Cancer as a homeostatic challenge: the role of the hypothalamus.

The initiation, progression, and metastatic spread of cancer elicits diverse changes in systemic physiology. In this way, cancer represents a novel homeostatic challenge to the host system. Here, we discuss how the hypothalamus, a critical brain region involved in homeostasis senses, integrates and responds to cancer-induced changes in physiology. Through this lens, cancer-associated changes in behavior (e.g., sleep disruption) and physiology (e.g., glucocorticoid dysregulation) can be viewed as the result of an inability to re-establish homeostasis. We provide examples at each level (receptor sensing, integration of systemic signals, and efferent regulatory pathways) of how homeostatic organization becomes disrupted across different cancers. Finally, we lay out predictions of this hypothesis and highlight outstanding questions that aim to guide further work in this area.

Environmental Enrichment: Disentangling the Influence of Novelty, Social, and Physical Activity on Cerebral Amyloid Angiopathy in a Transgenic Mouse Model.

Cerebral amyloid angiopathy (CAA) is the deposition of amyloid protein in the cerebral vasculature, a common feature in both aging and Alzheimer's disease (AD). However, the effects of environmental factors, particularly cognitive stimulation, social stimulation, and physical activity, on CAA pathology are poorly understood. These factors, delivered in the form of the environmental enrichment (EE) paradigm in rodents, have been shown to have beneficial effects on the brain and behavior in healthy aging and AD models. However, the relative importance of these subcomponents on CAA pathology has not been investigated. Therefore, we assessed the effects of EE, social enrichment (SOC), and cognitive enrichment (COG) compared to a control group that was single housed without enrichment (SIN) from 4 to 8 months of age in wild-type mice (WT) and Tg-SwDI mice, a transgenic mouse model of CAA that exhibits cognitive/behavioral deficits. The results show that individual facets of enrichment can affect an animal model of CAA, though the SOC and combined EE conditions are generally the most effective at producing physiological, cognitive/behavioral, and neuropathological changes, adding to a growing literature supporting the benefits of lifestyle interventions.

Voluntary Wheel Running Reduces Amyloid-ß42 and Rescues Behavior in Aged Tg2576 Mouse Model of Alzheimer's Disease.

Exercise has been shown to be protective against the risk of dementias, including Alzheimer's disease (AD). Intervention studies have demonstrated its ability to mitigate cognitive and behavioral impairments and reduce disease in both humans and animals. However, information is lacking in regard to the volume and intensity, as well as timing of exercise onset with respect to disease stage, which produces optimal benefits. Here, utilizing the Tg2576 mouse, a model of AD-like parenchymal amyloid pathology and cognitive impairment, we sought to understand the effects of different lengths of daily access to a running wheel on advanced stage disease. This study is the first to determine the benefits of long-term exercise (4 months of voluntary running) and different periods of daily access to a running wheel (0 h, 1 h, 3 h, and 12 h running wheel access) beginning in 14-month-old Tg2576 mice, an age with significant amyloid pathology. We found that exercising Tg2576 animals showed lower levels of some aspects of AD pathology and reduced behavioral dysfunction compared to sedentary Tg2576 animals. High intensity exercise, rather than high volume exercise, was generally most beneficial in reducing amyloid pathology. Our results suggest that engaging in vigorous exercise programs, even after living a sedentary life, may lead to a measurable reduction in AD pathology and preservation of some cognitive abilities.

Long-term voluntary wheel running does not alter vascular amyloid burden but reduces neuroinflammation in the Tg-SwDI mouse model of cerebral amyloid angiopathy.

BACKGROUND: Cardiovascular exercise (CVE) has been shown to be protective against cognitive decline in aging and the risk for dementias, including Alzheimer's Disease (AD). CVE has also been shown to have several beneficial effects on brain pathology and behavioral impairments in mouse models of AD; however, no studies have specifically examined the effects of CVE on cerebral amyloid angiopathy (CAA), which is the accumulation of amyloid-beta (Aß) in the cerebral vasculature. CAA may be uniquely susceptible to beneficial effects of CVE interventions due to the location and nature of the pathology. Alternatively, CVE may exacerbate CAA pathology, due to added stress on already compromised cerebral vasculature. METHODS: In the current study, we examined the effects of CVE over many months in mice, thereby modeling a lifelong commitment to CVE in humans. We assessed this voluntary CVE in Tg-SwDI mice, a transgenic mouse model of CAA that exhibits behavioral deficits, fibrillar vascular Aß pathology, and significant perivascular neuroinflammation. Various "doses" of exercise intervention (0 h ("Sedentary"), 1 h, 3 h, 12 h access to running wheel) were assessed from ~ 4 to 12 months of age for effects on physiology, behavior/cognitive performance, and pathology. RESULTS: The 12 h group performed the greatest volume of exercise, whereas the 1 h and 3 h groups showed high levels of exercise intensity, as defined by more frequent and longer duration running bouts. Tg-SwDI mice exhibited significant cerebral vascular Aß pathology and increased expression of pro-inflammatory cytokines as compared to WT controls. Tg-SwDI mice did not show motor dysfunction or altered levels of anxiety or sociability compared to WT controls, though Tg-SwDI animals did appear to exhibit a reduced tendency to explore novel environments. At all running levels, CAA pathology in Tg-SwDI mice was not significantly altered, but 12-h high-volume exercise showed increased insoluble Aß burden. However, CVE attenuated the expression of pro-inflammatory cytokines TNF-α and IL-6 and was generally effective at enhancing motor function and reducing anxiety-like behavior in Tg-SwDI mice, though alterations in learning and memory tasks were varied. CONCLUSIONS: Taken together, these results suggest that CAA can still develop regardless of a lifespan of substantial CVE, although downstream effects on neuroinflammation may be reduced and functional outcomes improved.

Temporal fine structure mediated recognition of speech in the presence of multitalker babble.

This experiment investigated the mechanisms of temporal fine structure (TFS) mediated speech recognition in multi-talker babble. The signal-to-noise ratio 50 (SNR-50) for naive-listeners was measured when the TFS was retained in its original form (ORIG-TFS), the TFS was time reversed (REV-TFS), and the TFS was replaced by noise (NO-TFS). The original envelope was unchanged. In the REV-TFS condition, periodicity cues for stream segregation were preserved, but envelope recovery was compromised. Both the mechanisms were compromised in the NO-TFS condition. The SNR-50 was lowest for ORIG-TFS followed by REV-TFS, which was lower than NO-TFS. Results suggest both stream segregation and envelope recovery aided TFS mediated speech recognition.