TCF7L2 regulates postmitotic differentiation programmes and excitability patterns in the thalamus.

Neuronal phenotypes are controlled by terminal selector transcription factors in invertebrates, but only a few examples of such regulators have been provided in vertebrates. We hypothesised that TCF7L2 regulates different stages of postmitotic differentiation in the thalamus, and functions as a thalamic terminal selector. To investigate this hypothesis, we used complete and conditional knockouts of Tcf7l2 in mice. The connectivity and clustering of neurons were disrupted in the thalamo-habenular region in Tcf7l2-/- embryos. The expression of subregional thalamic and habenular transcription factors was lost and region-specific cell migration and axon guidance genes were downregulated. In mice with a postnatal Tcf7l2 knockout, the induction of genes that confer thalamic terminal electrophysiological features was impaired. Many of these genes proved to be direct targets of TCF7L2. The role of TCF7L2 in terminal selection was functionally confirmed by impaired firing modes in thalamic neurons in the mutant mice. These data corroborate the existence of master regulators in the vertebrate brain that control stage-specific genetic programmes and regional subroutines, maintain regional transcriptional network during embryonic development, and induce terminal selection postnatally.

Association of muscular strength and targeted proteomics involved in brain health in children with overweight/obesity.

Muscular strength has been positively associated with better brain health indicators during childhood obesity. However, the molecular mechanisms underlying the positive impact of muscular strength in brain health are poorly understood. We aimed to study the association of muscular strength with neurology-related circulating proteins in plasma in children with overweight/obesity and to explore the role of cardiorespiratory fitness (CRF) as a confounder. The participants were 86 Caucasian children (10.1 ± 1.1 years old; 41% girls) from the ActiveBrains project. Muscular strength was measured by field and laboratory tests. CRF was assessed with an incremental treadmill test. Olink's technology was used to quantify 92 neurology-related proteins in plasma. Protein-protein interactions were computed using the STRING website. Muscular strength was positively associated with 12 proteins (BetaNGF, CDH6, CLEC10A, CLM1, FcRL2, HAGH, IL12, LAIR2, MSR1, SCARB2, SMOC2, and TNFRSF12A), and negatively associated with 12 proteins (CLEC1B, CTSC, CTSS, gal-8, GCP5, NAAA, NrCAM, NTRK2, PLXNB3, RSPO1, sFRP3, and THY1). After adjustment for CRF, muscular strength was positively associated with eight proteins (BetaNGF, CDH6, CLEC10A, FcRL2, LAIR2, MSR1, SCARB2, and TNFRSF12A) and negatively associated with two proteins (gal-8 and NrCAM). After applying FDR correction, only CLEC10A remained statistically significant. In conclusion, muscular strength was associated with blood circulating proteins involved in several biological processes, particularly anti-inflammatory response, lipid metabolism, beta amyloid clearance, and neuronal action potential propagation. More powered studies are warranted in pediatric populations to contrast or confirm our findings.

Applying trans-theoretical model for blood donation among Spanish adults: a cross-sectional study.

BACKGROUND: Relying solely on altruistic appeals may fail to fulfil the increasing demand for blood supplies. Current research has largely been attempted to determine and understand motives that serve as blood donation drivers. The Trans-Theoretical Model of behaviour change (TTM) can be used to conceptualise the process of intentional blood donation behaviour. METHODS: A cross sectional survey of Spanish adults was conducted. The final sample consisted of 504 individuals who were administered a self-report questionnaire including the measures of demographic characteristics, Stages of Change, Processes of Change, Self-efficacy and Decisional Balance. Data were analysed by frequency analysis, MANOVA/ANOVA and correlation analysis. RESULTS: Findings indicated that most of the behavioural and cognitive processes of change, self-efficacy and physical cons differentiated participants across the stages of change of blood donation. In contrast, eligibility cons and pros were less influential in stage transitions. Furthermore, significant correlations were observed between TTM constructs except for the physical cons and the processes of change. CONCLUSIONS: The present study extensively supports and replicates the applicability of the TTM to blood donation behaviour change and offers important implications for the development of effective stage-matched interventions to increase blood donation.

Associations between muscular strength and mental health in cognitively normal older adults: a cross-sectional study from the AGUEDA trial.

