Understanding grief in a time of COVID-19 - a hypothetical approach to challenges and support

This article develops preliminary understandings of loss and grief at both an individual and collective level following the COVID-19 outbreak. By examining relevant media and academic discourses, the authors analyse and envisage challenges and support for those experiencing loss during COVID-19. The discussion revisits and further relocates the ideas of good and bad deaths in the context of increased social constrains and inequalities. Further, two pairs of contrasting hypotheses are proposed to examine the impacts of COVID-19 on both bereaved individuals and society as a whole during and post the outbreak. The discussion captures a mixed picture of grief and bereavement, which highlights the importance of timely, holistic and continuous support. It is found that individual and collectives express diverse needs to respond to deaths and losses as a process of meaning-making. Further the significance of socio-cultural environments also become evident. These findings highlight community support during COVID-19 and further promote a grief literate culture as imperative to support individual and collective needs when confronted with loss and grief. This article provides timely and comprehensive accounts of possible challenges and support both for individual and collective experiences of loss and grief. These understandings could facilitate further research, informing better practice and policy decisions to support the bereaved in the context of COVID-19 and other disruptive world events

Savings and extinction of conditioned eyeblink responses in fragile X syndrome

The fragile X syndrome (FRAXA) is the most widespread heritable form of mental retardation caused by the lack of expression of the fragile X mental retardation protein (FMRP). This lack has been related to deficits in cerebellum-mediated acquisition of conditioned eyelid responses in individuals with FRAXA. In the present behavioral study, long-term effects of deficiency of FMRP were investigated by examining the acquisition, savings and extinction of delay eyeblink conditioning in male individuals with FRAXA. In the acquisition experiment, subjects with FRAXA displayed a significantly poor performance compared with controls. In the savings experiment performed at least 6 months later, subjects with FRAXA and controls showed similar levels of savings of conditioned responses. Subsequently, extinction was faster in subjects with FRAXA than in controls. These findings confirm that absence of the FMRP affects cerebellar motor learning. The normal performance in the savings experiment and aberrant performance in the acquisition and extinction experiments of individuals with FRAXA suggest that different mechanisms underlie acquisition, savings and extinction of cerebellar motor learning

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS), caused by silencing of the Fmr1 gene, is the most common form of inherited mental retardation. Epilepsy is reported to occur in 20–25% of individuals with FXS. However, no overall increased excitability has been reported in Fmr1 knockout (KO) mice, except for increased sensitivity to auditory stimulation. Here, we report that kindling increased the expressions of Fmr1 mRNA and protein in the forebrain of wild-type (WT) mice. Kindling development was dramatically accelerated in Fmr1 KO mice, and Fmr1 KO mice also displayed prolonged electrographic seizures during kindling and more severe mossy fiber sprouting after kindling. The accelerated rate of kindling was partially repressed by inhibiting N-methyl-D-aspartic acid receptor (NMDAR) with MK-801 or mGluR5 receptor with 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The rate of kindling development in WT was not effected by MPEP, however, suggesting that FMRP normally suppresses epileptogenic signaling downstream of metabolic glutamate receptors. Our findings reveal that FMRP plays a critical role in suppressing limbic epileptogenesis and predict that the enhanced susceptibility of patients with FXS to epilepsy is a direct consequence of the loss of an important homeostatic factor that mitigates vulnerability to excessive neuronal excitation

FMRP Mediates mGluR(5)-Dependent Translation of Amyloid Precursor Protein

Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Aβ) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding protein whose expression is lost in fragile X syndrome. Here we show that FMRP binds to the coding region of APP mRNA at a guanine-rich, G-quartet–like sequence. Stimulation of cortical synaptoneurosomes or primary neuronal cells with the metabotropic glutamate receptor agonist DHPG increased APP translation in wild-type but not fmr-1 knockout samples. APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment. Soluble Aβ(40) or Aβ(42) levels were significantly higher in multiple strains of fmr-1 knockout mice compared to wild-type controls. Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome

Synapses on demand require dendrites at the ready: How defining stages of dendritic development in vitro could inform studies of behaviorally driven information storage in the brain

