Biology subjects

Holt, A. G.

Publications and source records attributed to Holt, A. G..

11 recordsLinked to original sources

bioRxiv2026

Repeated Inertial Stimulation Reveals Divergent Plasticity in Peripheral and Central Vestibular Pathways

The vestibular system consists of peripheral end organs that provide the brain with temporally precise information about head position in space required for motor coordination and postural stability. Irregular vestibular afferents of the inner ear are particularly sensitive to rapid changes in acceleration, or jerk, which is necessary for making quick, corrective movements and postural adjustments. Vestibular short-latency evoked potentials (VsEPs) are waveforms that provide a measure of synchronous irregular afferent activity originating from peripheral (early peaks) and central (later peaks) vestibular pathways. These VsEPs are elicited by head jerk stimuli, commonly used preclinically. Previous studies have shown that early VsEP waves are dependent upon jerks of an adequate intensity, number, and duration. However, less is known about jerk characteristics necessary for generation of reliable VsEP signals centrally (later peaks). The present study examines the precise temporal dynamics of peripheral and central vestibular centers across a broad range of mechanical vestibular load in rats. We found differential changes in synchrony and timing driven by jerk repetition, intensity, and duration between early and late VsEP waves representing distinct anatomical components of the vestibular circuit. Our results suggest that central components are uniquely sensitive to jerk duration, intensity, and repetition, indicating a disconnect between peripheral and central neuronal recruitment, adaptive plasticity, and time-frequency dynamics. This work provides a foundation for using VsEP to assess jerk-induced physiological vestibular dysfunction and to understand how central relays differentially adapt to variations of mechanical vestibular stress compared with the precise, high-fidelity transmission observed in the periphery.

neuroscience↗

bioRxiv2025

The Effects of Living at Altitude on the Prevalence of Dementia

A lower incidence of dementia has been observed in populations residing at high altitudes compared to those at low altitudes. A possible cause is the inverse relationship between altitude and the partial pressure of inspired oxygen. This paper investigates the long term impact that living at altitude has on mitochondrial function. We use simulation methods to model the dynamics of a population of mtDNA and the proliferation of deletion mutants. Clonal expansion of these deletion mutants over many years impairs mitochondrial function resulting in cell death, notably in post-mitotic cells such as neurons. Neuron loss leads to cognitive impairment, progressing to dementia over time. Our results show that there is a moderate reduction in neuron loss rates and associated cognitive decline with respect to dementia in the elderly. These results are consistent with published data on the regional prevalence of dementia when plotted against altitude.

evolutionary biology↗

bioRxiv2024

Impact of mitochondrial fission and fusion onneuronal health and incidence of dementia

Mitochondria are highly dynamic structures that undergo constant remodeling by the process of fission and fusion. Using simulation methods we study the effects of neuron loss in humans due to the proliferation of deletion mutations. We implement two models of an organelle, namely, closed cristae (CC) and open mitochondrion (OM). With CC, mtDNA are confined to a cristae unless mixed by the process of fission and fusion. Conversely, mtDNA can diffuse freely throughout the organelle in the OM model. We also implement selective mitophagy in the CC model. Higher rates of mixing mtDNA increase the rate of neuron loss which, in turn, increases the prevalence of dementia. Selective mitophagy mitigates against the effect of high rate mixing. However, this mitigation is all or nothing. Even at nominal rates compared to mixing, neuron loss is almost completely eliminated resulting in minimal cognitive decline. These results do not fit the observations of normal aging and dementia prevalence in the elderly human population. This study brings into question the role that fission and fusion is believed play in the removal of defective mtDNA.

cell biology↗

bioRxiv2024

Stimulation of otolith irregular fibers produces a rostro-caudal gradient in activity in the vestibular nuclear complex (VNC), but not the vestibulocerebellum (VeCb)

The vestibular system is important for posture, balance, motor control, and spatial orientation. Each of the vestibular end organs have specialized neuroepithelia with both regular and irregular afferents. In otolith organs, the utricle and saccule, afferents most responsive to linear jerk (jerk - derivative of acceleration) are located in the striola and project centrally to the vestibular nuclear complex (VNC) as well as the uvula and nodulus of the vestibulocerebellum (VeCb). The pattern of central neuronal activation attributed to otolith irregular afferents is relatively unknown. To address this gap, c-Fos was used as a marker of neuronal activity to map the distribution of active neurons throughout the rostro-caudal extent of the VNC and VeCb. Immunohistochemistry for c-Fos was performed to assess activation of VNC and VeCb neurons in response to a linear jerk stimulus delivered in the naso-occipital plane. Activated neurons were distributed throughout the VNC, including the lateral vestibular nucleus (LVe), magnocellular medial vestibular nucleus (MVeMC), parvocellular medial vestibular nucleus (MVePC), spinal vestibular nucleus (SpVe), and superior vestibular nucleus (SuVe). Notably, after stimulation, the MVePC exhibited the greatest number of c-Fos labeled nuclei. Significant increases in c-Fos labeling were found in mid-rostrocaudal and caudal regions of the VNC in the LVe, MVe, and SpVe. Additionally, c-Fos labeling was observed across all regions of the VeCb after jerk stimulation. Significant increases in the number of labeled nuclei were found throughout the rostro-caudal extent of the nodulus and uvula. However, jerk stimulated increases in activity for the paraflocculus were restricted to the caudal VeCb. The distribution of neuronal activity suggests that regions receiving the greatest direct otolith input exhibit the most substantial changes in response to otolith derived, irregular fiber stimulation. HighlightsO_LINuclei with descending projections (LVe, MVePC, and SpVe) demonstrated the greatest change in activity after naso-occipital jerk stimulation. C_LIO_LINaso-occipital jerk stimulation preferentially activates caudal VNC neurons C_LIO_LINaso-occipital jerk stimulation activates neurons throughout the VeCb C_LIO_LIJerk stimulation in the naso-occipital plane has the greatest effects on activity in VNC and VeCb regions with the greatest inputs from afferents originating in gravity receptors C_LI

