Biology subjects

Dalmau, J.

Publications and source records attributed to Dalmau, J..

9 recordsLinked to original sources

bioRxiv2025

Pediatric Long COVID Is Characterized by Myeloid CCR6 Suppression and Immune Dysregulation

The biological mechanisms underlying long COVID in the pediatric population are poorly understood. Our study aimed to characterize the immune pathophysiology of long COVID in children and young people (CYP). We analyzed major immune cell compartments in PBMCs, as well as specific SARS-CoV-2 antibody response in CYP with (n=99) and without (n=18) long COVID at three months following acute infection. Our findings indicate that pediatric long COVID is associated with a dysregulated immune response characterized by altered innate immunity and overactivated T-, B- and NK-cell responses. Furthermore, CYP with long COVID had an impaired humoral response to SARS-CoV-2 marked by a dysregulated B-cell compartment and lower levels of anti-RBD IgG and IgA. This correlated with reduced neutralizing capacity against SARS-CoV-2. Random forest analysis identified CCR6 expression on myeloid cells as the most relevant biomarker that distinguishes long COVID from control individuals with 79% accuracy. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/671713v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1145480org.highwire.dtl.DTLVardef@1b7a635org.highwire.dtl.DTLVardef@fb13org.highwire.dtl.DTLVardef@63a49a_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Neuro-immunology in a mouse model of anti-NMDAR encephalitis and assessment of treatment approaches

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a disorder mediated by autoantibodies against the GluN1 subunit of NMDAR. It occurs with severe neuropsychiatric symptoms that often improve with immunotherapy. Clinical studies and animal models based on patients antibody transfer or NMDAR immunization suggest that the autoantibodies play a major pathogenic role. Yet, there is an important need of models offering an all-inclusive neuro-immunobiology of the disease together with a clinical course long enough to facilitate the assessment of potential new treatments. Toward this end, eight-week-old female mice (C57BL/6J) were immunized (days 1 and 28) with GluN1356-385 peptide or saline with AddaVax adjuvant and pertussis toxin. After symptom development ([~]day 35), subsets of mice were treated with an anti-CD20 (day 35), a positive allosteric modulator (PAM) of NMDAR (NMDAR-PAM, SGE-301) from days 45 to 71, or both. GluN1-antibody synthesis, epitope spreading, effects of antibodies on density and function of NMDAR, brain immunological infiltrates, microglial activation and NMDAR phagocytosis, and antibody synthesis in cultured inguinal and deep cervical lymph nodes (DCLN) were assessed with techniques including immunohistochemistry, calcium imaging, confocal and super-resolution microscopy, electrophysiology, or flow cytometry. Changes of memory and behaviour were assessed with a panel of behavioural tests, and clinical/subclinical seizures with brain-implanted electrodes. Immunized mice, but not controls, developed serum and CSF NMDAR-antibodies (IgG1 predominant) against the immunizing peptide and other GluN1 regions (epitope spreading) resulting in a decrease of synaptic and extrasynaptic NMDAR clusters and reduction of hippocampal plasticity. These findings were associated with brain inflammatory infiltrates, mainly B- and plasma cells, microglial activation, colocalization of NMDAR-IgG complexes with microglia, and presence of these complexes within microglial endosomes. Cultures of DCLC showed GluN1-antibody production. These findings were associated with psychotic-like behaviour (predominant at disease onset), memory deficit, depressive-like behaviour, abnormal movements (15% of mice), and lower threshold for developing pentylenetetrazole-induced seizures (hypoactivity, myoclonic jerks, continuous tonic-clonic) which correlated with regional cFOS expression. Most symptoms and neurobiological alterations were reversed by the anti-CD20 and PAM, alone or combined. Initial repopulation of B cells, by the end of the study, was associated with re-emergence of clinical-neurobiological alterations, which were abrogated by PAM. Overall, this model offers an all-inclusive neuro-immunobiology of the disease, allowing testing novel treatments, supporting the potential therapeutic role of NMDAR-PAM, and suggesting an immunological paradigm of systemic antigen presentation and brain NMDAR epitope spreading, which along the DCLN might contribute to fine-tune the polyclonal immune response.

neuroscience↗

bioRxiv2024

Episodic recruitment of attractor dynamics in frontal cortex reveals distinct mechanisms for forgetting and lack of cognitive control in short-term memory

