Biology subjects

Drew, P. J.

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

At least 19 recordsLinked to original sources

bioRxiv2026

Ultrafast venous and sagittal sinus constrictions in the brain driven by abdominal pressure

Nearly all the blood supplying the cortex exits via the bridging veins (BVs) that drain into the superior sagittal sinus (SSS), making these vessels key chokepoints for cerebral blood flow. Using optical imaging in head-fixed mice, we found that the SSS and BVs exhibit ultrafast contractions (<0.1 s) at the onset of locomotion, following whisker stimulation, and upon awakening from sleep. Contractions of the BV and SSS were strongly correlated with abdominal muscle EMG activity and were tightly correlated with respiration at rest. The rapid decrease in blood volume caused by venous constrictions resulted in spurious increases in fluorescence in mice expressing fluorescent reporter proteins, creating artifacts that mimic functional signals. Venous contractions with the same amplitude and dynamics could be generated in anesthetized mice by abdominal pressure application, showing that these contractions were generated by mechanical coupling with the abdomen. Externally imposed abdominal pressures also drove a rapid but transient increase in blood flow. Unlike the pial and parenchymal microvasculature whose diameters are controlled by local signals, the diameters of SSS/BV are dynamically controlled during behavior by abdominal muscle regulation of intracranial pressure, establishing a pathway for regulation of cerebral hemodynamics via mechanical coupling between the central nervous system and the viscera.

neuroscience↗

bioRxiv2025

Alcohol consumption drives sex- and region- specific disruption of somatostatin signaling in mice

The prefrontal cortex (PFC), which is thought to be disrupted early in the cycle of substance use and addiction [1], is comprised of a complex microcircuit of long-range glutamatergic pyramidal neurons controlled by GABAergic-expressing local inhibitory neurons [2, 3]. Somatostatin (SST)-expressing neurons are a subpopulation of these local GABAergic inhibitory cells and provide both peptidergic and GABAergic control over these PFC circuits [3, 4], and are disturbed following alcohol consumption in humans [5] and in rodent models [6, 7]. However, little is known about how endogenous SST peptide signaling is affected by alcohol. Using ex vivo electrophysiology, immunohistochemistry, in situ hybridization, and behavior, we demonstrate robust down-regulation of SST control over pyramidal output activity in the prelimbic (PL), but not infralimbic (IL), PFC after alcohol exposure. We also show this is likely mediated by changes in SST receptor expression levels and not disrupted expression or capacity for release of SST peptide, suggesting postsynaptic homeostatic changes to SST signaling following binge alcohol consumption in mice that may underlie post-alcohol dysregulation in mood. This provides insight into how voluntary alcohol consumption disrupts PFC peptide signaling and suggests a potential therapeutic target for the treatment of alcohol use disorder (AUD).

neuroscience↗

bioRxiv2025

Adolescent alcohol consumption alters sex-specific behaviors associated with prefrontal functional connectivity in mice

The prefrontal cortex (PFC) is one of the last brain regions to fully mature, making it particularly sensitive to drug use early in life. Both human and rodent studies find long-lasting behavioral changes after adolescent alcohol exposure that implicate underlying disruptions in PFC development, including structural abnormalities and altered brain functional connectivity. Few rodent studies have been conducted to understand the network-level implications of these disruptions. We assessed how adolescent binge-like alcohol consumption in a drinking in the dark (DID) model affected adult alcohol consumption, behavioral exploration, and brain-wide functional connectivity in mice. Approximately one month after the conclusion of DID, only female mice exposed to alcohol during adolescence exhibited aversion-resistant alcohol preference in adulthood. Adult females exhibited additional sex-specific changes in exploratory behavior in the elevated plus maze after adolescent alcohol consumption. Resting state neuroimaging revealed sex-specific changes in prefrontal cortical connections with sensory motor, hippocampal, striatal, and other networks, providing insights into the putative systems underlying deficits caused by adolescent alcohol exposure. Critically, our data corroborate a growing body of literature in human and rodent studies demonstrating that adolescent alcohol use may increase risk for adult alcohol use more strongly in females. Finally, we identify neural correlates of this effect that include both known and novel neural networks and tie these back to human datasets, allowing biological and mechanistic targets to be further explored for future study and interventions.

