Biology subjects

Howarth, C.

Publications and source records attributed to Howarth, C..

14 recordsLinked to original sources

bioRxiv2026

Epidermal microstructure and tactile sensitivity in the glabrous skin of hands and feet

Glabrous skin on the human palms and soles is specialised for mechanical interaction and is characterised by papillary ridges, an absence of hair follicles, and a thick stratum corneum. While gross morphological differences, such as the increased thickness of the plantar stratum corneum, are well-documented, the fine-scale structural features associated with individual ridges and whether they help explain differences in tactile perception remain poorly understood. Here, we employed optical coherence tomography, automated image segmentation, and 3D reconstruction to generate high-resolution models of the stratum corneum and viable epidermis across six sites on the hand and foot for 27 participants. Our morphological analysis revealed that while the stratum corneum was thicker on the foot sole than the hand, the thickness of the viable epidermis remained remarkably consistent across all sites. Furthermore, papillary ridge width increased in a distal-to-proximal fashion and was larger on the foot. We also found that internal ridge architecture was considerably more pronounced than the topography observable on the skin surface. Correlating these structural parameters with psychophysical measures, specifically absolute force and two-point discrimination thresholds, demonstrated distinct drivers for tactile sensitivity. Force thresholds were primarily governed by a combination of skin thickness and innervation density, and additionally on the foot by papillary ridge width and internal ridge depth. In contrast, spatial acuity was best predicted by innervation and papillary ridge width. These findings provide a precise quantification of glabrous skin morphology and offer new insights into the process of mechanotransduction by highlighting how tissue architecture might contribute to human tactile perception.

neuroscience↗

bioRxiv2025

Disassociating cerebral vasomotion from low frequency spontaneous neurovascular coupling

Vasomotion, vascular oscillations at [~]0.1 Hz, may serve as a biomarker and therapeutic target for neurodegenerative diseases, but its origins, structure across brain vasculature, and correlation with neural activity remain unclear. This study examined the spatiotemporal characteristics of cerebral vasomotion and its relationship to neural activity in anaesthetised Hooded Lister rats using simultaneous recordings of neuronal activity and haemodynamics in motor and whisker barrel cortices. In a subset of rats, tissue oxygen was also measured. Blood pressure was pharmacologically modulated to alter vascular oscillations. We found that vasomotion was driven by the arterial tree. Two prominent activity patterns emerged: global vasomotion across the entire hemisphere and phasic vasomotion seen as a travelling wave running through the surface arteries. Moreover, vasomotion was associated with low tissue oxygen and was largely independent of spontaneous neural activity and therefore not a product of neurovascular coupling.

neuroscience↗

bioRxiv2024

Characterizing vascular function in mouse models of Alzheimer's disease, atherosclerosis, and mixed Alzheimer's and atherosclerosis

SignificanceAlzheimers disease does not occur in isolation and there are many comorbidities associated with the disease - especially diseases of the vasculature. Atherosclerosis is a known risk factor for the subsequent development of Alzheimers disease, therefore understanding how both diseases interact will provide a greater understanding of co-morbid disease progression and aid the development of potential new treatments. AimThe current study characterizes hemodynamic responses and cognitive performance in APP/PS1 Alzheimers mice, atherosclerosis mice, and a mixed disease group (APP/PS1 & atherosclerosis) between the ages of 9 and 12 months. ApproachWhisker-evoked hemodynamic responses and recognition memory were assessed in awake mice, immunohistochemistry to assess amyloid pathology, and histology to characterize atherosclerotic plaque load. ResultsWe observed hemodynamic deficits in atherosclerosis mice (vs Alzheimers, mixed disease or wild-type mice), with reduced short-duration stimulus-evoked hemodynamic responses occurring when there was no concurrent locomotion during the stimulation period. Mixed Alzheimers and atherosclerosis models did not show differences in amyloid beta coverage in the cortex or hippocampus or atherosclerotic plaque burden in the aortic arch vs relevant Alzheimers or atherosclerosis controls. Consistent with the subtle vascular deficits and no pathology differences, we also observed no difference in performance on the novel object recognition task across groups. ConclusionsThese results emphasize the importance of experimental design for characterizing vascular function across disease groups, as locomotion and stimulus duration impacted the ability to detect differences between groups. Whilst atherosclerosis did reduce hemodynamic responses, these were recovered in the presence of co-occurring Alzheimers disease which may provide targets for future studies to explore the potentially contrasting vasodilatory mechanisms these diseases impact.

