Biology subjects

O'Herron, P.

Publications and source records attributed to O'Herron, P..

10 recordsLinked to original sources

bioRxiv2025

Dual inhibition of sEH and COX-2 Improved Cognition in Alzheimer's Disease via Enhanced Myogenic Response and Cerebral Artery Distensibility

Genetic studies have linked EPHX2 (encoding soluble epoxide hydrolase, sEH) and PTGS2 (encoding cyclooxygenase-2, COX-2) to Alzheimers disease (AD). Elevated levels of sEH and COX-2 found in AD patients and animals suggest their involvement in neurodegeneration, glial activation, vascular dysfunction, and inflammation. This study evaluated the effects of a new dual sEH/COX-2 inhibitor, PTUPB, on cerebrovascular function and cognition in TgF344-AD rats. The rats received oral PTUPB (2 mg/kg/day) for 25 days. Body weight, plasma glucose, and HbA1c levels remained stable between PTUPB- and vehicle-treated AD rats. PTUPB significantly improved recognition memory in AD rats, as detected by the Novel Object Recognition test. Pressure myography showed that PTUPB restored myogenic responses and increased the distensibility of the middle cerebral arteries (MCAs) in AD rats. Acute PTUPB (0.1 and 1 M) enhanced myogenic contraction in response to elevated perfusion pressure in AD MCAs, with minimal effects in wild-type vessels. Vehicle-treated AD rats displayed impaired functional hyperemia, whereas PTUPB (1 M) significantly restored this response. Transcriptomic analysis of cerebral vascular smooth muscle cells from AD rats indicated that PTUPB influences genes related to contractility, extracellular matrix remodeling, inflammation, and oxidative stress. These results provide new evidence that dual inhibition of sEH and COX-2 improves cognition in AD, likely by enhancing myogenic response and increasing cerebral artery distensibility. Our findings highlight the potential of PTUPB as a therapeutic approach for cerebrovascular dysfunction in AD.

neuroscience↗

bioRxiv2024

Blood pressure variability compromises vascular function in middle-aged mice

Blood pressure variability (BPV) has emerged as a significant risk factor for cognitive decline and dementia, independent of alterations in average blood pressure (BP). However, the impact of large BP fluctuations on neurovascular function remains poorly understood. In this study, we developed a novel murine model of BPV in middle-aged mice using intermittent Angiotensin II infusions. Radio telemetry confirmed that 24-hr BP averages in BPV mice remained comparable to controls, demonstrating BPV in the absence of hypertension. Chronic (20-25 days) BPV resulted in a blunted bradycardic response and cognitive deficits. Two-photon imaging revealed heightened pressure-evoked constrictions (myogenic response) in parenchymal arterioles of BPV mice. While sensory stimulus-evoked dilations (neurovascular coupling) were amplified at higher BP levels in control mice, this pressure-dependent effect was abolished in BPV mice. Our findings indicate that chronic BP fluctuations impair vascular function within the neurovascular complex and contribute to cognitive decline, emphasizing BPV as a critical factor in brain health.

physiology↗

bioRxiv2024

Inhibition of Soluble Epoxide Hydrolase Ameliorates Cerebral Blood Flow Autoregulation and Cognition in Alzheimer's Disease and Diabetes-Related Dementia Rat Models

Alzheimers Disease and Alzheimers Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1C levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.

molecular biology↗

bioRxiv2024

Cortical Acetylcholine Response to Deep Brain Stimulation of the Basal Forebrain

BackgroundDeep brain stimulation (DBS), the direct electrical stimulation of neuronal tissue in the basal forebrain to enhance release of the neurotransmitter acetylcholine, is under consideration as a method to improve executive function in patients with dementia. While some small studies indicate a positive response in the clinical setting, the relationship between DBS and acetylcholine pharmacokinetics is incompletely understood. ObjectiveWe examined the cortical acetylcholine response to different stimulation parameters of the basal forebrain. Methods2-photon imaging was combined with deep brain stimulation. Stimulating electrodes were implanted in the subpallidal basal forebrain, and the ipsilateral somatosensory cortex was imaged. Acetylcholine activity was determined using the GRABACh-3.0 muscarinic acetylcholine receptor sensor, and blood vessels were imaged with Texas red. ResultsExperiments manipulating pulse train frequency demonstrated that integrated acetylcholine induced fluorescence was insensitive to frequency, and that peak levels were achieved with frequencies from 60 to 130 Hz. Altering pulse train length indicated that longer stimulation resulted in higher peaks and more activation with sublinear summation. The acetylcholinesterase inhibitor donepezil increased the peak response to 10s of stimulation at 60Hz, and the integrated response increased 57% with the 2 mg/kg dose, and 126% with the 4 mg/kg dose. Acetylcholine levels returned to baseline with a time constant of 14 to 18 seconds in all experiments. ConclusionsThese data demonstrate that acetylcholine receptor activation is insensitive to frequency between 60 and 130 Hz. High peak responses are achieved with up to 900 pulses. Donepezil increases total acetylcholine receptor activation associated with DBS but did not change temporal kinetics. The long time constants observed in the cerebral cortex add to the evidence supporting volume in addition to synaptic transmission. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/605828v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@a06bborg.highwire.dtl.DTLVardef@4003f0org.highwire.dtl.DTLVardef@c286d1org.highwire.dtl.DTLVardef@1213d2c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Neurovascular coupling and briefCO2 interrogate distinct vascular regulations

