Highlights • Adult neurogenesis is regulated by the social environment in a species dependent manner. • Context mediates how social manipulations up- or down-regulate neurogenesis. • Adult generated ...neurons in various brain regions contribute to social processing.
Home-based walking exercise interventions are recommended for people with peripheral artery disease (PAD), but evidence of their efficacy has been mixed.
To investigate the effect of a home-based, ...walking exercise behavior change intervention delivered by physical therapists in adults with PAD and intermittent claudication compared with usual care.
Multicenter randomized clinical trial including 190 adults with PAD and intermittent claudication in 6 hospitals in the United Kingdom between January 2018 and March 2020; final follow-up was September 8, 2020.
Participants were randomized to receive a walking exercise behavior change intervention delivered by physical therapists trained to use a motivational approach (n = 95) or usual care (n = 95).
The primary outcome was 6-minute walking distance at 3-month follow-up (minimal clinically important difference, 8-20 m). There were 8 secondary outcomes, 3 of which were the Walking Estimated Limitation Calculated by History (WELCH) questionnaire (score range, 0 best performance to 100), the Brief Illness Perceptions Questionnaire (score range, 0 to 80 80 indicates negative perception of illness), and the Theory of Planned Behavior Questionnaire (score range, 3 to 21 21 indicates best attitude, subjective norms, perceived behavioral control, or intentions); a minimal clinically important difference was not defined for these instruments.
Among 190 randomized participants (mean age 68 years, 30% women, 79% White race, mean baseline 6-minute walking distance, 361.0 m), 148 (78%) completed 3-month follow-up. The 6-minute walking distance changed from 352.9 m at baseline to 380.6 m at 3 months in the intervention group and from 369.8 m to 372.1 m in the usual care group (adjusted mean between-group difference, 16.7 m 95% CI, 4.2 m to 29.2 m; P = .009). Of the 8 secondary outcomes, 5 were not statistically significant. At 6-month follow-up, baseline WELCH scores changed from 18.0 to 27.8 in the intervention group and from 20.7 to 20.7 in the usual care group (adjusted mean between-group difference, 7.4 95% CI, 2.5 to 12.3; P = .003), scores on the Brief Illness Perceptions Questionnaire changed from 45.7 to 38.9 in the intervention group and from 44.0 to 45.8 in the usual care group (adjusted mean between-group difference, -6.6 95% CI, -9.9 to -3.4; P < .001), and scores on the attitude component of the Theory of Planned Behavior Questionnaire changed from 14.7 to 15.4 in the intervention group and from 14.6 to 13.9 in the usual care group (adjusted mean between-group difference, 1.4 95% CI, 0.3 to 2.5; P = .02). Thirteen serious adverse events occurred in the intervention group, compared with 3 in the usual care group. All were determined to be unrelated or unlikely to be related to the study.
Among adults with PAD and intermittent claudication, a home-based, walking exercise behavior change intervention, compared with usual care, resulted in improved walking distance at 3 months. Further research is needed to determine the durability of these findings.
ISRCTN Identifier: 14501418; ClinicalTrials.gov Identifier: NCT03238222.
•Social relationships can cause or ameliorate stress.•Studies using group housing paradigms permit study of complex social interaction dynamics.•Studies in diverse rodents illustrate species-specific ...and conserved relationships between stress and sociality.•We examine these relationships in group-housed mice and rats, prairie and meadow voles, and mole-rats.•Consideration of natural ecology of organisms sheds light on species-specific behaviors.
A major feature of life in groups is that individuals experience social stressors of varying intensity and type. Social stress can have profound effects on health, social behavior, and ongoing relationships. Relationships can also buffer the experience of exogenous stressors. Social stress has most commonly been investigated in dyadic contexts in mice and rats that produce intense stress. Here we review findings from studies of diverse rodents and non-traditional group housing paradigms, focusing on laboratory studies of mice and rats housed in visible burrow systems, prairie and meadow voles, and mole-rats. We argue that the use of methods informed by the natural ecology of rodent species provides novel insights into the relationship between social stress, behavior and physiology. In particular, we describe how this ethologically inspired approach reveals how individuals vary in their experience of and response to social stress, and how ecological and social contexts impact the effects of stress. Social stress induces adaptive changes, as well as long-term disruptive effects on behavior and physiology.
