Neural activity of retinal ganglion cells under continuous, dynamically-modulated high frequency electrical stimulation.

Current retinal prosthetics are limited in their ability to precisely control firing patterns of functionally distinct retinal ganglion cell (RGC) types. The aim of this study was to characterise RGC responses to continuous, kilohertz-frequency-varying stimulation to assess its utility in controlling RGC activity.We usedpatch-clamp experiments to assess electrically-evoked ON and OFF RGC responses to frequency-varying pulse train sequences.

Astrocytic K clearance during disease progression in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which patients lose motor functions due to progressive loss of motor neurons in the cortex, brainstem, and spinal cord. 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. Astrocytes play an important role in maintaining ion homeostasis in the extracellular milieu and regulate multiple brain functions by altering their extracellular concentrations.

Six weeks of N-acetylcysteine antioxidant in drinking water decreases pathological fiber branching in MDX mouse dystrophic fast-twitch skeletal muscle.

It has been proposed that an increased susceptivity to oxidative stress caused by the absence of the protein dystrophin from the inner surface of the sarcolemma is a trigger of skeletal muscle necrosis in the destructive dystrophin deficient muscular dystrophies. Here we use the mdx mouse model of human Duchenne Muscular Dystrophy to test the hypothesis that adding the antioxidant NAC at 2% to drinking water for six weeks will treat the inflammatory phase of the dystrophic process and reduce pathological muscle fiber branching and splitting resulting in a reduction of mass in mdx fast-twitch EDL muscles. Animal weight and water intake was recorded during the six weeks when 2% NAC was added to the drinking water.

Associations between Sleep Quality and Heart Rate Variability: Implications for a Biological Model of Stress Detection Using Wearable Technology.

Introduction: The autonomic nervous system plays a vital role in the modulation of many vital bodily functions, one of which is sleep and wakefulness. Many studies have investigated the link between autonomic dysfunction and sleep cycles; however, few studies have investigated the links between short-term sleep health, as determined by the Pittsburgh Quality of Sleep Index (PSQI), such as subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction, and autonomic functioning in healthy individuals.

Aim: In this cross-sectional study, the aim was to investigate the links between short-term sleep quality and duration, and heart rate variability in 60 healthy individuals, in order to provide useful information about the effects of stress and sleep on heart rate variability (HRV) indices, which in turn could be integrated into biological models for wearable devices.

Sarcoplasmic reticulum calcium handling in unbranched, immediately post-necrotic fast-twitch mdx fibres is similar to wild-type littermates.

New Findings: What is the central question of this study? What are the early effects of dystrophin deficiency on sarcoplasmic reticulum Ca handling in the mdx mouse? What is the main finding and its importance? In the mdx mouse, Ca handling by the sarcoplasmic reticulum is little affected by the absence of dystrophin when looking at fibres without branches that have recently regenerated after massive myonecrosis. This has important implications for our understanding of Ca pathology in the mdx mouse.

Abstract: There is a variety of results in the literature regarding the effects of dystrophin deficiency on the Ca handling properties of the sarcoplasmic reticulum (SR) in the mdx mouse, an animal model of Duchenne muscular dystrophy.

Lifespan Analysis of Dystrophic 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 mouse model, we studied the morphological and contractile chronology of dystrophic skeletal muscle pathology in fast-twitch Extensor Digitorum Longus 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 (EC) of 20% strain with the greatest loss of ∼92% recorded in senescent 22-month-old mice.

Neuronal Deposition of Amyloid-β Oligomers and Hyperphosphorylated Tau Is Closely Connected with Cognitive Dysfunction in Aged Dogs.

Background: Canine cognitive dysfunction (CCD) is a progressive syndrome recognized in mature to aged dogs with a variety of neuropathological changes similar to human Alzheimer's disease (AD), for which it is thought to be a good natural model. However, the presence of hyperphosphorylated tau protein (p-Tau) in dogs with CCD has only been demonstrated infrequently.

Objective: The aim of the present study was to investigate the presence of p-Tau and amyloid-β oligomer (Aβo) in cerebral cortex and hippocampus of dogs with CCD, with focus on an epitope retrieval protocol to unmask p-Tau.

Dystrophin-negative slow-twitch soleus muscles are not susceptible to eccentric contraction induced injury over the lifespan of the mouse.

