Proteome of R1441C and G2019S LRRK2 knock in mice after striatal motor learning task
By onTo identify the signaling pathways that underlie motor learning deficits, the authors performed six-plex tandem mass tag (TMT) quantitative mass spectrometry (MS) to compare the protein expression in mice following the five days of the rotarod test.
Examining the brain’s response to intestinal permeability and inflammation in the dextran sulfate sodium-induced colitis model.
By onMice were treated with DSS under various schedules to study colitis. Tissues from colon and brain regions were analyzed using RNA sequencing to understand molecular changes linked to gut leakiness and colitis progression.
Tabular data of striatal motor learning experiments in LRRK2 KI mice
By onThe tabular data of the behavioral experiments described in the manuscript titled "R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations."
Tabular data of fast-scanning voltammetry and physiology experiments in LRRK2 KI mice
By onThe tabular data of fast-scanning cyclic voltammetry and physiology experiments from manuscript: "R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations." by Xenias et al.
Behavioral tests in rodents coupled with dopamine signaling manipulations
By onThese two protocols describe behavioral tests associated with Parkinson’s disease phenotypes in mice. The striatal motor learning protocol (rotarod test) is a two-phase paradigm assessing striatal motor learning under reversible dopamine antagonism.
Fast scan cyclic voltammetry
By onThis protocol describes the ex vivo fast-scan cyclic voltammetry (FSCV) technique for detecting dopamine in the dorsal striatum in mice.
Viral-mediated short-hairpin RNA knockdown
By onStereotaxic injection of viral vectors for gene knockdown experiments: The AAV vectors for knocking down the gene of interest were custom-made with Vector Biolabs using AAV-GFP-U6 vector for AAV1 packaging (Cat no, 7040, Vector Biolabs).
Macroscopic dynamics of neural networks with heterogeneous spiking thresholds
By onMean-field theory links the physiological properties of individual neurons to the emergent dynamics of neural population activity. These models provide an essential tool for studying brain function at different scales; however, for their application to neural populations on large scale, they need to account for differences between distinct neuron types. The Izhikevich single neuron model can account for a broad range of different neuron types and spiking patterns, thus rendering it an optimal candidate for a mean-field theoretic treatment of brain dynamics in heterogeneous networks. Here we derive the mean-field equations for networks of all-to-all coupled Izhikevich neurons with heterogeneous spiking thresholds. Using methods from bifurcation theory, we examine the conditions under which the mean-field theory accurately predicts the dynamics of the Izhikevich neuron network. To this end, we focus on three important features of the Izhikevich model that are subject here to simplifying assumptions: (i) spike-frequency adaptation, (ii) the spike reset conditions, and (iii) the distribution of single-cell spike thresholds across neurons. Our results indicate that, while the mean-field model is not an exact model of the Izhikevich network dynamics, it faithfully captures its different dynamic regimes and phase transitions. We thus present a mean-field model that can represent different neuron types and spiking dynamics. The model comprises biophysical state variables and parameters, incorporates realistic spike resetting conditions, and accounts for heterogeneity in neural spiking thresholds. These features allow for a broad applicability of the model as well as for a direct comparison to experimental data.
PyRates—A code-generation tool for modeling dynamical systems in biology and beyond
By onWe present PyRates, a code-generation tool for dynamical systems modeling applied to biological systems. Together with its extensions PyCoBi and RectiPy, PyRates provides a framework for modeling and analyzing complex biological systems via methods such as parameter sweeps, bifurcation analysis, and model fitting. We highlight the main features of this framework, with an emphasis on new features that have been introduced since the initial publication of the software, such as the extensive code generation capacities and widespread support for delay-coupled systems. Using a collection of mathematical models taken from various fields of biology, we demonstrate how PyRates enables analysis of the behavior of complex nonlinear systems using a diverse suite of tools. This includes examples where we use PyRates to interface a bifurcation analysis tool written in Fortran, to optimize model parameters via gradient descent in PyTorch, and to serve as a model definition interface for new dynamical systems analysis tools.
Neural heterogeneity controls computations in spiking neural networks
By onSignificance Neurons are the basic information-encoding units in the brain. In contrast to information-encoding units in a computer, neurons are heterogeneous, i.e., they differ substantially in their electrophysiological properties. How does the brain make use of this heterogeneous substrate to carry out its function of processing information and generating adaptive behavior? We analyze a mathematical model of networks of heterogeneous spiking neurons and show that neural heterogeneity provides a previously unconsidered means of controlling computational properties of neural circuits. We furthermore uncover different capacities of inhibitory vs. excitatory heterogeneity to regulate the gating of signals vs. the encoding and decoding of information, respectively. Our results reveal how a mostly overlooked property of the brain—neural heterogeneity—allows for the emergence of computationally specialized networks. Abstract The brain is composed of complex networks of interacting neurons that express considerable heterogeneity in their physiology and spiking characteristics. How does this neural heterogeneity influence macroscopic neural dynamics, and how might it contribute to neural computation? In this work, we use a mean-field model to investigate computation in heterogeneous neural networks, by studying how the heterogeneity of cell spiking thresholds affects three key computational functions of a neural population: the gating, encoding, and decoding of neural signals. Our results suggest that heterogeneity serves different computational functions in different cell types. In inhibitory interneurons, varying the degree of spike threshold heterogeneity allows them to gate the propagation of neural signals in a reciprocally coupled excitatory population. Whereas homogeneous interneurons impose synchronized dynamics that narrow the dynamic repertoire of the excitatory neurons, heterogeneous interneurons act as an inhibitory offset while preserving excitatory neuron function. Spike threshold heterogeneity also controls the entrainment properties of neural networks to periodic input, thus affecting the temporal gating of synaptic inputs. Among excitatory neurons, heterogeneity increases the dimensionality of neural dynamics, improving the network’s capacity to perform decoding tasks. Conversely, homogeneous networks suffer in their capacity for function generation, but excel at encoding signals via multistable dynamic regimes. Drawing from these findings, we propose intra-cell-type heterogeneity as a mechanism for sculpting the computational properties of local circuits of excitatory and inhibitory spiking neurons, permitting the same canonical microcircuit to be tuned for diverse computational tasks.