neuroscience↗

bioRxiv2024

Voluntary locomotion induces an early and remote hemodynamic decrease in the large cerebral veins

SignificanceBehavior regulates dural and cerebral vessels, with spontaneous locomotion inducing dural vessel constriction and increasing stimulus-evoked cerebral hemodynamic responses. It is vital to investigate the function of different vascular network components, surrounding and within the brain, to better understand the role of the neurovascular unit in health and neurodegeneration. AimWe characterized locomotion-induced hemodynamic responses across vascular compartments of the whisker barrel cortex: artery, vein, parenchyma, draining and meningeal vein. ApproachUsing 2D-OIS, hemodynamic responses during locomotion were recorded in 9-12-month-old awake mice: wild-type, Alzheimers disease (AD), atherosclerosis or mixed (atherosclerosis/AD) models. Within somatosensory cortex, responses were taken from pial vessels inside the whisker barrel region ([WBR]: "whisker artery" and "whisker vein"), a large vein from the sagittal sinus adjacent to the WBR (draining vein), and meningeal vessels from the dura mater (which do not penetrate cortical tissue). ResultsWe demonstrate that locomotion evokes an initial decrease in total hemoglobin (HbT) within the draining vein before the increase in HbT within WBR vessels. The locomotion event size influences the magnitude of the HbT increase in the pial vessels of the WBR, but not of the early HbT decrease within the draining veins. Following locomotion onset, an early HbT decrease was also observed in the overlying meningeal vessels, which unlike within the cortex did not go on to exceed baseline HbT levels during the remainder of the locomotion response. We show that locomotion-induced hemodynamic responses are altered in disease in the draining vein and whisker artery, suggesting this could be an important neurodegeneration biomarker. ConclusionThis initial reduction in HbT within the draining and meningeal veins potentially serves as a space saving mechanism, allowing for large increases in cortical HbT associated with locomotion. Given this mechanism is impacted by disease it may provide an important target for vascular-based therapeutic interventions.

neuroscience↗

bioRxiv2024

A pangenome and pantranscriptome of hexaploid oat

Oat grain is a traditional human food rich in dietary fiber that contributes to improved human health. Interest in the crop has surged in recent years owing to its use as the basis for plant-based milk analogs. Oat is an allohexaploid with a large, repeat-rich genome that was shaped by subgenome exchanges over evolutionary timescales. In contrast to many other cereal species, genomic research in oat is still at an early stage, and surveys of structural genome diversity and gene expression variability are scarce. Here, we present annotated chromosome-scale sequence assemblies of 33 wild and domesticated oats along with an atlas of gene expression across six tissues of different developmental stages in 23 accessions. We describe the interplay of gene expression diversity across subgenomes, accessions and tissues. Gene loss in the hexaploid is accompanied by compensatory up-regulation of the remaining homeologs, but this process is constrained by subgenome divergence. Chromosomal rearrangements have significantly impacted recent oat breeding. A large pericentric inversion associated with early flowering explains distorted segregation on chromosome 7D and a homeologous sequence exchange between chromosomes 2A and 2C in a semidwarf mutant has risen to prominence in Australian elite varieties. The oat pangeome will promote the adoption of genomic approaches to understanding the evolution and adaptation of domesticated oats and will accelerate their improvement.

genomics↗

bioRxiv2022

Nitric oxide is not responsible for the initial sensory-induced neurovascular coupling response in mouse cortex.

Neurovascular coupling ensures that changes in neural activity are accompanied by localised changes in cerebral blood flow. While much is known about the involvement of excitatory neurons in neurovascular coupling, the role of inhibitory interneurons is unresolved. While nNOS-expressing interneurons have been shown to be capable of eliciting vasodilation, the role of nitric oxide in functional hyperemia remains a matter of debate. Therefore in the present study we applied a combination of optogenetic and pharmacological approaches, 2-dimensional optical imaging spectroscopy, and electrophysiology to investigate the role of nitric oxide in neurovascular coupling responses evoked by nNOS-expressing interneurons and whisker stimulation in mouse sensory cortex. The haemodynamic response evoked by nNOS-expressing interneurons was significantly altered in the presence of the NOS inhibitor LNAME, revealing a large initial 20-HETE-dependent vasoconstriction. In contrast, the haemodynamic response induced by sensory stimulation was largely unchanged by LNAME. Our results suggest that while nitric oxide plays a key role in neurovascular responses evoked by nNOS-expressing interneurons it does not mediate the initial sensory-induced neurovascular coupling response in mouse cortex. Thus, our results call into question the involvement of nNOS-expressing interneurons and nitric oxide in sensory-evoked functional hyperemia.

