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Selective increases in inter-individual variability in response to environmental enrichment in female mice.

ABSTRACT: One manifestation of individualization is a progressively differential response of individuals to the non-shared components of the same environment. Individualization has practical implications in the clinical setting, where subtle differences between patients are often decisive for the success of an intervention, yet there has been no suitable animal model to study its underlying biological mechanisms. Here we show that enriched environment (ENR) can serve as a model of brain individualization. We kept 40 isogenic female C57BL/6JRj mice for 3 months in ENR and compared these mice to an equally sized group of standard-housed control animals, looking at the effects on a wide range of phenotypes in terms of both means and variances. Although ENR influenced multiple parameters and restructured correlation patterns between them, it only increased differences among individuals in traits related to brain and behavior (adult hippocampal neurogenesis, motor cortex thickness, open field and object exploration), in agreement with the hypothesis of a specific activity-dependent development of brain individuality.

SUBMITTER: Korholz JC

PROVIDER: S-EPMC6203437 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Selective increases in inter-individual variability in response to environmental enrichment in female mice.

Körholz Julia C JC Zocher Sara S Grzyb Anna N AN Morisse Benjamin B Poetzsch Alexandra A Ehret Fanny F Schmied Christopher C Kempermann Gerd G

eLife 20181026

One manifestation of individualization is a progressively differential response of individuals to the non-shared components of the same environment. Individualization has practical implications in the clinical setting, where subtle differences between patients are often decisive for the success of an intervention, yet there has been no suitable animal model to study its underlying biological mechanisms. Here we show that enriched environment (ENR) can serve as a model of brain individualization. ...[more]

PMID: 30362941

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Project description:Endogenous glucocorticoids have diverse physiological effects and are important regulators of metabolism, immunity, cardiovascular function, musculoskeletal health and central nervous system activity. Synthetic glucocorticoids have received widespread attention for their potent anti-inflammatory activity and have become an important class of drugs used to augment endogenous glucocorticoid activity for the treatment of a host of chronic inflammatory conditions. Chronic use of synthetic glucocorticoids is associated with a number of adverse effects as a result of the persistent dysregulation of glucocorticoid sensitive pathways. A failure to consider the pronounced circadian rhythmicity of endogenous glucocorticoids can result in either supraphysiological glucocorticoid exposure or severe suppression of endogenous glucocorticoid secretion, and is thought be a causal factor in the incidence of adverse effects during chronic glucocorticoid therapy. Furthermore, given that synthetic glucocorticoids have potent feedback effects on the hypothalamic-pituitary-adrenal (HPA) axis, physiological factors which can give rise to individual variability in HPA axis activity such as sex, age, and disease state might also have substantial implications for therapy. We use a semi-mechanistic mathematical model of the rodent HPA axis to study how putative sex differences and individual variability in HPA axis regulation can influence the effects of long-term synthetic exposure on endogenous glucocorticoid circadian rhythms. Model simulations suggest that for the same drug exposure, simulated females exhibit less endogenous suppression than males considering differences in adrenal sensitivity and negative feedback to the hypothalamus and pituitary. Simulations reveal that homeostatic regulatory variability and chronic stress-induced regulatory adaptations in the HPA axis network can result in substantial differences in the effects of synthetic exposure on the circadian rhythm of endogenous glucocorticoids. In general, our results provide insight into how the dosage and exposure profile of synthetic glucocorticoids could be manipulated in a personalized manner to preserve the circadian dynamics of endogenous glucocorticoids during chronic therapy, thus potentially minimizing the incidence of adverse effects associated with long-term use of glucocorticoids.