Neurovascular coupling (NVC), which mediates rapid increases in cerebral blood flow in response to neuronal activation, is commonly used to map brain activation or dysfunction. Here we tested the reemerging hypothesis that CO2 generated by neuronal metabolism contributes to NVC. We combined functional ultrasound and two-photon imaging in the mouse barrel cortex to examine specifically the onsets of local changes in vessel diameter, blood flow dynamics, vascular/perivascular/intracellular pH, and intracellular calcium signals along the vascular arbor in response to briefCO2, a short and strong hypercapnic challenge (10 s, 20%) and whisker stimulation. We report that briefCO2 reversibly acidifies all cells of the arteriole wall and the periarteriolar space 3-4 seconds prior to the arteriole dilation. During this prolonged lag period, NVC triggered by whisker stimulation is not affected by the acidification of the entire neurovascular unit. As it also persists under condition of continuous inflow of CO2, we conclude that CO2 is not involved in NVC.

neuroscience↗

bioRxiv2022

Mass red blood cell extravasation and tubular uptake results in toxic injury to the tubules during kidney ischemia from venous clamping

Vascular congestion is common in ischemic acute kidney injury (AKI) and represents densely packed red blood cells (RBC) in the kidney circulation. In this study we tested the hypothesis that vascular congestion directly promotes tubular injury. Studies were performed in male and female Wistar-Kyoto rats. Vascular congestion and tubular injury were examined between renal venous clamping, arterial clamping and venous clamping of blood perfused and blood free kidneys. Vessels were occluded for either 15 or 45 minutes without reperfusion. We found that venous clamping resulted in greater vascular congestion than arterial clamping, particularly in the outer-medullary region (P<0.001). Venous clamping resulted in significant tubular injury, including cell swelling, tubular degeneration and luminal cast formation following as little as 15 minutes of occlusion. Tubular injury was significantly less following arterial clamping (P<0.001). Numerous red droplets were observed within tubular cells which were most prominent following venous clamping. Electron microscopy and immunohistochemistry identified these as derived from RBCs and indicated that RBCs from congested renal capillaries were extravasated and phagocytosed by tubular cells. CD235a staining confirmed tubular uptake and secretion of RBCs. Cast formation and tubular swelling were absent from blood free kidneys following venous clamping (P<0.001). Our data demonstrate that congestion of the kidney results in the rapid, mass extravasation and uptake of RBCs by tubular cells causing toxic injury to the tubules. Tubular toxicity from extravasation of RBCs appears to be a major component of tubular injury in ischemic AKI which has not previously been recognized.

physiology↗

bioRxiv2021

The development of bi-directionally coupled self-organizing neurovascular networks captures orientation-selective neural and hemodynamic cortical responses

The network of neurons in the brain is considered the primary substrate of information processing. Despite growing evidence on the possible role of cerebral blood flow in information processing, the cerebrovascular network is generally viewed as an irrigation system that ensures a timely supply of oxygen, glucose, and nutrients to the neural tissue. However, a recent study has shown that cerebral microvessels, like neurons, also exhibit tuned responses to sensory stimuli. Tuned neural responses to sensory stimuli are certainly enhanced with experience-dependent Hebbian plasticity and other forms of learning. Hence it is possible that the densely interconnected microvascular network might also be subject to some form of plasticity or competitive learning rules during early postnatal development such that its fine-scale structure becomes optimized for metabolic delivery to a given neural micro-architecture. To explore the possibility of adaptive lateral interactions and tuned responses in cerebral microvessels, we modeled the cortical neurovascular network by interconnecting two laterally connected self-organizing networks (Laterally Interconnected Synergetically Self-Organizing Map - LISSOM). The afferent and lateral connections of the LISSOM were defined by trainable weights. By varying the topology of lateral connectivity in the vascular network layer, we observed that the partial correspondence of feature selectivity between neural and hemodynamic responses could be explained by lateral coupling across local blood vessels such that the central domain receives an excitatory drive of more blood flow and a more distal surrounding region where blood flow is reduced. Critically, our simulations suggest a new role for feedback from the vascular to the neural network because the radius of vascular perfusion seems to determine whether the cortical neural map develops into a clustered and columnar vs. salt-and-pepper organization.

