Biology subjects

Howarth, C.

Publications and source records attributed to Howarth, C..

3 recordsLinked to original sources

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↗