neuroscience↗

bioRxiv2025

Integrated Ultrasound Neuromodulation and Optical Neuroimaging in Awake Mice using a Transparent Ultrasound Transducer Cranial Window

Ultrasound neuromodulation is a rapidly advancing, non-invasive technique with significant therapeutic potential for treating various neurological disorders. Although extensive in vitro and in vivo studies have provided valuable insights into its modulatory effects, the underlying mechanisms remain poorly understood, limiting its clinical translation. Optical neuroimaging techniques can help investigate these mechanisms; however, the opacity and bulkiness of conventional ultrasound transducers pose significant challenges for their integration with in vivo ultrasound neuromodulation studies, particularly in awake rodents. To address these limitations, we propose a straightforward solution: a miniaturized lithium niobate-based transparent ultrasound transducer (TUT) integrated as a thinned-skull cranial window for ultrasound stimulation while facilitating multimodal optical neuroimaging in awake mice brain. Using laser speckle contrast imaging and intrinsic optical signal imaging, we studied changes in brain hemodynamics in response to various ultrasound stimulation sequences. Our experiments demonstrated that TUT cranial window can robustly induce neuromodulatory effects with observed increase in both cerebral blood flow and total hemoglobin, with peak and cumulative hemodynamic changes directionally correlated with ultrasound stimulation duration and intensity. Overall, these findings highlight that TUT cranial window can seamlessly integrate ultrasound stimulation and optical neuroimaging in awake mouse brain models, offering promising prospects for uncovering the underlying mechanisms of ultrasound neuromodulation.

neuroscience↗

bioRxiv2025

Gut-Brain Hydraulics: Brain motion and CSF circulation is driven by mechanical coupling with the abdomen

The brain moves within the skull, but the drivers and function of this motion are not understood. We visualized brain motion relative to the skull in awake head-fixed mice using high-speed, multi-plane two-photon microscopy. Brain motion was primarily rostrally and laterally directed, and was tightly correlated with locomotion, but not with respiration or the cardiac cycle. Electromyography recordings in abdominal muscles and microCT reconstructions of the trunk and spinal vasculature showed that brain motion was driven by abdominal muscle contractions that activate a hydraulic-like vascular connection between the nervous system and the abdominal cavity. Externally-applied abdominal pressure generated brain motion similar to those seen during abdominal muscle contractions. Simulations showed that brain motion drives substantial volumes of interstitial fluid through and out of the brain (at volumetric rates several times higher than production) into the subarachnoid space, in the opposite direction of fluid flow seen during sleep. The brain is hydraulically linked to the abdominal compartment, and fluid flow in the brain is coupled to body movements, providing a mechanism by which the mechanics of the viscera directly impact brain health.

neuroscience↗

bioRxiv2025

Type-I nNOS neurons orchestrate cortical neural activity and vasomotion

It is unknown how the brain orchestrates coordination of global neural and vascular dynamics. We sought to uncover the role of a sparse but unusual population of genetically distinct interneurons known as type-I nNOS neurons, using a novel pharmacological strategic to unilaterally ablate these neurons from the somatosensory cortex of mice. Region-specific ablation produced changes in both neural activity and vascular dynamics, decreased power in the delta-band of the local field potential, reduced sustained vascular responses to prolonged sensory stimulation, and abolished the post-stimulus undershoot in cerebral blood volume. Coherence between the left and right somatosensory cortex gamma-band power envelope and blood volume at ultra-low frequencies was decreased, suggesting type-1 nNOS neurons integrate long-range coordination of brain signals. Lastly, we observed decreases in the amplitude of resting-state blood volume oscillations and decreased vasomotion following the ablation of type-I nNOS neurons. This demonstrates that a small population of nNOS-positive neurons are indispensable for regulating both neural and vascular dynamics in the whole brain, raising the possibility that loss of these neurons could contribute to the development of neurodegenerative diseases and sleep disturbances.

neuroscience↗

bioRxiv2023

Dissecting Multiparametric Cerebral Hemodynamics using Integrated Ultrafast Ultrasound and Multispectral Photoacoustic Imaging

