Sleep Disturbances in Neurological Disease: A Target for Intervention.

Sleep is a biological function required for neurological and general health, but a significant and under-recognized proportion of the population has disturbed sleep. Here, we briefly overview the biology of sleep, sleep requirements over the lifespan, and common sleep disorders. We then turn our attention to five neurological diseases that significantly contribute to global disease burden and neurology practice makeup: epilepsy, headache, ischemic stroke, Parkinson's disease, and Alzheimer's disease. For each disease, we review evidence that sleep disturbances contribute to disease risk and severity and discuss existing data that addressing sleep disturbances may have disease-modifying effects. We provide recommendations derived from the literature and existing clinical guidelines to facilitate the evaluation and management of sleep disturbances within the context of each neurological disease. Finally, we synthesize identified needs and commonalities into future directions for the field and practical sleep-related recommendations for physicians caring for patients at risk for or currently suffering from neurological disease.

Maternal Western-style diet reduces social engagement and increases idiosyncratic behavior in Japanese macaque offspring.

Recent evidence in humans and animals indicates an association between maternal obesity and offspring behavioral outcomes. In humans, increased maternal body mass index has been linked to an increased risk of children receiving a diagnosis of early-emerging neurodevelopmental disorders such as Attention Deficit/Hyperactivity Disorder (ADHD) and/or Autism Spectrum Disorder (ASD). However, a limited number of preclinical studies have examined associations between maternal Western-Style Diet (mWSD) exposure and offspring social behavior. To our knowledge, this is the first study to investigate relationships between mWSD exposure and social behavior in non-human primates. Since aberrant social behavior is a diagnostic criterion for several neurodevelopmental disorders, the current study focuses on examining the influence of maternal nutrition and metabolic state on offspring social behavior in Japanese macaques (Macaca fuscata). We found that mWSD offspring initiated less affiliative social behaviors as well as proximity to a peer. Using path analysis, we found that the association between mWSD consumption and reduced offspring social engagement was statistically mediated by increased maternal interleukin (IL)-12 during the third trimester of pregnancy. Additionally, mWSD offspring displayed increased idiosyncratic behavior, which was related to alterations in maternal adiposity and leptin in the third trimester. Together, these results suggest that NHP offspring exposed to mWSD exhibit behavioral phenotypes similar to what is described in some early-emerging neurodevelopmental disorders. These results provide evidence that mWSD exposure during gestation may be linked to increased risk of neurodevelopmental disorders and provides targets for prevention and intervention efforts.

Adolescent female rats recovered from the activity-based anorexia display blunted hedonic responding.

OBJECTIVE: As patients with anorexia nervosa tend to "like" palatable tastants less than controls, we set out to model this preclinically by using the taste reactivity test (TRT) to assess hedonic state in rats following weight restoration from a bout of activity-based anorexia (ABA). METHOD: Female rats (n = 31) were surgically implanted with an intraoral catheter, which allowed experimenters to assess baseline TRT to six tastants. Following baseline TRT, animals were either exposed to the activity-based anorexia condition (ABA; 1.5HR chow/ad lib wheel until 25% weight loss), kept sedentary (SED; ad lib chow/locked wheel), given access to running wheels with ad lib chow access (RW; ad lib chow/wheel), or were body weight matched to the ABA group (BWM; restricted chow/locked wheel). Following 25% weight loss, wheels were locked and food returned to ABA rats. Paired RW groups had their wheels locked and paired BWM rats were given ad lib access to food. Animals were given 10 days to recover prior to a second TRT. Videos were analyzed for liking (tongue protrusions) and disliking (gape) behaviors. RESULTS: The ABA group displayed a significant within-subject reduction in cumulative lick responses to water and 1 M sucrose. Additionally, we found the SED and ABA group displayed a significant within-subject reduction in cumulative lick responses to .1 M sucrose. Positive hedonic responses did not decline in either the BWM or the RW groups. DISCUSSION: The data show a novel phenomenon that a history of ABA results in an anhedonia phenotype that mirrors aspects of AN. SIGNIFICANCE STATEMENT: Patients recovered from anorexia nervosa report anhedonia, or the lack of pleasure in consuming palatable foods. Unfortunately, the biological mechanism underpinning anhedonia in anorexia nervosa is not well understood. The current study assessed hedonic state in adolescent female rats prior to and 10 days recovered following the activity-based anorexia paradigm. Age-matched, running wheel-matched and body weight-matched control groups were also tested at the same time points.