Duchenne muscular dystrophy (DMD) is the second most common fatal genetic disease in humans and is characterized by the absence of a functional copy of the protein dystrophin from skeletal muscle. In dystrophin-negative humans and rodents, regenerated skeletal muscle fibers show abnormal branching. The number of fibers with branches and the complexity of branching increases with each cycle of degeneration/regeneration.

Minocycline Treatment Reduces Mass and Force Output From Fast-Twitch Mouse Muscles and Inhibits Myosin Production in C2C12 Myotubes.

Minocycline, a tetracycline-class of antibiotic, has been tested with mixed effectiveness on neuromuscular disorders such as amyotrophic lateral sclerosis, autoimmune neuritis and muscular dystrophy. The independent effect of minocycline on skeletal muscle force production and signalling remain poorly understood. Our aim here is to investigate the effects of minocycline on muscle mass, force production, myosin heavy chain abundance and protein synthesis.

Detection of retinal and blood Aβ oligomers with nanobodies.

Introduction: Abnormal retinal changes are increasingly recognized as an early pathological change in Alzheimer's disease (AD). Although amyloid beta oligomers (Aβo) have been shown to accumulate in the blood and retina of AD patients and animals, it is not known whether the early Aβo deposition precedes their accumulation in brain.

Methods And Results: Using nanobodies targeting Aβ and Aβ oligomers we were able to detect Aβ oligomers in the retina and blood but not in the brain of 3-month-old APP/PS1 mice.

Neuromodulation of Astrocytic K Clearance.

Potassium homeostasis is fundamental for brain function. Therefore, effective removal of excessive K+ from the synaptic cleft during neuronal activity is paramount. Astrocytes 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.

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.

Towards Controlling Functionally-Distinct Retinal Ganglion Cells In Degenerate Retina.

Present retinal neuroprostheses have limited performance capabilities due to indiscriminate activation of different neural pathways. Based on our success in differentially activating ON and OFF cells using high frequency stimuli in a healthy retina, in this study we explored whether we could achieve similar differential activation between these two cell types but in degenerate retina. We found that after blocking the synaptic network, ON retinal ganglion cells (RGCs) could be differentially activated at higher frequencies (4 - 6 kHz) and amplitudes (200 - 240 µA), and OFF RGCs at relatively lower amplitudes (80 - 160 µA) across all tested frequencies.

Neuromodulation of Glial Function During Neurodegeneration.

Glia, a non-excitable cell type once considered merely as the connective tissue between neurons, is nowadays acknowledged for its essential contribution to multiple physiological processes including learning, memory formation, excitability, synaptic plasticity, ion homeostasis, and energy metabolism. Moreover, as glia are key players in the brain immune system and provide structural and nutritional support for neurons, they are intimately involved in multiple neurological disorders. Recent advances have demonstrated that glial cells, specifically microglia and astroglia, are involved in several neurodegenerative diseases including Amyotrophic lateral sclerosis (ALS), Epilepsy, Parkinson's disease (PD), Alzheimer's disease (AD), and frontotemporal dementia (FTD).

Age-Specific Retinal and Cerebral Immunodetection of Amyloid-β Plaques and Oligomers in a Rodent Model of Alzheimer's Disease.

Background: Amyloid-β soluble oligomers (Aβo) are believed to be the cause of the pathophysiology underlying Alzheimer's disease (AD) and are normally detected some two decades before clinical onset of the disease. Retinal pathology associated with AD pathogenesis has previously been reported, including ganglion cell loss, accumulation of Aβ deposits in the retina, and reduction of nerve fiber layer thickness as well as abnormalities of the microvasculature.

Objective: This study's aim is to better understand the relationship between brain and retinal Aβo deposition and in particular to quantify levels of the toxic Aβo as a function of age in the retina of a rodent model of AD.

Neural activity of functionally different retinal ganglion cells can be robustly modulated by high-rate electrical pulse trains.

Objective: This study focused on characterising the response of four major functionally-different retinal ganglion cells (RGCs) to a high frequency stimulus (HFS) paradigm.

Approach: We used in vitro patch clamp experiments to assess the viability of evoking a differential response between different RGC types-OFF-Sustained, OFF-Transient, ON-Sustained and ON-Transient-under a wide range of HFS and stimulation amplitude combinations.

Main Results: Of the four types, we found that the OFF-Sustained, OFF-Transient and ON-Transient RGCs could be differentially activated at various frequency and amplitude combinations, in particular, OFF-Sustained cells can be differentially targeted between 20-100 µA at all frequencies, OFF-Transient cells between 150-240 µA at 1 kHz and ON-Transient between 180-240 µA and 4-6 kHz.