neuroscience↗

bioRxiv2021

Precise, 3-D optogenetic control of the diameter of single arterioles

Modulation of brain arteriole diameter is critical for maintaining cerebral blood pressure and controlling regional hyperemia during neural activity. However, studies of hemodynamic function in health and disease have lacked a method to control arteriole diameter independently with high spatiotemporal resolution. Here, we describe an all-optical approach to manipulate and monitor brain arteriole contractility in 3-dimensions using combined in vivo two-photon optogenetics and imaging. The expression of the red-shifted excitatory opsin, ReaChR, in vascular smooth muscle cells enabled rapid and repeated vasoconstriction controlled by brief light pulses. Two-photon activation of ReaChR using a spatial light modulator produced highly localized constrictions when targeted to individual arterioles within the neocortex. We demonstrate the utility of this method for examining arteriole contractile dynamics and creating transient focal blood flow reductions. Additionally, we show that optogenetic constriction can be used to reshape vasodilatory responses to sensory stimulation, providing a valuable tool to dissociate blood flow changes from neural activity.

neuroscience↗

bioRxiv2018

In Vivo Two-Photon Imaging of Neuronal and Vascular Responses in Mice Chronically Exposed to Ethanol

The effects of ethanol on brain function have been extensively studied using a variety of in vitro and in vivo techniques. For example, electrophysiological studies using brain slices from rodents and nonhuman primates have demonstrated that acute and chronic exposure to ethanol alters the intrinsic excitability and synaptic signaling of neurons within cortical and sub-cortical areas of the brain. In humans, neuroimaging studies reveal alterations in measures of brain activation and connectivity in subjects with alcohol use disorders. While complementary, these methods are inherently limited due to issues related to either disruption of normal sensory input (in vitro slice studies) or resolution (whole brain imaging). In the present study, we used 2-photon laser scanning microscopy in intact animals to assess the impact of chronic ethanol exposure on sensory evoked neuronal and vascular responses. Adult male C57BL/6J mice were exposed to 4 weekly cycles of chronic intermittent ethanol (CIE) exposure while control mice were exposed to air. After withdrawal ([≤] 72 hr), a cranial window was placed over the primary visual cortex (V1) and sensory evoked responses were monitored using the calcium indicator OGB-1. CIE exposure produced small but significant changes in response amplitude (decrease) and orientation selectivity of V1 neurons (increase). While arteriole diameter did not differ between control and CIE mice under baseline conditions, sensory-evoked dilation was enhanced in vessels from CIE exposed mice as compared to controls. This was accompanied by a reduced latency in response to stimulation. In separate experiments, pial arteriole diameter was measured in the barrel cortex of control and CIE exposed mice. Baseline diameter of barrel cortex arterioles was similar between control and CIE exposed mice but unlike vessels in V1, sensory-evoked dilation of barrel cortex arterioles was similar between the two groups. Together the results of these studies suggest that chronic exposure to alcohol induces changes in neurovascular coupling that are region dependent.

neuroscience↗

bioRxiv2018

The influence of cortical depth on neuronal responses in mouse visual cortex

With the advent of two-photon imaging as a tool for systems neuroscience, the mouse has become a preeminent model system for studying sensory processing. One notable difference that has been found however, between mice and traditional model species like cats and primates is the responsiveness of the cortex. In the primary visual cortex of cats and primates, nearly all neurons respond to simple visual stimuli like drifting gratings. In contrast, imaging studies in mice consistently find that only around half of the neurons respond to such stimuli. Here we show that visual responsiveness is strongly dependent on the cortical depth of neurons. Moving from superficial layer 2 down to layer 4, the percentage of responsive neurons increases dramatically, ultimately reaching levels similar to what is seen in other species. Over this span of cortical depth, neuronal response amplitude also increases and orientation selectivity moderately decreases. These depth dependent response properties may be explained by the distribution of thalamic inputs in mouse V1. Unlike in cats and primates where thalamic projections to the granular layer are constrained to layer 4, in mice they spread up into layer 2/3, qualitatively matching the distribution of response properties we see. These results show that the analysis of neural response properties must take into consideration not only the overall cortical lamina boundaries but also the depth of recorded neurons within each cortical layer. Furthermore, the inability to drive the majority of neurons in superficial layer 2/3 of mouse V1 with grating stimuli indicates that there may be fundamental differences in the role of V1 between rodents and other mammals.

neuroscience↗