Biology subjects

Perlman, K.

Publications and source records attributed to Perlman, K..

10 recordsLinked to original sources

bioRxiv2026

A multimodal characterization of the human uncinate fasciculus

The uncinate fasciculus (UF) is a hook-shaped long-range association white matter tract that serves to bidirectionally transmit information between the anterior temporal lobe and the orbitofrontal cortex. Neuroimaging studies have suggested that changes in UF microstructure are involved in the neurobiological sequalae of childhood abuse (CA). Given that the UF is not present in rodents, it is vastly understudied with no cellular and molecular information available. To this end, we aimed to perform a multimodal characterization of the UF between individuals diagnosed with depression who died by suicide with (DS-CA) and without a history of severe CA (DS) and psychiatrically healthy individuals (CTRL). Fresh frozen UF tissue was obtained from the Douglas Bell-Canada Brain Bank, with phenotypic information collected via psychological autopsy. Immunohistochemistry with PDGFR and NogoA was used to label oligodendrocyte precursor cell (OPC) and oligodendrocyte (OL), respectively, and stereology was performed to ascertain cell density and soma volume. Single nucleus RNA sequencing (snRNAseq) was used to generate a transcriptomic survey of the cell types found in the UF. Finally, spectral focusing Coherent Anti-Stokes Raman Scattering (sf-CARS) microscopy was employed in tandem with a custom AxonDeepSeg segmentation model to measure axon diameter, myelin thickness, and g-ratio. No group differences were observed in histology or ultrastructure metrics, but nearly 50 differentially expressed genes (DEG) were identified between groups. Interestingly NECTIN3, the top DEG downregulated in OL1 and OL3 of DS-CA, is a computationally predicted target of the microRNA MIR646, the host gene of which was significantly downregulated in multiple cell types in DS-CA. Age-associated changes were pronounced and observed in all modalities, including an age-related increase in OL density, extensive changes in glial gene expression, as well as decreases in axon diameter and g-ratio. This study serves as a foundational resource on the molecular and cellular properties of the human UF. Our results suggest that observable myelin-related traces of depression or CA are limited in the UF and highlights the need for future research on the cellular and molecular properties of white matter tracts during aging.

neuroscience↗

bioRxiv2025

A comprehensive characterization of the phospholipid and cholesterol composition of the uncinate fasciculus in the human brain: evidence of age-related alterations

The uncinate fasciculus (UF) is a long-range association fiber tract that serves to connect the anterior temporal lobe with the orbitofrontal cortex. The UF has been implicated via neuroimaging studies in the neurobiological vulnerability to psychiatric disorders posed by a history of childhood abuse (CA), as well as in the psychopathology underlying depressive disorders. Since the myelin sheath is highly enriched in lipids, white matter (WM) dysfunction may reflect alterations in the myelin lipid profile. In fact, our previous work showed that in the anterior cingulate cortex WM, there was a specific effect of CA in the choline glycerophospholipid fatty acids (FA) involved in the synthesis of arachidonic acid. Given that the UF does not exist in rodents, its molecular properties are highly understudied and its lipid composition is virtually unknown. As such, we sought to quantify the phospholipid FA and cholesterol quantities of the human postmortem UF and measure whether we could detect lipid-related or myelin-constituent gene/protein changes associated with CA and/or depression. Fresh-frozen left hemisphere UF samples were analyzed from individuals with depression who died by suicide with a history of severe CA (DS-CA), individuals with depression who died by suicide without a history of CA (DS), and non-psychiatric control subjects who died naturally or accidentally (CTRL). Phospholipids were separated by thin-layer chromatography. FA and non-derivatized cholesterol were quantified using gas chromatography-flame ionization detection. Relative expression of myelin-constituent genes (PLP1, MAG, CNP, MOG, PLLP, MBP, and MOBP) was measured by RT-qPCR, and levels of myelin-constituent proteins (MAG, MOG, MBP, and PLP) were measured by immunoblotting. We found no robust relationships between depression or CA and any lipid measures, nor in myelin-constituent gene and protein levels. However, in the phospholipids, we observed striking age relationships that varied across fractions, with an overall pattern of increases in monounsaturates and decreases in long chain omega-6 polyunsaturates with age. In tandem, we observed that most myelin-constituent genes and proteins showed decreasing trends with age, with PLP1 and MAG showing significantly decreasing relationships. We hypothesize that the changes in lipid composition and lipid-protein interactions contribute to age-related myelin deficits and declines in cognition. The absence of group differences highlights the importance of regional specificity in molecular studies assessing neurobiological correlates of psychiatric disorders.