neuroscience↗

bioRxiv2024

Ototoxicity-related Changes in GABA Immunolabeling Within the Rat Inferior Colliculus

Several studies suggest that hearing loss results in changes in the balance between inhibition and excitation in the inferior colliculus (IC). The IC is an integral nucleus within the auditory brainstem. The majority of ascending pathways from the lateral lemniscus (LL), superior olivary complex (SOC), and cochlear nucleus (CN) synapse in the IC before projecting to the thalamus and cortex. Many of these ascending projections provide inhibitory innervation to neurons within the IC. However, the nature and the distribution of this inhibitory input have only been partially elucidated in the rat.The inhibitory neurotransmitter, gamma aminobutyric acid (GABA), from the ventral nucleus of the lateral lemniscus (VNLL), provides the primary inhibitory input to the IC of the rat with GABA from other lemniscal and SOC nuclei providing lesser, but prominent innervation. There is evidence that hearing related conditions can result in dysfunction of IC neurons. These changes may be mediated in part by changes in GABA inputs to IC neurons. We have previously used gene micro-arrays in a study of deafness-related changes in gene expression in the IC and found significant changes in GAD as well as the GABA transporters and GABA receptors (Holt 2005). This is consistent with reports of age and trauma related changes in GABA (Bledsoe et al, 1995; Mossop et al, 2000; Salvi et al, 2000). Ototoxic lesions of the cochlea produced a permanent threshold shift. The number, intensity, and density of GABA positive axon terminals in the IC were compared in normal hearing and deafened rats. While the number of GABA immunolabeled puncta was only minimally different between groups, the intensity of labeling was significantly reduced. The ultrastructural localization and distribution of labeling was also examined. In deafened animals, the number of immuno gold particles was reduced by 78% in axodendritic and 82% in axosomatic GABAergic puncta. The affected puncta were primarily associated with small IC neurons. These results suggest that reduced inhibition to IC neurons contribute to the increased neuronal excitability observed in the IC following noise or drug induced hearing loss. Whether these deafness-diminished inhibitory inputs originate from intrinsic or extrinsic CNIC sources awaits further study.

neuroscience↗

bioRxiv2024

L-type calcium channel blockade with verapamil prevents noise induced neuronal dyssynchrony

Previous studies have established the protective effects of calcium channel blockade on the peripheral auditory system in response to noise exposure. While these studies implicate L-type calcium channels (LTCCs) in noise generated dysfunction in the auditory periphery, contributions of LTCCs to noise-induced central dysfunction remains unclear. To begin to elucidate the roles of LTCCs in hearing, peripheral and central auditory function were assessed longitudinally after LTCC blockade. Neuronal synchrony and activity were assessed by analyzing wave I (peripheral) and wave V (central) auditory brainstem responses (ABRs). Just prior to a noise exposure resulting in a temporary shift in hearing thresholds, rats were administered verapamil (LTCC blocker) or saline. Verapamil administration prevented the noise-induced decrease in ABR wave I and V amplitudes. Interestingly, when non-noise exposed animals were administered verapamil, wave V amplitude decreased, suggesting that LTCCs are critical for neuronal synchrony in the inferior colliculus. The inferior colliculus mediates inhibition of the acoustic startle reflex (giASR). Following noise exposure giASR was enhanced, but the enhancement was not prevented by LTCC blockade. These results suggest that while LTCCs are necessary for auditory-related synchronous activity, these channels do not contribute to noise-induced hyperactivity in the inferior colliculus.

neuroscience↗

bioRxiv2023

Using Manganese Enhanced Magnetic Resonance Imaging (MEMRI) to Assess Calcium Dependent Activity in Vestibular Pathways Following Linear Acceleration

