Biology subjects

Morley, J. W.

Publications and source records attributed to Morley, J. W..

5 recordsLinked to original sources

bioRxiv2024

Potassium homeostasis during disease progression of Alzheimers Disease

Alzheimers disease (AD) is an age-dependent neurodegenerative disorder characterized by neuronal loss leading to dementia and ultimately death. Whilst the loss of neurons is central to the disease, it is becoming clear that glia, specifically astrocytes, contribute to the onset and progression of neurodegeneration. Astrocytic role in retaining ion homeostasis in the extracellular milieu is fundamental for multiple brain functions, including synaptic plasticity and neuronal excitability, which are compromised during AD and affect neuronal signalling. In this study, we have measured the astrocytic K+ clearance rate in the hippocampus and somatosensory cortex of a mouse model for AD during disease progression. Our results establish that astrocytic [K+]o clearance in the hippocampus is reduced in symptomatic 5xFAD mice, and this decrease is region-specific. The decrease in the [K+]o clearance rate correlated with a significant reduction in the expression and conductivity of Kir4.1 channels and a decline in the number of primary connected astrocytes. Moreover, astrocytes in the hippocampus of symptomatic 5xFAD mice demonstrated increased reactivity which was accompanied by an increased excitability and altered spiking profile of nearby neurons. These findings indicate that the supportive function astrocytes typically provide to nearby neurons is diminished during disease progression, which affects the neuronal circuit signalling in this area and provides a potential explanation for the increased vulnerability of neurons in AD.

neuroscience↗

bioRxiv2021

SR Ca2+ handling in unbranched, immediately post-necrotic fast-twitch mdx fibres is similar to wt littermates

There is a lack of consensus in the literature regarding the effects of dystrophin deficiency on the Ca2+-handling properties of the SR in mdx mice, an animal model of Duchenne muscular dystrophy. One possible reason for this is that only a few studies control for the presence of branched fibres. Fibre branching, a consequence of degenerative-regenerative processes such as muscular dystrophy, has in itself a significant influence on the function of the SR. In our present study we attempt to detect early effects of dystrophin deficiency on SR Ca2+ handling by using unbranched fibres from the immediate post-necrotic stage in mdx mice (just regenerated following massive necrosis). Using kinetically-corrected Fura-2 fluorescence signals measured during twitch and tetanus, we analysed the amplitude, rise time and decay time of {Delta}[Ca2+]i in unfatigued and fatigued fibres. Decay was also resolved into SR pump and SR leak components. Fibres from mdx mice were similar in all respects to fibres from wt littermates apart from: (i) a longer rise time and slower rate of rise of [Ca2+]i during a tetanus; and (ii) a mitigation of the fall in {Delta}[Ca2+]i amplitude during the course of fatigue. Our findings suggest that the early effects of a loss of dystrophin on SR Ca2+ handling are only slight, and differ from the widely held view that there is significant Ca2+ pathology in mdx mice. It may be that Ca2+ pathology is magnified by progressive branching and degeneration. New findingsCentral question: What are the early effects of dystrophin deficiency on SR Ca2+ handling in the mdx mouse? Main finding: In the mdx mouse, Ca2+ handling by the SR is little affected by the absence of dystrophin when looking at fibres without branches that have just regenerated following massive myonecrosis. This has important implications for the traditional view that Ca2+ pathology is significant in the mdx mouse.

physiology↗

bioRxiv2021

Lifespan analysis of dystrophic mdx fast-twitch muscle morphology and its impact on contractile function

Duchenne muscular dystrophy is caused by the absence of the protein dystrophin from skeletal muscle and is characterized by progressive cycles of necrosis/regeneration. Using the dystrophin deficient mdx mouse model we studied the morphological and contractile chronology of dystrophic skeletal muscle pathology in fast twitch EDL muscles from animals 4-22 months of age containing 100% regenerated muscle fibers. Catastrophically, the older age groups lost [~]80% of their maximum force after one eccentric contraction of 20% strain, with the greatest loss [~]93% recorded in senescent 22 month old mdx mice. In old age groups there was minimal force recovery [~]24% after 120 minutes, correlated with a dramatic increase in the number and complexity of branched fibers. This data supports our two-stage model where a "tipping point" is reached when branched fibers rupture irrevocably on eccentric contraction. These findings have important implications for pre-clinical drug studies and genetic rescue strategies.

