among vulnerable older adults. This longitudinal study aimed to identify predictors of psychological distress trajectories among community-dwelling older adults in Quebec, Canada. METHODS: The study spanned four time points across 13 months and three waves of the COVID-19 pandemic. The sample included 645 community-dwelling older adults ages 60 years and older in Quebec. Participants completed telephone-based interviews that included the Kessler 6-item Psychological Distress Scale (K6) to assess psychological distress at each time point as well as information on socioeconomic, medical, psychological and COVID-19 related factors. Group-based trajectory modelling was used to identify distinct trajectories of psychological distress across time. RESULTS: Three group-based trajectories of psychological distress were identified: the resilient (50.5%), reactive (34.9%), and elevated distress groups (14.6%). Individuals with mobility issues, insomnia symptoms, COVID-19 related acute stress, general health anxiety, increased loneliness symptoms, and those unable to use technology to see others were more likely to be in the reactive and elevated groups than the resilient group. Those with past mental health problems had uniquely increased odds of being in the reactive group compared to the resilient group. Individuals living in poverty and those who reported taking psychotropic medication had increased odds of being in the elevated distress group compared to the resilient group. CONCLUSION: These findings characterized distinct trajectories of psychological distress in older adults and identified risk factors for elevated distress levels.

Experience of Parents of Children with Genetically Determined Leukoencephalopathies Regarding the Adapted Health Care Services During the COVID-19 Pandemic.

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. Because of the COVID-19 pandemic, many health care services were suspended, delayed or delivered remotely with telemedicine. We sought to explore the experience of parents of children with genetically determined leukoencephalopathies during the pandemic given the adapted health care services. We conducted semistructured interviews with 13 parents of 13 affected children. Three main themes were identified using thematic analysis: perceived impact of COVID-19 on health care services, benefits and challenges of telemedicine, and expectations of health care after the pandemic. Parents perceived a loss/delay in health care services while having a positive response to telemedicine. Parents wished telemedicine would remain in their care after the pandemic. This is the first study assessing the impact of COVID-19 on health care services in this population. Our results suggest that parents experience a higher level of stress owing to the shortage of services and the children's vulnerability.

Chronic hM3Dq signaling in microglia ameliorates neuroinflammation in male mice.

Microglia express muscarinic G protein-coupled receptors (GPCRs) that sense cholinergic activity and are activated by acetylcholine to potentially regulate microglial functions. Knowledge about how distinct types of muscarinic GPCR signaling regulate microglia function in vivo is still poor, partly due to the fact that some of these receptors are also present in astrocytes and neurons. We generated mice expressing the hM3Dq Designer Receptor Exclusively Activated by Designer Drugs (DREADD) selectively in microglia to investigate the role of muscarinic M3Gq-linked signaling. We show that activation of hM3Dq using clozapine N-oxide (CNO) elevated intracellular calcium levels and increased phagocytosis of FluoSpheres by microglia in vitro. Interestingly, whereas acute treatment with CNO increased synthesis of cytokine mRNA, chronic treatment attenuated LPS-induced cytokine mRNA changes in the brain. No effect of CNO on cytokine expression was observed in DREADD-negative mice. Interestingly, CNO activation of M3Dq in microglia was able to attenuate LPS-mediated decrease in social interactions. These results suggest that chronic activation of M3 muscarinic receptors (the hM3Dq progenitor) in microglia, and potentially other Gq-coupled GPCRs, can trigger an inflammatory-like response that preconditions microglia to decrease their response to further immunological challenges. Our results indicate that hM3Dq can be a useful tool to modulate neuroinflammation and study microglial immunological memory in vivo, which may be applicable for manipulations of neuroinflammation in neurodegenerative and psychiatric diseases.

Neuronal hypertrophy dampens neuronal intrinsic excitability and stress responsiveness during chronic stress.

KEY POINTS: The hypothalamic-pituitary-adrenal (HPA) axis habituates to repeated stress exposure. We studied hypothalamic corticotropin-releasing hormone (CRH) neurons that form the apex of the HPA axis in a mouse model of stress habituation using repeated restraint. The intrinsic excitability of CRH neurons decreased after repeated stress in a time course that coincided with the development of HPA axis habituation. This intrinsic excitability plasticity co-developed with an expansion of surface membrane area, which increased a passive electric load and dampened membrane depolarization in response to the influx of positive charge. We report a novel structure-function relationship for intrinsic excitability plasticity as a neural correlate for HPA axis habituation. ABSTRACT: Encountering a stressor immediately activates the hypothalamic-pituitary-adrenal (HPA) axis, but this stereotypic stress response also undergoes experience-dependent adaptation. Despite the biological and clinical importance, how the brain adjusts stress responsiveness in the long term remains poorly understood. We studied hypothalamic corticotropin-releasing hormone neurons that form the apex of the HPA axis in a mouse model of stress habituation using repeated restraint. Using patch-clamp electrophysiology in acute slices, we found that the intrinsic excitability of these neurons substantially decreased after daily repeated stress in a time course that coincided with their loss of stress responsiveness in vivo. This intrinsic excitability plasticity co-developed with an expansion of surface membrane area, which increased a passive electric load, and dampened membrane depolarization in response to the influx of positive charge. Multiphoton imaging and electron microscopy revealed that repeated stress augmented ruffling of the plasma membrane, suggesting an ultrastructural plasticity that may efficiently accommodate the membrane area expansion. Overall, we report a novel structure-function relationship for intrinsic excitability plasticity as a neural correlate for adaptation of the neuroendocrine stress response.