Forced Disruption of Anatomy Education in Australia and New Zealand: An Acute Response to the Covid-19 Pandemic.

Australian and New Zealand universities commenced a new academic year in February/March 2020 largely with "business as usual." The subsequent Covid-19 pandemic imposed unexpected disruptions to anatomical educational practice. Rapid change occurred due to government-imposed physical distancing regulations from March 2020 that increasingly restricted anatomy laboratory teaching practices.

Generating Brain Waves, the Power of Astrocytes.

Synchronization of neuronal activity in the brain underlies the emergence of neuronal oscillations termed "brain waves", which serve various physiological functions and correlate with different behavioral states. It has been postulated that at least ten distinct mechanisms are involved in the formulation of these brain waves, including variations in the concentration of extracellular neurotransmitters and ions, as well as changes in cellular excitability. In this mini review we highlight the contribution of astrocytes, a subtype of glia, in the formation and modulation of brain waves mainly due to their close association with synapses that allows their bidirectional interaction with neurons, and their syncytium-like activity via gap junctions that facilitate communication to distal brain regions through Ca waves.

The differential impact of acute microglia activation on the excitability of cholinergic neurons in the mouse medial septum.

The medial septal nucleus is one of the basal forebrain nuclei that projects cholinergic input to the hippocampus and cortex. Two of the hallmarks of Alzheimer's disease (AD) are a significant loss of cholinergic transmission and neuroinflammation, and it has been suggested that these two hallmarks are causally linked to the medial septum. Therefore, we have investigated the age-related susceptibility of medial septal cholinergic neurons to glial activation, mediated via peripheral administration of lipopolysaccharide (500 μg/kg) into ChAT(BAC)-eGFP mice at different ages (3-22 months).

Mediating Retinal Ganglion Cell Spike Rates Using High-Frequency Electrical Stimulation.

Recent retinal studies have directed more attention to sophisticated stimulation strategies based on high-frequency (>1.0 kHz) electrical stimulation (HFS). In these studies, each retinal ganglion cell (RGC) type demonstrated a characteristic stimulus-strength-dependent response to HFS, offering the intriguing possibility of focally targeting retinal neurons to provide useful visual information by retinal prosthetics.

Hierarchical and Nonlinear Dynamics in Prefrontal Cortex Regulate the Precision of Perceptual Beliefs.

Actions are shaped not only by the content of our percepts but also by our confidence in them. To study the cortical representation of perceptual precision in decision making, we acquired functional imaging data whilst participants performed two vibrotactile forced-choice discrimination tasks: a fast-slow judgment, and a same-different judgment. The first task requires a comparison of the perceived vibrotactile frequencies to decide which one is faster.

Peripheral Nerve Activation Evokes Machine-Learnable Signals in the Dorsal Column Nuclei.

The brainstem dorsal column nuclei (DCN) are essential to inform the brain of tactile and proprioceptive events experienced by the body. However, little is known about how ascending somatosensory information is represented in the DCN. Our objective was to investigate the usefulness of high-frequency (HF) and low-frequency (LF) DCN signal features (SFs) in predicting the nerve from which signals were evoked.

Rod Photoreceptor Activation Alone Defines the Release of Dopamine in the Retina.

Retinal dopamine is released by a specialized subset of amacrine cells in response to light and has a potent influence on how the retina responds to, and encodes, visual information. Here, we address the critical question of which retinal photoreceptor is responsible for coordinating the release of this neuromodulator. Although all three photoreceptor classes-rods, cones, and melanopsin-containing retinal ganglion cells (mRGCs)-have been shown to provide electrophysiological inputs to dopaminergic amacrine cells (DACs), we show here that the release of dopamine is defined only by rod photoreceptors.

Computational Models And Tools For Developing Sophisticated Stimulation Strategies For Retinal Neuroprostheses.

Improvements to the efficacy of retinal neuroprostheses can be achieved by developing more sophisticated neural stimulation strategies to enable selective or preferential activation of specific retinal ganglion cells (RGCs). Computational models are particularly well suited for these investigations. The electric field can be accurately described by mathematical formalisms, and the population-based neural responses to the electrical stimulation can be investigated at resolutions well beyond those achievable by current state-of-the-art biological techniques.