Age and Sex-Related Changes to Gene Expression in the Mouse Spinal Cord

McCallum-Loudeac, Jeremy; Anderson, Greg M.; Wilson, Megan J.

doi:10.1007/s12031-019-01371-3

Cited by 7 publications

(5 citation statements)

References 76 publications

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“…Moreover, genetic deletion of TDP-43 in mouse oligodendrocytes leads to decreased expression of Srebf2 , disrupted cholesterol metabolism, and a severe demyelination phenotype [ 58 ]. Combined with our results, these studies point to a potential effect of human FUS on myelin or oligodendrocytes development/differentiation, which could explain the lack of alteration in 25-day-old animals and their existence in 60-day-old animals when the developmental myelination period is over in the mouse spinal cord [ 44 , 45 ]. Moreover, cholesterol-related genes are already downregulated in 25-day-old FUS +/+ mice, suggesting an early involvement [ 6 ].…”

Section: Discussionsupporting

confidence: 57%

“…Our data showed that the lipidome of 25-day-old animals was significantly different compared to 60-day-old animals, with a major proportion of increased individual lipid concentrations. In the mouse spinal cord, puberty is accompanied by a significant increase in axonal extension, synapse remodeling, myelination, and non-neuronal cell numbers [ 44 , 45 ]. Therefore, the lipid composition varies drastically during postnatal mouse development and could hide slight presymptomatic disease-related alterations in FUS +/+ mice.…”

Section: Discussionmentioning

confidence: 99%

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Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

Burg

Rossaert

Moisse

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disorder of the motor system. While the etiology is still incompletely understood, defects in metabolism act as a major contributor to the disease progression. Recently, histone deacetylase (HDAC) inhibition using ACY-738 has been shown to restore metabolic alterations in the spinal cord of a FUS mouse model of ALS, which was accompanied by a beneficial effect on the motor phenotype and survival. In this study, we investigated the specific effects of HDAC inhibition on lipid metabolism using untargeted lipidomic analysis combined with transcriptomic analysis in the spinal cord of FUS mice. We discovered that symptomatic FUS mice recapitulate lipid alterations found in ALS patients and in the SOD1 mouse model. Glycerophospholipids, sphingolipids, and cholesterol esters were most affected. Strikingly, HDAC inhibition mitigated lipid homeostasis defects by selectively targeting glycerophospholipid metabolism and reducing cholesteryl esters accumulation. Therefore, our data suggest that HDAC inhibition is a potential new therapeutic strategy to modulate lipid metabolism defects in ALS and potentially other neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

Burg

Rossaert

Moisse

et al. 2021

IJMS

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“…IGF-1, as previously noted, broadly increases oligodendrogenesis; therefore, this upregulation of IGF-1 may contribute towards progesterone-induced promotion of OL proliferation and differentiation. Furthermore, DHT increases IGFBP-5 expression in human embryonic-derived NSCs [285], and both estradiol and DHT increase IGFBP-5 expression in the spinal cord of male mice [306]. Altogether, further work testing combinations of hormones is needed to better explore and define the complex relationships between hormonal systems and their effects on oligodendrogenesis.…”

Section: Future Directionsmentioning

confidence: 99%

Hormonal Regulation of Oligodendrogenesis I: Effects across the Lifespan

et al. 2021

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The brain’s capacity to respond to changing environments via hormonal signaling is critical to fine-tuned function. An emerging body of literature highlights a role for myelin plasticity as a prominent type of experience-dependent plasticity in the adult brain. Myelin plasticity is driven by oligodendrocytes (OLs) and their precursor cells (OPCs). OPC differentiation regulates the trajectory of myelin production throughout development, and importantly, OPCs maintain the ability to proliferate and generate new OLs throughout adulthood. The process of oligodendrogenesis, the creation of new OLs, can be dramatically influenced during early development and in adulthood by internal and environmental conditions such as hormones. Here, we review the current literature describing hormonal regulation of oligodendrogenesis within physiological conditions, focusing on several classes of hormones: steroid, peptide, and thyroid hormones. We discuss hormonal regulation at each stage of oligodendrogenesis and describe mechanisms of action, where known. Overall, the majority of hormones enhance oligodendrogenesis, increasing OPC differentiation and inducing maturation and myelin production in OLs. The mechanisms underlying these processes vary for each hormone but may ultimately converge upon common signaling pathways, mediated by specific receptors expressed across the OL lineage. However, not all of the mechanisms have been fully elucidated, and here, we note the remaining gaps in the literature, including the complex interactions between hormonal systems and with the immune system. In the companion manuscript in this issue, we discuss the implications of hormonal regulation of oligodendrogenesis for neurological and psychiatric disorders characterized by white matter loss. Ultimately, a better understanding of the fundamental mechanisms of hormonal regulation of oligodendrogenesis across the entire lifespan, especially in vivo, will progress both basic and translational research.

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“…The current study is also limited by the subject demographics; we only used male rats, and we only examined adult and aged animals. Sex is a critically relevant biological variable for the response to spinal cord injury in normal adults and has been implicated in differences in spinal cord inflammation and gene expression with normal aging (48, 49). Age-dependent changes may occur in a progressive or stepwise manner, necessitating further study with young, middle aged, and aged cohorts.…”

Section: Discussionmentioning

confidence: 99%

Contrast-enhanced ultrasound imaging detects anatomical and functional changes in rat cervical spine microvasculature with normal aging

Harmon,

Chandran,

Chandrasekaran

et al. 2024

Preprint

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Normal aging is associated with significant deleterious cerebrovascular changes; these have been implicated in disease pathogenesis and increased susceptibility to ischemic injury. While these changes are well documented in the brain, few studies have been conducted in the spinal cord. Here, we utilize specialized contrast-enhanced ultrasound (CEUS) imaging to investigate age-related changes in cervical spinal vascular anatomy and hemodynamics in male Fisher 344 rats, a common strain in aging research. Aged rats (24-26 mo., N=6) exhibited significant tortuosity in the anterior spinal artery and elevated vascular resistance compared to adults (4-6 mo., N=6; tortuosity index 2.20±0.15 vs 4.74±0.45, p<0.05). Baseline blood volume was lower in both larger vessels and the microcirculation in the aged cohort, specifically in white matter (4.44e14±1.37e13 vs 3.66e14±2.64e13 CEUS bolus AUC, p<0.05). To elucidate functional differences, animals were exposed to a hypoxia challenge; whereas adult rats exhibited significant functional hyperemia in both gray and white matter (GM: 1.13±0.10-fold change from normoxia, p<0.05; WM: 1.16±0.13, p<0.05), aged rats showed no response. Immunohistochemistry revealed reduced pericyte coverage and activated microglia behavior in aged rats, which may partially explain the lack of vascular response. This study provides the first in vivo description of age-related hemodynamic differences in the cervical spinal cord.

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Age and Sex-Related Changes to Gene Expression in the Mouse Spinal Cord

Cited by 7 publications

References 76 publications

Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

Hormonal Regulation of Oligodendrogenesis I: Effects across the Lifespan

Contrast-enhanced ultrasound imaging detects anatomical and functional changes in rat cervical spine microvasculature with normal aging

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