Bill Greenough's work provides a framework for thinking about synaptogenesis not only as a key step in the initial wiring of neural systems according to a species typical plan (i.e., experience‐expectant development), but also as a mechanism for storing information based an individual's unique experience over its lifetime (i.e., experience‐dependent plasticity). Analysis of synaptic development in vitro brings a new opportunity to test the limits of expectant‐expectant development at the level of the individual neuron. We analyzed dendritic growth, synapse formation, and the development of specialized cytoplasmic microdomains during development in cultured hippocampal neurons, to determine if the timing of each of these events is correlated. Taken together, the findings reported here support the hypotheses that (1) dendritic development is rate limiting in synapse formation and (2) synaptic circuits are assembled in a step‐wise fashion consistent with a stage‐specific shift from genomically pre‐programmed to activity‐dependent mechanisms. © 2011 Wiley Periodicals, Inc. Dev Psychobiol 53:443–455, 2011.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86892/1/20560_ftp.pd

A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome

Intelligence testing in children with intellectual disabilities (ID) has significant limitations. The normative samples of widely used intelligence tests, such as the Wechsler Intelligence Scales, rarely include an adequate number of subjects with ID needed to provide sensitive measurement in the very low ability range, and they are highly subject to floor effects. The IQ measurement problems in these children prevent characterization of strengths and weaknesses, poorer estimates of cognitive abilities in research applications, and in clinical settings, limited utility for assessment, prognosis estimation, and planning intervention. Here, we examined the sensitivity of the Wechsler Intelligence Scale for Children (WISC-III) in a large sample of children with fragile X syndrome (FXS), the most common cause of inherited ID. The WISC-III was administered to 217 children with FXS (age 6–17 years, 83 girls and 134 boys). Using raw norms data obtained with permission from the Psychological Corporation, we calculated normalized scores representing each participant’s actual deviation from the standardization sample using a z-score transformation. To validate this approach, we compared correlations between the new normalized scores versus the usual standard scores with a measure of adaptive behavior (Vineland Adaptive Behavior Scales) and with a genetic measure specific to FXS (FMR1 protein or FMRP). The distribution of WISC-III standard scores showed significant skewing with floor effects in a high proportion of participants, especially males (64.9%–94.0% across subtests). With the z-score normalization, the flooring problems were eliminated and scores were normally distributed. Furthermore, we found correlations between cognitive performance and adaptive behavior, and between cognition and FMRP that were very much improved when using these normalized scores in contrast to the usual standardized scores. The results of this study show that meaningful variation in intellectual ability in children with FXS, and probably other populations of children with neurodevelopmental disorders, is obscured by the usual translation of raw scores into standardized scores. A method of raw score transformation may improve the characterization of cognitive functioning in ID populations, especially for research applications

NPTX2 and cognitive dysfunction in Alzheimer’s Disease

This is the final version of the article. Available from eLife Sciences Publications via the DOI in this record.Memory loss in Alzheimer’s disease (AD) is attributed to pervasive weakening and loss of synapses. Here, we present findings supporting a special role for excitatory synapses connecting pyramidal neurons of the hippocampus and cortex with fast-spiking parvalbumin (PV) interneurons that control network excitability and rhythmicity. Excitatory synapses on PV interneurons are dependent on the AMPA receptor subunit GluA4, which is regulated by presynaptic expression of the synaptogenic immediate early gene NPTX2 by pyramidal neurons. In a mouse model of AD amyloidosis, Nptx2-/- results in reduced GluA4 expression, disrupted rhythmicity, and increased pyramidal neuron excitability. Postmortem human AD cortex shows profound reductions of NPTX2 and coordinate reductions of GluA4. NPTX2 in human CSF is reduced in subjects with AD and shows robust correlations with cognitive performance and hippocampal volume. These findings implicate failure of adaptive control of pyramidal neuron-PV circuits as a pathophysiological mechanism contributing to cognitive failure in AD.DNA.This study was supported by NIMH MH100024 (PFW), (R35 NS-097966) (PFW), P50 AG005146-27 (PFW, JCT), Down Syndrome Research and Treatment Foundation and Research Down Syndrome (MX and RR), NIA AG05131 (DS, SE, DG), Alzheimer’s Disease Drug Discovery Foundation (DX, DG) and in part by the Intramural Research Program, National Institute on Aging, and National Institutes on Child Health and Development, NIH