Maternal High-Fat Diet Induces Long-Lasting Defects in Bone Structure in Rat Offspring Through Enhanced Osteoclastogenesis.

Maternal stressors during the prenatal and perinatal periods are associated with increased susceptibility for and severity of chronic disease phenotypes in adult offspring. In this study, we used a rat model of maternal high-fat diet (HFD) exposure during pregnancy and lactation to investigate the impact on skeletal homeostasis in offspring. In the distal femur, young male and female offspring (up to 3 weeks of age) from dams fed a HFD exhibited marked increases in trabecular bone volume relative to offspring from dams fed a chow diet, but this was followed by sustained bone loss. By 15 weeks of age, male offspring of HFD fed dams exhibited a 33% reduction in trabecular bone volume fraction that histomorphometric analyses revealed was due to a nearly threefold increase in the abundance of bone-resorbing osteoclasts, while there were no differences between female control and HFD offspring by 15 weeks of age. The osteoblastic differentiation of male offspring-derived bone marrow stromal cells was not affected by maternal diet. However, osteoclastic precursors isolated from the male offspring of HFD fed dams exhibited enhanced differentiation in vitro, forming larger osteoclasts with higher expression of the fusion marker DC-STAMP. This effect appears to be mediated by a cell autonomous increase in the sensitivity of precursors to RANKL. Taken together, these results suggest that maternal stressors like HFD exposure have persistent consequences for the skeletal health of offspring that may ultimately lead to a predisposition for osteopenia/osteoporosis.

Ankyrin-G Heterozygous Knockout Mice Display Increased Sensitivity to Social Defeat Stress.

The ANK3 locus has been repeatedly found to confer an increased risk for bipolar disorder. ANK3 codes for Ankyrin-G (Ank-G), a scaffold protein concentrated at axon initial segments, nodes of Ranvier, and dendritic spines, where it organizes voltage-gated sodium and potassium channels and cytoskeletal proteins. Mice with homozygous conditional knockout of Ank-G in the adult forebrain display hyperactivity and reduced anxiety-like behaviors, responsive to mood stabilizers. Their behavior switches to a depression-like phenotype when exposed to chronic social defeat stress (SDS), and then spontaneously reverts to baseline hyperactivity. Ank-G heterozygous conditional knockouts (Ank-G Het cKO) have not previously been characterized. Here, we describe the behavior of Ank-G Het cKO mice compared to littermate controls in the open field, elevated plus maze, and forced swim test, under both unstressed and stressed conditions. We found that Ank-G Het cKO is not significantly different from controls at baseline or after chronic SDS. The chronic stress-induced "depression-like" behavioral phenotype is persistent for at least 28 days and is responsive to fluoxetine. Strikingly, Ank-G Het cKO mice display increased sensitivity to a short duration SDS, which does not affect controls. The heterozygous Ank-G genetic model may provide novel insights into the role of Ank-G in the pathophysiology of stress sensitivity and "depression-like" phenotypes and could be useful for studying Ank-G-related gene-environment interactions.

Maternal stressors and the developmental origins of neuropsychiatric risk.

