Biology subjects

Cathomas, F.

Publications and source records attributed to Cathomas, F..

11 recordsLinked to original sources

bioRxiv2024

Astrocyte-derived extracellular matrix proteins regulate synapse remodeling in stress-induced depression

Major depressive disorder (MDD) is a common mood condition affecting multiple brain regions and cell types. Changes in astrocyte function contribute to depressive-like behaviors. However, while neuronal mechanisms driving MDD have been studied in some detail, molecular mechanisms by which astrocytes promote depression have not been extensively explored. To uncover astrocyte contributions to MDD, we subjected male mice to chronic social defeat stress precipitated by encounters with a dominant male. Animals exposed to this treatment exhibit symptoms indicative of MDD, including reduced social interactions, anxiety, despair, and anhedonia. We then measured astrocyte translating mRNA expression changes in mice that underwent chronic social defeat and control animals using ribosome affinity purification. Bioinformatic analyses reveal significant alterations in the prefrontal cortex (PFC), consistent with previous studies implicating this brain region in MDD. Expression of genes encoding extracellular matrix (ECM) proteins, cell-cell interaction proteins, and proteins controlling glutamatergic synaptic function are significantly altered. These changes correlate with perturbation of glutamatergic transmission, measured by electrophysiology, and increased synaptic cleft size. Among ECM genes, increased expression of mRNA encoding the synaptic remodeling protein secreted protein acidic and rich in cysteine (Sparc) correlates the most with the depressive phenotype. Furthermore, presence of SPARC and other ECM proteins in synaptosomes is also increased and overexpressing Sparc in PFC partially alleviates stress symptoms. Our results raise the possibility that increased expression of Sparc may be a natural protective mechanism against stress-induced synaptic dysfunction in depression.

neuroscience↗

bioRxiv2024

Sex-Specific Regulation of Stress Susceptibility by the Astrocytic Gene Htra1

Major depressive disorder (MDD) is linked to impaired structural and synaptic plasticity in limbic brain regions. Astrocytes, which regulate synapses and are influenced by chronic stress, likely contribute to these changes. We analyzed astrocyte gene profiles in the nucleus accumbens (NAc) of humans with MDD and mice exposed to chronic stress. Htra1, which encodes an astrocyte-secreted protease targeting the extracellular matrix (ECM), was significantly downregulated in the NAc of males but upregulated in females in both species. Manipulating Htra1 in mouse NAc astrocytes bidirectionally controlled stress susceptibility in a sex-specific manner. Such Htra1manipulations also altered neuronal signaling and ECM structural integrity in NAc. These findings highlight astroglia and the brains ECM as key mediators of sex-specific stress vulnerability, offering new approaches for MDD therapies.

neuroscience↗

bioRxiv2023

Circulating senescent myeloid cells drive blood brain barrier breakdown and neurodegeneration

Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing MAPK activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some patients with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we show that LCH-ND is caused by myeloid cells that are clonal with peripheral LCH cells. We discovered that circulating BRAFV600E+ myeloid cells cause the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiate into senescent, inflammatory CD11a+ macrophages that accumulate in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent novel and targetable mechanisms of ND.

cell biology↗

bioRxiv2023

Chemokine receptor 5 signaling in PFC mediates stress susceptibility in female mice

Chronic stress induces changes in the periphery and the central nervous system (CNS) that contribute to neuropathology and behavioral abnormalities associated with psychiatric disorders. In this study, we examined the impact of peripheral and central inflammation during chronic social defeat stress (CSDS) in female mice. Compared to male mice, we found that female mice exhibited heightened peripheral inflammatory response and identified C-C motif chemokine ligand 5 (CCL5), as a stress-susceptibility marker in females. Blocking CCL5 signaling in the periphery promoted resilience to CSDS. In the brain, stress-susceptible mice displayed increased expression of C-C chemokine receptor 5 (CCR5), a receptor for CCL5, in microglia in the prefrontal cortex (PFC). This upregulation was associated with microglia morphological changes, their increased migration to the blood vessels, and enhanced phagocytosis of synaptic components and vascular material. These changes coincided with neurophysiological alterations and impaired blood-brain barrier (BBB) integrity. By blocking CCR5 signaling specifically in the PFC were able to prevent stress-induced physiological changes and rescue social avoidance behavior. Our findings are the first to demonstrate that stress-mediated dysregulation of the CCL5-CCR5 axis triggers excessive phagocytosis of synaptic materials and neurovascular components by microglia, resulting in disruptions in neurotransmission, reduced BBB integrity, and increased stress susceptibility. Our study provides new insights into the role of cortical microglia in female stress susceptibility and suggests that the CCL5-CCR5 axis may serve as a novel sex-specific therapeutic target for treating psychiatric disorders in females.

