Biology subjects

Reid, M. A.

Publications and source records attributed to Reid, M. A..

6 recordsLinked to original sources

bioRxiv2026

Altered Dorsolateral Prefrontal Glutamate Dynamics During Working Memory in Trauma-Exposed Individuals With and Without PTSD: A 7T Functional Magnetic Resonance Spectroscopy Study

Post-traumatic stress disorder (PTSD) has been associated with impairments in cognitive function, including working memory, and may involve altered glutamatergic regulation in the prefrontal cortex. In this study, we used 7T functional magnetic resonance spectroscopy (fMRS) to examine dorsolateral prefrontal cortex (DLPFC) glutamate during working memory in individuals with PTSD, trauma exposure without PTSD (TE), and no trauma exposure (NT). Eighty participants (27 PTSD, 27 TE, 26 NT) underwent baseline MRS followed by fMRS during a letter n-back task. A linear mixed-effects model was used to evaluate glutamate concentrations across baseline, 0-back, 1-back, 2-back, and post-task fixation conditions. Behavioral performance was assessed using repeated-measures ANOVA for percentage correct, reaction time, and the discrimination index (d) across the 0-back, 1-back, and 2-back conditions. Glutamate differed significantly by group, condition, and the group x condition interaction. Individuals with PTSD exhibited lower glutamate than NT at baseline and during the 0-back, 1-back, and 2-back conditions. TE participants also showed lower glutamate than NT during the 1-back and 2-back conditions. Within-group analyses showed higher glutamate during the 0-back, 1-back, and 2-back conditions than at baseline in the NT group, whereas these baseline-to-task differences were limited in the PTSD and TE groups. Accuracy decreased and reaction time increased with increasing working memory load, and discrimination (d) was lower in PTSD than NT. These findings demonstrate altered DLPFC glutamate dynamics during working memory in PTSD and trauma-exposed individuals. Functional MRS provides complementary information beyond resting-state MRS by characterizing glutamatergic responses during cognitive engagement and may improve our understanding of neurochemical alterations associated with trauma and PTSD.

neuroscience↗

bioRxiv2024

Prefrontal metabolite alterations in individuals with posttraumatic stress disorder: a 7T magnetic resonance spectroscopy study

BackgroundEvidence from animal and human studies suggests glutamatergic dysfunction in posttraumatic stress disorder (PTSD). The purpose of this study was to investigate glutamate abnormalities in the dorsolateral prefrontal cortex (DLFPC) of individuals with PTSD using 7T MRS, which has better spectral resolution and signal-to- noise ratio than lower field strengths, thus allowing for better spectral quality and higher sensitivity. We hypothesized that individuals with PTSD would have lower glutamate levels compared to trauma-exposed individuals without PTSD and individuals without trauma exposure. Additionally, we explored potential alterations in other neurometabolites and the relationship between glutamate and psychiatric symptoms. MethodsIndividuals with PTSD (n=27), trauma-exposed individuals without PTSD (n=27), and individuals without trauma exposure (n=26) underwent 7T MRS to measure glutamate and other neurometabolites in the left DLPFC. The severities of PTSD, depression, anxiety, and dissociation symptoms were assessed. ResultsWe found that glutamate was lower in the PTSD and trauma-exposed groups compared to the group without trauma exposure. Furthermore, N-acetylaspartate (NAA) was lower and lactate was higher in the PTSD group compared to the group without trauma exposure. Glutamate was negatively correlated with depression symptom severity in the PTSD group. Glutamate was not correlated with PTSD symptom severity. ConclusionIn this first 7T MRS study of PTSD, we observed altered concentrations of glutamate, NAA, and lactate. Our findings provide evidence for multiple possible pathological processes in individuals with PTSD. High-field MRS offers insight into the neurometabolic alterations associated with PTSD and is a powerful tool to probe trauma- and stress-related neurotransmission and metabolism in vivo.

