Biology subjects

Murrough, J. W.

Publications and source records attributed to Murrough, J. W..

6 recordsLinked to original sources

bioRxiv2026

A proteomic feasibility study connecting metabolic and synaptic pathway alterations in serum and extracellular vesicles to characterize treatment-resistant depression

Treatment-resistant depression (TRD) remains a major clinical challenge, yet the biological processes distinguishing TRD from non-treatment-resistant depression (nTRD) are incompletely defined. While circulating serum proteomes reflect broad systemic alterations associated with depression, extracellular vesicles (EVs) could provide a more selective representation of intercellular signaling relevant to treatment resistance. Here, we carried out a pilot study to evaluate the extent that parallel proteomic profiling of serum and serum-derived EVs could distinguish healthy controls (CON), nTRD, and TRD individuals. In this exploratory and hypothesis-generating study, serum proteomes exhibited robust global differences between depression groups and controls, largely reflecting shared systemic biology across nTRD and TRD. In contrast, EV proteomes showed limited global separation but revealed subtype-associated pathway differences. Relative to controls, nTRD EVs were enriched for immune and inflammatory pathways. By contrast, TRD EVs were characterized by enrichment of mitochondrial metabolism, oxidative phosphorylation, translational initiation, and MYC-regulated pathways, together with depletion of synaptic signalling, membrane trafficking, and cytoskeletal pathways. Comparative analysis of pathways significant in both contrasts revealed that these bioenergetic and translational signatures were selectively amplified in TRD relative to nTRD. Our exploratory analyses identified that the circulating EV cargo may reflect a treatment-resistance-specific reorganization of biological pathways not apparent in bulk serum proteomics. This study highlights parallel serum and EV proteomics as a complementary approach for molecular stratification in antidepressant resistance.

neuroscience↗

bioRxiv2026

Molecular dissection of protein complexes isolated from sections of human brain

Molecular studies of brain receptors and transporters have typically relied on recombinant systems, limiting insight into their organization in native tissue. Here, we develop nanobody-based immunoprecipitation coupled with native mass spectrometry to interrogate endogenous protein assemblies from post-mortem mouse and human brain sections. We exemplify our approach by characterizing the synaptic proteins VGluT1 and mGluR2. From a single mouse brain, we discover mGluR2/3 heterodimers, alongside mGluR2 homodimers. Considering regions of human brain heterodimeric mGluR2/3 is highly abundant in the OFC and sgACC ([~]70% and 50%, respectively) and forms regional-specific interactions with additional synaptic proteins. In a modest cohort of biobanked human tissue, associated with depression and suicide, we find increased mGluR2/3 in the OFC. Consistent with this, mice exhibit similar associations between heterodimer levels and stress-susceptibility. Overall, our approach provides a direct means for establishing molecular-behavioural links at the level of receptor organization in brain.

biochemistry↗

bioRxiv2025

Basal Ganglia Dopamine Availability and Immune Activation Interact and Relate to Anhedonia Severity among Youth with Depression

Anhedonia emerges in adolescence, has putative substrates in neural reward and dopamine systems, and is a hallmark of poor course in depression. Psychoneuroimmunology models suggest altered immune and reward systems may jointly underlie its development. When dopamine availability (rather than function) is considered, immune activation may be understood as a moderator amplifying how lower dopamine levels translate into motivational deficits. This cross-sectional study analyzed data from 55 youth with current depression (Mage=21.4 years; Female=75%). Plasma was assayed for relative quantification of 92 immune proteins, followed by dimensionality reduction via principal component (PC) analysis, forming five PC scores. Dopamine availability was indexed by basal ganglia tissue iron, quantified by MRI R2, a measure detectable in youth. Anhedonia was assessed using the Snaith-Hamilton Pleasure Scale (SHAPS), thought to capture overall anhedonia, and Positive Valence Systems Scale (PVSS), which provides overall, anticipatory, and consummatory anhedonia scores. PC1 scores--whose loadings indicated broadly distributed immune protein elevations consistent with general immune activation--moderated the relationship between basal ganglia dopamine availability and anhedonia: At higher PC1 levels, lower dopamine availability was linked to greater overall anhedonia (as measured by SHAPS) and anticipatory anhedonia, but not to consummatory anhedonia. Lower PC2 scores were associated with greater PVSS overall and consummatory anhedonia. Analyses examining individual basal ganglia regions suggest potential differences in dopaminergic-immune interactions across these regions, with effects most consistently observed in the putamen. Findings highlight nuanced neuroimmune pathways underlying anhedonia components in youth and support inflammation-based models of depression emphasizing dopaminergic-immune interplay.

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↗

bioRxiv2021

The Long Noncoding RNA FEDORA is a Cell-Type- and Sex-Specific Regulator of Depression

Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify dramatic baseline sex differences in expression of long noncoding RNAs (lncRNAs) in human postmortem brain tissue that are profoundly lost in depression. One such lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and upregulated in several cortical regions of depressed females but not males. We found that virally-expressing FEDORA selectively either in neurons or in oligodendrocytes of prefrontal cortex promoted depression-like behavioral abnormalities in female mice only, changes associated with cell-type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic significance for depressed women. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.

neuroscience↗

bioRxiv2018

Ultra-high field MRI reveals mood-related circuit disturbances in depression: A systematic comparison between 3-Tesla and 7-Tesla

Ultra-high field 7-Tesla (7T) MRI has the potential to advance our understanding of neuropsychiatric disorders, including major depressive disorder (MDD). To date, few studies have quantified the advantage of resting state functional MRI (fMRI) at 7T compared to 3-Tesla (3T). We conducted a series of experiments that demonstrate the improvement in temporal signal-to-noise ratio (TSNR) of a multi-echo fMRI protocol with ultra-high field 7T, compared to 3T MRI in healthy controls (HC). We also directly tested the enhancement in ultra-high field 7T fMRI signal power by examining the ventral tegmental area (VTA), a small midbrain structure that is critical to the expected neuropathology of MDD but difficult to discern with standard 3T MRI. We demonstrate 200-300% improvement in TSNR and resting state functional connectivity coefficients provided by ultra-high field 7T fMRI compared to 3T, indicating enhanced power for detection of functional neural architecture. A multi-echo based acquisition protocol and signal denoising pipeline afforded greater gain in signal power at ultra-high field compared to classic acquisition and denoising pipelines. Furthermore, ultra-high field fMRI revealed mood-related neuro-circuit disturbances in patients with MDD compared to HC, which were not detectable with 3T fMRI. Ultra-high field 7T fMRI may provide an effective tool for studying functional neural architecture relevant to MDD and other neuropsychiatric disorders.

neuroscience↗