Biology subjects

Pillai, A. R.

Publications and source records attributed to Pillai, A. R..

3 recordsLinked to original sources

bioRxiv2025

Mitochondrial Response to Psychological Stress and Its Medial Prefrontal Biomarker Correlates

BackgroundStress response obligates increased mitochondrial activities to meet stress-induced high energy requirement. This stress-mitochondrial response process involves glucocorticoid but also multiple alternative pathways that are top-down regulated by the medial prefrontal cortex (mPFC). These pathways are important for many neuropsychiatric conditions that are sensitive to stress. However, the field lacks a reliable, clinically accessible stress-mitochondrial response paradigm to study the process in humans. MethodWe used an established psychological stress challenge combined with assaying salivary cell-free mitochondrial DNA (cf-mtDNA), thought to reflect heightened mitochondrial changes or disruptions, in 35 healthy individuals (21 males). We also explored if these stress-induced cf-mtDNA marker elevations were associated brain metabolites as measured by magnetic resonance spectroscopy (MRS), as well as high-resolution brain imaging based cortical thickness focusing on the mPFC. ResultsWe found that salivary cf-mtDNA was significant elevated immediately after the stress challenge (p=2.0x10-7) and gradually declined after. Exploratory causal analysis showed that this cf-mtDNA response was not primarily driven by cortisol response. Instead, individuals with higher baseline dACC lactate+ levels, thought to in part reflect mitochondrial dysfunctions, was significantly associated with the cf-mtDNA response (r=0.80, p<0.001). Higher mtDNA response was also significantly associated with thinner dorsomedial prefrontal cortex (r=-0.52, p=0.01). Age had a U-shape effect such that cf-mtDNA response trended lower in earlier adulthood but higher in older people, explaining 33.8% of the ct-mtDNA response variance (p=0.003). ConclusionThis stress challenge-salivary cf-mtDNA assay paradigm may offer a new, non-invasive approach to evaluate the stress-mitochondrial pathway functioning in aging, psychopharmacology, and neuropsychiatric conditions where psychological stress plays a role.

neuroscience↗

bioRxiv2025

Blood and Neuronal Extracellular Vesicle Mitochondrial Disruptions in Schizophrenia

The high energy demand of the human brain obligates robust mitochondrial energy metabolism, while mitochondrial dysfunctions have been linked to neuropsychiatric disorders including schizophrenia spectrum disorders (SSD). However, in vivo assessments that can directly inform brain mitochondrial functioning and its etiopathophysiological path to SSD remain difficult to obtain. We hypothesized that system and brain mitochondrial dysfunctions in SSD may be indexed by elevated cell-free mitochondrial DNA (cf-mtDNA) levels in the blood and in neuronal extracellular vesicles (nEVs). We also explored if these mtDNA marker elevations were associated brain metabolites as measured by magnetic resonance spectroscopy (MRS). We examined blood cf-mtDNA in 58 SSD patients and 33 healthy controls, followed by assessing nEV mtDNA and metabolite levels using MRS in a subgroup of patients and controls. We found that people with SSD had significantly elevated cf-mtDNA levels in both the blood (p=0.0002) and neuronal EVs (p=0.003) compared to controls. These mtDNA abnormalities can be linked back to brain lactate+ levels such that higher blood and nEV mtDNA levels were significantly associated with higher lactate+ levels measured at the anterior cingulate cortex (r=0.53, 0.53; p=0.008, 0.03, respectively) in SSD patients. Furthermore, higher developmental stress and trauma were significantly associated with higher cf-mtDNA levels in both the blood and neuronal EVs in SSD patients (r=0.29, 0.49; p=0.01, 0.03, respectively). In conclusion, if replicated and fully developed, blood and neuronal EV-based cell free mtDNA may provide a clinically accessible biomarker to more directly evaluate the mitochondrial hypothesis and the abnormal bioenergetics pathways in schizophrenia.

neuroscience↗

bioRxiv2022

Cholinergic forebrain activation improves cognition, boosts neurotrophin receptors, and lowers Aβ42 levels in the cerebral cortex of 5xFAD mice.

The biological basis of Alzheimers dementia has been hypothesized in terms of basal forebrain cholinergic decline, and in terms reflecting the neuropathologies surrounding beta amyloid and tau. To shed light on the contributions of these different biological elements, we performed five month intermittent stimulation of the basal forebrain, which projects to the cortical mantle, in 5xFAD Alzheimers model mice and wild-type littermates, and subjected mice to behavioral testing and tissue analysis. The 5xFAD mice performed worse in water maze testing than their littermates. Stimulation improved both classes of mice, and removed performance differences between genotypes by the fifth testing day. Stimulated groups had two to four-fold increases in immunoblot measures of each of the neurotrophin receptors tropomyosin receptor kinase A and B. Stimulation also led to lower tissue A{beta}42 and beta amyloid cleavage enzyme 1 in 5xFAD mice. Despite the lack of strong direct projections from the basal forebrain stimulation region to the hippocampus, the hippocampal tissues in stimulated mice had more nerve growth factor receptor, and lower levels of beta secretase for amyloid. These data support a causal relation between forebrain cholinergic pathways and cognitive decline dependent on A{beta}42. Activation of cholinergic brain pathways improves neurotrophin pathways and reduces A{beta}42 accumulation. The recruitment of both classes of neurotrophin receptors in the process suggests a serine protease cleavage intermediary between cholinergic response and neurotrophin activation.

neuroscience↗