Brain development is impaired in c-fos -/- mice.
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ABSTRACT:
SUBMITTER: Velazquez FN
PROVIDER: S-EPMC4621926 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:?-Synuclein (?SYN) is genetically and neuropathologically linked to a spectrum of neurodegenerative diseases including Parkinson's disease, dementia with Lewy bodies, and related disorders. Cognitive impairment is recapitulated in several ?SYN transgenic mouse lines. However, the mechanisms of dysfunction in affected neurons are largely unknown. Here we measured neuronal activity induced gene products in the limbic system of ?SYN transgenic mice upon fear conditioning (FC). Induction of the synaptic plasticity marker c-Fos was significantly reduced in the amygdala and hippocampus of (Thy1)-h[A30P]?SYN transgenic mice in an age-dependent manner. Similarly, the neuronal activity inducible polo-like kinase 2 (Plk2) that can phosphorylate ?SYN at the pathological site serine-129 was up-regulated in both brain regions upon FC. Plk2 inductions were also significantly impaired in aged (Thy1)-h[A30P]?SYN transgenic mice, both in the amygdala and hippocampus. Plk2 inductions in the amygdala after FC were paralleled by a small but significant increase in the number of neuronal cell bodies immunopositive for serine-129 phosphorylated ?SYN in young but not aged (Thy1)-h[A30P]?SYN transgenic mice. In addition, we observed in the aged hippocampus a distinct type of apparently unmodified transgenic ?SYN profiles resembling synaptic accumulations of ?SYN. Thus, the cognitive decline observed in aged ?SYN transgenic mice might be due to impairment of neurotransmission and synaptic plasticity in the limbic system by distinct ?SYN species.
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Project description:GLUT4 in muscle and adipose tissue is important in maintaining glucose homeostasis. However, the role of insulin-responsive GLUT4 in the central nervous system has not been well characterized. To assess its importance, a selective knockout of brain GLUT4 (BG4KO) was generated by crossing Nestin-Cre mice with GLUT4-floxed mice. BG4KO mice had a 99% reduction in GLUT4 protein expression throughout the brain. Despite normal feeding and fasting glycemia, BG4KO mice were glucose intolerant, demonstrated hepatic insulin resistance, and had reduced glucose uptake in the brain. In response to hypoglycemia, BG4KO mice had impaired glucose sensing, noted by impaired epinephrine and glucagon responses and impaired c-fos activation in the hypothalamic paraventricular nucleus. Moreover, in vitro glucose sensing of glucose-inhibitory neurons from the ventromedial hypothalamus was impaired in BG4KO mice. In summary, BG4KO mice are glucose intolerant, insulin resistant, and have impaired glucose sensing, indicating a critical role for brain GLUT4 in sensing and responding to changes in blood glucose.
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Project description:The kidney is a major organ in which fluid balance and waste excretion is regulated. To obtain mature functions of the kidney, normal renal developmental processes need to be preceded. Comprehensive genetic programs underlying renal development during prenatal life have been widely studied. However, postnatal renal development, from infancy to juvenile period, have not been studied yet. Here, we investigated if structural and functional kidney development was still undergoing in early life by analyzing renal transcriptional networks of infant (4 weeks old) and juvenile (7 weeks old) mice. We further examined the effects of dehydration on kidney development. Kidneys at 4 weeks and 7 weeks old showed significantly distinctive functional network of genes. Gene sets related to cell cycle regulators and immature glomerular barrier integrity (COL4A1, COL4A2) were enriched in infantile kidneys while genes associated with ion transport and drug metabolism (CYP450 family) were shown in juvenile kidneys. Dehydration during infancy suppressed renal growth by interrupting SHH signaling pathway which targets cell cycle regulators. Importantly, disruption of developmental program ultimately led to long-term alterations in renal filtration function, by causing a decline in glomerular filtration barrier integrity. Taken together, we provide meaningful perspectives of renal development in infancy which suggests molecular and physiological background why infants are more vulnerable to dehydration than adults. These results provide new insights into the systemic effects of dehydration on renal development and may propose possible markers for clinical application in pediatric dehydration. Total RNA obtained from isolated kidneys subjected to water restriction for 1 week (RES 1W, 4-week-old) and 4 weeks (RES 4W, 7-week-old), and each group was compared to control group; CON 1W (4-week-old), CON 4W (7-week-old) respectively.
2016-07-01 | E-GEOD-75604 | biostudies-arrayexpress
Project description:BackgroundHigh-level alcohol consumption causes neuroplastic changes in the brain that promote pathological drinking behavior. Some of these changes have been characterized in defined brain circuits and cell types, but unbiased approaches are needed to explore broader patterns of adaptations.MethodsWe used whole-brain c-Fos mapping and network analysis to assess patterns of neuronal activity during alcohol withdrawal and following reaccess in a well-characterized model of alcohol dependence. Mice underwent 4 cycles of chronic intermittent ethanol to increase voluntary alcohol consumption, and a subset underwent forced swim stress to further escalate consumption. Brains were collected either 24 hours (withdrawal) or immediately following a 1-hour period of alcohol reaccess. c-fos counts were obtained for 110 brain regions using iDISCO and ClearMap. Then, we classified mice as high or low drinkers and used graph theory to identify changes in network properties associated with high-drinking behavior.ResultsDuring withdrawal, chronic intermittent ethanol mice displayed widespread increased c-Fos expression relative to air-exposed mice, independent of forced swim stress. Reaccess drinking reversed this increase. Network modularity, a measure of segregation into communities, was increased in high-drinking mice after alcohol reaccess relative to withdrawal. The cortical amygdala showed increased cross-community coactivation during withdrawal in high-drinking mice, and cortical amygdala silencing in chronic intermittent ethanol mice reduced voluntary drinking.ConclusionsAlcohol withdrawal in dependent mice causes changes in brain network organization that are attenuated by reaccess drinking. Olfactory brain regions, including the cortical amygdala, drive some of these changes and may play an important but underappreciated role in alcohol dependence.
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