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Genetic inactivation of hypoxia inducible factor 1-alpha (HIF-1?) in adult hippocampal progenitors impairs neurogenesis and pattern discrimination learning.

ABSTRACT: HIF-1? is a hypoxia-inducible protein that regulates many cellular processes, including neural stem cell maintenance. Previous work demonstrated constitutive stabilization of HIF-1? in neural stem cells (NSCs) of the adult mouse subventricular zone (SVZ) and hippocampal subgranular zone (SGZ). Genetic inactivation of NSC-encoded HIF-1? in the adult SVZ results in gradual loss of NSCs, but whether HIF-1? is required for the maintenance of SGZ hippocampal progenitors and adult hippocampal neurogenesis has not been determined. Here we tested the hypothesis that HIF-1? plays an essential role in the maintenance of adult hippocampal neurogenesis using Nestin-CreERT2/R26R-YFP/Hif1afl/fl triple transgenic mice, in which HIF-1? was genetically inactivated in nestin+ hippocampal progenitors and their downstream progeny following tamoxifen exposure. We found that disruption of HIF-1? gene expression resulted in a marked 50% reduction of adult-generated dentate granule cells (DGCs) that was highly correlated with impaired hippocampal function, as assessed using two behavioral assays of pattern discrimination. These behavioral tests included the A-B contextual fear-conditioning task and the trial-unique, delayed nonmatching-to-location (TUNL) touch-screen operant chamber task. Our findings identify HIF-1? as a novel regulator of adult hippocampal neurogenesis under non-pathological conditions, and underscore the importance of neurogenesis for pattern discrimination learning.

SUBMITTER: Carrica L

PROVIDER: S-EPMC6389421 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Genetic inactivation of hypoxia inducible factor 1-alpha (HIF-1α) in adult hippocampal progenitors impairs neurogenesis and pattern discrimination learning.

Carrica Lauren L Li Lu L Newville Jessie J Kenton Johnny J Gustus Kymberly K Brigman Jonathan J Cunningham Lee Anna LA

Neurobiology of learning and memory 20181203

HIF-1α is a hypoxia-inducible protein that regulates many cellular processes, including neural stem cell maintenance. Previous work demonstrated constitutive stabilization of HIF-1α in neural stem cells (NSCs) of the adult mouse subventricular zone (SVZ) and hippocampal subgranular zone (SGZ). Genetic inactivation of NSC-encoded HIF-1α in the adult SVZ results in gradual loss of NSCs, but whether HIF-1α is required for the maintenance of SGZ hippocampal progenitors and adult hippocampal neurogen ...[more]

PMID: 30521851

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Project description:IntroductionSystemic sclerosis is an autoimmune disease characterized by tissue fibrosis and microangiopathy. Vascular changes such as a decrease in capillary density diminish blood flow and impair tissue oxygenation. Reliable ways to monitor disease activity and predict disease progression are desired in the process of patient selection for clinical trials and to optimize individual patient outcomes. Hypoxia-inducible factor-1 (HIF-1) is a dimeric protein complex that plays an integral role in the body's response to hypoxia. Our study aimed to investigate the potential abnormalities of HIF-1α plasma concentration and its possible association with disease activity and vascular abnormalities in patients with systemic sclerosis.MethodsBlood plasma levels of HIF-1α were measured in patients with systemic sclerosis (n = 50) and in healthy individuals (n = 30) using commercially available ELISA test kits.ResultsThe results showed a marked increase in HIF-1α levels in patients with systemic sclerosis (3.042 ng/ml [2.295-7.749]) compared to the control group (1.969 ng/ml [1.531-2.903] p < 0.01). Patients with diffuse cutaneous SSc (2.803 ng/ml, IQR 2.221-8.799) and limited cutaneous SSc (3.231 ng/ml, IQR 2.566-5.502) exhibited elevated serum HIF-1α levels compared to the control group (p < 0.01). We found a notable increase in HIF-1α plasma concentration in patients with an "active" pattern (6.625 ng/ml, IQR 2.488-11.480) compared to those with either an "early" pattern (2.739, IQR 2.165-3.282, p < 0.05) or a "late" pattern (2.983 ng/ml, IQR 2.229-3.386, p < 0.05). Patients with no history of digital ulcers had significantly higher levels of HIF-1α (4.367 ng/ml, IQR 2.488-9.462) compared to patients with either active digital ulcers (2.832 ng/ml, IQR 2.630-3.094, p < 0.05) or healed digital ulcers (2.668 ng/ml, IQR 2.074-2.983, p < 0.05).ConclusionsOur results indicate that HIF-1α may serve as a biomarker in assessing microcirculatory changes in individuals with systemic sclerosis.

Dataset Information

Genetic inactivation of hypoxia inducible factor 1-alpha (HIF-1?) in adult hippocampal progenitors impairs neurogenesis and pattern discrimination learning.

Publications

Genetic inactivation of hypoxia inducible factor 1-alpha (HIF-1α) in adult hippocampal progenitors impairs neurogenesis and pattern discrimination learning.

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