Biology subjects

Drew, P. J.

Publications and source records attributed to Drew, P. J..

24 records · Page 2Linked to original sources

bioRxiv2020

Arterial pulsations drive oscillatory flow of CSF but not directional pumping

The brain lacks a traditional lymphatic system for metabolite clearance. The existence a "glymphatic system" where metabolites are removed from the brains extracellular space by convective exchange between interstitial fluid (ISF) and cerebrospinal fluid (CSF) along the paravascular spaces (PVS) around cerebral blood vessels has been controversial for nearly a decade. While recent work has shown clear evidence of directional flow of CSF in the PVS in anesthetized mice, the driving force for the observed fluid flow remains elusive. The heartbeat-driven peristaltic pulsation of arteries has been proposed as a probable driver of directed CSF flow. In this study, we use rigorous fluid dynamic simulations to provide a physical interpretation for peristaltic pumping of fluids. Our simulations match the experimental results and show that arterial pulsations only drive oscillatory motion of CSF in the PVS. The observed directional CSF flow can be explained by naturally occurring and/or experimenter-generated pressure differences.

neuroscience↗

bioRxiv2019

Functional hyperemia drives fluid exchange in the paravascular space

Maintaining the ionic and chemical composition of the extracellular spaces in the brain is extremely important for its health and function. However, the brain lacks a conventional lymphatic system to remove metabolic waste. It has been proposed that the fluid movement through the paravascular space (PVS) surrounding penetrating arteries can help remove metabolites from the brain. The dynamics of fluid movement in the PVS and its interaction with arterial dilation and brain mechanics are not well understood. Here, we performed simulations to understand how arterial pulsations and dilations interact with brain deformability to drive fluid flow in the PVS. In simulations with compliant brain tissue, arterial pulsations did not drive appreciable flows in the PVS. In contrast, when the artery dilated with dynamics like those seen during functional hyperemia, there was a marked movement of fluid through the PVS. Our simulations suggest that in addition to its other purposes, functional hyperemia may serve to increase fluid exchange between the PVS and the subarachnoid space, improving the clearance of metabolic waste. We measured displacement of the blood vessels and the brain tissue simultaneously in awake, head-fixed mice using two-photon microscopy. Our measurements show that brain tissue can deform in response to fluid movement in the PVS, as predicted by simulations. The results from our simulations and experiments show that the deformability of the soft brain tissue needs to be accounted for when studying fluid flow and metabolite transport in the brain.

neuroscience↗

bioRxiv2019

Spatial and temporal patterns of nitric oxide diffusion and degradation drive emergent cerebrovascular dynamics

Nitric oxide (NO) is a gaseous signaling molecule that plays an important role in neurovascular coupling. NO produced by neurons diffuses into the smooth muscle surrounding cerebral arterioles, driving vasodilation. However, the rate of NO degradation in hemoglobin is orders of magnitude higher than in brain tissue, though how this might impact NO signaling dynamics is not completely understood. We used simulations to investigate how the spatial and temporal patterns of NO generation and degradation impacted dilation of a penetrating arteriole in cortex. We found that the spatial location of NO production and the size of the vessel both played an important role in determining its responsiveness to NO. The much higher rate of NO degradation and scavenging of NO in the blood relative to the tissue drove emergent vascular dynamics. Large vasodilation events could be followed by post-stimulus constrictions driven by the increased degradation of NO by the blood, and vasomotion-like 0.1-0.3 Hz oscillations could also be generated. We found that these dynamics could be enhanced by elevation of free hemoglobin in the plasma, which occurs in diseases such as malaria and sickle cell anemia, or following blood transfusions. Finally, we show that changes in blood flow during hypoxia or hyperoxia could be explained by altered NO degradation in the parenchyma. Our simulations suggest that many common vascular dynamics may be emergent phenomenon generated by NO degradation by the blood or parenchyma.

neuroscience↗

bioRxiv2019

Cerebral oxygenation during locomotion is modulated by respiration

In the brain, increased neural activity is correlated with an increase of cerebral blood flow and increased tissue oxygenation. However, how cerebral oxygen dynamics are controlled in the behaving animals remains unclear. Here, we investigated to what extent the cerebral oxygenation varies during natural behaviors that change the whole-body homeostasis, specifically exercise. We measured oxygen levels in the cortex of awake, head-fixed mice during locomotion using polarography, spectroscopy, and two-photon phosphorescence lifetime measurements of oxygen sensors. We found that locomotion significantly and globally increases cerebral oxygenation, specifically in areas involved in locomotion, as well as in the frontal cortex and the olfactory bulb. The oxygenation increase persisted when neural activity and functional hyperemia were blocked, occurred both in the tissue and in arteries feeding the brain, and was tightly correlated with respiration rate and the phase of respiration cycle. Thus, respiration provides a dynamic pathway for modulating cerebral oxygenation.

neuroscience↗

bioRxiv2019

An oligarchy of NO-producing interneurons controls basal and evoked blood flow in the cortex

Changes in cortical neural activity are coupled to changes in local arterial diameter and blood flow. However, the neuronal types and the signaling mechanisms that control the basal diameter of cerebral arteries or their evoked dilations are not well understood. Using chronic two-photon microscopy, electrophysiology, chemogenetics, and pharmacology in awake, head-fixed mice, we dissected the cellular mechanisms controlling the basal diameter and evoked dilation in cortical arteries. We found that modulation of overall neural activity up or down caused corresponding increases or decreases in basal arterial diameter. Surprisingly, modulation of pyramidal neuron activity had minimal effects on basal or evoked arterial dilation. Instead, the neurally-mediated component of arterial dilation was largely regulated through nitric oxide released by neuronal nitric oxide synthase (nNOS)-expressing neurons, whose activity was not reflected in electrophysiological measures of population activity. Our results show that cortical hemodynamic signals are not controlled by the average activity of the neural population, but rather the activity of a small oligarchy of neurons.

neuroscience↗

bioRxiv2018

Anatomical basis and physiological role of cerebrospinal fluid transport through the murine cribriform plate

Cerebrospinal fluid (CSF) flows through the brain, transporting chemical signals and removing waste. CSF production in the brain is balanced by a constant outflow of CSF, the anatomical basis of which is poorly understood. Here we characterized the anatomy and physiological function of the CSF outflow pathway along the olfactory sensory nerves through the cribriform plate, and into the nasal epithelia. Chemical ablation of olfactory sensory nerves greatly reduced outflow of CSF through the cribriform plate. The reduction in CSF outflow did not cause an increase in intracranial pressure (ICP), consistent with an alteration in the pattern of CSF drainage or production. Our results suggest that damage to olfactory sensory neurons (such as from air pollution) could contribute to altered CSF turnover and flow, providing a potential mechanism for neurological diseases.

neuroscience↗