Opposing associations between sedentary time and decision-making competence in young adults revealed by functional connectivity in the dorsal attention network.

How daily physical activity and sedentary time relate to human judgement and functional connectivity (FC) patterns that support them remains underexplored. We investigated the relationships between accelerometer-measured moderate-to-vigorous physical activity (MVPA) and sedentary time to decision-making competence (DMC) in young adults using a comprehensive Adult-Decision Making Competence battery. We applied graph theory measures of global and local efficiency to test the mediating effects of FC in cognitively salient brain networks (fronto-parietal; dorsal attention, DAN; ventral attention; and default mode), assessed from the resting-state fMRI. Sedentary time was related to lower susceptibility to a framing bias. However, once global and local efficiency of the DAN were considered we observed (1) higher susceptibility to framing with more sedentary time, mediated through lower local and global efficiency in the DAN, and (2) lower susceptibility to framing with more sedentary time. MVPA was not related to DMC or graph theory measures. These results suggest that remaining sedentary may reduce neurofunctional readiness for top-down control and decrease engagement of deliberate thought, required to ignore irrelevant aspects of a problem. The positive effect suggests that the relationship between sedentary time and DMC may be moderated by unmeasured factors such as the type of sedentary behavior.

Increased bone morphogenetic protein signaling contributes to age-related declines in neurogenesis and cognition.

Aging is associated with decreased neurogenesis in the hippocampus and diminished hippocampus-dependent cognitive functions. Expression of bone morphogenetic protein 4 (BMP4) increases with age by more than 10-fold in the mouse dentate gyrus while levels of the BMP inhibitor, noggin, decrease. This results in a profound 30-fold increase in phosphorylated-SMAD1/5/8, the effector of canonical BMP signaling. Just as observed in mice, a profound increase in expression of BMP4 is observed in the dentate gyrus of humans with no known cognitive abnormalities. Inhibition of BMP signaling either by overexpression of noggin or transgenic manipulation not only increases neurogenesis in aging mice, but remarkably, is associated with a rescue of cognitive deficits to levels comparable to young mice. Additive benefits are observed when combining inhibition of BMP signaling and environmental enrichment. These findings indicate that increased BMP signaling contributes significantly to impairments in neurogenesis and to cognitive decline associated with aging, and identify this pathway as a potential druggable target for reversing age-related changes in cognition.

BMP receptor 1A regulates development of hypothalamic circuits critical for feeding behavior.

Hypothalamic neural circuits are known to regulate energy homeostasis and feeding behavior, but how these circuits are established during development is not well understood. Here we report that embryonic neural progenitors that express the transcription factor OLIG1 contribute neurons to the ventral hypothalamus including the arcuate nucleus (ARH), a center that regulates feeding behavior. Ablation of bone morphogenetic protein receptor 1a (BMPR1A) in the OLIG1 lineage resulted in hypophagia, hypoglycemia, and weight loss after the second postnatal week with death by week 4. Differentiation and specification of inhibitory hypothalamic neurons contributing to melanocortin and dopaminergic systems were abnormal in the BMPR1A-deficient ARH. Although the hypophagia promoted expression of the orexigenic neuropeptide agouti related protein (AgRP) in the BMPR1A-deficient ARH, there was a profound decrease of AgRP(+) axonal terminals in the mutant ARH targets including dorsomedial and paraventricular hypothalamic nuclei. Projection of AgRP(+) neurons to these nuclei is known to be regulated by leptin. Leptin injection in neonatal mice increased bone morphogenic protein (BMP) signaling in the ventral hypothalamus, and blocking BMP signaling prevented leptin-induced neurite outgrowth in ARH explant cultures. These findings suggest that BMPR1A signaling is critical for postnatal establishment of leptin-responsive orexigenic fibers from ARH to multiple hypothalamic nuclei. More generally these observations indicate that BMPR1A signaling regulates postnatal establishment of OLIG1 lineage-derived ARH neuronal circuits that are critical for leptin-mediated feeding behavior.

HeyL regulates the number of TrkC neurons in dorsal root ganglia.

The basic-helix-loop-helix transcription factor HeyL is expressed at high levels by neural crest progenitor cells (NCPs) that give rise to neurons and glia in dorsal root ganglia (DRG). Since HeyL expression was observed in these NCPs during the period of neurogenesis, we generated HeyL null mutants to help examine the factor's role in ganglion neuronal specification. Homozygous null mutation of HeyL reduced the number of TrkC(+) neurons in DRG at birth including the subpopulation that expresses the ETS transcription factor ER81. Conversely, null mutation of the Hey paralog, Hey1, increased the number of TrkC(+) neurons. Null mutation of HeyL increased expression of the Hey paralogs Hey1 and Hey2, suggesting that HeyL normally inhibits their expression. Double null mutation of both Hey1 and HeyL rescued TrkC(+) neuron numbers to control levels. Thus, the balance between HeyL and Hey1 expression regulates the differentiation of a subpopulation of TrkC(+) neurons in the DRG.

