Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons.

Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by the deposition of hyperphosphorylated tau in patient brains. However, the mechanisms leading to neurodegeneration remain largely unknown. Here, we combined single-cell analyses of FTD patient brains with a stem cell culture and transplantation model of FTD. We identified disease phenotypes in FTD neurons carrying the MAPT-N279K mutation, which were related to oxidative stress, oxidative phosphorylation, and neuroinflammation with an upregulation of the inflammation-associated protein osteopontin (OPN). Human FTD neurons survived less and elicited an increased microglial response after transplantation into the mouse forebrain, which we further characterized by single nucleus RNA sequencing of microdissected grafts. Notably, downregulation of OPN in engrafted FTD neurons resulted in improved engraftment and reduced microglial infiltration, indicating an immune-modulatory role of OPN in patient neurons, which may represent a potential therapeutic target in FTD.

Human Induced Pluripotent Stem Cell Models of Frontotemporal Dementia With Tau Pathology.

Neurodegenerative dementias are the most common group of neurodegenerative diseases affecting more than 40 million people worldwide. One of these diseases is frontotemporal dementia (FTD), an early onset dementia and one of the leading causes of dementia in people under the age of 60. FTD is a heterogeneous group of neurodegenerative disorders with pathological accumulation of particular proteins in neurons and glial cells including the microtubule-associated protein tau, which is deposited in its hyperphosphorylated form in about half of all patients with FTD. As for other patients with dementia, there is currently no cure for patients with FTD and thus several lines of research focus on the characterization of underlying pathogenic mechanisms with the goal to identify therapeutic targets. In this review, we provide an overview of reported disease phenotypes in induced pluripotent stem cell (iPSC)-derived neurons and glial cells from patients with tau-associated FTD with the aim to highlight recent progress in this fast-moving field of iPSC disease modeling. We put a particular focus on genetic forms of the disease that are linked to mutations in the gene encoding tau and summarize mutation-associated changes in FTD patient cells related to tau splicing and tau phosphorylation, microtubule function and cell metabolism as well as calcium homeostasis and cellular stress. In addition, we discuss challenges and limitations but also opportunities using differentiated patient-derived iPSCs for disease modeling and biomedical research on neurodegenerative diseases including FTD.

Cognitive-Behavioral and Emotion-Focused Couple Therapy: Similarities and Differences.

Background: Couples and families often seek therapy to deal with relational distress, which is a result of external or internal factors of the relationship. Two approaches are acknowledged to be most effective in dealing with relationship distress or psychological disorders in couples: (a) cognitive behavioral couple therapy with new directions (CBCT) and (b) emotion-focused couple therapy (EFCT). In this article we investigate how much CBCT and EFCT really differ with regard to working with emotions, which is claimed to be a major focus of EFCT, and whether there exist significant differences in efficacy between these two approaches. Method: This article critically reviews the theoretical background, process, techniques and outcomes associated with CBCT and EFCT in an effort to challenge the assumptions noted above. Results: There is no evidence that EFCT is more emotion-focused than CBCT. Both approaches were repeatedly examined with RCT studies with follow-ups. In sum, no significant differences in effect size were found between CBCT and EFCT. Conclusion: CBCT and EFCT are both effective in reducing couples' distress.

Dyadic Coping in Couples: A Conceptual Integration and a Review of the Empirical Literature.

The present review on dyadic coping (DC) aims at providing a critical integration of both the conceptual and empirical DC literature and overcoming the limitations of past reviews by (a) describing, comparing, and integrating all the DC models, (b) presenting and integrating findings from studies based on DC models, and (c) suggesting directions for further research. The DC models identified and compared include: The congruence model (Revenson, 1994), the relationship-focused model (Coyne and Smith, 1991; O'Brien and DeLongis, 1996), the communal coping model (Lyons et al., 1998), the systemic-transactional model (Bodenmann, 1995, 1997), the relational-cultural model (Kayser et al., 2007), and the developmental-contextual coping model (Berg and Upchurch, 2007). After discussing each DC model, we advance a conceptual integration of all models, which serves as the framework to organize the review of the empirical literature. This integration includes the following DC dimensions: (a) Stress Communication, (b) Positive DC by One Partner (supportive DC, empathic responding, delegated DC, active engagement), (c) Positive Conjoint DC (common, collaborative, communal, mutual responsiveness); (d) Negative DC by One Partner (protective buffering, overprotection, and hostility/ambivalence), and (e) Negative Conjoint DC (common negative DC, disengaged avoidance). Developmental, relational, and contextual variables are included as factors shaping DC. To be included in the empirical review, articles had to be published in or a peer-reviewed journal in English and/or German before 2017 and include an original empirical study guided by one of the DC models. The review included 139 studies and, with the exception of the congruence model whose findings were discussed separately, findings were presented for overall DC and each of the dimensions identified in the conceptual integration. Findings were grouped also according to whether the stressor related or not to a medical or mental health condition. Demographic and cultural factors affecting DC were discussed. Overall, the empirical review suggests that in Western couples, positive individual, and conjoint DC forms, taken together or separately, have individual and relational benefits for couples coping with stress in general and/or mental health or medical stressors. Research on DC can be expanded to include other populations and stressors and use improved designs.

