Garcia, A. J. | bioRxiv Science

bioRxiv2019

A role for Hypoxia Inducible Factor 1a (HIF1a) in intermittent hypoxia-dependent changes in spatial memory and synaptic plasticity

Intermittent hypoxia (IH), a key feature of sleep apnea, increases the oxygen regulated transcription factor Hypoxia Inducible Factor 1a (HIF1a). Although recognized for its role in IH-dependent changes in cardio-respiratory physiology, it remains unclear how IH-dependent HIF1a signaling affects neurophysiology underlying learning and memory. This study examines how IH affects hippocampal associated learning and memory in wildtype mice and mice heterozygous for the HIF1a gene (HIF1a+/-). In wild-type mice, ten days of IH impaired performance in the Barnes maze increased hippocampal HIF1a and elevated protein carbonyls. These behavioral and biochemical effects of IH were accompanied by a decrease in the N-Methyl-D-Aspartate receptor (NMDAr) and an attenuation of long-term potentiation (LTP) in area CA1. In HIF1a+/-, IH did not impair Barnes maze performance, increase hippocampal HIF1a, or enhance protein carbonyl content. At the network level, IH neither led to a decrease in NMDAr nor impaired LTP. Concurrent antioxidant treatment during IH mitigated the IH-dependent effects on the Barnes maze performance and LTP in wildtype mice. Our findings indicate that IH-dependent HIF1a signaling leads to oxidative stress and reduces NMDAr to impair LTP in area CA1, which contributes to IH-dependent deficits in learning and memory associated with the hippocampus.\n\nSignificanceIntermittent Hypoxia is a hallmark of sleep apnea and decreases the threshold for cognitive deficit. We demonstrate that intermittent hypoxia-dependent HIF1a signaling contributes to impairments in hippocampal associated memory. This is co-incidental with HIF1a-mediated alternations in synaptic physiology and increased oxidative stress.\n\nKey pointsO_LIIntermittent hypoxia (IH) is a hallmark of sleep apnea and is known to cause learning and memory deficits.\nC_LIO_LIHypoxia Inducible Factor 1a (HIF1a), is associated with IH-dependent changes in physiology.\nC_LIO_LIIH exposure causes increased hippocampal HIF1a in wild type mice and is associated with elevated oxidative stress, impairments to spatial memory, and suppression of long term potentiation (LTP).\nC_LIO_LIIH-dependent suppression of LTP is co-incidental with diminished NMDA receptor contribution to glutamatergic transmission.\nC_LIO_LIFollowing IH, mice heterozygous for HIF1a (HIF1a+/-) do not show an increase in HIF1a and oxidative stress, or changes in either behavior or glutamatergic transmission.\nC_LI

neuroscience↗

bioRxiv2019

Wnt7a-releasing synthetic hydrogel enhances local skeletal muscle regeneration and muscle stem cell engraftment

Skeletal muscle possesses efficient ability to regenerate upon minor injuries, but its capacity to regenerate is severely compromised with traumatic injuries and muscle-associated diseases. Recent evidence suggests that skeletal muscle regeneration can be accelerated by transplantation of muscle satellite cells (MuSCs) or treatment with promyogenic factors, such as Wingless-type MMTV Integrated 7a (Wnt7a) protein. Although direct intramuscular injection is the simplest method to deliver MuSCs and Wnt7a for regenerative therapy, direct injection is not viable in many clinical cases where the structural integrity is severely compromised. To address this challenge, we engineered a synthetic poly(ethylene glycol) (PEG)-based hydrogel to facilitate the co-delivery of pro-myogenic factors, such as Wnt7a, and MuSCs to skeletal muscles affected by severe trauma or muscular dystrophies. Wnt7a release rate can be controlled by modulating the polymer density of the hydrogel, and this release rate can be further accelerated through the proteolytic degradation of the hydrogel. Treating cryo-injured tibialis anterior (TA) muscles with Wnt7a-loaded hydrogels resulted in an accelerated regenerative response, measured by increased muscle fiber cross-sectional area, bulk TA mass, and number of Pax7+ MuSCs at the injury site, compared to the TA muscles treated with Wnt7a-free hydrogels. Co-delivery of Wnt7a and primary MuSCs using the synthetic hydrogel to the cryo-injured TA muscles significantly increased cellular migration during the engraftment process. This work provides a synthetic biomaterial platform for advancing treatment strategies of skeletal muscle trauma and diseases, specifically in conditions where direct intramuscular injection may be challenging.

bioengineering↗