Objective: To examine the associations between muscular strength and mental health. Design: We used baseline data of 91 cognitively healthy older adults (71.69 ± 3.91 years old, 57 % women) participating in the AGUEDA randomized controlled trial. Methods: Muscular strength was assessed using both objective (i.e., handgrip strength, biceps curl, squats, and isokinetic test) and perceived (i.e., International Fitness Scale) indicators. Psychological ill-being indicators: anxiety, depression, stress, and loneliness; and psychological well-being indicators: satisfaction with life, self-esteem, and emotional well-being) were assessed using a set of valid and reliable self-reported questionnaires. Linear regression analyses were performed adjusting for sex, age, years of education, body mass index , alcohol, diet, and smoking (model 1), and additionally by cardiorespiratory fitness (model 2). Results: Elbow extension was positively associated with stress in model 1 (ß = 0.252, 95 % Confidence Interval [95 % CI] = 0.007 to 0.497, p = 0.044), and even after further adjustment for cardiorespiratory fitness (ß = 0.282, 95 % CI = 0.032 to 0.532, p = 0.028). Perceived strength was negatively associated with depressive symptoms in model 1 (ß = -0.271, 95 % CI = -0.491 to -0.049, p = 0.017) and model 2 reported associations tending towards significant (ß = -0.220, 95 % CI = -0.445 to 0.005, p = 0.055). Handgrip strength was positively associated with self-esteem in model 1 (ß = 0.558, 95 % CI = 0.168 to 0.949, p = 0.006) and model 2 (ß = 0.546, 95 % CI = 0.135 to 0.956, p = 0.010). No further associations were found among other muscular strength and mental health variables. Conclusion: Handgrip had a moderate association with self-esteem and there was a small association between perceived strength with depressive symptoms and elbow extension with stress. No other associations were observed between muscular strength and mental health outcomes in cognitively normal older adults.

Active Gains in brain Using Exercise During Aging (AGUEDA): protocol for a randomized controlled trial.

Alzheimer's disease is currently the leading cause of dementia and one of the most expensive, lethal and severe diseases worldwide. Age-related decline in executive function is widespread and plays a key role in subsequent dementia risk. Physical exercise has been proposed as one of the leading non-pharmaceutical approaches to improve executive function and ameliorate cognitive decline. This single-site, two-arm, single-blinded, randomized controlled trial (RCT) will include 90 cognitively normal older adults, aged 65-80 years old. Participants will be randomized to a 24-week resistance exercise program (3 sessions/week, 60 min/session, n = 45), or a wait-list control group (n = 45) which will be asked to maintain their usual lifestyle. All study outcomes will be assessed at baseline and at 24-weeks after the exercise program, with a subset of selected outcomes assessed at 12-weeks. The primary outcome will be indicated by the change in an executive function composite score assessed with a comprehensive neuropsychological battery and the National Institutes of Health Toolbox Cognition Battery. Secondary outcomes will include changes in brain structure and function and amyloid deposition, other cognitive outcomes, and changes in molecular biomarkers assessed in blood, saliva, and fecal samples, physical function, muscular strength, body composition, mental health, and psychosocial parameters. We expect that the resistance exercise program will have positive effects on executive function and related brain structure and function, and will help to understand the molecular, structural, functional, and psychosocial mechanisms involved.

Prosomeric Hypothalamic Distribution of Tyrosine Hydroxylase Positive Cells in Adolescent Rats.