Selective decrease of cholinergic signaling from pedunculopontine and laterodorsal tegmental nuclei has little impact on cognition but markedly increases susceptibility to stress.

The pedunculopontine tegmental nucleus (PPT) and laterodorsal tegmental nucleus (LDT) are heterogeneous brainstem structures that contain cholinergic, glutamatergic, and GABAergic neurons. PPT/LDT neurons are suggested to modulate both cognitive and noncognitive functions, yet the extent to which acetylcholine (ACh) signaling from the PPT/LDT is necessary for normal behavior remains uncertain. We addressed this issue by using a mouse model in which PPT/LDT cholinergic signaling is highly decreased by selective deletion of the vesicular ACh transporter (VAChT) gene. This approach interferes exclusively with ACh signaling, leaving signaling by other neurotransmitters from PPT/LDT cholinergic neurons intact and sparing other cells. VAChT mutants were examined on different PPT/LDT-associated cognitive domains. Interestingly, VAChT mutants showed no attentional deficits and only minor cognitive flexibility impairments while presenting large deficiencies in both spatial and cued Morris water maze (MWM) tasks. Conversely, working spatial memory determined with the Y-maze and spatial memory measured with the Barnes maze were not affected, suggesting that deficits in MWM were unrelated to spatial memory abnormalities. Supporting this interpretation, VAChT mutants exhibited alterations in anxiety-like behavior and increased corticosterone levels after exposure to the MWM, suggesting altered stress response. Thus, PPT/LDT VAChT-mutant mice present little cognitive impairment per se, yet they exhibit increased susceptibility to stress, which may lead to performance deficits in more stressful conditions.-Janickova, H., Kljakic, O., Rosborough, K., Raulic, S., Matovic, S., Gros, R., Saksida, L. M., Bussey, T. J., Inoue, W., Prado, V. F., Prado, M. A. M. Selective decrease of cholinergic signaling from pedunculopontine and laterodorsal tegmental nuclei has little impact on cognition but markedly increases susceptibility to stress.

Chronic stress dampens excitatory synaptic gain in the paraventricular nucleus of the hypothalamus.

KEY POINTS: Glutamatergic synaptic inputs to corticotrophin-releasing hormone (CRH) secreting neurons in the paraventricular nucleus of the hypothalamus (PVN) are required for stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. These synapses also undergo stress-induced plasticity, thereby influencing HPA axis stress adaptation. By using patch clamp electrophysiology, we show that, in adult non-stressed mice, action potentials at these glutamatergic afferents elicit multiquantal transmission to the postsynaptic PVN-CRH neurons (i.e. synaptic multiplicity). Mechanistically, synaptic multiplicity results from multivesicular release at common synaptic sites, which is facilitated upon elevation of release probability, effectively increasing the upper limit of the dynamic range of synaptic transmission. Following chronic variable stress, functional PVN glutamate synapse number increases, although its synaptic multiplicity paradoxically decreases. These two contrasting synaptic changes can, respectively, increase the baseline excitatory drive while also limiting the capacity for potentiation, and may preferentially increase the baseline excitatory drive onto PVN-CRH neurons. ABSTRACT: The activation of the hypothalamic-pituitary-adrenal (HPA) axis relies on excitation of neuroendocrine neurons in the paraventricular nucleus of the hypothalamus (PVN) that secrete corticotrophin-releasing hormone (CRH). Afferent glutamate synapses onto these PVN-CRH neurons convey critical excitatory inputs during stress, and also undergo stress-induced plasticity, highlighting their roles in both stress activation and adaptation of the HPA axis. In the present study, using whole-cell patch clamp recordings from PVN-CRH neurons in brain slices from adult mice, we found that the amplitude of action potential-dependent spontaneous EPSCs (sEPSCs) was larger than that of action potential independent miniature EPSCs (mEPSCs), suggesting that action potentials at individual axons recruited multiquantal transmission onto the same postsynaptic neurons (i.e. synaptic multiplicity). The large, putative multiquantal sEPSCs had fast rise times similar to mEPSCs, and were abolished by replacing extracellular Ca2+ with Sr2+ , indicating Ca2+ -dependent synchronous release of multiple vesicles. Application of a low affinity, fast dissociating competitive AMPA receptor antagonist γ-d-glutamylglycine revealed that synaptic multiplicity resulted from multivesicular release targeting a common population of postsynaptic receptors. High-frequency afferent stimulation facilitated synaptic multiplicity, effectively increasing the upper limit of the dynamic range of synaptic transmission. Finally, we found that chronic variable stress (CVS), a stress model known to cause basal HPA axis hyperactivity, increased sEPSCs frequency but paradoxically decreased synaptic multiplicity. These results suggest that the CVS-induced synaptic changes may elevate the baseline excitatory drive at the same time as limiting the capacity for potentiation, and may contribute to the basal HPA axis hyperactivity.