Biology subjects

McGregor, E. R.

Publications and source records attributed to McGregor, E. R..

3 recordsLinked to original sources

bioRxiv2026

Acetyl-CoA availability regulates neuronal metabolism, growth, and synaptic activity

The metabolite acetyl-CoA plays a central role in cellular metabolic homeostasis. As part of the secretory pathway, acetyl-CoA is imported into the endoplasmic reticulum (ER) by a membrane-bound transporter AT-1 (SLC33A1). AT-1 has been linked to peripheral neuropathy (heterozygous mutations), developmental delay with premature death (homozygous mutations) and intellectual disability with progeria (duplication). These phenotypes can be reproduced in the mouse. Here, we show that AT-1 overexpression in primary neurons impacts diverse phenotypes related to neuronal function and plasticity. At the gene level, AT-1 induces brain aging signatures, and key differences in ribosomal and synaptic processes were identified in both the transcriptome and the proteome. Changes in mitochondria-associated pathways were reflected in an increase in expression of mitochondrial master regulator PGC-1 and its target genes. Functionally, marked differences in mitochondrial membrane potential, architecture, and respiration were detected. Tracing experiments indicated altered glucose utilization in glycogen storage and nucleotide production. Shifts in redox metabolism were linked to differences in levels of NAD-dependent SIRT1 and CtBP2, with consequences for acetylated lysine modification. Depletion of lipid stores was associated with greater plasticity in fuel substrate utilization and a major shift in cellular lipid composition. These broad-scale changes in metabolism were coincident with reduced expression of synaptic proteins and reduced activity among synaptic networks, indicating that neuronal electrophysiology and network communication are coordinated at least in part through neuronal acetyl-CoA metabolism.

cell biology↗

bioRxiv2025

Systems biology analysis of vasodynamics in mouse cerebral arterioles during resting state and functional hyperemia

Cerebral hemodynamics is tightly regulated by arteriolar vasodynamics. In this study, a systems biology approach was employed to investigate how the interplay between passive, myogenic, neurogenic, and astrocytic responses shapes arteriolar vasodynamics in small rodents. A model of neurovascular coupling is proposed in which neurons inhibit and dampen the myogenic response to promote vasodilation during activation, and facilitate the myogenic response to promote rapid vasoconstriction immediately post-activation. In this model, inhibition of the myogenic response is mediated by the hyperpolarization of smooth muscle and endothelial cells. Dampening and facilitation of the response are mediated by neuronal production of nitric oxide and release of neuropeptide Y, respectively. We also introduce a model for gliovascular coupling, in which astrocytes periodically inhibit the myogenic response upon detecting an increase in myogenic activity through interactions between their endfeet and arterioles. Our study revealed that in the resting state, the interplay between the delayed myogenic response and passive distension, acting as negative and positive feedbacks respectively, generates undamped oscillations in vessel diameter, known as vasomotion. In the active state, these oscillations are disrupted by the neurogenic and astrocytic responses. The biophysical model of arteriolar vasodynamics presented in this study lays the foundation for quantitative analysis of cerebral hemodynamics for cerebrovascular health diagnostics and hemodynamic neuroimaging. Author summaryCerebral hemodynamic imaging is widely used to investigate brain function in-vivo. These signals are primarily shaped by arteriolar vasodynamics, which result from a combination of physiological processes mediated by multiple interacting cell types. A biophysical model of this dynamics offers a valuable computational framework for achieving more accurate and quantitative interpretation of hemodynamic signals. In this study, I applied a computational biology approach to incorporate several well-established cellular signaling pathways into a unified model, which was used to investigate system-level arteriolar behavior and identify missing or less understood mechanisms involved in cerebral blood flow regulation. Our results show that arteriolar vasodynamics is not solely driven by neurogenic responses; astrocytic response and hemo-vascular interactions also play important roles in shaping the observed dynamics. The model also provided a means to explore how in-silico analysis of hemodynamic signals can reveal potential cellular-level impairments that manifest as system-level changes in cerebral hemodynamics. Incorporating our proposed biophysical model into cerebral hemodynamic analysis can improve the fidelity of hemodynamic imaging--enabling more accurate inference of regional neuronal and astrocytic activity from hemodynamic signals, and enhancing our ability to diagnose cerebrovascular pathologies.

neuroscience↗

bioRxiv2023

Mitochondrial regulator PGC-1a in neuronal metabolism and brain aging

The brain is a high energy tissue, and the cell types of which it is comprised are distinct in function and in metabolic requirements. The transcriptional co-activator PGC-1a is a master regulator of mitochondrial function and is highly expressed in the brain; however, its cell-type specific role in regulating metabolism has not been well established. Here, we show that PGC-1a is responsive to aging and that expression of the neuron specific PGC-1a isoform allows for specialization in metabolic adaptation. Transcriptional profiles of the cortex from male mice show an impact of age on immune, inflammatory, and neuronal functional pathways and a highly integrated metabolic response that is associated with decreased expression of PGC-1a. Proteomic analysis confirms age-related changes in metabolism and further shows changes in ribosomal and RNA splicing pathways. We show that neurons express a specialized PGC-1a isoform that becomes active during differentiation from stem cells and is further induced during the maturation of isolated neurons. Neuronal but not astrocyte PGC-1a responds robustly to inhibition of the growth sensitive kinase GSK3b, where the brain specific promoter driven dominant isoform is repressed. The GSK3b inhibitor lithium broadly reprograms metabolism and growth signaling, including significantly lower expression of mitochondrial and ribosomal pathway genes and suppression of growth signaling, which are linked to changes in mitochondrial function and neuronal outgrowth. In vivo, lithium treatment significantly changes the expression of genes involved in cortical growth, endocrine, and circadian pathways. These data place the GSK3b/PGC-1a axis centrally in a growth and metabolism network that is directly relevant to brain aging.

cell biology↗