Most of the studies on neurochemical mapping, connectivity, and physiology in the hypothalamic region were carried out in rats and under the columnar morphologic paradigm. According to the columnar model, the entire hypothalamic region lies ventrally within the diencephalon, which includes preoptic, anterior, tuberal, and mamillary anteroposterior regions, and sometimes identifying dorsal, intermediate, and ventral hypothalamic partitions. This model is weak in providing little or no experimentally corroborated causal explanation of such subdivisions. In contrast, the modern prosomeric model uses different axial assumptions based on the parallel courses of the brain floor, alar-basal boundary, and brain roof (all causally explained). This model also postulates that the hypothalamus and telencephalon jointly form the secondary prosencephalon, separately from and rostral to the diencephalon proper. The hypothalamus is divided into two neuromeric (transverse) parts called peduncular and terminal hypothalamus (PHy and THy). The classic anteroposterior (AP) divisions of the columnar hypothalamus are rather seen as dorsoventral subdivisions of the hypothalamic alar and basal plates. In this study, we offered a prosomeric immunohistochemical mapping in the rat of hypothalamic cells expressing tyrosine hydroxylase (TH), which is the enzyme that catalyzes the conversion of L-tyrosine to levodopa (L-DOPA) and a precursor of dopamine. This mapping was also combined with markers for diverse hypothalamic nuclei [agouti-related peptide (Agrp), arginine vasopressin (Avp), cocaine and amphetamine-regulated transcript (Cart), corticotropin releasing Hormone (Crh), melanin concentrating hormone (Mch), neuropeptide Y (Npy), oxytocin/neurophysin I (Oxt), proopiomelanocortin (Pomc), somatostatin (Sst), tyrosine hidroxilase (Th), and thyrotropin releasing hormone (Trh)]. TH-positive cells are particularly abundant within the periventricular stratum of the paraventricular and subparaventricular alar domains. In the tuberal region, most labeled cells are found in the acroterminal arcuate nucleus and in the terminal periventricular stratum. The dorsal retrotuberal region (PHy) contains the A13 cell group of TH-positive cells. In addition, some TH cells appear in the perimamillary and retromamillary regions. The prosomeric model proved useful for determining the precise location of TH-positive cells relative to possible origins of morphogenetic signals, thus aiding potential causal explanation of position-related specification of this hypothalamic cell type.

Dopaminergic Modulation of Forced Running Performance in Adolescent Rats: Role of Striatal D1 and Extra-striatal D2 Dopamine Receptors.

Improving exercise capacity during adolescence impacts positively on cognitive and motor functions. However, the neural mechanisms contributing to enhance physical performance during this sensitive period remain poorly understood. Such knowledge could help to optimize exercise programs and promote a healthy physical and cognitive development in youth athletes. The central dopamine system is of great interest because of its role in regulating motor behavior through the activation of D1 and D2 receptors. Thus, the aim of the present study is to determine whether D1 or D2 receptor signaling contributes to modulate the exercise capacity during adolescence and if this modulation takes place through the striatum. To test this, we used a rodent model of forced running wheel that we implemented recently to assess the exercise capacity. Briefly, rats were exposed to an 8-day period of habituation in the running wheel before assessing their locomotor performance in response to an incremental exercise test, in which the speed was gradually increased until exhaustion. We found that systemic administration of D1-like (SCH23390) and/or D2-like (raclopride) receptor antagonists prior to the incremental test reduced the duration of forced running in a dose-dependent manner. Similarly, locomotor activity in the open field was decreased by the dopamine antagonists. Interestingly, this was not the case following intrastriatal infusion of an effective dose of SCH23390, which decreased motor performance during the incremental test without disrupting the behavioral response in the open field. Surprisingly, intrastriatal delivery of raclopride failed to impact the duration of forced running. Altogether, these results indicate that the level of locomotor response to incremental loads of forced running in adolescent rats is dopamine dependent and mechanistically linked to the activation of striatal D1 and extra-striatal D2 receptors.

A Handful of Details to Ensure the Experimental Reproducibility on the FORCED Running Wheel in Rodents: A Systematic Review.

A well-documented method and experimental design are essential to ensure the reproducibility and reliability in animal research. Experimental studies using exercise programs in animal models have experienced an exponential increase in the last decades. Complete reporting of forced wheel and treadmill exercise protocols would help to ensure the reproducibility of training programs. However, forced exercise programs are characterized by a poorly detailed methodology. Also, current guidelines do not cover the minimum data that must be included in published works to reproduce training programs. For this reason, we have carried out a systematic review to determine the reproducibility of training programs and experimental designs of published research in rodents using a forced wheel system. Having determined that most of the studies were not detailed enough to be reproducible, we have suggested guidelines for animal research using FORCED exercise wheels, which could also be applicable to any form of forced exercise.

Intracranial pressure analysis software: A mapping study and proposal.