neuroscience↗

bioRxiv2025

Ultrastructural Analysis of Human Uncinate Fasciculus with Spectral-Focusing Coherent Anti-Stokes Raman Spectroscopy

Characterizing the ultrastructure of myelin in the human brain is key to understanding the neurobiology of both health and disease. In postmortem human brain tissue, electron microscopy is often technically unfeasible due to poorer tissue quality. The uncinate fasciculus (UF) is a long-range white matter association tract that connects the anterior temporal lobe with the orbitofrontal cortex. The UF is not present in rodents yet is highly expanded in humans and non-human primates. As such, its molecular and ultrastructural properties are virtually unknown. Here, we develop and validate a novel spectral-focusing Coherent Anti-Stokes Raman Spectroscopy (sf-CARS) system coupled with a custom AxonDeepSeg segmentation model to characterize UF ultrastructure in the human postmortem brain (n=6). We provide a proof of concept of this new methodological pipeline in the UF temporal segment and observe that the mean axon diameter detected is 0.93 {micro}m {+/-} 0.54 and mean myelin thickness is 0.48 {micro}m {+/-} 0.14. We also observe that the UF axons are thicker than those in the anterior cingulate cortex white matter. We detail and validate the full methodology, including tissue fixation and sectioning, sf-CARS acquisition settings, as well as the AxonDeepSeg deep learning model parameters such that this pipeline can be utilized by others in the field.

neuroscience↗

bioRxiv2025

Characterizing neuronal cell bodies in human postmortem cerebral white matter tracts

Until the discovery of white matter neurons (WMN) in the 19th century, white matter (WM) was considered to be completely devoid of neuronal cell bodies. Despite evidence consistently showing evident neuronal soma within cortical WM and their purported implication in neuropsychiatric disorders, these neurons are understudied and have not been characterized in human long-range WM tracts. Using postmortem human brain tissue, we investigated the presence, densities and proportions of excitatory/inhibitory neurons in the uncinate fasciculus (UF) and corpus callosum (CC). We also investigated the ventromedial prefrontal cortex (vmPFC) to validate our methods by comparing our results with previously reported densities of neurons in cortical WM. To identify WMN, we employed fluorescence in situ hybridization with excitatory (SLC17A7) and inhibitory (GAD1) neuronal markers and subsequently validated these neurons at the protein level with NeuN immunohistochemistry. We found that the density of WMN in the vmPFC corresponded with previous independent estimates. The UF displayed a similar, though slightly lower density of WMN compared to the vmPFC, while the CC had a far lower density of WMN than both of these regions. Due to the higher-than-expected density of WMN in the UF, we validated the findings at a second location along the UF temporal segment and confirmed the presence of substantial numbers of WMN in this tract. This research constitutes the first ever validated observation of WMN in human long-range WM tracts, laying the foundation for future research on the phenotype and function of these neurons, and how they may be affected in brain disorders.

neuroscience↗

bioRxiv2025

Characterizing Oligodendrocyte-Lineage Cells and Myelination in the Basolateral Amygdala: Insights from a Novel Methodology in Postmortem Human Brain

