Biology subjects

Yamoah, E. N.

Publications and source records attributed to Yamoah, E. N..

5 recordsLinked to original sources

bioRxiv2026

Metabolic Perturbation Exacerbates Sinoatrial Node Dysfunction in Heart Failure

Heart failure (HF) affects approximately 6.2 million people in the United States, with a 5-year mortality exceeding 50%. Bradyarrhythmia, a known complication in HF due to sinoatrial node (SAN) dysfunction (SAND), increases the morbidity and mortality of HF patients. Insights into the mechanistic underpinnings of SAND in HF could therefore uncover vital therapeutic targets to improve clinical outcomes. The SAN cells are endowed with a dense mitochondrial network crucial for sustaining their pacemaking function on a beat-to-beat basis. We have previously demonstrated significant disruptions in the mitochondrial-sarcoplasmic reticulum connectomics, resulting in abnormal mitochondrial Ca2+ handling and impaired mitochondrial function in HF. Here, we hypothesize that the metabolic perturbation is one of the critical mechanisms underlying SAND. To this end, we took advantage of a multi-omics approach combined with ultra-resolution imaging and functional analyses to decipher the metabolic shift that transpires in the HF SAN. Our findings revealed significant metabolic remodeling within the SAN mitochondria in HF, with a diminished reliance on fatty acid {beta}-oxidation, enhanced utilization of ketone bodies, and heightened dependence on carbohydrate catabolism. Notably, metabolomics analyses identified the pronounced increase of glucosylceramides and ceramides as one of the mechanisms leading to mitochondrial dysfunction. We directly test this hypothesis and demonstrate that ceramides induce a dose-dependent metabolic shift from oxidative phosphorylation to glycolysis. Importantly, these alterations lead to a significant impairment in SAN automaticity in a dose-dependent manner. Collectively, the findings support the notion that ceramides are not only markers of metabolic derangement, but also active mediators of mitochondrial and metabolic dysfunction in the SAN. Overall, the study provides evidence that ceramides may be a potential therapeutic target for mitigating SAND in HF.

physiology↗

bioRxiv2023

Genetic and pharmacologic alterations of claudin9 levels suffice to induce functional and mature inner hair cells

Hearing loss is the most common form of sensory deficit. It occurs predominantly due to hair cell (HC) loss. Mammalian HCs are terminally differentiated by birth, making HC loss challenging to replace. Here, we show the pharmacogenetic downregulation of Cldn9, a tight junction protein, generates robust supernumerary inner HCs (IHCs) in mice. The ectopic IHC shared functional and synaptic features akin to typical IHCs and were surprisingly and remarkably preserved for at least fifteen months >50% of the mouses life cycle. In vivo, Cldn9 knockdown using shRNA on postnatal days (P) P2-7 yielded analogous functional ectopic IHCs that were equally durably conserved. The findings suggest that Cldn9 levels coordinate embryonic and postnatal HC differentiation, making it a viable target for altering IHC development pre- and post-terminal differentiation.

neuroscience↗

bioRxiv2022

Repressor element 1-silencing transcription factor deficiency yields profound hearing loss through Kv7.4 channel upsurge in auditory neurons and hair cells

Repressor element 1-silencing transcription factor (REST) is a transcriptional repressor that recognizes neuron-restrictive silencer elements in the mammalian genomes in a tissue- and cell-specific manner. The identity of REST target genes and molecular details of how REST regulates them are emerging. We performed conditional null deletion of Rest (cKO) in murine hair cells (HCs) and auditory neurons, spiral ganglion neurons (SGNs). Null-deletion of full-length REST resulted in normal HCs and SGNs development but manifested with progressive hearing loss in adulthood. We found that deletion of REST results in an increased abundance of Kv7.4 channels at the transcript, protein, and function levels. Specifically, we found that SGNs and HCs from Rest cKO mice displayed increased Kv7.4 expression and augmented Kv7 currents; SGNs excitability was also significantly reduced. Administration of Kv7.4 channel activator, fasudil, recapitulated progressive hearing loss in mice. In contrast, inhibition of the Kv7.4 channel by XE991 rescued the auditory phenotype of Rest cKO mice. Previous studies identified some loss-of-function mutations within the Kv7.4-coding gene, Kcnq4, as a causative factor for progressive hearing loss in mice and humans. Thus, the present findings revealed that a critical homeostatic Kv7.4 channel level is required for proper auditory functions.

neuroscience↗

bioRxiv2021

ISL1 is an essential determinant of structural and functional tonotopic representation of sound

A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1Cre strategies. In the absence of Isl1, spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central compensatory plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.

neuroscience↗

bioRxiv2021

Intrinsic mechanical sensitivity of auditory neurons as a contributor to sound-driven neural activity

Mechanosensation - by which mechanical stimuli are converted into a neuronal signal - is the basis for the sensory systems of hearing, balance, and touch. Mechanosensation is unmatched in speed and its diverse range of sensitivities, reaching its highest temporal limits with the sense of hearing; however, hair cells (HCs) and the auditory nerve (AN) serve as obligatory bottlenecks for sounds to engage the brain. Like other sensory neurons, auditory neurons use the canonical pathway for neurotransmission and millisecond-duration action potentials (APs). How the auditory system utilizes the relatively slow transmission mechanisms to achieve ultrafast speed and high audio-frequency hearing remains an enigma. Here, we address this paradox and report that the AN is mechanically sensitive, and minute mechanical displacement profoundly affects its response properties. Sound-mimicking sinusoidal mechanical and electrical current stimuli affect phase-locked responses. In a phase-dependent manner, the two stimuli can also evoke suppressive responses. We propose that mechanical sensitivity interacts with synaptic responses to shape responses in the AN, including frequency tuning and temporal phase-locking. The combination of neurotransmission and mechanical sensation to control spike patterns gives the AN a secondary receptor role, an emerging theme in primary neuronal functions.

neuroscience↗