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"Reynolds, John J."
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Coincidence of cholinergic pauses, dopaminergic activation and depolarisation of spiny projection neurons drives synaptic plasticity in the striatum
Dopamine-dependent long-term plasticity is believed to be a cellular mechanism underlying reinforcement learning. In response to reward and reward-predicting cues, phasic dopamine activity potentiates the efficacy of corticostriatal synapses on spiny projection neurons (SPNs). Since phasic dopamine activity also encodes other behavioural variables, it is unclear how postsynaptic neurons identify which dopamine event is to induce long-term plasticity. Additionally, it is unknown how phasic dopamine released from arborised axons can potentiate targeted striatal synapses through volume transmission. To examine these questions we manipulated striatal cholinergic interneurons (ChIs) and dopamine neurons independently in two distinct in vivo paradigms. We report that long-term potentiation (LTP) at corticostriatal synapses with SPNs is dependent on the coincidence of pauses in ChIs and phasic dopamine activation, critically accompanied by SPN depolarisation. Thus, the ChI pause defines the time window for phasic dopamine to induce plasticity, while depolarisation of SPNs constrains the synapses eligible for plasticity.
It remains unclear how corticostriatal synapses utilize reward prediction error signaling in order to reinforce reward-related behaviors. Here, the authors show that potentiation of corticostriatal synapses requires phasic dopamine activation, pauses in striatal cholinergic interneuron firing, and depolarization of spiny projection neurons.
Journal Article
Ultrasound-Mediated Blood–Brain Barrier Disruption for Drug Delivery: A Systematic Review of Protocols, Efficacy, and Safety Outcomes from Preclinical and Clinical Studies
Ultrasound-mediated blood–brain barrier (BBB) disruption has garnered focus as a method of delivering normally impenetrable drugs into the brain. Numerous studies have investigated this approach, and a diverse set of ultrasound parameters appear to influence the efficacy and safety of this approach. An understanding of these findings is essential for safe and reproducible BBB disruption, as well as in identifying the limitations and gaps for further advancement of this drug delivery approach. We aimed to collate and summarise protocols and parameters for achieving ultrasound-mediated BBB disruption in animal and clinical studies, as well as the efficacy and safety methods and outcomes associated with each. A systematic search of electronic databases helped in identifying relevant, included studies. Reference lists of included studies were further screened to identify supplemental studies for inclusion. In total, 107 articles were included in this review, and the following parameters were identified as influencing efficacy and safety outcomes: microbubbles, transducer frequency, peak-negative pressure, pulse characteristics, and the dosing of ultrasound applications. Current protocols and parameters achieving ultrasound-mediated BBB disruption, as well as their associated efficacy and safety outcomes, are identified and summarised. Greater standardisation of protocols and parameters in future preclinical and clinical studies is required to inform robust clinical translation.
Journal Article
Harnessing Ultrasound for Targeting Drug Delivery to the Brain and Breaching the Blood–Brain Tumour Barrier
Despite significant advances in developing drugs to treat brain tumours, achieving therapeutic concentrations of the drug at the tumour site remains a major challenge due to the presence of the blood–brain barrier (BBB). Several strategies have evolved to enhance brain delivery of chemotherapeutic agents to treat tumours; however, most approaches have several limitations which hinder their clinical utility. Promising studies indicate that ultrasound can penetrate the skull to target specific brain regions and transiently open the BBB, safely and reversibly, with a high degree of spatial and temporal specificity. In this review, we initially describe the basics of therapeutic ultrasound, then detail ultrasound-based drug delivery strategies to the brain and the mechanisms by which ultrasound can improve brain tumour therapy. We review pre-clinical and clinical findings from ultrasound-mediated BBB opening and drug delivery studies and outline current therapeutic ultrasound devices and technologies designed for this purpose.
Journal Article
DONSON and FANCM associate with different replisomes distinguished by replication timing and chromatin domain
Duplication of mammalian genomes requires replisomes to overcome numerous impediments during passage through open (eu) and condensed (hetero) chromatin. Typically, studies of replication stress characterize mixed populations of challenged and unchallenged replication forks, averaged across S phase, and model a single species of “stressed” replisome. Here, in cells containing potent obstacles to replication, we find two different lesion proximal replisomes. One is bound by the DONSON protein and is more frequent in early S phase, in regions marked by euchromatin. The other interacts with the FANCM DNA translocase, is more prominent in late S phase, and favors heterochromatin. The two forms can also be detected in unstressed cells. ChIP-seq of DNA associated with DONSON or FANCM confirms the bias of the former towards regions that replicate early and the skew of the latter towards regions that replicate late.
Eukaryotic replisomes are multiprotein complexes. Here the authors reveal two distinct stressed replisomes, associated with DONSON and FANCM, displaying a bias in replication timing and chromatin domain.
