bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.10.26.465949

Pharmacological impacts on schizophrenia functional analysis: a postmortem proteome study.

Shukla, R.·Alnafisah, R. S.·Reigle, J.·O'Donovan, S. M.·Funk, A. J.·Meller, J. M.·McCullumsmith, R. E.
View original source ↗Export metadata ↓

Abstract

Schizophrenia (SCZ) is a severe and debilitating mental illness. Antipsychotic drugs (APDs) are used to treat both positive and negative SCZ symptoms, by influencing the cellular, subcellular-synaptic, and molecular processes. We posit that these effects influence our understanding of SCZ. To address this, we analyzed postmortem dorsolateral prefrontal cortex grey matter samples from control and SCZ subjects (n=10/group) using liquid-chromatography mass-spectrometry-based proteomics. We retrieved SCZ-altered and APD-influenced proteome-sets using linear and mixed linear models, respectively, and validated them experimentally using independent cohorts and insilico using published datasets. Functional analysis of proteome-sets was contrasted at the biological pathway, cell-type, subcellular-synaptic, and drug-target levels. The SCZ-altered proteome was conserved across several studies from DLPFC and other brain areas and was dependent on drug effect. At the pathway level, we observed an aberrant extracellular event and, except for homeostasis, signal-transduction, cytoskeleton, and dendrites associated downregulated changes, the APDs compensated for the majority of the SCZ-altered pathways. At the cell-type level, the up-and down-regulated SCZ-altered events were associated with two different subsets of striatum projecting layer-5 pyramidal-neurons regulating dopaminergic secretion. At the subcellular synaptic level, compensatory pre- and post-synaptic events were observed. At the drug target level, dopaminergic processes influence the SCZ-altered up-regulated proteome, whereas non-dopaminergic and a diverse array of non-neuromodulatory mechanisms influence the SCZ-altered down-regulated proteome. While these findings are dependent on pharmacological effects, they are also consistent with previous SCZ studies, implying the need to re-evaluate previous results. We discuss our findings in the context of cortico-striatal influence in SCZ-pathology.

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Shukla, R., Alnafisah, R. S., Reigle, J., O'Donovan, S. M., Funk, A. J., Meller, J. M., McCullumsmith, R. E.. 2021-10-28. Pharmacological impacts on schizophrenia functional analysis: a postmortem proteome study.. https://doi.org/10.1101/2021.10.26.465949

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Distinguishing evidence accumulation from choice confidence in neural signatures of perceptual decision making

Human electrophysiology research has identified the centro-parietal positivity (CPP) as an apparent neural correlate of sensory evidence accumulation during perceptual decision-making. The CPP has also been shown to closely scale with subjective confidence. Coupled with the fact of its domain-generality and lack of choice selectivity, this observation raises the possibility that the CPP might in fact trace subjective confidence rather than cumulative evidence, two quantities that are closely correlated in most experiments. To disentangle confidence from cumulative evidence, we used predictive cues with 80% validity to manipulate prior expectations of participants during a contrast discrimination task while recording electroencephalography (EEG). At the time of decision termination, confidence is expected to reach a higher level for validly cued versus invalidly cued choices, whereas the opposite would be expected of a cumulative evidence signal due to biased decision starting points. As expected, valid cues led to faster, more accurate and more confident responses compared to invalid and neutral cues. At the neural level, cues produced systematic increases in preparation of the expected action prior to evidence onset as indexed by premotor mu/beta activity, consistent with cue-biased criterion adjustments. The pre-response CPP amplitude was significantly reduced for validly cued choices and the effect remained even when matching for confidence. Together these findings suggest that the CPP is not a direct read-out of subjective confidence, but an evidence accumulation signal that contributes to both decision formation and confidence estimation.

neuroscience↗
bioRxiv2026

A Neurocompliant Ionic Conductive Hydrogel Orchestrates Glial and Vascular Remodeling to Mitigate Traumatic Brain Injury

Developing conductive scaffolds for neural regeneration is often hindered by the cytotoxicity and mechanical mismatch inherent to conventional electronic fillers. Here, we report an ultrasoft ionically conductive hydrogel engineered by grafting choline-based bioionic liquids (BIL) onto fish gelatin (FiBGel). Systematic optimization yields brain-mimetic conductivity (0.25-0.68 S/m), elastic moduli (0.6-0.9 kPa), and physiological water content (72-81%). In 3D culture, the matrix drives spontaneous neurogenesis, achieving ~90% MAP2+ neurons with robust calcium signaling, while concurrently supporting endothelial network formation. We report the first intracerebral administration of a BIL hydrogel, demonstrating remarkable biocompatibility and immunomodulation. In a traumatic brain injury model, a single FiBGel dose halves reactive astrogliosis, enhances cortical revascularization, and limits lesion cavity expansion. Leveraging an FDA-recognized micronutrient, FiBGel offers a translatable strategy that integrates neuromechanics, conductivity, immune modulation, and vascular support within one injectable scaffold for minimally invasive treatment of brain injuries.

neuroscience↗
bioRxiv2026

Changes in anterior cingulate connectivity associated with response to antidepressant treatment for major depressive disorder

Background: Resting-state functional connectivity (rsFC) involving the anterior cingulate cortex (ACC) and the hippocampal formation has been implicated in major depressive disorder (MDD) and antidepressant response. However, it remains unclear whether connectivity changes in distinct ACC subdivisions and hippocampal formation reflect general antidepressant effects or are specifically associated with clinical improvement. Methods: Forty-one, unmedicated adults with MDD underwent functional MRI before and after 8 weeks of sertraline or bupropion treatment. Seed-based rsFC analyses examined subgenual ACC (sgACC), pregenual ACC (pgACC), dorsal ACC (dACC), and hippocampal formation connectivity. Linear mixed-effects models tested whether connectivity change was associated with treatment response, remission, and dimensional improvement in depressive symptoms. Results: Thirty individuals (73.2%) responded to treatment and 26 (63.4%) achieved remission. Overall, rsFC decreased pre- to post-treatment between (1) dACC and pgACC (but not sgACC and hippocampal formation) and (2) cortical regions primarily involving default mode and frontoparietal networks. When considering treatment response, differences in sgACC and pgACC connectivity with temporal and inferior frontal regions emerged (increased in responders vs. decreased in non-responders). Remission was similarly associated with increased sgACC connectivity with temporal and prefrontal regions, and increased sgACC connectivity with temporal cortical regions related to greater reductions in depressive symptoms. Conclusions: Antidepressant treatment was associated with distinct patterns of ACC connectivity change, with general reductions in dorsal and pregenual connectivity but increases in subgenual and pregenual connectivity associated with favorable clinical outcomes. Findings suggest that changes in sgACC/pgACC connectivity are particularly relevant to antidepressant treatment response. Keywords: Major depressive disorder; Resting-state functional connectivity; Anterior cingulate cortex; Antidepressant treatment; Treatment response; Subgenual anterior cingulate cortex.

neuroscience↗