scholarly journals Brain expressed FKBP5 delineates a therapeutic subtype of severe mental illness

2021 ◽  
Author(s):  
Natalie Matosin ◽  
Janine Arloth ◽  
Silvia Martinelli ◽  
Darina Czamara ◽  
Malosree Maitra ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Psychiatric Disorders ◽  
Dorsolateral Prefrontal Cortex ◽  
Large Scale ◽  
Early Adulthood ◽  
Pyramidal Cells ◽  
Later Life ◽  
Superficial Layer ◽  
Treatment Development ◽  
Dorsolateral Prefrontal

SUMMARYDeducing genes capable of classifying biologically-distinct psychiatric subtypes, and their targets for treatment, is a priority approach in psychiatry. FKBP5 is one such gene with strong evidence of utility to delineate a trans-diagnostic psychiatric subtype. Yet how brain-expressed FKBP5 is affected in psychiatric disorders in humans is not fully understood and critical for propelling FKBP5-targeting treatment development. We performed a large-scale postmortem study (n=895) of FKBP5 using dorsolateral prefrontal cortex samples derived from individuals with severe psychiatric disorders with a comprehensive battery of bulk/single-cell omics and histological analyses. We observed consistently heightened FKBP5 mRNA and protein in psychopathology, moderated by genotype and age, and accompanied by DNA methylation changes in key enhancers. These effects were most prominent in superficial-layer pyramidal cells. Heightened FKBP5 was also differentially associated with downstream pathways according to age, being specifically associated with synaptic transmission in early adulthood, and neuroinflammation and neurodegeneration in later life.

Cluster Analysis–Based Physiological Classification and Morphological Properties of Inhibitory Neurons in Layers 2–3 of Monkey Dorsolateral Prefrontal Cortex

2005 ◽  
Vol 94 (5) ◽  
pp. 3009-3022 ◽  
Author(s):  
Leonid S. Krimer ◽  
Aleksey V. Zaitsev ◽  
Gabriela Czanner ◽  
Sven Kröner ◽  
Guillermo González-Burgos ◽  
...  
Keyword(s):  
Cluster Analysis ◽  
Prefrontal Cortex ◽  
Dorsolateral Prefrontal Cortex ◽  
Pyramidal Cells ◽  
Inhibitory Neurons ◽  
Morphological Properties ◽  
Electrophysiological Properties ◽  
Dorsolateral Prefrontal ◽  
Fast Spiking ◽  
Monkey Prefrontal Cortex

In primates, little is known about intrinsic electrophysiological properties of neocortical neurons and their morphological correlates. To classify inhibitory cells (interneurons) in layers 2–3 of monkey dorsolateral prefrontal cortex we used whole cell voltage recordings and intracellular labeling in slice preparation with subsequent morphological reconstructions. Regular spiking pyramidal cells have been also included in the sample. Neurons were successfully segregated into three physiological clusters: regular-, intermediate-, and fast-spiking cells using cluster analysis as a multivariate exploratory technique. When morphological types of neurons were mapped on the physiological clusters, the cluster of regular spiking cells contained all pyramidal cells, whereas the intermediate- and fast-spiking clusters consisted exclusively of interneurons. The cluster of fast-spiking cells contained all of the chandelier cells and the majority of local, medium, and wide arbor (basket) interneurons. The cluster of intermediate spiking cells predominantly consisted of cells with the morphology of neurogliaform or vertically oriented (double-bouquet) interneurons. Thus a quantitative approach enabled us to demonstrate that intrinsic electrophysiological properties of neurons in the monkey prefrontal cortex define distinct cell types, which also display distinct morphologies.

scholarly journals Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

2020 ◽  
Author(s):  
Kristen R. Maynard ◽  
Leonardo Collado-Torres ◽  
Lukas M. Weber ◽  
Cedric Uytingco ◽  
Brianna K. Barry ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Web Application ◽  
Dorsolateral Prefrontal Cortex ◽  
Large Scale ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Sequencing Data ◽  
Dorsolateral Prefrontal ◽  
Transcriptomics Data

AbstractWe used the 10x Genomics Visium platform to define the spatial topography of gene expression in the six-layered human dorsolateral prefrontal cortex (DLPFC). We identified extensive layer-enriched expression signatures, and refined associations to previous laminar markers. We overlaid our laminar expression signatures onto large-scale single nuclei RNA sequencing data, enhancing spatial annotation of expression-driven clusters. By integrating neuropsychiatric disorder gene sets, we showed differential layer-enriched expression of genes associated with schizophrenia and autism spectrum disorder, highlighting the clinical relevance of spatially-defined expression. We then developed a data-driven framework to define unsupervised clusters in spatial transcriptomics data, which can be applied to other tissues or brain regions where morphological architecture is not as well-defined as cortical laminae. We lastly created a web application for the scientific community to explore these raw and summarized data to augment ongoing neuroscience and spatial transcriptomics research (http://research.libd.org/spatialLIBD).

scholarly journals A data-driven approach to the automated mapping of functional brain topographies across species