The power of listening: Lending an ear to the partner during dyadic coping conversations.

Although active, responsive listening is widely assumed to be essential for well-functioning intimate relationships, the manner in which this important behavior might promote closeness remains unknown. To test the prediction that listening may be especially influential when partners disclose experiences of stress, we instructed 365 heterosexual couples to hold two 8-min conversations in which each partner discussed a stressful personal experience while the other partner was asked to respond as he or she ordinarily would. We coded expressions of stress and listening behavior at 10-s intervals during these conversations, applied actor-partner multilevel models to compute a variable capturing the covariation between one partner's stress expression and the other partner's listening behavior, and then used that variable in regression analyses to predict observed dyadic coping behaviors, self-reports of the quality of dyadic coping in general, and self-reports of relationship satisfaction. Attentive listening while the other partner expressed stress was significantly linked with better dyadic coping behaviors and higher relationship satisfaction. Partners displaying less attentive listening during the partner's stress expression also engaged in more problem-oriented coping and more negative dyadic coping. Because attentive listening during disclosure of stress covaries in expected ways with support provision and judgments of relationship quality, appreciating the context-specific effects of active listening merits careful consideration as an intervention target in couple therapy and in relationship education programs. (PsycINFO Database Record

Enhanced synaptic plasticity and spatial memory in female but not male FLRT2-haplodeficient mice.

The Fibronectin Leucine-Rich Transmembrane protein 2 (FLRT2) has been implicated in several hormone -and sex-dependent physiological and pathological processes (including chondrogenesis, menarche and breast cancer); is known to regulate developmental synapses formation, and is expressed in the hippocampus, a brain structure central for learning and memory. However, the role of FLRT2 in the adult hippocampus and its relevance in sex-dependent brain functions remains unknown. We here used adult single-allele FLRT2 knockout (FLRT2+/-) mice and behavioral, electrophysiological, and molecular/biological assays to examine the effects of FLRT2 haplodeficiency on synaptic plasticity and hippocampus-dependent learning and memory. Female and male FLRT2+/- mice presented morphological features (including body masses, brain shapes/weights, and brain macroscopic cytoarchitectonic organization), indistinguishable from their wild type counterparts. However, in vivo examinations unveiled enhanced hippocampus-dependent spatial memory recall in female FLRT2+/- animals, concomitant with augmented hippocampal synaptic plasticity and decreased levels of the glutamate transporter EAAT2 and beta estrogen receptors. In contrast, male FLRT2+/- animals exhibited deficient memory recall and decreased alpha estrogen receptor levels. These observations propose that FLRT2 can regulate memory functions in the adulthood in a sex-specific manner and might thus contribute to further research on the mechanisms linking sexual dimorphism and cognition.

Zooming in: A microanalysis of couples' dyadic coping conversations after experimentally induced stress.

Growing evidence that social support in times of stress is crucial for well-functioning relationships raises important questions about how intimate partners elicit specific forms of supportive behavior. To explore the process of support elicitation, we exposed either the male or female partner in a relationship to a standardized laboratory stressor (N = 127 couples), videotaped their subsequent reunion, and then coded those interactions at a microanalytic level to investigate links between expressions of stress and partner responses to those expressions. Multilevel analyses indicated that the type of stress expression served as a cue for the dyadic coping reaction of the partner. For example, problem-oriented stress expression within a 10-s interval of the conversation was strongly linked to problem-oriented dyadic coping in the same or following time sequence, while emotion-oriented stress expressions were associated with emotion-oriented dyadic coping reactions. These findings enhance the understanding of the link between different stress expressions and dyadic coping reactions and offer important implications for couple interventions. (PsycINFO Database Record