IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury.

Neuroinflammation contributes to secondary injury cascades following traumatic brain injury (TBI), with alternating waves of inflammation and resolution. Interleukin-1 (IL-1), a critical neuroinflammatory mediator originating from brain endothelial cells, microglia, astrocytes, and peripheral immune cells, is acutely overexpressed after TBI, propagating secondary injury and tissue damage. IL-1 affects blood-brain barrier permeability, immune cell activation, and neural plasticity.

Long-Term Intranasal Insulin Aspart: A Profile of Gene Expression, Memory, and Insulin Receptors in Aged F344 Rats.

Intranasal insulin is a safe and effective method for ameliorating memory deficits associated with pathological brain aging. However, the impact of different formulations and the duration of treatment on insulin's efficacy and the cellular processes targeted by the treatment remain unclear. Here, we tested whether intranasal insulin aspart, a short-acting insulin formulation, could alleviate memory decline associated with aging and whether long-term treatment affected regulation of insulin receptors and other potential targets.

Tau drives translational selectivity by interacting with ribosomal proteins.

There is a fundamental gap in understanding the consequences of tau-ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity.

Aging-Related Calcium Dysregulation in Rat Entorhinal Neurons Homologous with the Human Entorhinal Neurons in which Alzheimer's Disease Neurofibrillary Tangles First Appear.

Aging is the leading risk factor for idiopathic Alzheimer's disease (AD), indicating that normal aging processes promote AD and likely are present in the neurons in which AD pathogenesis originates. In AD, neurofibrillary tangles (NFTs) appear first in entorhinal cortex, implying that aging processes in entorhinal neurons promote NFT pathogenesis. Using electrophysiology and immunohistochemistry, we find pronounced aging-related Ca2 + dysregulation in rat entorhinal neurons homologous with the human neurons in which NFTs originate.

Acute psychosocial stress in mid-aged male rats causes hyperthermia, cognitive decline, and increased deep sleep power, but does not alter deep sleep duration.

Aging is associated with altered sleep architecture and worsened hippocampus-dependent cognition, highly prevalent clinical conditions that detract from quality of life for the elderly. Interestingly, exposure to psychosocial stress causes similar responses in young subjects, suggesting that age itself may act as a stressor. In prior work, we demonstrated that young animals show loss of deep sleep, deficits in cognition, and elevated body temperature after acute stress exposure, whereas aged animals are hyporesponsive on these measures.

FK506-Binding Protein 12.6/1b, a Negative Regulator of [Ca], Rescues Memory and Restores Genomic Regulation in the Hippocampus of Aging Rats.

Hippocampal overexpression of FK506-binding protein 12.6/1b (), a negative regulator of ryanodine receptor Ca release, reverses aging-induced memory impairment and neuronal Ca dysregulation. Here, we tested the hypothesis that also can protect downstream transcriptional networks from aging-induced dysregulation.

Tunable somatosensory stimulation for selective sleep restriction studies in rodents.

Many methods for sleep restriction in rodents have emerged, but most are intrusive, lack fine control, and induce stress. Therefore, a versatile, non-intrusive means of sleep restriction that can alter sleep in a controlled manner could be of great value in sleep research. In previous work, we proposed a novel system for closed-loop somatosensory stimulation based on mechanical vibration and applied it to the task of restricting Rapid Eye Movement (REM) sleep in mice [1].

Transcriptional signatures of brain aging and Alzheimer's disease: What are our rodent models telling us?

Aging is the biggest risk factor for idiopathic Alzheimer's disease (AD). Recently, the National Institutes of Health released AD research recommendations that include: appreciating normal brain aging, expanding data-driven research, using open-access resources, and evaluating experimental reproducibility. Transcriptome data sets for aging and AD in humans and animal models are available in NIH-curated, publically accessible databases.

Reversal of Aging-Related Neuronal Ca2+ Dysregulation and Cognitive Impairment by Delivery of a Transgene Encoding FK506-Binding Protein 12.6/1b to the Hippocampus.

Unlabelled: Brain Ca2+ regulatory processes are altered during aging, disrupting neuronal, and cognitive functions. In hippocampal pyramidal neurons, the Ca2+ -dependent slow afterhyperpolarization (sAHP) exhibits an increase with aging, which correlates with memory impairment. The increased sAHP results from elevated L-type Ca2+ channel activity and ryanodine receptor (RyR)-mediated Ca2+ release, but underlying molecular mechanisms are poorly understood.

Intranasal Insulin Improves Age-Related Cognitive Deficits and Reverses Electrophysiological Correlates of Brain Aging.

Peripheral insulin resistance is a key component of metabolic syndrome associated with obesity, dyslipidemia, hypertension, and type 2 diabetes. While the impact of insulin resistance is well recognized in the periphery, it is also becoming apparent in the brain. Recent studies suggest that insulin resistance may be a factor in brain aging and Alzheimer's disease (AD) whereby intranasal insulin therapy, which delivers insulin to the brain, improves cognition and memory in AD patients.

Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats.

Vitamin D is an important calcium-regulating hormone with diverse functions in numerous tissues, including the brain. Increasing evidence suggests that vitamin D may play a role in maintaining cognitive function and that vitamin D deficiency may accelerate age-related cognitive decline. Using aging rodents, we attempted to model the range of human serum vitamin D levels, from deficient to sufficient, to test whether vitamin D could preserve or improve cognitive function with aging.

The metastasis suppressor NME1 regulates expression of genes linked to metastasis and patient outcome in melanoma and breast carcinoma.

