bioRxiv Science⌕ Search

Biology subjects

Lienard, J.

Publications and source records attributed to Lienard, J..

2 recordsLinked to original sources

Topological basal ganglia model with dopamine-modulated spike-timing-dependent plasticity reproduces reinforcement learning, discriminatory learning, and neuropsychiatric disorders

The basal ganglia (BG) are central to action selection and reinforcement learning, yet how the topological organization of the BG circuit with dopamine (DA) D1- and D2-receptors shape learning remains unclear. We present a topologically organized spiking model of macaque BG with cortico-striatal inputs organized into competing channels, D1/D2 medium spiny neurons (MSNs), three-factor DA-modulated STDP for cortical synapses, asymmetric intra-striatal collaterals, and partially overlapping direct/indirect pathways. We validate resting activity and action selection, then study conditioning and generalization-discrimination learning using DA bursts (CS+) and dips (CS). Two structural determinants emerged. First, pathway overlap ({lambda}) trades off selection efficiency and learning speed: higher overlap degrades GPi-based selection efficiency during conditioning, yet accelerates convergence during discrimination by strengthening D2 influence on GPi. Second, lateral inhibition from MSN-D2 to MSNs ({kappa}) helps constrain competing actions but is not sufficient alone; robust discrimination requires DA-dip-dependent up-modulation of D2 collateral efficacy (), which speeds and, at low overlap, enables convergence. Simulations under Parkinsonian and schizophrenia-like settings showed different deficits. A hypodopaminergic "Parkinsonian" STDP regime (D1 LTP loss, D2 LTD loss) impaired conditioning and failed to enhance discrimination. In contrast, attenuated D2 plasticity during DA dips (modeling methamphetamine-induced changes/schizophrenia-related dysregulation) selectively disrupted discrimination while sparing conditioning. Finally, we demonstrate efficient scaling on the Fugaku supercomputer to rodent and non-human primate-relevant sizes, supporting large-scale, biologically grounded BG simulations. Together, the results highlight how pathway overlap and D2 collateral dynamics jointly regulate the speed and reliability of discrimination learning, and how specific DA perturbations map to distinct learning impairments.

neuroscience↗

Intra-granuloma accumulation and inflammatory differentiation of neutrophils underlie mycobacterial ESX-1-mediated immunopathology

The conserved ESX-1 type VII secretion system is a major virulence determinant of pathogenic mycobacteria, including Mycobacterium tuberculosis and Mycobacterium marinum. ESX-1 is known to interact with infected macrophages, but its potential roles in regulating other host cells and immunopathology have remained largely unexplored. Using a murine M. marinum infection model we identify neutrophils and Ly6C+MHCII+ monocytes as the main cellular reservoirs for the bacteria. We show that ESX-1 promotes intra-granuloma accumulation of neutrophils and that neutrophils have a previously unrecognized required role in executing ESX-1-mediated pathology. To explore if ESX-1 also regulates the function of recruited neutrophils we performed single cell RNA-seq analysis indicating that ESX-1 drives newly recruited uninfected neutrophils into an inflammatory phenotype via an extrinsic mechanism. In contrast, monocytes restricted the accumulation of neutrophils and immunopathology, demonstrating a major host-protective function for monocytes specifically by suppressing ESX-1-mediated neutrophilic inflammation. iNOS activity was required for the suppressive mechanism and we identified Ly6C+MHCII+ monocytes as the main iNOS-expressing cell type in the infected tissue. These results suggest that ESX-1 mediates immunopathology by driving neutrophil accumulation and phenotypic differentiation in the infected tissue, and they demonstrate an antagonistic interplay between monocytes and neutrophils by which monocytes suppress host-detrimental neutrophilic inflammation. Author SummaryThe ESX-1 type VII secretion system is required for virulence of pathogenic mycobacteria, including Mycobacterium tuberculosis. ESX-1 interacts with infected macrophages, but its potential roles in regulating other host cells and immunopathology have remained largely unexplored. We demonstrate that ESX-1 promotes immunopathology by driving intra-granuloma accumulation of neutrophils, which upon arrival adopt an inflammatory phenotype in an ESX-1-dependent manner. In contrast, monocytes limited the accumulation of neutrophils and neutrophil-mediated pathology via an iNOS-dependent mechanism, suggesting a major host-protective function for monocytes specifically by restricting ESX-1-mediated neutrophilic inflammation. These findings provide insight into how ESX-1 promotes disease, and they reveal an antagonistic functional relationship between monocytes and neutrophils that may regulate immunopathology not only in mycobacterial infection, but also in other infections as well as in inflammatory conditions and cancer.

microbiology↗