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.
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.
Dynamic behaviour restructuring mediates dopamine-dependent credit assignment
By onSource data for Nature manuscript: Dynamic behavior restructuring mediates dopamine-dependent credit assignment.
Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19
By onThe authors concluded that after a fatal course of COVID-19, microscopic changes, when present, in the rostral, intracranial portion of the olfactory circuitry generally reflected neurodegenerative processes seen elsewhere in the brain.
RASP: Optimal single fluorescent puncta detection in complex cellular backgrounds
By onRASP, a bioimaging-segmentation method, outperforms existing methods by removing false positives + detecting features across various spatial scales. RASP enables precise analysis of cellular and tissue environments, down to single protein levels.
Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition
By onThis study reveals that TBK1 is recruited to lysosomes when amino acids are abundant where it phosphorylates Rab7 and thus relieves Rab7-dependent suppression of mTORC1 signaling from lysosomes.
Synchronous Measurements of Extracellular Action Potentials and Neurochemical Activity with Carbon Fiber Electrodes in Nonhuman Primates
By onThe authors developed methods for synchronous measures of neuron spikes and dopamine signals in the monkey striatum. These methods will help advance our understanding of the interactions between neuromodulator signaling and neuronal activity.
Chemically induced senescence in human stem cell-derived neurons promotes phenotypic presentation of neurodegeneration
By onModeling age-related neurodegenerative disorders with human stem cells are difficult due to the embryonic nature of stem cell-derived neurons. We developed a chemical cocktail to induce senescence of iPSC-derived neurons to address this challenge. We first screened small molecules that induce embryonic fibroblasts to exhibit features characteristic of aged fibroblasts. We then optimized a cocktail of small molecules that induced senescence in fibroblasts and cortical neurons without causing DNA damage. The utility of the “senescence cocktail” was validated in motor neurons derived from ALS patient iPSCs which exhibited protein aggregation and axonal degeneration substantially earlier than those without cocktail treatment. Our “senescence cocktail” will likely enhance the manifestation of disease-related phenotypes in neurons derived from iPSCs, enabling the generation of reliable drug discovery platforms.
Mechanism of human PINK1 activation at the TOM complex in a reconstituted system
By onThe authors demonstrate an essential role of the pore-containing subunit TOM40 and its structurally associated subunits TOM7 and TOM22 for PINK1 activation.
Generation of locus coeruleus norepinephrine neurons from human pluripotent stem cells
By onCentral norepinephrine (NE) neurons, located mainly in the locus coeruleus (LC), are implicated in diverse psychiatric and neurodegenerative diseases and are an emerging target for drug discovery. To facilitate their study, we developed a method to generate 40–60% human LC-NE neurons from human pluripotent stem cells. The approach depends on our identification of ACTIVIN A in regulating LC-NE transcription factors in dorsal rhombomere 1 (r1) progenitors. In vitro generated human LC-NE neurons display extensive axonal arborization; release and uptake NE; and exhibit pacemaker activity, calcium oscillation and chemoreceptor activity in response to CO2. Single-nucleus RNA sequencing (snRNA-seq) analysis at multiple timepoints confirmed NE cell identity and revealed the differentiation trajectory from hindbrain progenitors to NE neurons via an ASCL1-expressing precursor stage. LC-NE neurons engineered with an NE sensor reliably reported extracellular levels of NE. The availability of functional human LC-NE neurons enables investigation of their roles in psychiatric and neurodegenerative diseases and provides a tool for therapeutics development.
Dopamine neuron activity encodes the length of upcoming contralateral movement sequences
By onHere the authors investigate whether dopamine neurons encode a general motivation signal or modulate movement kinematics.
Generation of the iPSC line FINi002-A from a male Parkinson’s disease patient carrying compound heterozygous mutations in the PRKN gene
By onGeneration of the iPSC line FINi002-A from a male Parkinson's disease patient carrying compound heterozygous mutations in the PRKN gene. Primary fibroblasts from a skin biopsy of a male PD patient were reprogrammed using transiently present non-replicating Sendai viruses. We envisage the usefulness of this iPSC line, carrying a common and well-studied missense mutation in the RING1 domain of the PARKIN protein, for the elucidation of PARKIN-dependent mechanisms of PD using in vitro and in vivo models.
Neuronal dysfunction and gene modulation by non-coding RNA in Parkinson’s disease and synucleinopathies
By onThis review discusses recent literature focused on the role of RNA-based mechanisms involved in different aspects of neuronal pathology in Parkinson’s disease and synucleinopathy models.
Loss of primary cilia and dopaminergic neuroprotection in pathogenic LRRK2-driven and idiopathic Parkinson’s disease
By onActivating LRRK2 mutations causes Parkinson's disease. Here, the data strongly suggest that loss of cilia in specific striatal cell types decreases neuroprotection for dopamine neurons in mice and human Parkinson's disease.
Kufor-Rakeb Syndrome-Associated Psychosis: A Novel Loss-of-Function ATP13A2 Variant and Response to Treatment
By onATP13A2 mutations cause Kufor-Rakeb syndrome, leading to parkinsonism with various neurological symptoms. Quetiapine showed promise in treating associated psychosis with good tolerance, suggesting its potential for managing such cases effectively.