physiology↗

bioRxiv2020

Steady state evoked potential (SSEP) responses in the primary and secondary somatosensory cortices of anesthetized cats: nonlinearity characterized by harmonic and intermodulation frequencies

When presented with an oscillatory sensory input at a particular frequency, F [Hz], neural systems respond with the corresponding frequency, f [Hz], and its multiples. When the input includes two frequencies (F1 and F2) and they are nonlinearly integrated in the system, responses at intermodulation frequencies (i.e., n1*f1+n2*f2 [Hz], where n1 and n2 are non-zero integers) emerge. Utilizing these properties, the steady state evoked potential (SSEP) paradigm allows us to characterize linear and nonlinear neural computation performed in cortical neurocircuitry. Here, we analyzed the steady state evoked local field potentials (LFPs) recorded from the primary (S1) and secondary (S2) somatosensory cortex of anesthetized (ketamine-xylazine) cats while we presented slow (F1=23Hz) and fast (F2=200Hz) somatosensory vibration to the contralateral paw pads and digits. Over 9 experimental sessions, we recorded LFPs from N=1620 and N=1008 bipolar-referenced sites in S1 and S2 using electrode arrays. Power spectral analyses revealed strong responses at 1) the fundamental (f1, f2), 2) its harmonic, 3) the intermodulation frequencies, and 4) broadband frequencies (50-150Hz). To compare the computational architecture in S1 and S2, we employed simple computational modeling. Our modeling results necessitate nonlinear computation to explain SSEP in S2 more than S1. Combined with our current analysis of LFPs, our paradigm offers a rare opportunity to constrain the computational architecture of hierarchical organization of S1 and S2 and to reveal how a large-scale SSEP can emerge from local neural population activities.

neuroscience↗

bioRxiv2019

Neuromodulation of astrocytic K+ clearance

Potassium homeostasis is a fundamental requirement for normal brain function. Therefore, effective removal of excessive K+ accumulation from the synaptic cleft during neuronal activity is paramount. Astrocytes, one of the most common subtype of glial cells in the brain, play a key role in K+ clearance from the extracellular milieu using various mechanisms, including uptake via Kir channels and the Na+-K+ ATPase, and spatial buffering through the astrocytic gap-junction coupled network. Recently we showed that alterations in the concentrations of extracellular potassium ([K+]{degrees}) or impairments of the astrocytic clearance mechanism effect the resonance and oscillatory behaviour of both individual and networks of neurons recorded from C57/BL6 mice of both sexes. These results indicate that astrocytes have the potential to modulate neuronal network activity, however the cellular effectors that may affect the astrocytic K+ clearance process are still unknown. In this study, we have investigated the impact of neuromodulators, which are known to mediate changes in network oscillatory behaviour, on the astrocytic clearance process. Our results suggest that some neuromodulators (5-HT; NA) affect astrocytic spatial buffering via gap-junctions, while others (DA; Histamine) affect the uptake mechanism via Kir channels. These results suggest that neuromodulators can affect network oscillatory activity through parallel activation of both neurons and astrocytes, establishing a synergistic mechanism to recruitment of neurons into ensamble of networks to maximise the synchronous network activity. Significance statementNeuromodulators are known to mediate changes in network oscillatory behaviour and thus impact on brain states. In this study we show that certain neuromodulators directly affect distinct stages of astrocytic K+ clearance, promoting neuronal excitability and network oscillations through parallel activation of both neurons and astrocytes, thus establishing a synergistic mechanism to maximise the synchronous network activity.

neuroscience↗