Transdifferentiation, the process of converting from one cell type to another without going through a pluripotent state, has great promise for regenerative medicine. The identification of key ...transcription factors for reprogramming is currently limited by the cost of exhaustive experimental testing of plausible sets of factors, an approach that is inefficient and unscalable. Here we present a predictive system (Mogrify) that combines gene expression data with regulatory network information to predict the reprogramming factors necessary to induce cell conversion. We have applied Mogrify to 173 human cell types and 134 tissues, defining an atlas of cellular reprogramming. Mogrify correctly predicts the transcription factors used in known transdifferentiations. Furthermore, we validated two new transdifferentiations predicted by Mogrify. We provide a practical and efficient mechanism for systematically implementing novel cell conversions, facilitating the generalization of reprogramming of human cells. Predictions are made available to help rapidly further the field of cell conversion.
Puberty is a key developmental milestone that marks an individual’s maturation in several ways including, but not limited to, reproductive maturation, changes in behaviors and neural organization. ...The timing at which puberty occurs is variable both within individuals of the same species and between species. These variations can be aligned with ecological cues that delay or suppress puberty. Naked mole-rats are colony-living rodents where reproduction is restricted to a few animals; all other animals are pubertally-suppressed. Animals removed from suppressive colony cues can reproductively mature, presenting the unique opportunity to study adult-onset puberty. Recently, we found that RFRP-3 administration sustains pubertal delay in naked mole-rats removed from colony. In this review, we explore what is known about regulators that control puberty onset, the role of stress/social status in pubertal timing, the status of knowledge of pubertal suppression in naked mole-rats and what comes next.
•Puberty onset is marked by the release of GnRH in the hypothalamus.•GnRH is modulated by several key neuropeptides (e.g. RFRP-3, KISS1, KNDy neurons).•Neuropeptides regulating GnRH interact with endo-/exogenous cues to alter pubertal timing.•Naked mole-rats remain pubertally-suppressed unless removed from the suppressive colony cues.•Naked mole-rats allow us to explore how social environment/stress control puberty.
Group living occurs across the animal kingdom and can shape fundamental aspects of individual biology, including the microbes inhabiting the animal gut. The naked mole-rat,
Heterocephalus glaber
, ...exhibits extreme cooperative breeding (eusociality) and presents an ideal opportunity to study the effects of social structure on the mammalian gut microbiota. Within colonies reproduction is limited to few animals, while the remaining members are non-reproductive, form linear dominance hierarchies, and show evidence of task specialization with stable yet plastic behavioral phenotypes. Here, we sequenced the gut bacteria of naked mole-rats across 6 replicate captive colonies and longitudinally during a colony removal experiment. Colony had much larger effects than social phenotype or status on the diversity and composition of gut bacteria. Our longitudinal experiment revealed that over the course of 2 months, the gut bacteria of previously unfamiliar, newly paired animals did not become more similar. In comparison to mice housed in the same facility, the naked mole-rat gut microbiome exhibited substantial compositional differences including the near absence of Lactobacillaceae and the enrichment of Prevotellaceae. Our study provides new insight into the factors shaping gut bacterial communities in social animals and indicates a prominent role of social group membership but not social phenotype.
Significance statement
The social groups to which animals belong can be strong determinants of the composition of their associated gut microbial communities (i.e., gut microbiome). However, less is known about the link between social status within animal groups and the gut microbiome. We studied this relationship in the naked mole-rat,
Heterocephalus glaber
, which exhibits extreme cooperative breeding (eusociality). Animals within naked mole-rat colonies show clear social hierarchies and evidence of social phenotypes. Across replicate colonies, we found that colony but not social phenotype or status had large effects on the diversity and composition of gut bacteria. During a colony removal experiment, the gut bacteria of newly paired but previously unfamiliar animals did not become more similar over the course of 2 months. Our results show that when decoupled from differences in diet or exposure to microbes, within colony social roles and their accompanying unique physiology and social experience may have little effect on gut microbiota. In contrast, gut bacterial diversity and composition was strongly shaped by colony membership despite being exposed to identical environmental conditions.