neuroscience↗

bioRxiv2022

Nucleotide metabolism is linked to cysteine availability

The small molecule erastin inhibits the cystine-glutamate antiporter, system xc-, which leads to intracellular cysteine and glutathione depletion. This can cause ferroptosis, which is an oxidative cell death process characterized by uncontrolled lipid peroxidation. Erastin and other ferroptosis inducers have been shown to affect metabolism but the metabolic effects of these drugs have not been systematically studied. To this end, we investigated how erastin impacts global metabolism in cultured cells and compared this metabolic profile to that caused by the ferroptosis inducer RSL3 or in-vivo cysteine deprivation. Common among the metabolic profiles were alterations in nucleotide and central carbon metabolism. Supplementing nucleosides to cysteine-deprived cells rescued cell proliferation in certain contexts, showing that these alterations to nucleotide metabolism can affect cellular fitness. While GPX4 inhibition caused a similar metabolic profile as cysteine deprivation, nucleoside treatment did not rescue cell viability or proliferation under RSL3 treatment, suggesting that these metabolic changes have varying importance in different scenarios of ferroptosis. Together, our study shows how global metabolism is affected during ferroptosis, and points to nucleotide metabolism as an important target of cysteine deprivation.

cell biology↗

bioRxiv2020

Digoxin Targets Central Carbon Metabolism and Remodels the Tumor Microenvironment

Cancer therapies targeting metabolism have been limited due to a lack of understanding of the controlling properties of vulnerable pathways. The Na+/K+ ATPase is responsible for a large portion of cellular energy demands but how these demands influence metabolism and create metabolic liabilities are not known. Using metabolomic approaches, we first show that digoxin, a cardiac glycoside widely used in humans, acts through disruption to central carbon metabolism via on target inhibition of the Na+/K+ ATPase that was fully recovered by expression of an allele resistant to digoxin. We further show in vivo that administration of digoxin inhibits glycolysis in both malignant and healthy cells, particularly within clinically relevant cardiac tissue, while exhibiting tumor-specific cytotoxic activity in an allografted soft tissue sarcoma. Single-cell expression analysis of over 31,000 cells within the sarcoma shows that acute Na+/K+ ATPase inhibition shifts the immune composition of the tumor microenvironment, leading to selective alterations to metabolic programs in specific immune cells thus acting both through tumor cell and microenvironmental (e.g. macrophage) cells. These results provide evidence that altering energy demands can be used to regulate glycolysis with cell-type specific consequences in a multicellular environment of biomedical interest.

cancer biology↗

bioRxiv2019

Dietary methionine restriction targets one carbon metabolism in humans and produces broad therapeutic responses in cancer

Nutrition exerts profound effects on health and dietary interventions are commonly used to treat diseases of metabolic etiology. Although cancer has a substantial metabolic component, the principles that define whether nutrition may be used to influence tumour outcome are unclear. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. In contrast, whether specific dietary interventions could influence the metabolic pathways that are targeted in standard cancer therapies is not known. We now show that dietary restriction of methionine (MR), an essential amino acid, and the reduction of which has aging and obesogenic properties, influences cancer outcome through controlled and reproducible changes to one carbon metabolism. This pathway metabolizes methionine and further is the target of a host of cancer interventions involving chemotherapy and radiation. MR produced therapeutic responses in chemoresistant RAS-driven colorectal cancer patient derived xenografts and autochthonous KRASG12D+/-;TP53-/- -driven soft tissue sarcomas resistant to radiation. Metabolomics revealed the therapeutic mechanisms to occur through tumor cell autonomous effects on the flux through one carbon metabolism that impacted redox and nucleotide metabolism, thus interacting with the antimetabolite or radiation intervention. Finally, in a controlled and tolerated feeding study in humans, MR resulted in similar effects on systemic metabolism as obtained in responsive mice. These findings provide evidence that a targeted dietary manipulation can affect specific tumor cell metabolism to mediate broad aspects of cancer outcome.

cancer biology↗

bioRxiv2018

Acetate is generated de novo from glucose metabolism in mammals and is coupled to central carbon metabolism

In cases of nutritional excess, there is incomplete catabolism of a nutritional source and secretion of a waste product (overflow metabolism), such as the conversion of glucose to lactate (the Warburg Effect) in tumors. Here we report that excess glucose metabolism generates acetate, a key nutrient whose source has been unclear. Conversion of pyruvate, the product of glycolysis, to acetate occurs through two mechanisms: 1) coupling to reactive oxygen species (ROS), and 2) a neomorphic enzyme activity from keto acid dehydrogenases that enable it to function as a pyruvate decarboxylase. Furthermore, we demonstrate that glucose-derived acetate is sufficient to maintain acetyl-coenzyme A (Ac-CoA) pools and cell proliferation in certain limited metabolic environments such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency. Thus, de novo acetate production is coupled to the activity of central carbon metabolism providing possible regulatory mechanisms and links to pathophysiology.

biochemistry↗