Introduction Intracranial pressure (ICP) monitoring and analysis are techniques that are, each year, applied to millions of patients with pathologies with million of patients annually. The detection of the so called A and B-waves, and the analysis of subtle changes in C-waves, which are present in ICP waveform, may indicate decreased intracranial compliance, and may improve the clinical outcome. Despite the advances in the field of computerized data analysis, the visual screening of ICP continues to be the means principally employed to detect these waves. To the best of our knowledge, no review study has addressed automated ICP analysis in sufficient detail and a need to research the state of the art of ICP analysis has, therefore, been identified. Methodology This paper presents a systematic mapping study to provide answers to 7 research questions: publication time, venue and source trends, medical tasks undertaken, research methods used, computational systems developed, validation methodology, tools and systems employed for evaluation and research problems identified. An ICP software prototype is presented and evaluated as a consequence of the results. Results A total of 23 papers, published between 1990 and 2020, were selected from 6 online databases. After analyzing these papers, the following information was obtained: diagnosis and monitoring medical tasks were addressed to the same extent, and the main research method used was evaluation research. Several computational systems were identified in the papers, the main one being image classification, while the main analysis objective was single pulse analysis. Correlation with expert analysis was the most frequent validation method, and few of the papers stated the use of a published dataset. Few authors referred to the tools used to build or evaluate the proposed solutions. The most frequent research problem was the need for new analysis methods. These results have inspired us to propose a software prototype with which provide an automated solution that integrates ICP analysis and monitoring techniques. Conclusions The papers in this study were selected and classified with regard to ICP automated analysis methods. Several research gaps were identified, which the authors of this study have employed as a based on which to recommend future work. Furthermore, this study has identified the need for an empirical comparison between methods, which will require the use and development of certain standard metrics. An in-depth analysis conducted by means of systematic literature review is also required. The software prototype evaluation provided positive results, showing that the prototype may be a reliable system for A-wave detection.

Hypothalamic Crh/Avp, Plasmatic Glucose and Lactate Remain Unchanged During Habituation to Forced Exercise.

It has been demonstrated that physical activity contributes to a healthier life. However, there is a knowledge gap regarding the neural mechanisms producing these effects. One of the keystones to deal with this problem is to use training programs with equal loads of physical activity. However, irregular motor and stress responses have been found in murine exercise models. Habituation to forced exercise facilitates a complete response to a training program in all rodents, reaching the same load of physical activity among animals. Here, it was evaluated if glucose and lactate - which are stress biomarkers - are increased during the habituation to exercise. Sprague-Dawley rats received an 8-days habituation protocol with progressive increments of time and speed of running. Then, experimental and control (non-habituated) rats were subjected to an incremental test. Blood samples were obtained to determine plasmatic glucose and lactate levels before, immediately after and 30 min after each session of training. Crh and Avp mRNA expression was determined by two-step qPCR. Our results revealed that glucose and lactate levels are not increased during the habituation period and tend to decrease toward the end of the protocol. Also, Crh and Avp were not chronically activated by the habituation program. Lactate and glucose, determined after the incremental test, were higher in control rats without previous contact with the wheel, compared with habituated and wheel control rats. These results suggest that the implementation of an adaptive phase prior to forced exercise programs might avoid non-specific stress responses.

Habituation Training Improves Locomotor Performance in a Forced Running Wheel System in Rats.

Increasing evidence supports that physical activity promotes mental health; and regular exercise may confer positive effects in neurological disorders. There is growing number of reports that requires the analysis of the impact of physical activity in animal models. Exercise in rodents can be performed under voluntary or forced conditions. The former presents the disadvantage that the volume and intensity of exercise varies from subject to subject. On the other hand, a major challenge of the forced training protocol is the low level of performance typically achieved within a given session. Thus, the aim of the present study was to evaluate the effectiveness of gradual increasing of the volume and intensity (training habituation protocol) to improve the locomotor performance in a forced running-wheel system in rats. Sprague-Dawley rats were randomly assigned to either a group that received an exercise training habituation protocol, or a control group. The locomotor performance during forced running was assessed by an incremental exercise test. The experimental results reveal that the total running time and the distance covered by habituated rats was significantly higher than in control ones. We conclude that the exercise habituation protocol improves the locomotor performance in forced running wheels.