Short-term memory (STM) is prone to failure, especially during prolonged memory maintenance or under limited cognitive control. Despite predictive mechanistic frameworks based on persistent neural activity and attractor states, a direct assessment of network dynamics during multifactorial STM failure is still missing. We addressed this in a delayed-response task where mice maintained a prospective response during a long variable delay. Mice behavior episodically switched between a task-engaged state described by an attractor model, and a task-disengaged state purely determined by previous choices. During task engagement, the anterolateral motor cortex (ALM) showed delay persistent activity stably encoding correct choices, whereas the encoding reversed during the delay in error trials. In contrast, in task-disengaged phases ALM showed no clear traces of attractor dynamics and instead exhibited enhanced synchrony at [~] 4-5Hz. Thus, ALM switches between distinct error-generating dynamics: in control-capable trials, transitions between memory attractors cause forgetting errors, whereas non-memory errors are caused by the dissociation of ALM during the mnemonic period reflecting the lack of cognitive control.

neuroscience↗

bioRxiv2022

Anti-NMDAR encephalitis antibodies cause long-lasting degradation of the hippocampal neural representation of memory

N-methyl D-aspartate receptor (NMDAR) encephalitis is an immune-mediated disorder characterized by a complex neuropsychiatric syndrome together with a reduction of NMDAR. Although in most patients the life-threatening symptoms of the acute stage resolve with immunotherapy, memory and executive functions remain altered for several months or years. A mechanistic explanation for these long-lasting cognitive effects is still lacking and previous animal models have not explored this effect. Here, we combined repeat calcium imaging of the same population of hundreds of hippocampal CA1 neurons for three months along with two behavioral tasks to assess retrograde and anterograde memory loss using a reported mouse model of cerebroventricular transfer of patients CSF antibodies. We measured how memory-related neuronal activity is affected by the presence of NMDAR antibodies during the induction of the model and its long-lasting recovery. In addition, we developed a computational model that provides a mechanistic explanation for the long-term antibody-mediated impairment of memory. The findings show that the presence of antibodies leads to an increase of CA1 neuronal firing rate, resulting in a reduction of the amount of information encoded by these cells. Furthermore, the antibodies cause a degradation of the hippocampal neuronal response stability over time, providing a neural correlate of memory dysfunction. All these neuronal alterations span the 3 months of recordings, and in some cases beyond the last recording point. The computational model shows that a reduction of NMDAR is sufficient to cause the changes observed in neuronal activity, including the different involvement of excitatory and inhibitory inputs to CA1 neurons. Altogether, we show that the antibody-mediated reduction of NMDAR leads to long-term changes in hippocampal neuronal activity which extend far beyond the antibody clearance, providing a mechanism that can account for the cognitive deficits observed in the protracted recovery of patients with anti-NMDAR encephalitis.

neuroscience↗

bioRxiv2022

Single-cell CD8+ dynamics in PLWH uncover the depletion of TIGIT+ memory HIV-1-specific cells during long-term ART

The co-expression of inhibitory receptors (IRs) is a hallmark of CD8+ T-cell exhaustion (Tex) in people living with HIV-1 (PLWH). Understanding alterations of IRs expression in PLWH on long-term antiretroviral treatment (ART) remains elusive but is critical to overcoming CD8+ Tex and designing novel HIV-1 cure immunotherapies. To address this, we combine high-dimensional supervised and unsupervised analysis of IRs concomitant with functional markers across the CD8+ T-cell landscape on 24 PLWH over a decade on ART. We define irreversible alterations of IRs co-expression patterns in CD8+ T cells not mitigated by ART and identify negative associations between the frequency of TIGIT+ and TIGIT+TIM-3+ and CD4+ T-cell levels. Moreover, changes in total, SEB-activated, and HIV-1-specific CD8+ T-cells delineate a complex reshaping of memory and effector-like cellular clusters on ART. Indeed, we identify a selective reduction of HIV-1 specific-CD8+ T-cell memory-like clusters sharing TIGIT expression and low CD107a that can be recovered by mAb TIGIT blockade independently of IFN{gamma} and IL-2. Collectively, these data characterize with unprecedented detail the patterns of IRs expression and functions across the CD8+ T-cell landscape and indicate the potential of TIGIT as a target for Tex precision immunotherapies in PLWH at all ART stages.

immunology↗

bioRxiv2022

Human NMDAR autoantibodies disrupt excitatory-inhibitory balance leading to hippocampal network hypersynchrony