NME1 is a well-documented metastasis suppressor gene, with suppressor activity demonstrated across a wide spectrum of human cancers including melanoma and carcinomas of the breast, stomach and thyroid. A primary aim of the current study was to identify profiles of genes whose expression is regulated by NME1 in cell lines of melanoma and thyroid carcinoma origin. Impact of NME1 was determined by forcing its expression transiently in cell lines using a novel Ad5-based adenoviral vector (Ad5-NME1), followed 48 h later by analysis of RNA expression profiles using the U133A microarray chip.

Aged rats are hypo-responsive to acute restraint: implications for psychosocial stress in aging.

Cognitive processes associated with prefrontal cortex and hippocampus decline with age and are vulnerable to disruption by stress. The stress/stress hormone/allostatic load hypotheses of brain aging posit that brain aging, at least in part, is the manifestation of life-long stress exposure. In addition, as humans age, there is a profound increase in the incidence of new onset stressors, many of which are psychosocial (e.

Glucocorticoid-dependent hippocampal transcriptome in male rats: pathway-specific alterations with aging.

Although glucocorticoids (GCs) are known to exert numerous effects in the hippocampus, their chronic regulatory functions remain poorly understood. Moreover, evidence is inconsistent regarding the long-standing hypothesis that chronic GC exposure promotes brain aging/Alzheimer disease. Here, we adrenalectomized male F344 rats at 15 months of age, maintained them for 3 months with implanted corticosterone (CORT) pellets producing low or intermediate (glucocorticoid receptor-activating) blood levels of CORT, and performed microarray/pathway analyses in hippocampal CA1.

Effect of high-fat diet on metabolic indices, cognition, and neuronal physiology in aging F344 rats.

The prevalence of obesity and type 2 diabetes increases with age. Despite this, few studies have examined these conditions simultaneously in aged animals, and fewer studies have measured the impact of these conditions on brain function. Using an established animal model of brain aging (F344 rats), we investigated whether a high-fat diet (HFD) exacerbates cognitive decline and the hippocampal calcium-dependent afterhyperpolarization (a marker of age-dependent calcium dysregulation).

Hippocampal CA1 transcriptional profile of sleep deprivation: relation to aging and stress.

Background: Many aging changes seem similar to those elicited by sleep-deprivation and psychosocial stress. Further, sleep architecture changes with age suggest an age-related loss of sleep. Here, we hypothesized that sleep deprivation in young subjects would elicit both stress and aging-like transcriptional responses.

Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer's disease.

Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma-type (PPAR-γ) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipid profiles, and reduce inflammation. Recent work also suggests that TZDs may be beneficial in Alzheimer's disease (AD), ameliorating cognitive decline early in the disease process. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted.

Autotaxin and its product lysophosphatidic acid suppress brown adipose differentiation and promote diet-induced obesity in mice.

Brown adipose tissue is a thermogenic organ that dissipates stored energy as heat to maintain body temperature. This process may also provide protection from development of diet-induced obesity. We report that the bioactive lipid mediator lysophosphatidic acid (LPA) markedly decreases differentiation of cultured primary brown adipocyte precursors, whereas potent selective inhibitors of the LPA-generating enzyme autotaxin (ATX) promote differentiation.

Gene expression analysis of urine sediment: evaluation for potential noninvasive markers of interstitial cystitis/bladder pain syndrome.

Purpose: We determined whether gene expression profiles in urine sediment could provide noninvasive markers for interstitial cystitis/bladder pain syndrome with and/or without Hunner lesions.

Materials And Methods: Fresh catheterized urine was collected and centrifuged from 5 controls, and 5 Hunner lesion-free and 5 Hunner lesion bearing patients. RNA was extracted from pelleted material and quantified by gene expression microarray using the GeneChip® Human Gene ST Array.

Reversal of glial and neurovascular markers of unhealthy brain aging by exercise in middle-aged female mice.

Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain.

Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that threatens to reach epidemic proportions as our population ages. Although much research has examined molecular pathways associated with AD, relatively few such studies have focused on the disease's critical early stages. In a prior microarray study we correlated gene expression in hippocampus with degree of Alzheimer's disease and found close associations between upregulation of apparent glial transcription factor/epigenetic/tumor suppressor genes and incipient AD.

Deep sleep and parietal cortex gene expression changes are related to cognitive deficits with age.

Background: Age-related cognitive deficits negatively affect quality of life and can presage serious neurodegenerative disorders. Despite sleep disruption's well-recognized negative influence on cognition, and its prevalence with age, surprisingly few studies have tested sleep's relationship to cognitive aging.

Methodology: We measured sleep stages in young adult and aged F344 rats during inactive (enhanced sleep) and active (enhanced wake) periods.

Disrupting function of FK506-binding protein 1b/12.6 induces the Ca²+-dysregulation aging phenotype in hippocampal neurons.

With aging, multiple Ca(2+)-associated electrophysiological processes exhibit increased magnitude in hippocampal pyramidal neurons, including the Ca(2+)-dependent slow afterhyperpolarization (sAHP), L-type voltage-gated Ca(2+) channel (L-VGCC) activity, Ca(2+)-induced Ca(2+) release (CICR) from ryanodine receptors (RyRs), and Ca(2+) transients. This pattern of Ca(2+) dysregulation correlates with reduced neuronal excitability/plasticity and impaired learning/memory and has been proposed to contribute to unhealthy brain aging and Alzheimer's disease. However, little is known about the underlying molecular mechanisms.