Identification of estrogen-responsive genes involved in breast cancer metastases to the bone.

Bone metastasis is the most common metastasis in breast cancer patients. Clinical observations propose strong association between estrogen receptor (ER)-positive tumors and the development of bone metastases. We hypothesized of biologically diverse sets of hormone-dependent tumors predisposed to bone metastases and of possible role of ER-signaling pathways in the development and progression of bone metastases. We developed a novel in vitro estrogen (E2)-responsive model system, in which breast cancer cells and bone cells express high levels of either ERalpha or ERbeta. Using co-culture approach and gene array technology we identified E2-responsive genes involved in the interaction between cancer cells and bone cells. We detected 13 genes that were altered solely by ERalpha and 11 genes that were regulated solely by ERbeta in cancer cells. Only 5 genes were modified by both ERalpha and ERbeta. Interestingly, the majority of genes in bone cells were altered through ERbeta. Two genes, namely MacMarcks and Muc-1, whose changes in expressions in cancer cells in response to E2 were highly significant, were selected for immunohistochemical analysis using tissue microarrays of 59 infiltrating ductal carcinomas. Our results indicated that both MacMarcks and Muc-1 were expressed at high frequency in ER-positive tumors. The correlation between ERalpha- and ERbeta-status of hormone-dependent tumors with combined expression of these two markers might suggest a more aggressive tumor phenotype associated with bone metastases. Further analysis of tissues with clinicopathological characteristics and known bone metastatic disease will indicate potential prognostic values of these and other markers in the development of bone metastases in a subgroup of "bad" hormone-dependent breast cancer.

MCT-1 oncogene contributes to increased in vivo tumorigenicity of MCF7 cells by promotion of angiogenesis and inhibition of apoptosis.

Overexpression of a novel oncogene MCT-1 (multiple copies in a T cell malignancy) causes malignant transformation of murine fibroblasts. To establish its role in the pathogenesis of breast cancer in humans, we generated stable transfectants of MCF7 breast cancer cells negative for endogenous MCT-1 (MCF7-MCT-1). Overexpression of MCT-1 in these cells resulted in a slight elevation of estrogen receptor-alpha, and higher rates of DNA synthesis and growth in response to estradiol compared with the empty vector control (MCF7-EV). The pure antiestrogen fulvestrant inhibited the estradiol-stimulated proliferation of MCF7-MCT-1 cells. The MCF7-MCT-1 clones showed increased invasiveness in the presence of 50% serum compared with the MCF7-EV. In a tumor xenograft model, MCT-1-overexpressing cells showed higher take rates and formed significantly larger tumors than MCF7-EV controls. When we examined angiogenic phenotype and molecular mediators of angiogenesis in MCF7-MCT-1 tumors in vivo, we found greater microvascular density and lower apoptosis in the MCF7-MCT-1 tumors compared with MCF7-EV controls accompanied by a dramatic decline in the levels of angiogenesis inhibitor, thrombospondin-1 (TSP1). In vitro, blocking TSP1 in the medium conditioned by MCT-1-negative cells restored its angiogenic potential to that of the MCF7-MCT-1 cells. Conversely, despite an increase in mRNA encoding vascular endothelial growth factor upon MCT-1 overexpression, vascular endothelial growth factor protein levels have not been notably altered. Taken together, our results suggest that MCT-1 may contribute to the pathogenesis and progression of human breast cancer via at least two routes: promotion of angiogenesis through the decline of TSP1 and inhibition of apoptosis.

A low blood ethanol level is associated with improved cytokine production in aged mice after traumatic injury.

BACKGROUND: Many trauma patients have been consuming alcohol at the time of injury. Although high concentrations of alcohol are correlated with poor outcome, few studies have examined the effects of low levels of alcohol. We examined the effects of low alcohol exposure after burn injury using a murine model. METHODS: Three- and 18-month-old mice were given ethanol or saline 30 minutes before a 15% total body surface area burn injury. Twenty-four hours after injury, cellular immune responses, including delayed-type hypersensitivity response and splenocyte proliferation were examined, along with production of interferon-gamma, interleukin (IL)-2, and IL-4. RESULTS: Alcohol administration resulted in a significant increase in interferon-gamma in the aged, but not young, burn-injured mice. Likewise, slight increases in IL-2, IL-4, and the delayed-type hypersensitivity response were observed. CONCLUSION: Low levels of ethanol at the time of injury are associated with partial restoration of immune responses in aged mice.