A5052308829- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Neuroscience of respiration and sleep
- Photoreceptor and optogenetics research
- Virus-based gene therapy research
- Neuroinflammation and Neurodegeneration Mechanisms
- Neuroendocrine regulation and behavior
- Ion channel regulation and function
- Heart Rate Variability and Autonomic Control
- CRISPR and Genetic Engineering
- Stress Responses and Cortisol
- Neuroscience and Neural Engineering
- Cellular transport and secretion
- RNA Interference and Gene Delivery
- Olfactory and Sensory Function Studies
- Sleep and Wakefulness Research
- Lipid Membrane Structure and Behavior
- Adenosine and Purinergic Signaling
- Genetic Neurodegenerative Diseases
- Adipose Tissue and Metabolism
- Vagus Nerve Stimulation Research
- Cancer, Hypoxia, and Metabolism
- Nerve injury and regeneration
- Mitochondrial Function and Pathology
- Eicosanoids and Hypertension Pharmacology
University of Bristol
2013-2024
NIHR Bristol Cardiovascular Biomedical Research Unit
2008-2016
University College London
2015
University of Helsinki
2015
Case Western Reserve University
2008
University of Florida
2008
Harvard University
1997
Max Planck Institute of Psychiatry
1990-1996
Astrocytes provide structural and metabolic support for neuronal networks, but direct evidence demonstrating their active role in complex behaviors is limited. Central respiratory chemosensitivity an essential mechanism that, via regulation of breathing, maintains constant levels blood brain pH partial pressure CO2. We found that astrocytes the brainstem chemoreceptor areas are highly chemosensitive. They responded to physiological decreases with vigorous elevations intracellular Ca2+...
Abstract Astrocytes produce and release L -lactate as a potential source of energy for neurons. Here we present evidence that -lactate, independently its caloric value, serves an astrocytic signalling molecule in the locus coeruleus (LC). The LC is principal norepinephrine to frontal brain thus one most influential modulatory centers brain. Optogenetically activated astrocytes which excites neurons triggers norepinephrine. Exogenous within physiologically relevant concentration range mimics...
In terrestrial mammals, the oxygen storage capacity of CNS is limited, and neuronal function rapidly impaired if supply interrupted even for a short period time. However, tension monitored by peripheral (arterial) chemoreceptors not sensitive to regional differences in partial pressure (P<sub>O<sub>2</sub></sub>) that reflect variable levels activity or local tissue hypoxia, pointing necessity functional brain sensor. This experimental animal (rats mice) study shows astrocytes, most numerous...
Innate mechanisms of inter-organ protection underlie the phenomenon remote ischaemic preconditioning (RPc) in which episode(s) ischaemia and reperfusion tissues from heart reduce myocardial ischaemia/reperfusion injury. The uncertainty surrounding mechanism(s) underlying RPc centres on whether humoral factor(s) produced during tissue released into systemic circulation mediate RPc, or a neural signal is required. While these two hypotheses may not be incompatible, one approach to clarify...
Abstract Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient oxygen supply 1,2 . Astrocytes, the ubiquitous glial neighbours neurons, govern brain glucose uptake metabolism 3,4 , but exact mechanisms metabolic coupling between neurons astrocytes that ensure on-demand support neuronal energy needs are not fully understood 5,6 Here we show, using experimental in vitro vivo animal models, activity-dependent activation is mediated...
Pontospinal noradrenergic neurons are thought to form part of a descending endogenous analgesic system that exerts inhibitory influences on spinal nociception. Using optogenetic targeting, we tested the hypothesis excitation locus ceruleus (LC) is antinociceptive. We transduced rat LC by direct injection lentiviral vector expressing channelrhodopsin2 under control PRS promoter. Subsequent optoactivation evoked repeatable, robust, antinociceptive (+4.7°C ± 1.0, p < 0.0001) or...
Abstract Astrocytes are implicated in modulation of neuronal excitability and synaptic function, but it remains unknown if these glial cells can directly control activities motor circuits to influence complex behaviors vivo. This study focused on the vital respiratory rhythm-generating preBötzinger (preBötC) determined how compromised function local astrocytes affects breathing conscious experimental animals (rats). Vesicular release mechanisms were disrupted by virally driven expression...
Systemic arterial hypertension has been previously suggested to develop as a compensatory condition when central nervous perfusion/oxygenation is compromised. Principal sympathoexcitatory C1 neurons of the rostral ventrolateral medulla oblongata (whose activation increases sympathetic drive and blood pressure) are highly sensitive hypoxia, but mechanisms this O2 sensitivity remain unknown. Here, we investigated potential linking brainstem hypoxia high systemic pressure in spontaneously...
