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  • Peripheral MC1R Activation Modulates Immune Responses and is Neuroprotective in a Mouse Model of Parkinson’s Disease

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    Preprint: The present study investigates the impact of NDP-MSH, a synthetic melanocortin receptor (MCR) agonist that does not cross BBB, on the immune system and the nigrostriatal dopaminergic system in mouse model of PD.

  • Rethinking the network determinants of motor disability in Parkinson’s disease

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    For roughly the last 30 years, the notion that striatal dopamine (DA) depletion was the critical determinant of network pathophysiology underlying the motor symptoms of Parkinson’s disease (PD) has dominated the field. While the basal ganglia circuit model underpinning this hypothesis has been of great heuristic value, the hypothesis itself has never been directly tested. Moreover, studies in the last couple of decades have made it clear that the network model underlying this hypothesis fails to incorporate key features of the basal ganglia, including the fact that DA acts throughout the basal ganglia, not just in the striatum. Underscoring this point, recent work using a progressive mouse model of PD has shown that striatal DA depletion alone is not sufficient to induce parkinsonism and that restoration of extra-striatal DA signaling attenuates parkinsonian motor deficits once they appear. Given the broad array of discoveries in the field, it is time for a new model of the network determinants of motor disability in PD.

  • A leaky gut dysregulates gene networks in the brain associated with immune activation, oxidative stress, and myelination in a mouse model of colitis

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    The gut and brain are interconnected in human disease. Colitis models show reproducible genetic programs affecting both colon and brain, highlighting immune activation and potential therapeutic targets in the gut-brain axis.

  • Anionic nanoplastic contaminants promote Parkinson’s disease–associated α-synuclein aggregation

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    Studies show nanoplastic pollution can trigger α-synuclein protein fibrils formation and spread in the brain, potentially linking nanoplastics to Parkinson's disease and related dementias.

  • Central and peripheral innate and adaptive immunity in Parkinson’s disease

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    Parkinson’s disease is a chronic inflammatory disorder affecting multiple systems. Innovative immunomodulatory interventions are needed to address central and peripheral immune responses during disease onset and progression.

  • Calcium influx into astrocytes plays a pivotal role in inflammation-driven behaviors

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    Systemic inflammation can lead to astrogliosis, affecting neuronal activity linked to depressive behaviors. Orai1 calcium channel is crucial in this.Deleting Orai1 in astrocytes prevents astrogliosis, preserving normal neuronal activity and behavior.

  • Macroscopic dynamics of neural networks with heterogeneous spiking thresholds

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    Mean-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

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    We 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

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    Significance 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

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    The 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

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    Lysosomes 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?

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    Biallelic 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

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    Our 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

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    The authors explore how cellular energy production and demand are matched.

  • Dynamic behaviour restructuring mediates dopamine-dependent credit assignment

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    Source 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

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    The 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

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    RASP, 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

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    This 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

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    The 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

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    Modeling 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.

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Aligning Science Across Parkinson's
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