animal behavior and cognition↗

bioRxiv2023

ZBTB7A regulates MDD-specific chromatin signatures and astrocyte-mediated stress vulnerability in orbitofrontal cortex

Hyperexcitability in the orbitofrontal cortex (OFC) is a key clinical feature of anhedonic domains of Major Depressive Disorder (MDD). However, the cellular and molecular substrates underlying this dysfunction remain unknown. Here, cell-population-specific chromatin accessibility profiling in human OFC unexpectedly mapped genetic risk for MDD exclusively to non-neuronal cells, and transcriptomic analyses revealed significant glial dysregulation in this region. Characterization of MDD-specific cis-regulatory elements identified ZBTB7A - a transcriptional regulator of astrocyte reactivity - as an important mediator of MDD-specific chromatin accessibility and gene expression. Genetic manipulations in mouse OFC demonstrated that astrocytic Zbtb7a is both necessary and sufficient to promote behavioral deficits, cell-type-specific transcriptional and chromatin profiles, and OFC neuronal hyperexcitability induced by chronic stress - a major risk factor for MDD. These data thus highlight a critical role for OFC astrocytes in stress vulnerability and pinpoint ZBTB7A as a key dysregulated factor in MDD that mediates maladaptive astrocytic functions driving OFC hyperexcitability.

neuroscience↗

bioRxiv2023

Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress-induced gene expression and behavior

BackgroundMajor depressive disorder (MDD), along with related mood disorders, is a debilitating illness that affects millions of individuals worldwide. While chronic stress increases incidence levels of mood disorders, stress-mediated disruptions in brain function that precipitate these illnesses remain elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding precise roles for serotonin in the precipitation of mood disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this phenomenon has not yet been explored following stress and/or AD exposures. MethodsWe employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress to examine the impact of stress exposures on H3K4me3Q5ser dynamics, as well as associations between the mark and stress-induced gene expression. We additionally assessed stress-induced regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy to reduce H3K4me3Q5ser levels in DRN and examine the impact on stress-associated gene expression and behavior. ResultsWe found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to rescue stress-mediated gene expression and behavior. ConclusionsThese findings establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity in DRN.

neuroscience↗

bioRxiv2022

Social stress induces autoimmune responses against the brain to promote stress susceptibility

Clinical studies have revealed a high comorbidity between autoimmune and psychiatric disorders, including major depressive disorder (MDD). However, the mechanisms connecting autoimmunity and depression remain unclear. Here, we aim to identify the processes linking adaptive immune abnormalities and depression. To examine this relationship, we analyzed antibody responses and autoimmunity in the chronic social defeat stress (CSDS) model in mice, and in clinical samples from patients with MDD. We show that socially stressed mice have elevated serum antibody concentrations. Activation of social stress-induced antibody responses were confirmed by detecting expansion of specific T and B cell populations particularly in the cervical lymph nodes, where brain-derived antigens are preferentially delivered. IgG antibody concentrations in the brain were significantly higher in stress-susceptible mice than in unstressed mice, and positively correlated with social avoidance. IgG antibodies accumulated around the blood vessels in brain sections from stress-susceptible mice. Moreover, sera from stress-susceptible mice exhibited high reactivity against brain tissue, and brain-reactive IgG antibody levels positively correlated with depression-like behavior. Similarly, in humans, increased peripheral levels of brain-reactive IgG antibodies were associated with increased anhedonia. Furthermore, high stress-resilience was observed in B cell-depleted mice, confirming a causal link between antibody-producing cells and depression-like behavior. This study provides novel mechanistic insights connecting stress-induced autoimmune reactions against the brain and stress susceptibility. Therapeutic strategies targeting autoimmune responses can therefore be devised to treat patients with MDD featuring immune abnormalities.

immunology↗

bioRxiv2022

Region-specific CREB function regulates distinct forms of regret associated with resilience versus susceptibility to chronic stress

Regret describes recognizing that alternative actions could have led to better outcomes. This can transform into behavioral consequences, altering subsequent valuations, but remains unclear if regret derives from a generalized computation for mistake appraisal or instead is made up of dissociable action-specific processes. Using a novel neuroeconomic decision-making paradigm, we found mice were differentially sensitive to fundamentally distinct types of missed opportunities following exposure to chronic social defeat stress or manipulations of CREB, a key transcription factor implicated in chronic stress action. Bias to make compensatory decisions after rejecting high-value offers (regret type I) was unique to stress-susceptible mice. Bias following the converse operation, accepting low-value offers (regret type II), was enhanced in stress-resilient and absent in stress-susceptible mice. CREB function in either the medial prefrontal cortex or nucleus accumbens was required to suppress regret type I but differentially affected regret type II. We provide insight into how adaptive versus maladaptive stress-response traits may be related to fundamentally distinct forms of counterfactual thinking and could steer psychotherapy for mood disorders such as depression toward unveiling circuit-specific computations through a careful description of decision narrative.

neuroscience↗

bioRxiv2021

Sex-specific blood-brain barrier alterations and vascular biomarkers underlie chronic stress responses in mice and human depression.