Understanding brain-wide hemodynamic responses to different stimuli at high spatiotemporal resolutions can help study neuro-disorders and brain functions. However, the existing brain imaging technologies have limited resolution, sensitivity, imaging depth and provide information about only one or two hemodynamic parameters. To address this, we propose a multimodal functional ultrasound and photoacoustic (fUSPA) imaging platform, which integrates ultrafast ultrasound and multispectral photoacoustic imaging methods in a compact head-mountable device, to quantitatively map cerebral blood volume (CBV), cerebral blood flow (CBF), oxygen saturation (SO2) dynamics as well as contrast agent enhanced brain imaging with high spatiotemporal resolutions. After systematic characterization, the fUSPA system was applied to quantitatively study the changes in brain hemodynamics and vascular reactivity at single vessel resolution in response to hypercapnia stimulation. Our results show an overall increase in brain-wide CBV, CBF, and SO2, but regional differences in singular cortical veins and arteries and a reproducible anti-correlation pattern between venous and cortical hemodynamics, demonstrating the capabilities of the fUSPA system for providing multiparametric cerebrovascular information at high-resolution and sensitivity, that can bring insights into the complex mechanisms of neurodiseases.

bioengineering↗

bioRxiv2023

Aging drives cerebrovascular network remodeling and functional changes in the mouse brain

Aging is the largest risk factor for neurodegenerative disorders, and commonly associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts the vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods (serial two-photon tomography and light sheet microscopy) and in vivo imaging (wide-field optical spectroscopy and two-photon imaging) to determine detailed changes in aged cerebrovascular networks. Whole-brain vascular tracing showed an overall [~]10% decrease in vascular length and branching density with [~]7% increase in vascular radii in aged brains. Light sheet imaging with 3D immunolabeling revealed increased arteriole tortuosity of aged brains. Notably, vasculature and pericyte densities showed selective and significant reductions in the deep cortical layers, hippocampal network, and basal forebrain areas. We also found a significant increase in blood extravasation, implying compromised blood-brain barrier function in aged brains. Moreover, in vivo imaging in awake mice identified a reduction of baseline and on-demand blood oxygenation despite relatively intact neurovascular coupling. Collectively, we uncover regional vulnerabilities of cerebrovascular network and physiological changes that can mediate cognitive decline in normal aging. Highlight- Brain-wide mapping of vasculature and pericyte changes with normal aging - Simplified vascular network with tortuous vessels in aged brains - Vascular rarefication in the deep cortical layers, hippocampus, and the basal forebrain - Intact neurovascular coupling but lower blood oxygenation in aged animals

neuroscience↗

bioRxiv2023

Arousal state transitions occlude sensory-evoked neurovascular coupling in neonatal mice

In the adult sensory cortex, increases in neural activity elicited by sensory stimulation usually drives vasodilation mediated by neurovascular coupling. However, whether neurovascular coupling is the same in neonatal animals as adults is controversial, as both canonical and inverted responses have been observed. We investigated the nature of neurovascular coupling in unanesthetized neonatal mice using optical imaging, electrophysiology, and BOLD fMRI. We find in neonatal (postnatal day 15, P15) mice, sensory stimulation induces a small increase in blood volume/BOLD signal, often followed by a large decrease in blood volume. An examination of arousal state of the mice revealed that neonatal mice were asleep a substantial fraction of the time, and that stimulation caused the animal to awaken. As cortical blood volume is much higher during REM and NREM sleep than the awake state, awakening occludes any sensory-evoked neurovascular coupling. When neonatal mice are stimulated during an awake period, they showed relatively normal (but slowed) neurovascular coupling, showing that that the typically observed constriction is due to arousal state changes. These result show that sleep-related vascular changes dominate over any sensory-evoked changes, and hemodynamic measures need to be considered in the context of arousal state changes. Significance StatementIn the adult brain, increases in neural activity are often followed by vasodilation, allowing activity to be monitored using optical or magnetic resonance imaging. However, in neonates, sensory stimulation can drive vasoconstriction, whose origin was not understood. We used optical and magnetic resonance imaging approaches to investigate hemodynamics in neonatal mice. We found that sensory-induced vasoconstriction occurred when the mice were asleep, as sleep is associated with dilation of the vasculature of the brain relative to the awake state. The stimulus awakens the mice, causing a constriction due to the arousal state change. Our study shows the importance of monitoring arousal state, particularly when investigating subjects that may sleep, and the dominance arousal effects on brain hemodynamics.