Project description:The manner in which laboratory rodents are housed is driven by economics (minimal use of space and resources), ergonomics (ease of handling and visibility of animals), hygiene, and standardization (reduction of variation). This has resulted in housing conditions that lack sensory and motor stimulation and restrict the expression of species-typical behavior. In mice, such housing conditions have been associated with indicators of impaired welfare, including abnormal repetitive behavior (stereotypies, compulsive behavior), enhanced anxiety and stress reactivity, and thermal stress. However, due to concerns that more complex environmental conditions might increase variation in experimental results, there has been considerable resistance to the implementation of environmental enrichment beyond the provision of nesting material. Here, using 96 C57BL/6 and SWISS female mice, respectively, we systematically varied environmental enrichment across four levels spanning the range of common enrichment strategies: (1) bedding alone; (2) bedding + nesting material; (3) deeper bedding + nesting material + shelter + increased vertical space; and (4) semi-naturalistic conditions, including weekly changes of enrichment items. We studied how these different forms of environmental enrichment affected measures of animal welfare, including home-cage behavior (time-budget and stereotypic behavior), anxiety (open field behavior, elevated plus-maze behavior), growth (food and water intake, body mass), stress physiology (glucocorticoid metabolites in fecal boluses and adrenal mass), brain function (recurrent perseveration in a two-choice guessing task) and emotional valence (judgment bias). Our results highlight the difficulty in making general recommendations across common strains of mice and for selecting enrichment strategies within specific strains. Overall, the greatest benefit was observed in animals housed with the greatest degree of enrichment. Thus, in the super-enriched housing condition, stereotypic behavior, behavioral measures of anxiety, growth and stress physiology varied in a manner consistent with improved animal welfare compared to the other housing conditions with less enrichment. Similar to other studies, we found no evidence, in the measures assessed here, that environmental enrichment increased variation in experimental results.

Project description:BackgroundExercise protocols applied during hospitalization can prevent functional and cognitive decline in older adults. The purpose of this study was to examine the individual response of acutely hospitalized patients to usual care and to physical exercise on functional capacity, muscle strength, and cognitive function and to assess the relationship with mortality at 1 year post-discharge.MethodsIn a single-blind randomized clinical trial, 370 hospitalized patients [56.5% women; mean age (standard deviation) 87.3 (4.9) years] were allocated to an exercise intervention group (IG, n = 185) or a control group (CG, n = 185). The participants were older adults aged 75 years or older in an acute care unit in a tertiary public hospital in Navarra, Spain. The usual care group received habitual hospital care, which included physical rehabilitation when needed. The in-hospital intervention included individualized multicomponent exercise training programme performed during 5-7 consecutive days (two sessions/day). Functional capacity was assessed with the Short Physical Performance Battery (SPPB) test and the Gait Velocity Test (GVT). Handgrip strength and cognitive function were also measured at admission and discharge. Patients in both groups were categorized as responders (Rs), non-responders (NRs), and adverse responders (ARs) based on the individual response to each treatment during hospitalization.ResultsThe prevalence of Rs was higher and the prevalence of NRs and ARs was lower in the intervention group than in the control group for functional capacity (SPPB IG: Rs 85.3%, NRs 8.7%, ARs 6.0% vs. CG: Rs 37.9%, NRs 28.8%, ARs 33.3% and GVT IG: Rs 51.2%, NRs 47.3, ARs 1.6% vs. CG: Rs 18.0%, NRs 67.7%, ARs 14.3%), muscle strength (IG: Rs 62.3%, NRs 26.5%, ARs 11.3% vs. CG: Rs 20.0%, NRs 38.0%, ARs 42.0%), and cognition (IG: Rs 41.5%, NRs 57.1%, ARs 1.4% vs. CG: Rs 13.8%, NRs 76.6%, ARs 9.7%) (all P < 0.001). The ARs for the GVT in the control group and the ARs for the SPPB in the intervention group had a significantly higher rate of mortality than the NRs and Rs in the equivalent groups (0.01 and 0.03, respectively) at follow-up.ConclusionsOlder patients performing an individualized exercise intervention presented higher prevalence of Rs and a lower prevalence of NRs and ARs for functional capacity, muscle strength, and cognitive function than those who were treated with usual care during acute hospitalization. An adverse response on functional capacity in older patients to physical exercise or usual care during hospitalization was associated with mortality at 1 year post-discharge.

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Selective increases in inter-individual variability in response to environmental enrichment in female mice.

Publications

Selective increases in inter-individual variability in response to environmental enrichment in female mice.

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