Journal Article
The Sheep as a Large Animal Model for the Investigation and Treatment of Human Disorders
An essential aim of biomedical research is to translate basic science information obtained from preclinical research using small and large animal models into clinical practice for the benefit of humans. Research on rodent models has enhanced our understanding of complex pathophysiology, thus providing potential translational pathways. However, the success of translating drugs from pre-clinical to clinical therapy has been poor, partly due to the choice of experimental model. The sheep model, in particular, is being increasingly applied to the field of biomedical research and is arguably one of the most influential models of human organ systems. It has provided essential tools and insights into cardiovascular disorder, orthopaedic examination, reproduction, gene therapy, and new insights into neurodegenerative research. Unlike the widely adopted rodent model, the use of the sheep model has an advantage over improving neuroscientific translation, in particular due to its large body size, gyrencephalic brain, long lifespan, more extended gestation period, and similarities in neuroanatomical structures to humans. This review aims to summarise the current status of sheep to model various human diseases and enable researchers to make informed decisions when considering sheep as a human biomedical model.
Journal Article
A cellular mechanism of reward-related learning
Positive reinforcement helps to control the acquisition of learned behaviours. Here we report a cellular mechanism in the brain that may underlie the behavioural effects of positive reinforcement. We used intracranial self-stimulation (ICSS) as a model of reinforcement learning
1
, in which each rat learns to press a lever that applies reinforcing electrical stimulation to its own substantia nigra
2
,
3
. The outputs from neurons of the substantia nigra terminate on neurons in the striatum in close proximity to inputs from the cerebral cortex on the same striatal neurons
4
. We measured the effect of substantia nigra stimulation on these inputs from the cortex to striatal neurons and also on how quickly the rats learned to press the lever. We found that stimulation of the substantia nigra (with the optimal parameters for lever-pressing behaviour) induced potentiation of synapses between the cortex and the striatum, which required activation of dopamine receptors. The degree of potentiation within ten minutes of the ICSS trains was correlated with the time taken by the rats to learn ICSS behaviour. We propose that stimulation of the substantia nigra when the lever is pressed induces a similar potentiation of cortical inputs to the striatum, positively reinforcing the learning of the behaviour by the rats.
Journal Article
Mutations in PNKP cause microcephaly, seizures and defects in DNA repair
Christopher Walsh and colleagues describe a new recessive genetic disease characterized by microcephaly, early-onset intractable seizures and developmental delay (MCSZ). The authors identify mutations in
PNKP
that result in this severe disease and show that
PNKP
mutations disrupt DNA repair.
Maintenance of DNA integrity is crucial for all cell types, but neurons are particularly sensitive to mutations in DNA repair genes, which lead to both abnormal development and neurodegeneration
1
. We describe a previously unknown autosomal recessive disease characterized by microcephaly, early-onset, intractable seizures and developmental delay (denoted MCSZ). Using genome-wide linkage analysis in consanguineous families, we mapped the disease locus to chromosome 19q13.33 and identified multiple mutations in
PNKP
(polynucleotide kinase 3′-phosphatase) that result in severe neurological disease; in contrast, a splicing mutation is associated with more moderate symptoms. Unexpectedly, although the cells of individuals carrying this mutation are sensitive to radiation and other DNA-damaging agents, no such individual has yet developed cancer or immunodeficiency. Unlike other DNA repair defects that affect humans,
PNKP
mutations universally cause severe seizures. The neurological abnormalities in individuals with MCSZ may reflect a role for PNKP in several DNA repair pathways.
Journal Article
Therapeutic ultrasound: an innovative approach for targeting neurological disorders affecting the basal ganglia
The basal ganglia are involved in motor control and action selection, and their impairment manifests in movement disorders such as Parkinson’s disease (PD) and dystonia, among others. The complex neuronal circuitry of the basal ganglia is located deep inside the brain and presents significant treatment challenges. Conventional treatment strategies, such as invasive surgeries and medications, may have limited effectiveness and may result in considerable side effects. Non-invasive ultrasound (US) treatment approaches are becoming increasingly recognized for their therapeutic potential for reversibly permeabilizing the blood–brain barrier (BBB), targeting therapeutic delivery deep into the brain, and neuromodulation. Studies conducted on animals and early clinical trials using ultrasound as a therapeutic modality have demonstrated promising outcomes for controlling symptom severity while preserving neural tissue. These results could improve the quality of life for patients living with basal ganglia impairments. This review article explores the therapeutic frontiers of ultrasound technology, describing the brain mechanisms that are triggered and engaged by ultrasound. We demonstrate that this cutting-edge method could transform the way neurological disorders associated with the basal ganglia are managed, opening the door to less invasive and more effective treatments.
Journal Article