Somatic cell reprogramming into induced pluripotent stem cells (iPSCs) induces changes in genome architecture reflective of the embryonic stem cell (ESC) state. However, only a small minority of ...cells typically transition to pluripotency, which has limited our understanding of the process. Here, we characterize the DNA regulatory landscape during reprogramming by time-course profiling of isolated sub-populations of intermediates poised to become iPSCs. Widespread reconfiguration of chromatin states and transcription factor (TF) occupancy occurs early during reprogramming, and cells that fail to reprogram partially retain their original chromatin states. A second wave of reconfiguration occurs just prior to pluripotency acquisition, where a majority of early changes revert to the somatic cell state and many of the changes that define the pluripotent state become established. Our comprehensive characterization of reprogramming-associated molecular changes broadens our understanding of this process and sheds light on how TFs access and change the chromatin during cell-fate transitions.
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•Regulatory element accessibility during reprogramming reveals distinct dynamic phases•Oct4/Sox2 recruit somatic transcription factors to transiently accessible sites•Oct4/Sox2 preferentially bind to closed chromatin in MEFs•Profiling of cells that fail to reprogram reveals they maintain a MEF chromatin state
Knaupp and Buckberry et al. show that during reprogramming cells undergo major chromatin remodeling in three phases. Further, they find that Oct4 and Sox2 extensively target sites where the DNA is only accessible during the intermediate stages of reprogramming, which coincides with somatic transcription factor displacement and recruitment to those sites.
Naked mole-rats are a long-lived rodent species (current lifespan >37 years) and an increasingly popular biomedical model. Naked mole-rats exhibit neuroplasticity across their long lifespan. Previous ...studies have begun to investigate their neurogenic patterns. Here, we test the hypothesis that neuronal maturation is extended in this long-lived rodent. We characterize cell proliferation and neuronal maturation in established rodent neurogenic regions over 12 months following seven days of consecutive BrdU injection. Given that naked mole-rats are eusocial (high reproductive skew where only a few socially-dominant individuals reproduce), we also looked at proliferation in brain regions relevant to the social-decision making network. Finally, we measured co-expression of EdU (newly-born cells), DCX (immature neuron marker), and NeuN (mature neuron marker) to assess the timeline of neuronal maturation in adult naked mole-rats. This work reaffirms the subventricular zone as the main source of adult cell proliferation and suggests conservation of the rostral migratory stream in this species. Our profiling of socially-relevant brain regions suggests that future work which manipulates environmental context can unveil how newly-born cells integrate into circuitry and facilitate adult neuroplasticity. We also find naked mole-rat neuronal maturation sits at the intersection of rodents and long-lived, non-rodent species: while neurons can mature by 3 weeks (rodent-like), most neurons mature at 5 months and hippocampal neurogenic levels are low (like long-lived species). These data establish a timeline for future investigations of longevity- and socially-related manipulations of naked mole-rat adult neurogenesis.
The social environment can alter pubertal timing through neuroendocrine mechanisms that are not fully understood; it is thought that stress hormones (e.g., glucocorticoids or corticotropin-releasing ...hormone) influence the hypothalamic-pituitary-gonadal axis to inhibit puberty. Here, we use the eusocial naked mole-rat, a unique species in which social interactions in a colony (i.e. dominance of a breeding female) suppress puberty in subordinate animals. Removing subordinate naked mole-rats from this social context initiates puberty, allowing for experimental control of pubertal timing. The present study quantified gene expression for reproduction- and stress-relevant genes acting upstream of gonadotropin-releasing hormone in brain regions with reproductive and social functions in pre-pubertal, post-pubertal, and opposite sex-paired animals (which are in various stages of pubertal transition). Results indicate sex differences in patterns of neural gene expression. Known functions of genes in brain suggest stress as a key contributing factor in regulating male pubertal delay. Network analysis implicates neurokinin B (Tac3) in the arcuate nucleus of the hypothalamus as a key node in this pathway. Results also suggest an unappreciated role for the nucleus accumbens in regulating puberty.
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