The beneficial effects of physical activity (PA) are well documented, yet the mechanisms by which PA prevents disease and improves health outcomes are poorly understood. To identify major gaps in ...knowledge and potential strategies for catalyzing progress in the field, the NIH convened a workshop in late October 2014 entitled “Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits.” Presentations and discussions emphasized the challenges imposed by the integrative and intermittent nature of PA, the tremendous discovery potential of applying “-omics” technologies to understand interorgan crosstalk and biological networking systems during PA, and the need to establish an infrastructure of clinical trial sites with sufficient expertise to incorporate mechanistic outcome measures into adequately sized human PA trials. Identification of the mechanisms that underlie the link between PA and improved health holds extraordinary promise for discovery of novel therapeutic targets and development of personalized exercise medicine.
This Perspective reports on the NIH October 2014 workshop “Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits,” where major gaps in knowledge, as well as potential strategies for catalyzing progress in the field of physical activity, were discussed and the outcome consensus points reached.
Vascular contributions to cognitive impairment and dementia (VCID) are characterized by the aging neurovascular unit being confronted with and failing to cope with biological insults due to systemic ...and cerebral vascular disease, proteinopathy including Alzheimer's biology, metabolic disease, or immune response, resulting in cognitive decline. This report summarizes the discussion and recommendations from a working group convened by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke to evaluate the state of the field in VCID research, identify research priorities, and foster collaborations. As discussed in this report, advances in understanding the biological mechanisms of VCID across the wide spectrum of pathologies, chronic systemic comorbidities, and other risk factors may lead to potential prevention and new treatment strategies to decrease the burden of dementia. Better understanding of the social determinants of health that affect risks for both vascular disease and VCID could provide insight into strategies to reduce racial and ethnic disparities in VCID.
Schizophrenia is a disease syndrome with major public health implications. The primary advance in pharmacotherapeutics was in 1952 with the introduction of antipsychotic medications (ie, ...chlorpromazine, dopamine D2 antagonism). Barriers to progress have been substantial, but many will be subject to rapid change based on current knowledge. There are attractive psychopathology indications for drug discovery (eg, impaired cognition and negative symptoms), and drugs with efficacy in these domains may have application across a number of disease classes. These pathologies are observed prior to psychosis raising the possibility of very early intervention and secondary prevention. Success in drug discovery for cognition and negative symptom pathologies may bring forth issues in ethics as the potential for enhancing normal function is explored.
The World Health Organization reports that 47.5 million people are affected by dementia worldwide. With aging populations and 7.7 million new cases each year, the burden of illness due to dementia ...approaches crisis proportions. Despite significant advances in our understanding of the biology of Alzheimer’s disease (AD), the leading dementia diagnosis, the actual causes of dementia in affected individuals are unknown except for rare fully penetrant genetic forms. Evidence from epidemiology and pathology studies indicates that damage to the vascular system is associated with an increased risk of many types of dementia. Both Alzheimer’s pathology and cerebrovascular disease increase with age. How AD affects small blood vessel function and how vascular dysfunction contributes to the molecular pathology of Alzheimer’s are areas of intense research. The science of vascular contributions to cognitive impairment and dementia (VCID) integrates diverse aspects of biology and incorporates the roles of multiple cell types that support the function of neural tissue. Because of the proven ability to prevent and treat cardiovascular disease and hypertension with population benefits for heart and stroke outcomes, it is proposed that understanding and targeting the biological mechanisms of VCID can have a similarly positive impact on public health.