neuroscience↗

bioRxiv2022

Bidirectional alterations in brain temperature profoundly modulate spatiotemporal neurovascular responses in-vivo: Implications for theragnostics

Neurovascular coupling (NVC) is a mechanism that, amongst other known and latent critical functions, ensures activated brain regions are adequately supplied with oxygen and glucose. This biological phenomenon underpins non-invasive perfusion-related neuroimaging techniques and recent reports have implicated NVC impairment in several neurodegenerative disorders. Yet, much remains unknown regarding NVC in health and disease, and only recently has there been burgeoning recognition of a close interplay with brain thermodynamics. Accordingly, we developed a novel multi-modal approach to systematically modulate cortical temperature and interrogate the spatiotemporal dynamics of sensory-evoked NVC. We show that changes in cortical temperature profoundly and intricately modulate NVC, with low temperatures associated with diminished oxygen delivery, and high temperatures inducing a distinct vascular oscillation. These observations provide novel insights into the relationship between NVC and brain thermodynamics, with important implications for brain-temperature related therapies, functional biomarkers of elevated brain temperature, and in-vivo methods to study neurovascular coupling.

neuroscience↗

bioRxiv2021

The effects of locomotion on sensory-evoked haemodynamic responses in the cortex of awake mice

Investigating neurovascular coupling in awake rodents is becoming ever more popular due, in part, to our increasing knowledge of the profound impacts that anaesthesia can have upon brain physiology. Although awake imaging brings with it many advantages, we still do not fully understand how voluntary locomotion during imaging affects sensory-evoked haemodynamic responses. In this study we investigated how evoked haemodynamic responses can be affected by the amount and timing of locomotion. Using an awake imaging set up, we used 2D-Optical Imaging Spectroscopy (2D-OIS) to measure changes in cerebral haemodynamics within the sensory cortex of the brain during either 2s whisker stimulation or spontaneous (no whisker stimulation) experiments, whilst animals could walk on a spherical treadmill. We show that locomotion alters haemodynamic responses. The amount and timing of locomotion relative to whisker stimulation is important, and can significantly impact sensory-evoked haemodynamic responses. If locomotion occurred before or during whisker stimulation, the amplitude of the stimulus-evoked haemodynamic response was significantly altered. Therefore, monitoring of locomotion during awake imaging is necessary to ensure that conclusions based on comparisons of evoked haemodynamic responses (e.g., between control and disease groups) are not confounded by the effects of locomotion.

neuroscience↗

bioRxiv2020

Assessment of Neurovascular Coupling & Cortical Spreading Depression in Mixed Models of Atherosclerosis & Alzheimer's Disease

Neurovascular coupling is a critical brain mechanism whereby changes to blood flow accompany localised neural activity. The breakdown of neurovascular coupling is linked to the development and progression of several neurological conditions including dementia. In this study, we examined cortical haemodynamics in preparations that modelled Alzheimers disease (J20-AD) and atherosclerosis (PCSK9-ATH) between 9-12m of age. We report novel findings with atherosclerosis where neurovascular decline is characterised by significantly reduced blood volume, levels of oxyhaemoglobin & deoxyhaemoglobin, in addition to global neuroinflammation. In the comorbid mixed model (J20-PCSK9-MIX), we report a 3x fold increase in hippocampal amyloid-beta plaques. A key finding was that cortical spreading depression (CSD) due to electrode insertion into the brain was worse in the diseased animals and led to a prolonged period of hypoxia. These findings suggest that systemic atherosclerosis can be detrimental to neurovascular health and that having cardiovascular comorbidities can exacerbate pre-existing Alzheimers-related amyloid-plaques.