Specific autoantibodies against the NMDA-receptor (NMDAR) GluN1 subunit cause severe and debilitating NMDAR-encephalitis. Autoantibodies induce prototypic disease symptoms resembling schizophrenia, including psychosis and cognitive dysfunction. Using a mouse passive transfer model applying human monoclonal anti-GluN1-autoantibodies, we observed CA1 pyramidal neuron hypoexcitability, reduced AMPA-receptor (AMPAR) signaling, and faster synaptic inhibition resulting in disrupted excitatory-inhibitory balance. Functional alterations were supported by widespread remodeling of the hippocampal proteome, including changes in glutamatergic and GABAergic neurotransmission. At the network level, anti-GluN1-autoantibodies amplified gamma oscillations and disrupted theta-gamma coupling. A data-informed network model revealed that lower AMPAR strength and faster GABAA-receptor current kinetics chiefly account for these abnormal oscillations. As predicted by our model and evidenced experimentally, positive allosteric modulation of AMPARs alleviated aberrant gamma activity and thus reinforced the causative effects of the excitatory-inhibitory imbalance. Collectively, NMDAR-hypofunction-induced aberrant synaptic, cellular, and network dynamics provide new mechanistic insights into disease symptoms in NMDAR-encephalitis and schizophrenia.

neuroscience↗

bioRxiv2019

Disrupted serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia

We report markedly reduced working memory-related serial dependence with preserved memory accuracy in anti-NMDAR encephalitis and schizophrenia. We argue that NMDAR-related changes in cortical excitation, while quickly destabilizing persistent neural activity, cannot fully account for a reduction of memory-dependent biases. Rather, our modeling results support a disruption of a memory mechanism operating on a longer timescale, such as short-term potentiation.

neuroscience↗

bioRxiv2019

Perceptual spatial suppression and sensitivity for motion are weakened in schizophrenia

Perceptual spatial suppression is a phenomenon in which the perceived strength of a stimulus in some region of the space is reduced when the stimulus is surrounded by other stimuli. For contrast perception, several studies suggest that spatial suppression is reduced in patients with schizophrenia. For motion perception, only one study has been conducted in a cohort of 16 patients, suggesting that spatial suppression is reduced. It is unknown, however, whether this reduction is related to the lower IQ that schizophrenic patients usually show; as there is evidence that spatial suppression for motion increases with IQ in healthy individuals. Here, we sought to determine the spatial suppression for motion in a larger cohort of 33 patients with schizophrenia controlling for IQ. We found a weakened spatial suppression in patients with schizophrenia, consistent with the previous study (g = 0.47, CI = [0.055, 0.88], combining the previous and our study). For comparison, we performed a meta-analysis on spatial suppression for contrast and found a similar effect size. We found that patients had a lower IQ than controls, but this difference did not explain their weaker spatial suppression. Further, we found that spatial suppression of patients, but not controls increased with their IQ and decreased with age in both groups. Finally, as we estimated lapses of attention, we could estimate motion sensitivity and found that it was decreased in patients. We speculate about possible alterations in neurotransmission that might explain the reduced spatial suppression and sensitivity that we found.

neuroscience↗

bioRxiv2019

High-throughput task to study memory recall during spatial navigation in rodents

Spatial navigation is the most frequently used behavioral paradigm to study hippocampal dependent memory formation in rodents. However, commonly used tasks can present some limitations: i) they are labor intensive, preventing the implementation of parallel testing for high-throughput experimentation; ii) yield a low number of repeated trials, curtailing the statistical power; iii) are hard to combine with neural recordings, because tethering sometimes interferes with behavior; iv) are not based on overt behavioral responses that can be precisely timed, making difficult the identification of the underlying neural events; v) produce a low spatial coverage, limiting the characterization of neuronal patterns related to spatial information. To circumvent these limitations, we developed a spatial memory task that required minimal human intervention, allowed simultaneous and unsupervised testing of several mice, and yielded a high number of recall trials per session (up to ~20). Moreover, because recall sessions could be repeated over many days, the task provided enough statistical power to characterize in detail the animals behavior during memory recall, even to quantify the decay in spatial accuracy of memories as they are stacked across days. In addition, the task is compatible with neural activity recordings. Together, these features make our task a valuable tool to start dissecting the neural circuit dynamics underlying spatial memory recall.

neuroscience↗