Biology subjects

Shabir, O.

Publications and source records attributed to Shabir, O..

7 recordsLinked to original sources

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↗

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

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↗