The basolateral amygdala (BLA) plays a key role in the pathophysiology of depressive disorders and trauma, yet oligodendrocyte-lineage cells and myelin in this brain region remain understudied in humans. This may be due, at least in part, to the lack of a cost-effective, antibody-based method to isolate oligodendrocytes (OL) and OL precursor cells (OPC) from postmortem brain tissue that is compatible with molecular biology applications. This study aimed to 1) create and validate a method for isolating OPC and OL nuclei from frozen postmortem grey matter; 2) compare OPC and OL gene expression in the BLA between individuals with depression who died by suicide (with or without a history of childhood abuse) and matched controls; and 3) provide histological characterizations of OPC, OL, and myelin in the BLA. Frozen left-hemisphere BLA samples were obtained from brain donors with well-characterized phenotypic information. Immunolabeled nuclei were sorted into OPC (SOX10+/CRYAB-) and OL (SOX10+/CRYAB+) populations, and RNA was measured using a custom Nanostring codeset. Fluorescence in situ hybridization was used to determine OPC (PDGFR+) and OL (MYRF+) densities, and immunofluorescence was used to label axons (NF-H) and myelin (MBP) for myelin area fraction. The method successfully isolated OPC and OL nuclei with correct transcriptomic profiles. In the OL fraction, MOBP was found to be significantly decreased in depressed individuals with a history of child abuse compared to controls, but no other genes showed significant group differences in either fraction. However, significant age-related patterns were observed in both fractions. Furthermore, no significant differences in cell densities or myelin coverage were observed across groups. Lastly, a strong significant correlation between OL density and myelin area fraction was identified. This study provides a novel sorting method and a comprehensive characterization of OL-lineage gene expression, cell densities, and myelin in the human BLA.

neuroscience↗

bioRxiv2023

Proteomic evidence of astrocytic dysfunction in the olfactory bulb of depressed suicides

The olfactory bulb (OB), a major structure of the limbic system, has been understudied in human investigations of psychopathologies such as depression. To explore more directly the molecular features of the OB in depression, a global comparative proteome analysis was carried out with human post-mortem OB samples from 11 males having suffered from depression and 12 healthy controls. We identified 188 differentially abundant proteins (with adjusted p<0.05) between depressed cases and controls. Gene ontology and gene enrichment analyses suggested that these proteins are involved in biological processes including the complement and coagulation cascades. Cell type enrichment analysis displayed a significant reduction in several canonical astrocytic proteins in OBs from depressed patients. Furthermore, using RNA-fluorescence in-situ hybridization, we observed a decrease in the percentage of ALDH1L1+ cells expressing canonical astrocytic markers including ALDOC, NFIA, GJA1 (connexin 43) and SLC1A3 (EAAT1). These results are consistent with previous reports of downregulated astrocytic marker expression in other brain regions in depressed patients. We also conducted a comparative phosphoproteomic analysis of OB samples and found a dysregulation of proteins involved in neuronal and astrocytic functions. To determine whether OB astrocytic abnormalities is specific to humans, we also performed proteomics on the OB of socially defeated male mice, a commonly used model of depression. Cell-type specific analysis revealed that in socially defeated animals, the most striking OB protein alterations were associated with oligodendrocyte- lineage cells rather than with astrocytes, highlighting an important species difference. Overall, this study further highlights cerebral astrocytic abnormalities as a consistent feature of depression in humans.

neuroscience↗

bioRxiv2022

Cell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes

Major depressive disorder (MDD) is a common, heterogenous, and potentially serious psychiatric illness. Diverse brain cell types have been implicated in MDD etiology. Significant sexual differences exist in MDD clinical presentation and outcome, and recent evidence suggests different molecular bases for male and female MDD. We evaluated over 160,000 nuclei from 71 female and male donors, leveraging new and pre-existing single-nucleus RNA-sequencing data from the dorsolateral prefrontal cortex. Cell type specific transcriptome-wide threshold-free MDD-associated gene expression patterns were similar between the sexes, but significant differentially expressed genes (DEGs) diverged. Among 7 broad cell types and 41 clusters evaluated, microglia and parvalbumin interneurons contributed the most DEGs in females, while deep layer excitatory neurons, astrocytes, and oligodendrocyte precursors were the major contributors in males. Further, the Mic1 cluster with 38% of female DEGs and the ExN10_L46 cluster with 53% of male DEGs, stood out in the meta-analysis of both sexes.

neuroscience↗

bioRxiv2021

Fatty acid dysregulation in the anterior cingulate cortex of depressed suicides with a history of child abuse