neuroscience↗

bioRxiv2022

Somatostatin peptide signaling dampens cortical circuits and promotes exploratory behavior

Somatostatin (SST) neurons in the prelimbic (PL) cortex mediate a variety of behavioral states. However, little is known about the actions of somatostatin peptide signaling in shaping cortical functioning and behavior. Here, we sought to characterize the unique physiological and behavioral roles of the SST peptide in the PL cortex. We employed a combination of ex vivo pharmacologic and optogenetic electrophysiology, in vivo calcium monitoring, and in vivo peptide pharmacology to explore the role of SST neuron and peptide signaling in the mouse PL cortex. Whole-cell slice electrophysiology was conducted in pyramidal and GABAergic neurons in the PL cortex of C57BL/6J and SST-IRES-Cre male and female mice to characterize the pharmacological mechanism of SST signaling. Fiber photometry of GCaMP6f fluorescent calcium signals from SST neurons was conducted to characterize the activity profile of SST neurons during exploration of an elevated plus maze (EPM) and open field test (OFT). We further used local delivery of both a broad SST receptor (SSTR) agonist and antagonist into bilateral PL cortex to test causal effects of SST administration and receptor blockade on these same exploratory behaviors. SSTR activation broadly hyperpolarized layer 2/3 pyramidal neurons in the PL cortex in both male and female mice ex vivo, an effect that was recapitulated with optogenetic stimulation of SST neurons, through both monosynaptic and polysynaptic GABA neuron-mediated mechanisms of action. This hyperpolarization was blocked by pre-application of the SSTR antagonist cyclo-somatostatin (cyclo-SST) and was non-reversible. SST neurons in PL were activated during EPM and OFT exploration, indicating task-related recruitment of these neurons. Lastly, in line with this exploration-related activity profile, SSTR agonist administration directly into the PL enhanced open arm exploration in the EPM, while in vivo administration of an antagonist had no effect. Together, this work describes a broad ability for SST peptide signaling to modulate microcircuits within the prefrontal cortex and related exploratory behaviors.

neuroscience↗

bioRxiv2022

Arousal state dependence of the cortical blood volume - pupil diameter relationship

Arousal state affects neural activity and vascular dynamics in the cortex, with sleep associated with large changes in the local field potential (LFP) and increases in cortical blood flow. We investigated the relationship between pupil diameter and blink rate with neural activity and blood volume in the somatosensory cortex in male and female unanesthetized, head-fixed mice. We monitored these variables while the mice were awake, during periods of rapid eye movement (REM), and non-rapid eye movement (NREM) sleep. Pupil diameter was smaller during sleep than in the awake state. Changes in pupil diameter were coherent with both gamma-band power and blood volume in the somatosensory cortex, but the strength and sign of this relationship varied with arousal state. We observed a strong negative correlation between pupil diameter and both gamma-band power and blood volume during periods of awake rest and NREM sleep, though the correlations between pupil diameter and these signals became positive during periods of alertness, active whisking, and REM. Blinking was associated with increases in arousal and decreases in blood volume when the mouse was asleep. Bilateral coherence in gamma-band power and in blood volume dropped following awake blinking, indicating a reset of neural and vascular activity. Using only eye metrics (pupil diameter and eye motion), we could determine the mouses arousal state ( Awake, NREM, REM) with greater than 90% accuracy with a 5 second resolution. There is a strong relationship between pupil diameter and hemodynamics signals in mice, reflecting the pronounced effects of arousal on cerebrovascular dynamics. Significance StatementDetermining arousal state is a critical component of any neuroscience experiment. Pupil diameter and blinking are influenced by arousal state, as are hemodynamics signals in the cortex. We investigated the relationship between cortical hemodynamics and pupil diameter and found that pupil diameter was strongly related to the blood volume in the cortex. Mice were more likely to be awake after blinking than before, and blinking resets neural activity. Pupil diameter and eye motion can be used as a reliable, non-invasive indicator of arousal state. As mice transition from wake to sleep and back again over a timescale of seconds, monitoring pupil diameter and eye motion permits the non-invasive detection of sleep events during behavioral or resting-state experiments.