Abstract Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. BTBR T+tf/J ...(BTBR) is an inbred mouse strain that displays robust behavioral phenotypes with analogies to all three of the diagnostic symptoms of autism, including low social interactions, reduced vocalizations in social settings, and high levels of repetitive self-grooming. Autism-relevant phenotypes in BTBR offer translational tools to discover neurochemical mechanisms underlying unusual mouse behaviors relevant to symptoms of autism. Because repetitive self-grooming in mice may be a displacement behavior elevated by stressors, we investigated neuroendocrine markers of stress and behavioral reactivity to stressors in BTBR mice, as compared to C57BL/6J (B6), a standard inbred strain with high sociability. Radioimmunoassays replicated previous findings that circulating corticosterone is higher in BTBR than in B6. Higher basal glucocorticoid receptor mRNA and higher oxytocin peptide levels were detected in the brains of BTBR as compared to B6. No significant differences were detected in corticotrophin releasing factor (CRF) peptide or CRF mRNA. In response to behavioral stressors, BTBR and B6 were generally similar on behavioral tasks including stress-induced hyperthermia, elevated plus-maze, light ↔ dark exploration, tail flick, acoustic startle and prepulse inhibition. BTBR displayed less reactivity than B6 to a noxious thermal stimulus in the hot plate, and less immobility than B6 in both the forced swim and tail suspension depression-related tasks. BTBR, therefore, exhibited lower depression-like scores than B6 on two standard tests sensitive to antidepressants, did not differ from B6 on two well-validated anxiety-like behaviors, and did not exhibit unusual stress reactivity to sensory stimuli. Our findings support the interpretation that autism-relevant social deficits, vocalizations, and repetitive behaviors are not the result of abnormal stress reactivity in the BTBR mouse model of autism.
Highlights ► Normal sex differences in anxiety behavior are reversed in Nrg1Tn rats. ► Adolescent stress exposure ameliorates sex differences in anxiety behavior. ► Disruption of Type II NRG1 ...disrupts fear learning and extinction. ► A gene by stress by sex interaction was revealed in extinction of fear memory.
The Stroke Preclinical Assessment Network (SPAN) is a multicenter preclinical trial platform using rodent models of transient focal cerebral ischemia to address translational failure in experimental ...stroke. In addition to centralized randomization and blinding and large samples, SPAN aimed to introduce heterogeneity to simulate the heterogeneity embodied in clinical trials for robust conclusions. Here, we report the heterogeneity introduced by allowing the 6 SPAN laboratories to vary most of the biological and experimental model variables and the impact of this heterogeneity on middle cerebral artery occlusion (MCAo) performance. We included the modified intention-to-treat population of the control mouse cohort of the first SPAN trial (n=421) and examined the biological and procedural independent variables and their covariance. We then determined their impact on the dependent variables cerebral blood flow drop during MCAo, time to achieve MCAo, and total anesthesia duration using multivariable analyses. We found heterogeneity in biological and procedural independent variables introduced mainly by the site. Consequently, all dependent variables also showed heterogeneity among the sites. Multivariable analyses with the site as a random effect variable revealed filament choice as an independent predictor of cerebral blood flow drop after MCAo. Comorbidity, sex, use of laser Doppler flow to monitor cerebral blood flow, days after trial onset, and maintaining anesthesia throughout the MCAo emerged as independent predictors of time to MCAo. Total anesthesia duration was predicted by most independent variables. We present with high granularity the heterogeneity introduced by the biological and model selections by the testing sites in the first trial of cerebroprotection in rodent transient filament MCAo by SPAN. Rather than trying to homogenize all variables across all sites, we embraced the heterogeneity to better approximate clinical trials. Awareness of the heterogeneity, its sources, and how it impacts the study performance may further improve the study design and statistical modeling for future multicenter preclinical trials.
Chronic administration of phencyclidine (PCP) has been advanced as a valid animal model of the social deficit symptoms of schizophrenia. In these studies, the cumulative time that male rats treated ...once a day for 14 days with PCP actively engaged in social behavior was decreased approximately 75% relative to saline-treated control animals. In addition, these socially impaired rats had an increase in the relative amount of noncontact interactions compared with saline-injected peers. Social behaviors were preferentially affected by PCP treatment because in two anxiety-related behavioral assays, the open field and light/dark emergence tests, there was a failure to differentiate between the PCP-treated rats and saline-injected control rats. Considering the general importance of the neuropeptides oxytocin and vasopressin in male social behaviors, studies of molecular markers related to these neuropeptides were performed. Hypothalamic oxytocin mRNA expression was significantly decreased while oxytocin receptor binding was increased in the central nucleus of the amygdala following chronic PCP treatment. Given the significance of central nucleus of the amygdala in social behavior, oxytocin was infused into the central nucleus of experimental and control male rats, and their postinfusion social interaction and open field behaviors were analyzed. A bilateral infusion of 1 mug of oxytocin into the central amygdala selectively restored the normal quantity and quality of social behavior in chronic PCP-treated male rats without altering open field behaviors. These findings suggest that deficits in the central oxytocinergic system may underlie the social impairment exhibited in this animal model of schizophrenia.
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