Prevalence, symptoms, and treatment of depression all point toward major sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice however it remains unknown if it contributes to this sexual dimorphism. Here, we report that chronic social and subchronic variable stress promoted sex-specific blood-brain barrier (BBB) molecular and morphological alterations in mood-related brain regions. Viral-mediated functional manipulation leading to a targeted disruption of the BBB induced anxiety- and depression-like behaviors including social avoidance and anhedonia. Endothelium cell-specific transcriptomic profiling revealed key pathways and novel genes involved in maladaptive stress responses vs resilience. We also confirmed BBB leakiness in the brain of stressed females which led us to explore and identify circulating vascular biomarkers of chronic stress that could inform on diagnosis and treatment. Importantly, these pre-clinical findings were validated in human blood and postmortem brain samples from depressed women, thus highlighting their translational value. By revealing a sex-specific causal role of BBB dysfunction in stress responses and depression, our results implicate vascular impairment as a major factor underlying mood disorders.

neuroscience↗

bioRxiv2020

Increased random exploration in schizophrenia is associated with inflammation

One aspect of goal-directed behavior, which is known to be impaired in patients with schizophrenia (SZ), is balancing between exploiting a familiar choice with known reward value and exploring a lesser known but potentially more rewarding option. Despite its relevance to several symptom domains of SZ, this has received little attention in SZ research. In addition, while there is increasing evidence that SZ is associated with chronic low-grade inflammation, few studies have investigated how this relates to specific behaviors, such as balancing exploration and exploitation. We therefore assessed behaviors underlying the exploration-exploitation trade-off using a three-armed bandit task in 45 patients with SZ and 19 healthy controls (HC). This task allowed us to dissociate goal-unrelated (random) from goal-related (directed) exploration and correlate them with psychopathological symptoms. Moreover, we assessed a broad range of inflammatory proteins in the blood and related them to bandit task behavior. We found that, compared to HC, patients with SZ showed reduced task performance. This impairment was due to a shift from exploitation to random exploration, which was associated with symptoms of disorganization. Relative to HC, patients with SZ showed a pro-inflammatory blood profile. Furthermore, high sensitivity C-reactive protein (CRP) positively correlated with random exploration, but not with directed exploration or exploitation. In conclusion, we show that low-grade inflammation in patients with SZ is associated with random exploration, which can be considered a behavioral marker for disorganization. CRP may constitute a marker for severity of, and a potential treatment target for maladaptive exploratory behaviors.

molecular biology↗

bioRxiv2019

Shared and dissociable features of apathy and reward system dysfunction in bipolar I disorder and schizophrenia

BackgroundBipolar disorder I (BD-I) is defined by episodes of mania, depression, and euthymic states. These episodes are among other symptoms characterized by altered reward processing and negative symptoms (NS), in particular apathy. However, the neural correlates of these deficits are not well understood. MethodsWe first assessed the severity of negative symptoms in 25 euthymic BD-I patients compared to 25 healthy controls (HC) and 27 patients with schizophrenia (SZ). Then, we investigated ventral and dorsal striatal activation during reward anticipation in a Monetary Incentive Delayed Task and its association with NS. ResultsIn BD-I patients NS were clearly present and the severity of apathy was comparable to SZ patients. Apathy scores in the BD-I group but not in the SZ group correlated with sub-syndromal depression scores. At the neural level, we found significant ventral and dorsal striatal activation in BD-I patients and no group differences with HC or SZ patients. In contrast to patients with SZ, apathy did not correlate with striatal activation during reward anticipation. Explorative whole brain analyses revealed reduced extra-striatal activation in BD-I patients compared to HC and an association between reduced activation of the inferior frontal gyrus and apathy. ConclusionThis study found that in BD-I patients apathy is present to an extent comparable to schizophrenia, but is more strongly related to sub-syndromal depressive symptoms. The findings support the view of different pathophysiological mechanisms underlying apathy in the two disorders and suggest that extra-striatal dysfunction may contribute to impaired reward processing and apathy in BD-I.

neuroscience↗