neuroscience↗

bioRxiv2020

Neurovascular Function in a Novel Model of Experimental Atherosclerosis

ObjectiveAtherosclerosis is a major risk factor for dementia. The aims of this study were to determine if experimental atherosclerosis leads to altered neurovascular function and causes neurovascular damage. Approach and ResultsWe analysed cerebral blood volume in male C57BL6/J mice injected with an adeno-associated virus (AAV) vector for mutated proprotein convertase subtilisin/kexin type 9 (PCSK9D377Y) fed a Western diet for 35 weeks to induce atherosclerosis (ATH) and 9-12m male wild-type (WT) C57BL/6J. We imaged blood volume responses to sensory stimulation and vascular reactivity gas challenges in the cortex of the brain through a thinned cranial window using 2D-optical imaging spectroscopy (2D-OIS). Neural activity was also recorded with multi-channel electrodes. Stimulation-evoked cortical haemodynamics, in terms of cerebral blood volume, were significantly reduced in ATH mice compared to WT and evoked neural activity was also significantly lower. However, vascular reactivity as assessed by 10% hypercapnia, remained intact in ATH mice. Immunohistochemistry in ATH mice revealed a reduced number of cortical neurons and pericytes in the cortex, but increased astrogliosis. qRT-PCR revealed significantly enhanced TNF & IL1{beta} in ATH mice compared to WT as well as significant upregulation of eNOS. ConclusionSystemic atherosclerosis causes significant neurovascular decline by 9m in atherosclerotic mice characterised by reduced neural activity, associated with loss of neurons and subsequent reduced cortical haemodynamics in response to physiological stimulations. The altered neurovascular function in ATH mice is chiefly mediated by TNF. HighlightsO_LISystemic atherosclerosis leads to significantly reduced stimulus-evoked hemodynamic responses in the cortex by 9m of age in the rAAV8-mPCSK9-D377Y mouse model of atherosclerosis compared to wild-type controls. C_LIO_LIReduced cerebral haemodynamics are related to reduced neural activity in the cortex that could be due to a loss of cortical neurons potentially caused by significant TNFa-mediated neuroinflammation. C_LI

neuroscience↗

bioRxiv2019

Enhanced Cerebral Blood Volume under Normobaric Hyperoxia in the J20-hAPP Mouse Model of Alzheimer's Disease

Early impairments to neurovascular coupling have been proposed to be a key pathogenic factor in the onset and progression of Alzheimers disease (AD). Studies have shown impaired neurovascular function in several mouse models of AD, including the J20-hAPP mouse. In this study, we aimed to investigate early neurovascular changes using wild-type (WT) controls and J20-hAPP mice at 6-9 months of age, by measuring cerebral haemodynamics and neural activity to physiological sensory stimulations. A thinned cranial window was prepared to allow access to cortical vasculature and imaged using 2D-optical imaging spectroscopy (2D-OIS). After chronic imaging sessions where the skull was intact, a terminal acute imaging session was performed where an electrode was inserted into the brain to record simultaneous neural activity. We found that cerebral haemodynamic changes were significantly enhanced in J20-hAPP mice compared with controls in response to physiological stimulations, potentially due to the significantly higher neural activity (hyperexcitability) seen in the J20-hAPP mice. Thus, neurovascular coupling remained preserved under a chronic imaging preparation. Further, under hyperoxia, the baseline blood volume and saturation of all vascular compartments in the brains of J20-hAPP mice were substantially enhanced compared to WT controls, but this effect disappeared under normoxic conditions. This study highlights novel findings not previously seen in the J20-hAPP mouse model, and may point towards a potential therapeutic strategy by driving an increased baseline blood flow to the brain, thereby potentially enhancing the clearance of beta-amyloid.

neuroscience↗

bioRxiv2019

Sodium nitroprusside prevents the detrimental effects of glucose on the neurovascular unit and behaviour in zebrafish

