Biology subjects

Giraud, J.

Publications and source records attributed to Giraud, J..

3 recordsLinked to original sources

bioRxiv2024

Astrocyte-induced firing in primary afferent axons

The mesencephalic trigeminal nucleus is unique in that it contains the cell bodies of large-caliber primary afferents that are usually located in the periphery in the dorsal root ganglia or trigeminal ganglia. The activity of these afferents is typically associated with proprioception of the jaw-closing muscles or mechanoreception on the teeth and periodontal ligament. However, like other large-caliber afferents from the body which display ectopic firing in neuropathic pain models, these afferents exhibit increased excitability and ectopic discharges even in a relatively mild muscle pain model. These discharges normally emerge from subthreshold membrane oscillations (SMOs) supported by a persistent sodium current (INaP) which is exquisitely sensitive to extracellular Ca2+-decreases. We have shown in the trigeminal main sensory nucleus that the release of a Ca2+-binding astrocytic protein, S100{beta}, is sufficient to modulate this sodium current. Here, we explore if this astrocyte-dependent mechanism contributes to emergence of this hyperexcitability and aim to localize the cellular site where ectopic discharge may arise using whole-cell patch-clamp recordings, confocal imaging, and immunohistochemistry methods on mice brain slices. We found that astrocytes, by lowering [Ca2+]e at focal points along the axons of NVmes neurons through S100{beta}, enhance the amplitude of the NaV1.6-dependent SMOs leading to ectopic firing. These findings suggest a crucial role for astrocytes in excitability regulation and raise questions about this neuron-astrocyte interaction as a key contributor to hyperexcitability in several pathologies.

neuroscience↗

bioRxiv2023

Phase-amplitude coupling of NREM sleep oscillations is unaffected by pre-sleep learning but related to overnight memory gains depending on the declarative learning paradigm

There is growing evidence in humans linking the temporal coupling between spindles and slow oscillations during NREM sleep with the overnight stabilization of memories encoded from daytime experiences in humans. However, whether the type and strength of learning influence that relationship is still unknown. Here we tested whether the amount or type of verbal word-pair learning prior to sleep affects subsequent phase-amplitude coupling (PAC) between spindles and slow oscillations (SO). We measured the strength and preferred timing of such coupling in the EEG of 41 healthy human participants over a post-learning and control night, to compare intra-individual changes with inter-individual differences. We leveraged learning paradigms of varying word-pair (WP) load: 40 WP learned to a minimum criterion of 60% correct (n=11); 40 WP presented twice (n=15); 120 WP presented twice (n=15). There were no significant differences in the preferred phase or strength between the control and post-learning nights, in all learning conditions. We observed an overnight consolidation effect (improved performance at delayed recall) for the criterion learning condition only, and only in this condition was the overnight change in memory performance significantly positively correlated with the phase of SO-spindle coupling. These results suggest that the coupling of brain oscillations during human NREM sleep are stable traits that are not modulated by the amount of pre-sleep learning, yet are implicated in the sleep-dependent consolidation of memory.

neuroscience↗

bioRxiv2022

TREM1+ regulatory myeloid cells expand in steatohepatitis-HCC and associate with poor prognosis and therapeutic resistance to anti-PD-1 blockade

Hepatocellular carcinoma (HCC) is an inflammation-associated cancer arising from viral and non-viral etiologies. Immune checkpoint blockade primarily benefits patients with viral HCC. Expansion of suppressive myeloid cells is a hallmark of chronic inflammation and cancer, but their heterogeneity in HCC is not fully resolved and might underlie immunotherapy resistance in the steatohepatitis setting. Here, we present a high resolution atlas of hepatic innate immune cells from patients with HCC that unravels a steatohepatitis contexture characterized by the emergence of high entropy myeloid cell states and myeloid-biased NK cell differentiation. We identify a discrete population of tumor-infiltrating myeloid cells, predominant in the steatohepatitis setting, that expresses a variety of myeloid lineage-affiliated genes, including granulocyte, macrophage and dendritic cell features, and can be identified in HCC tumors based on selective dual expression of TREM1 and CD163. Functional characterization reveals that TREM1+ CD163+ myeloid cells highly express TGF{beta} and IL-13RA, localize to HCC fibrotic lesions, and potently suppress T cell effector functions ex vivo, a function further potentiated by TREM1 engagement. We refer to this population as TREM1+ CD163+ regulatory myeloid cells (TREM1+CD163+ Mreg). Deconvolution analyses in large cohorts of patients with HCC and other solid tumors reveals that the density of TREM1+ CD163+ Mreg increases in advanced stages, associates with poor prognosis, and therapeutic resistance to PD-1 blockade. Our data support myeloid subset-targeted immunotherapies to treat HCC and identify TREM1 as a therapeutic target. HIGHLIGHTSO_LIAtlas of hepatic innate immune cells (100,000 transcriptomes) from patients with HCC C_LIO_LICore signatures to identify, discriminate and localize innate lymphoid and myeloid cells C_LIO_LIA population of TREM1+CD163+ myeloid cells, referred to as TREM1+CD163+ Mreg, expands in steatohepatitis HCC C_LIO_LITREM1+CD163+ Mreg express granulocyte- and macrophage/dendritic cell-lineage genes C_LIO_LITREM1+CD163+ Mreg potently suppress T cell effector functions, which is potentiated by TREM1 engagement by cognate ligands C_LIO_LITREM1+CD163+ Mreg produce high levels of TGF{beta} and populate fibrotic lesions C_LIO_LIThe density of TREM1+CD163+ Mreg increases in advanced HCC and associate with poor patient survival C_LIO_LIThe density of TREM1+CD163+ Mreg associates with resistance to immune checkpoint blockade in other solid tumors C_LI

immunology↗