The spontaneously hypertensive rat (SHR) replicates many clinically relevant features of human essential hypertension and also exhibits behavioral symptoms attention-deficit/hyperactivity disorder dementia. SHR phenotype is highly complex cannot be explained by a single genetic or physiological mechanism. Nevertheless, numerous studies including our own work have revealed striking differences in central catecholaminergic transmission such as increased vesicular catecholamine content the...
Mechanosensitivity is a well-known feature of astrocytes, however, its underlying mechanisms and functional significance remain unclear. There evidence that astrocytes are acutely sensitive to decreases in cerebral perfusion pressure may function as intracranial baroreceptors, tuned monitor brain blood flow. This study investigated the mechanosensory signaling brainstem these cells reside alongside cardiovascular control circuits mediate increases heart rate induced by falls perfusion. It...
Tricyclic antidepressants (TCAs) are associated with cardiovascular side effects including prolongation of the QT interval ECG. In this report we studied two TCAs (imipramine and amitriptyline) on ionic current mediated by cloned HERG potassium channels. Voltage clamp measurements currents were made from CHO cells transiently transfected cDNA. HERG‐encoded channels inhibited in a reversible manner both imipramine amitriptyline. tail (I ) following test pulses to +20 mV an IC 50 3.4±0.4 μ M...
Heart failure may lead to hypoperfusion and hypooxygenation of tissues this is often exacerbated by central obstructive sleep apnoeas associated with recurrent episodes systemic hypoxia which triggers release ATP within the CNS circuits controlling sympathetic outflow. Using in vitro vivo models we tested two hypotheses: (1) activated brainstem astroglia via activate sympathoexcitatory neurones rostral ventrolateral medulla (RVLM); (2) actions RVLM contribute sympathoexcitation, progression...
Discovery of neuroprotective pathways is one the major priorities for neuroscience. Astrocytes are natural neuroprotectors and it likely that brain resilience can be enhanced by mobilizing their protective potential. Among G‐protein coupled receptors expressed astrocytes, two highly related receptors, GPR37L1 GPR37, particular interest. Previous studies suggested these activated a peptide Saposin C its neuroactive fragments (prosaptide TX14(A)), which were demonstrated to in various animal...
Astrocytes modulate synaptic transmission via release of gliotransmitters such as ATP, glutamate, D-serine and L-lactate. One the main problems when studying role astrocytes in vitro vivo is lack suitable tools for their selective activation. Optogenetic actuators can be used to manipulate astrocytic activity by expression variants channelrhodopsin-2 (ChR2) or other optogenetic with aim initiate intracellular events Ca(2+) ([Ca(2+)]i) and/or cAMP increases. We have developed an array...
Abstract The spinal dorsal horn receives a dense innervation of noradrenaline‐containing fibers that originate from pontine neurons in the A5, locus coeruleus (LC), and A7 cell groups. These pontospinal are believed to constitute component endogenous analgesic system. We used an adenoviral vector with catecholaminergic‐selective promoter (AVV‐PRS) retrogradely label noradrenergic projecting lumbar (L4–L5) enhanced green fluorescent protein (EGFP) or monomeric red (mRFP). Retrogradely labeled...
The mechanisms of neurovascular coupling underlying generation BOLD fMRI signals remain incompletely understood. It has been proposed that release vasoactive substances by astrocytes couples neuronal activity to changes in cerebrovascular blood flow. However, the role responses remains controversial. Astrocytes communicate via ATP, and here we tested hypothesis purinergic signaling plays a fMRI. An established paradigm was used trigger forepaw region somatosensory cortex (SSFP) an...
Information on the distribution and biology of G-protein coupled receptor 4 (GPR4) in brain is limited. It currently thought that GPR4 couples to Gs proteins may mediate central respiratory sensitivity CO2. Using a knock-in mouse model, abundant expression was detected cerebrovascular endothelium neurones dorsal raphe, retro-trapezoidal nucleus locus coeruleus lateral septum. A similar confirmed using RNAscope situ hybridisation. In HEK293 cells, overexpressing GPR4, it highly constitutively...
The vesicle priming protein Munc13-1 is regulated by diacylglycerol (DAG) and therefore hypothesized to play a role in the control of neurotransmitter release phospholipase C (PLC)-coupled receptors. We combined voltage-clamp recordings voltage-gated Ca2+ channels (VGCCs) high-resolution capacitance measurements investigate mechanism receptor-mediated modulation exocytosis bovine chromaffin cells. Activation endogenous H1 G(q)-protein-coupled receptors (G(q)PCRs) histamine potentiated...
Abstract Inorganic polyphosphate (polyP) is present in every cell and highly conserved from primeval times. In the mammalian cells, polyP plays multiple roles including control of bioenergetics signal transduction. brain, mediates signaling between astrocytes via activation purinergic receptors, however, mechanisms release remain unknown. Here we report identification polyP‐containing vesicles cortical main triggers that evoke vesicular release. cultured astrocytes, was localized...