Diabetes is associated with dysfunction of the neurovascular unit, although the mechanisms of this are incompletely understood, and currently no treatment exists to prevent these negative effects. We previously found that the NO donor sodium nitroprusside (SNP) prevents the detrimental effect of glucose on neurovascular coupling in zebrafish. We therefore sought to establish the wider effects of glucose exposure on both the neurovascular unit and on behaviour in zebrafish and the ability of SNP to prevent these.\n\nWe incubated 4 days post fertilisation (dpf) zebrafish embryos in 20mM glucose or mannitol for five days until 9dpf, with or without 0.1mM SNP co-treatment for 24h (8-9dpf), and quantified vascular nitric oxide reactivity, vascular mural cell number, expression of a klf2a reporter, glial fibrillary acidic protein (GFAP) and TRPV4, as well as spontaneous neuronal activation at 9dpf, all in the optic tectum. We also assessed the effect on light/dark preference and locomotory characteristics during free-swimming studies.\n\nWe find that glucose exposure significantly reduced nitric oxide reactivity, klf2a reporter expression, vascular mural cell number and TRPV4 expression, while significantly increasing spontaneous neuronal activation and GFAP expression (all in the optic tectum). Furthermore, when we examined larval behaviour we found glucose exposure significantly altered light/dark preference and high and low speed locomotion while in light. Co-treatment with SNP reversed all these molecular and behavioural effects of glucose exposure.\n\nOur findings comprehensively describe the negative effects of glucose exposure on the vascular anatomy, molecular phenotype, and function of the optic tectum and on whole organism behaviour. We also show that SNP or other NO donors may represent a therapeutic strategy to ameliorate the complications of diabetes on the neurovascular unit.

neuroscience↗

bioRxiv2019

Key aspects of neurovascular control mediated by specific populations of inhibitory cortical interneurons

Inhibitory interneurons can evoke vasodilation and vasoconstriction, making them potential cellular drivers of neurovascular coupling. However, the specific regulatory roles played by particular interneuron subpopulations remain unclear. Our purpose was therefore to adopt a cell-specific optogenetic approach to investigate how somatostatin (SST) and neuronal nitric oxide synthase (NOS1)-expressing interneurons might influence neurovascular relationships. In mice, specific activation of SST- or NOS1-interneurons was sufficient to evoke haemodynamic changes similar to those evoked by physiological whisker stimulation. In the case of NOS1-interneurons, robust haemodynamic changes occurred with minimal changes in neural activity. Conversely, activation of SST-interneurons produced robust changes in evoked neural activity with shallow cortical excitation and pronounced deep layer cortical inhibition. This often resulted in a central increase in blood volume with corresponding surround decrease, analogous to the negative BOLD signal. These results demonstrate the role of specific populations of cortical interneurons in the active control of neurovascular function.

neuroscience↗

bioRxiv2018

Neurovascular coupling preserved in a chronic mouse model of Alzheimers disease: Methodology is critical.

Neurovascular coupling is the process by which neural activity causes localised changes in cerebral blood flow. Impaired neurovascular coupling has been suggested as an early pathogenic factor in Alzheimers disease (AD), and if so, could serve as an early biomarker of cerebral pathology. We have established an anaesthetic regime in which evoked hemodynamic responses are comparable to those in awake mice. This protocol was adapted to allow repeated measurements of neurovascular function over three months in the hAPP-J20 mouse model of AD (J20-AD) and wild-type (WT) controls. Animals were 9-12 months old at the start of the experiment, which is when deficits due to the disease condition would be expected. Mice were chronically prepared with a cranial window through which optical imaging spectroscopy (OIS) was used to generate functional maps of the cerebral blood volume and saturation changes evoked by whisker stimulation and vascular reactivity challenges. Unexpectedly, the hemodynamic responses were largely preserved in the J20-AD group. This result failed to confirm previous investigations using the J20-AD model. However, a final acute electrophysiology and OIS experiment was performed to measure both neural and hemodynamic responses concurrently. In this experiment, previously reported deficits in neurovascular coupling in the J20-AD model were observed. This suggests that J20-AD mice may be more susceptible to the physiologically stressing conditions of an acute experimental procedure compared to WT animals. These results therefore highlight the importance of experimental procedure when determining the characteristics of animal models of human disease.\n\nSignificance StatementUsing a chronic anaesthetised preparation, we measured hemodynamic responses evoked by sensory stimulation and respiratory gases in the J20-AD mouse model of Alzheimers Disease over a period of 3 months. We showed that neurovascular responses were preserved compared to age matched wildtype controls. These results failed to confirm previous investigations reporting a marked reduction of neurovascular coupling in the J20-AD mouse model. However, when our procedure involved acute surgical procedures, previously reported neurovascular deficits were observed. The effects of acute electrode implantation were caused by disturbances to baseline physiology rather than a consequence of the disease condition. These results highlight the importance of experimental procedure when determining the characteristics of animal models of human disease.

neuroscience↗