Child abuse (CA) strongly increases the lifetime risk of suffering from major depression and predicts an unfavorable course for the illness. Severe CA has been associated with a specific dysregulation of oligodendrocyte function and thinner myelin sheaths in the human anterior cingulate cortex (ACC) white matter. Given that myelin is extremely lipid-rich, it is plausible that these findings may be accompanied by a disruption of the lipid profile that composes the myelin sheath. This is important to explore since the composition of fatty acids (FA) in myelin phospholipids can influence its stability, permeability, and compactness. Therefore, the objective of this study was to quantify and compare FA concentrations in postmortem ACC white matter in the choline glycerophospholipid pool (ChoGpl), a key myelin phospholipid pool, between adult depressed suicides with a history of CA (DS-CA) matched depressed suicides without CA (DS) and healthy non-psychiatric controls (CTRL). Total lipids were extracted according to the Folch method and separated into respective classes using thin-layer chromatography. FA methyl esters from the ChoGpl fraction were quantified using gas chromatography. Our analysis revealed a strong age-related decrease in most FAs, and specific effects of CA in FAs from the arachidonic acid synthesis pathway, which was further validated with RNA-sequencing data. Furthermore, the concentration of most FAs was found to decrease with age. By extending the previous molecular level findings linking CA with altered myelination in the ACC, these results provide further insights regarding white matter alterations associated with early-life adversity.

neuroscience↗

bioRxiv2020

Child abuse associates with increased recruitment of perineuronal nets in the ventromedial prefrontal cortex: evidence for an implication of oligodendrocyte progenitor cells

Child abuse (CA) is a strong predictor of psychopathologies and suicide, altering normal trajectories of brain development in areas closely linked to emotional responses such as the prefrontal cortex (PFC). Yet, the cellular underpinnings of these enduring effects are unclear. Childhood and adolescence are marked by the protracted formation of perineuronal nets (PNNs), which orchestrate the closure of developmental windows of cortical plasticity by regulating the functional integration of parvalbumin interneurons (PV) into neuronal circuits. Using well-characterized post-mortem brain samples, we show that a history of CA is specifically associated with increased densities and morphological complexity of WFL-labeled PNNs in the ventromedial PFC (BA11/12), possibly suggesting increased recruitment and maturation of PNNs. Through single-nucleus sequencing and fluorescent in-situ hybridization, we found that the expression of canonical components of PNNs is enriched in oligodendrocyte progenitor cells (OPCs), and that they are upregulated in CA victims. These correlational findings suggest that early-life adversity may lead to persistent patterns of maladaptive behaviors by reducing the neuroplasticity of cortical circuits through the enhancement of developmental OPC-mediated PNN formation.

neuroscience↗

bioRxiv2019

Differential Treatment Benefit Prediction For Treatment Selection in Depression: A Deep Learning Analysis of STAR*D and CO-MED Data

BackgroundDepression affects one in nine people, but treatment response rates remain low. There is significant potential in the use of computational modelling techniques to predict individual patient responses and thus provide more personalized treatment. Deep learning is a promising computational technique that can be used for differential treatment selection based on predicted remission probability.\n\nMethodsUsing STAR*D and CO-MED trial data, we employed deep neural networks to predict remission after feature selection. Differential treatment benefit was estimated in terms of improvement of population remission rates after application of the model for treatment selection using both naive and conservative approaches. The naive approach assessed population remission rate in five sets of 200 patients held apart from the training set; the conservative approach used bootstrapping for sample generation and focused on population remission rate for patients who actually received the drug predicted by the model compared to the general population.\n\nResultsOur deep learning model predicted remission in a pooled CO-MED/STAR*D dataset (including four treatments) with an AUC of 0.69 using 17 input features. Our naive analysis showed an improvement of remission of over 30% (from a 34.33% population remission rate to 46.12%). Our conservative analysis showed a 7.2% improvement in population remission rate (p= 0.01, C.I. 2.48% {+/-} .5%).\n\nConclusionOur model serves as proof-of-concept that deep learning has utility in differential prediction of antidepressant response when selecting from a number of treatment options. These models may have significant real-world clinical implications.

neuroscience↗