neuroscience↗

bioRxiv2021

Awake mouse brain photoacoustic and optical imaging through a transparent ultrasound cranial window

Optical resolution photoacoustic microscopy (OR-PAM) can map the cerebral vasculature at capillary level resolution. However, the OR-PAM setups bulky imaging head makes awake mouse brain imaging challenging and inhibits its integration with other optical neuroimaging modalities. Moreover, the glass cranial windows used for optical microscopy are unsuitable for OR-PAM due to the acoustic impedance mismatch between the glass plate and the tissue. To overcome these challenges, we propose a lithium niobate based transparent ultrasound trans-ducer (TUT) as a cranial window on a thinned mouse skull. The TUT cranial window simplifies the imaging head considerably due to its dual functionality as an optical window and ultrasound transducer. The window remains stable for six weeks, with no noticeable inflammation and minimal bone regrowth. The TUT windows potential is demonstrated by imaging the awake mouse cerebral vasculature using OR-PAM, intrinsic optical signal imaging and two-photon microscopy. The TUT cranial window can potentially also be used for ultrasound stimulation and simultaneous multimodal imaging of the awake mouse brain.

bioengineering↗

bioRxiv2021

Arterial vasodilation drives convective fluid flow in the brain: a poroelastic model

The movement of fluid into, through, and out of the brain plays an important role in clearing metabolic waste. However, there is controversy regarding the mechanisms driving fluid movement, and whether the movement metabolic waste is primarily driven by diffusion or convection. The dilation of penetrating arterioles in the brain in response to increases in neural activity (neurovascular coupling) is an attractive candidate for driving fluid circulation, as it drives deformation of the brain tissue and of the paravascular space around arteries, resulting in fluid movement. We simulated the effects of vasodilation on fluid movement into and out of the brain using a novel poroelastic model of brain tissue. We found that arteriolar dilations could drive convective flow through the brain radially outward from the arteriole, and that this flow is sensitive to the dynamics of the dilation. Simulations of sleep-like conditions, with larger vasodilations and increased extracellular volume in the brain showed enhanced movement of fluid from the paravascular space into the brain. Our simulations suggest that both sensory-evoked and sleep-related arteriolar dilations can drive convective flow of cerebrospinal fluid from the paravascular space into the brain tissue around arterioles.

neuroscience↗

bioRxiv2021

The cellular architecture of microvessels, pericytes and neuronal cell types in organizing regional brain energy homeostasis in mice

Cerebrovasculature and its mural cells must meet dynamic energy demands of different neuronal cell types across the brain, but their spatial relationship is largely unknown. Here, we apply brain-wide mapping methods to create a comprehensive cellular-resolution resource comprising the distribution of and quantitative relationship between cerebrovasculature, pericytes, and glutamatergic and GABAergic neurons, including neuronal nitric oxide synthase-positive (nNOS+) neurons and their subtypes, as well as simulation-ready vascular tracing data in mice. We discover strikingly high densities of vasculature and pericytes with high blood perfusion in primary motor-sensory cortices compared to association cortices that show significant positive and negative correlation with parvalbumin+ and nNOS+ neurons, respectively. Thalamo-striatal areas linked to primary motor-sensory cortices also contain high densities of vasculature and pericytes compared to association areas. Collectively, our results unveil a finely tuned spatial relationship between cerebrovascular network and neuronal cell composition in meeting regional energy needs of the brain.

neuroscience↗

bioRxiv2020

Iliski, a software for robust calculation of transfer functions

1.Understanding the relationships between biological events is paramount to unravel pathophysiological mechanisms. These relationships can be modeled with Transfer Functions (TFs), with no need of a priori hypotheses as to the shape of the transfer function. Here we present Iliski, a software dedicated to TFs computation between two signals. It includes different pre-treatment routines and TF computation processes: deconvolution, deterministic and non-deterministic optimization algorithms that are adapted to disparate datasets. We apply Iliski to data on neurovascular coupling, an ensemble of biological events that link neuronal activity to local changes of blood flow, highlighting the software benefits and caveats in the computation and evaluation of TFs. We also propose a workflow that will help users to choose the best computation according to the dataset. Iliski is available under the open-source license CC BY 4.0 on GitLab (https://gitlab.com/AliK_A/iliski) and can be used on the most common operating systems, either within the MATLAB environment, or as a standalone application.