RectiPy software package
By onRecurrent neural network training in Python (RectiPy) is a software package developed by Richard Gast that allows for lightweight implementations of recurrent neural networks (RNNs) based on ordinary or delayed differential equations. The main purpose of the software is to provide a tool that allows for the implementation of biologically informed spiking neural networks and optimize the parameters of these networks via gradient descent. As such, RectiPy can be used to optimize a spiking network model of the basal ganglia to fit neural activity recordings, for example. RectiPy provides an intuitive YAML interface for model definition, and leverages PyRates to translate these model definitions into PyTorch functions. This way, users can easily define their own neuron models, spike-based or rate-based, and use them to create a RNN model. All model training, testing, as well as numerical integration of the differential equations is also performed in PyTorch. Thus, RectiPy comes with all the gradient-based optimization and parallelization features that PyTorch provides. RectiPy is freely available at https://github.com/pyrates-neuroscience/RectiPy and comes with a full online documentation and various use examples:
Targeted detection of SNCA CNVs in SOX10+ nuclei from oligodendrocytes containing alpha-synuclein inclusions isolated from human post-mortem brain
By onThis protocol describes the detection of low-level genomic mosaics in the human brain using DNA immunofluorescence-fluorescence in situ hybridisation, known as immuno-FISH, to analyze copy number variants in the SNCA gene related to PD & MSA.
Raw data associated with each Figure and Supplementary Figures from “Novel green fluorescent polyamines to analyze ATP13A2 and ATP13A3 activity in the mammalian polyamine transport system”
By onRaw data associated with each Figure and Supplementary Figures from "Novel green fluorescent polyamines to analyze ATP13A2 and ATP13A3 activity in the mammalian polyamine transport system"
Preparation of fresh paraformaldehyde for mouse perfusion and tissue fixation
By onPreparation of fresh paraformaldehyde for mouse perfusion and tissue fixation.
Polyamines in Parkinson’s Disease: Balancing Between Neurotoxicity and Neuroprotection
By onThe polyamines putrescine, spermidine, and spermine are abundant polycations of vital importance in mammalian cells. Their cellular levels are tightly regulated by degradation and synthesis, as well as by uptake and export. Here, we discuss the delicate balance between the neuroprotective and neurotoxic effects of polyamines in the context of Parkinson's disease (PD). Polyamine levels decline with aging and are altered in patients with PD, whereas recent mechanistic studies on ATP13A2 (PARK9) demonstrated a driving role of a disturbed polyamine homeostasis in PD. Polyamines affect pathways in PD pathogenesis, such as α-synuclein aggregation, and influence PD-related processes like autophagy, heavy metal toxicity, oxidative stress, neuroinflammation, and lysosomal/mitochondrial dysfunction. We formulate outstanding research questions regarding the role of polyamines in PD, their potential as PD biomarkers, and possible therapeutic strategies for PD targeting polyamine homeostasis.
Lyso-IP: Uncovering Pathogenic Mechanisms of Lysosomal Dysfunction
By onLysosomes are ubiquitous membrane-bound organelles found in all eukaryotic cells. Outside of their well-known degradative function, lysosomes are integral in maintaining cellular homeostasis. Growing evidence has shown that lysosomal dysfunction plays an important role not only in the rare group of lysosomal storage diseases but also in a host of others, including common neurodegenerative disorders, such as Alzheimer disease and Parkinson disease. New technological advances have significantly increased our ability to rapidly isolate lysosomes from cells in recent years. The development of the Lyso-IP approach and similar methods now allow for lysosomal purification within ten minutes. Multiple studies using the Lyso-IP approach have revealed novel insights into the pathogenic mechanisms of lysosomal disorders, including Niemann-Pick type C disease, showing the immense potential for this technique. Future applications of rapid lysosomal isolation techniques are likely to greatly enhance our understanding of lysosomal dysfunction in rare and common neurodegeneration causes.
Is Gauchian genotyping of GBA1 variants reliable?
By onBiallelic GBA1 mutations cause Gaucher disease & increase Parkinson's risk. Gauchian software aids in detecting GBA1 variants but may miss rare mutations and recombination events, limiting its diagnostic utility in GD and Parkinsonism studies.
α-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson’s disease
By onOur findings suggest that disruption of mitochondrial function, and the subsequent bioenergetic deficit, is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD.
Ca2+ channels couple spiking to mitochondrial metabolism in substantia nigra dopaminergic neurons
By onThe authors explore how cellular energy production and demand are matched.
Motor learning selectively strengthens cortical and striatal synapses of motor engram neurons Dataset
By onThis upload includes 1) ImageJ macros / scripts for minor automated cell counting for brain slides with immunostaining and 2) MATLAB functions / scripts for minor automated spine location cluster analysis (nearest neighbor distance / index).