Reliable methods for repetitive and longitudinal assessment of central vestibular pathway function in vivo are rather limited. Manganese-enhanced magnetic resonance imaging (MEMRI) has been used in various sensory systems to evaluate neuronal activity in central pathways, but MEMRI assessment of central vestibular pathways has been minimal. The present study addressed this gap in knowledge by assessing whether Mn2+ can be taken up in an activity-dependent manner through voltage-gated calcium channels in the vestibular nuclear complex (VNC) and the vestibulocerebellum (VeCb) of rats with and without mild linear acceleration stimulation. R1 maps were collected prior to, one day after, and two weeks after Mn2+ administration in stimulated and non-stimulated rats. Analysis of MRI R1 values showed that one day after Mn2+ administration the VNC and VeCb had significantly greater R1 values that returned to baseline levels after two weeks. Non-stimulated rats had greater R1 values than stimulated rats. Mid rostro-caudal sections of the VNC had greater R1 values than rostral and caudal VNC sections. R1 values also indicated that Mn2+ was differentially taken up across subdivisions of the VNC and VeCb. These results correlate well with expected patterns of neuronal activity after linear acceleration. MEMRI is a sensitive tool that may be used to evaluate activity patterns in central vestibular nuclei, proving useful for studying underlying mechanisms of central vestibular dysfunction.

neuroscience↗

bioRxiv2023

The long term effects of uncoupling interventions as a therapy for dementia in humans

In this paper we use simulation methods to study a hypothetical uncoupling agent as a therapy for dementia. We simulate the proliferation of mitochondrial deletion mutants amongst a population of wild-type in human neurons. Mitochondria play a key role in ATP generation. Clonal expansion can lead to the wild-type being overwhelmed by deletions such that a diminished population can no longer fulfill a cells energy requirement, eventually leading its demise. The intention of uncoupling is to reduce the formation of deletion mutants by reducing mutation rate. However, a consequence of uncoupling is that the energy production efficacy is also reduced which in turn increases wild-type copy number in order to compensate for the energy deficit. The results of this paper showed that uncoupling reduced the severity of dementia, however, there was some increase in cognitive dysfunction pre-onset of dementia. The effectiveness of uncoupling was dependent upon the timing of intervention relative to the onset of dementia and would necessitate predicting its onset many years in advance.

systems biology↗

bioRxiv2023

The prevalence of dementia in humans could be the result of a functional adaptation

In this paper we propose that high copy number of the mitochondrial genome in neurons is a functional adaptation. We simulated the proliferation of deletion mutants of the human mitochondrial genome in a virtual mitochondrion and recorded the cell loss rates due to deletions overwhelming the wild-type. Our results showed that cell loss increased with mtDNA copy number. Given that neuron loss equates to cognitive dysfunction, it would seem counter-intuitive that there would be a selective pressure for high copy number over low. However, for a low copy number, the onset of cognitive decline, while mild, started early in life. Whereas, for high copy number, it did not start until middle age but progressed rapidly. There could have been an advantage to high copy number in the brain if it delayed the onset of cognitive decline until after reproductive age. The prevalence of dementia in our aged population is a consequence of this functional adaptation.

evolutionary biology↗

bioRxiv2022

A comparison of mtDNA deletion mutant proliferation mechanisms

In this paper we use simulation methods to investigate the proliferation of deletion mutations of mitochondrial DNA in neurons. We simulate three mtDNA proliferation mechanisms, namely, random drift, replicative advantage and vicious cycle. For each mechanism, we investigated the effect mutation rates have on neuron loss within a human host. We also compare heteroplasmy of each mechanism at mutation rates that yield the levels neuron loss that would be associated with dementia. Both random drift and vicious cycle predicted high levels of heteroplasmy, while replicative advantage showed a small number of dominant clones with a low background of heteroplasmy.

systems biology↗

bioRxiv2020

The significance of mitochondrial DNA half-life to the lifespan of post-mitotic cells

The proliferation of mitochondrial DNA (mtDNA) with deletion mutations has been linked to aging, and age related neurodegenerative conditions. In this study we model effect of mtDNA half-life on mtDNA competition and selection. Individual cells effectively form a closed ecosystem containing a large population of independently replicating mtDNA. We would expect competition and selection to occur between wild type mtDNA and various mutant variants. There is a symbiotic relationship between the cell and the mitochondria, and unrestricted mtDNA replication would be detrimental to the host cell. Deletion mutations of mtDNA are relatively common and give a replication advantage to the shorter sequence, as this could be lethal to the host cell, we would expect to see differences in mtDNA replication in short and long lived cells. In this paper, we use a computer simulation of mtDNA replication, where mtDNA sequences may undergo deletion errors and give rise to mutant species that can compete with the wild type. This study focuses on longer lived cells where the wild type mtDNA is expected to be more susceptible to displacement by mutants. Our simulations confirm that deletion mutations have a replication advantage over the wild type due to decreased replication time. Wild type survival times diminished with increased mutation probabilities. The relationship between survival time and mutation rate was non-linear; a ten-fold increase in mutation probability resulted in a halving in wild type survival time. In contrast a modest increase in the mtDNA half-life had a profound affect on the wild type survival time in the presence of deletion mutants, thereby, mitigating the replicative advantage of shorter sequence mutations. Given the relevance of mitochondrial dysfunction to various neurodegenerative conditions, we propose that therapies to increase mtDNA half-life could be a therapeutic strategy.

cell biology↗