bioinformatics↗

bioRxiv2020

Origins of 1/f-like tissue oxygenation fluctuations in the murine cortex

The concentration of oxygen in the brain spontaneously fluctuates, and the power distribution in these fluctuations has 1/f-like dynamics. Though these oscillations have been interpreted as being driven by neural activity, the origins of these 1/f-like oscillations is not well understood. Here, to gain insight of the origin of the 1/f-like oxygen fluctuations, we investigated the dynamics of tissue oxygenation and neural activity in awake behaving mice. We found that oxygen signal recorded from the cortex of mice had 1/f-like spectra. However, band-limited power in the local field potential, did not show corresponding 1/f-like fluctuations. When local neural activity was suppressed, the 1/f-like fluctuations in oxygen concentration persisted. Two-photon measurements of erythrocyte spacing fluctuations ( stalls) and mathematical modelling show that stochastic fluctuations in erythrocyte flow and stalling could underlie 1/f-like dynamics in oxygenation. These results show discrete nature of erythrocytes and their irregular flow, rather than neural activity, could drive 1/f-like fluctuations in tissue oxygenation.

neuroscience↗

bioRxiv2020

Intranasal Administration of Functionalized Soot Particles Disrupts Olfactory Sensory Neuron Progenitor Cells in the Neuroepithelium

Exposure to air pollution has been linked to the development of neurodegenerative diseases and anosmia, but the underlying mechanism is not known. Additionally, the loss of olfactory function often precedes the onset of neurodegenerative diseases. Chemical ablation of olfactory sensory neurons blocks the drainage of cerebrospinal fluid (CSF) through the cribriform plate and alters normal CSF production and/or circulation. Damage to this drainage pathway could contribute to the development of neurodegenerative diseases and could link olfactory sensory neuron health and neurodegeneration. Here, we investigated the impact of intranasal treatment of combustion products (laboratory-generated soots) and their oxygen functionalized derivatives on mouse olfactory sensory neurons, olfactory nerve cell progenitors, and the behavior of the mouse. We found that after a month of every-other-day intranasal treatment of soots, there was minimal effect on olfactory sensory neuron anatomy or exploratory behavior in the mouse. However, oxygen-functionalized soot caused a large decrease in globose basal cells, which are olfactory progenitor cells. These results suggest that exposure to air pollution damages the olfactory neuron progenitor cells, and could lead to decreases in the number of olfactory neurons, potentially disrupting CSF drainage.

neuroscience↗

bioRxiv2020

Neurovascular coupling and bilateral connectivity during NREM and REM sleep

Hemodynamic signals in the brain are used as surrogates of neural activity, but how these hemodynamic signals depend on arousal state is poorly understood. Here, we monitored neural activity and hemodynamic signals in un-anesthetized, head-fixed mice to understand how sleep and awake states impact cerebral hemodynamics. In parallel with electrophysiological recordings, we used intrinsic optical signal imaging to measure bilateral changes in cerebral hemoglobin ([HbT]), and two-photon laser scanning microscopy (2PLSM) to measure dilations of individual arterioles. We concurrently monitored body motion, whisker movement, muscle EMG, cortical LFP, and hippocampal LFP to classify the arousal state of the mouse into awake, NREM sleep, or REM sleep. We found that mice invariably fell asleep during imaging, and these sleep states were interspersed with periods of awake. During both NREM and REM sleep, mice showed large increases in [HbT] relative to the awake state, showing increase in hemoglobin and arteriole diameter two to five times larger than those seen in response to sensory stimulation. During NREM sleep, the amplitude of bilateral low-frequency oscillations in [HbT] increased markedly, and coherency between neural activity and hemodynamic signals was higher than the awake resting and REM states. Bilateral correlations in neural activity and [HbT] were highest during NREM sleep, and lowest in the awake state. Our results show that hemodynamic signals in the cortex are strongly modulated by arousal state, with hemodynamic changes during sleep being substantially larger than sensory-evoked responses. These results underscore the critical importance of behavioral monitoring during studies of spontaneous activity, as sleep-related hemodynamics dominate measures of neurovascular coupling and functional connectivity.

neuroscience↗