The maternal environment during pregnancy is critical for fetal development and perinatal perturbations can prime offspring disease risk. Here, we briefly review evidence linking two well-characterized maternal stressors - psychosocial stress and infection - to increased neuropsychiatric risk in offspring. In the current climate of increasing obesity and globalization of the Western-style diet, maternal overnutrition emerges as a pressing public health concern. We focus our attention on recent epidemiological and animal model evidence showing that, like psychosocial stress and infection, maternal overnutrition can also increase offspring neuropsychiatric risk. Using lessons learned from the psychosocial stress and infection literature, we discuss how altered maternal and placental physiology in the setting of overnutrition may contribute to abnormal fetal development and resulting neuropsychiatric outcomes. A better understanding of converging pathophysiological pathways shared between stressors may enable development of interventions against neuropsychiatric illnesses that may be beneficial across stressors.

Nitrated meat products are associated with mania in humans and altered behavior and brain gene expression in rats.

Mania is a serious neuropsychiatric condition associated with significant morbidity and mortality. Previous studies have suggested that environmental exposures can contribute to mania pathogenesis. We measured dietary exposures in a cohort of individuals with mania and other psychiatric disorders as well as in control individuals without a psychiatric disorder. We found that a history of eating nitrated dry cured meat but not other meat or fish products was strongly and independently associated with current mania (adjusted odds ratio 3.49, 95% confidence interval (CI) 2.24-5.45, p < 8.97 × 10-8). Lower odds of association were found between eating nitrated dry cured meat and other psychiatric disorders. We further found that the feeding of meat preparations with added nitrate to rats resulted in hyperactivity reminiscent of human mania, alterations in brain pathways that have been implicated in human bipolar disorder, and changes in intestinal microbiota. These findings may lead to new methods for preventing mania and for developing novel therapeutic interventions.

Maternal high-fat diet results in cognitive impairment and hippocampal gene expression changes in rat offspring.

Consumption of a high-fat diet has long been known to increase risk for obesity, diabetes, and the metabolic syndrome. Further evidence strongly suggests that these same metabolic disorders are associated with an increased risk of cognitive impairment later in life. Now faced with an expanding global burden of obesity and increasing prevalence of dementia due to an aging population, understanding the effects of high-fat diet consumption on cognition is of increasingly critical importance. Further, the developmental origins of many adult onset neuropsychiatric disorders have become increasingly clear, indicating a need to investigate effects of various risk factors, including diet, across the lifespan. Here, we use a rat model to assess the effects of maternal diet during pregnancy and lactation on cognition and hippocampal gene expression of offspring. Behaviorally, adult male offspring of high-fat fed dams had impaired object recognition memory and impaired spatial memory compared to offspring of chow-fed dams. In hippocampus, we found decreased expression of Insr, Lepr, and Slc2a1 (GLUT1) among offspring of high-fat fed dams at postnatal day 21. The decreased expression of Insr and Lepr persisted at postnatal day 150. Together, these data provide additional evidence to suggest that maternal exposure to high-fat diet during pregnancy and lactation can have lasting effects on the brain, behavior, and cognition on adult offspring.

A toolbox of immunoprecipitation-grade monoclonal antibodies to human transcription factors.

A key component of efforts to address the reproducibility crisis in biomedical research is the development of rigorously validated and renewable protein-affinity reagents. As part of the US National Institutes of Health (NIH) Protein Capture Reagents Program (PCRP), we have generated a collection of 1,406 highly validated immunoprecipitation- and/or immunoblotting-grade mouse monoclonal antibodies (mAbs) to 737 human transcription factors, using an integrated production and validation pipeline. We used HuProt human protein microarrays as a primary validation tool to identify mAbs with high specificity for their cognate targets. We further validated PCRP mAbs by means of multiple experimental applications, including immunoprecipitation, immunoblotting, chromatin immunoprecipitation followed by sequencing (ChIP-seq), and immunohistochemistry. We also conducted a meta-analysis that identified critical variables that contribute to the generation of high-quality mAbs. All validation data, protocols, and links to PCRP mAb suppliers are available at http://proteincapture.org.