2018 ◽  
Author(s):  
Wolfgang M. Pauli
Keyword(s):  
Animal Models ◽  
Psychiatric Disorders ◽  
Large Scale ◽  
Brain Regions ◽  
Behavioral Neuroscience ◽  
Open Questions ◽  
Dorsolateral Prefrontal ◽  
Neuroimaging Data ◽  
Data Driven Approach ◽  
Species Mapping

AbstractBehavioral neuroscience has made great strides in developing animal models of human behavior and psychiatric disorders. Animal models allow for the formulation of hypotheses regarding the mechanisms underlying psychiatric disorders, and the opportunity to test these hypotheses using procedures that are too invasive for human participants. However, recent scientific reviews have highlighted the low success rate of translating results from animal models into clinical interventions in humans. A potential roadblock is that bidirectional functional mappings between the human and rodent brain are incomplete. To narrow this gap, we created a framework, Neurobabel, for performing large-scale automated synthesis of human neuroimaging data and behavioral neuroscience data. By leveraging the semantics of how researchers within each field describe their studies, this framework enables region to region mapping of brain regions across species, as well as cross-species mapping of psychological functions. As a proof of concept, we utilize the framework to create a functional cross-species mapping between the amygdala and hippocampus for fear-related and spatial memories, respectively. We then proceed to address two open questions in the field: (1) Do rodents have a dorsolateral prefrontal cortex? (2) Which human brain region corresponds to the rodent prelimbic cortex?

scholarly journals Regional heterogeneity in gene expression, regulation and coherence in hippocampus and dorsolateral prefrontal cortex across development and in schizophrenia

2018 ◽  
Author(s):  
L Collado-Torres ◽  
EE Burke ◽  
A Peterson ◽  
JH Shin ◽  
RE Straub ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Brain Region ◽  
Dorsolateral Prefrontal Cortex ◽  
Large Scale ◽  
Brain Regions ◽  
Second Phase ◽  
Regional Heterogeneity ◽  
Surrogate Variable Analysis ◽  
Dorsolateral Prefrontal

AbstractRecent large-scale genomics efforts have better characterized the molecular correlates of schizophrenia in postmortem human neocortex, but not hippocampus which is a brain region prominently implicated in its pathogenesis. Here in the second phase of the BrainSeq Consortium (Phase II), we have generated RiboZero RNA-seq data for 900 samples across both the dorsolateral prefrontal cortex (DLPFC) and the hippocampus (HIPPO) for 551 individuals (286 affected by schizophrenia disorder: SCZD). We identify substantial regional differences in gene expression, in both pre- and post-natal life, and find widespread differences in how genes are regulated across development. By extending quality surrogate variable analysis (qSVA) to multiple brain regions, we identified 48 and 245 differentially expressed genes (DEG) by SCZD diagnosis (FDR<5%) in HIPPO and DLPFC, respectively, with surprisingly minimal overlap in DEG between the two brain regions. We further identified 205,618 brain region-dependent eQTLs (FDR<1%) and found that 124 GWAS risk loci contain eQTLs in at least one of the regions. We also identify potential molecular correlates of in vivo evidence of altered prefrontal-hippocampal functional coherence in schizophrenia. These results underscore the complexity and regional heterogeneity of the transcriptional correlates of schizophrenia, and suggest future schizophrenia therapeutics may need to target molecular pathologies localized to specific brain regions.

S149. Gene Expression in Dorsolateral Prefrontal Cortex: A Master Regulator Analysis of Major Psychiatric Disorders

2019 ◽  
Vol 85 (10) ◽  
pp. S354
Author(s):  
Bianca Pfaffenseller ◽  
Giovana Bristot ◽  
Marco Antônio De Bastiani ◽  
Flávio Kapczinski ◽  
Márcia Kauer-Sant’Anna
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Psychiatric Disorders ◽  
Dorsolateral Prefrontal Cortex ◽  
Master Regulator ◽  
Dorsolateral Prefrontal

Functional Properties of Fast Spiking Interneurons and Their Synaptic Connections With Pyramidal Cells in Primate Dorsolateral Prefrontal Cortex

2005 ◽  
Vol 93 (2) ◽  
pp. 942-953 ◽  
Author(s):  
Guillermo González-Burgos ◽  
Leonid S. Krimer ◽  
Nadya V. Povysheva ◽  
German Barrionuevo ◽  
David A. Lewis
Keyword(s):  
Prefrontal Cortex ◽  
Dorsolateral Prefrontal Cortex ◽  
Pyramidal Cells ◽  
Synaptic Connections ◽  
Electrophysiological Properties ◽  
Axonal Arborization ◽  
Presynaptic Mechanisms ◽  
Dorsolateral Prefrontal ◽  
Fast Spiking

Recent studies suggest that fast-spiking (FS) interneurons of the monkey dorsolateral prefrontal cortex (DLPFC) exhibit task-related firing during working-memory tasks. To gain further understanding of the functional role of FS neurons in monkey DLPFC, we described the in vitro electrophysiological properties of FS interneurons and their synaptic connections with pyramidal cells in layers 2/3 of areas 9 and 46. Extracellular spike duration was found to distinguish FS cells from non-FS interneuron subtypes. However, a substantial overlap in extracellular spike duration between these populations would make classification of individual interneurons difficult. FS neurons could be divided into two main morphological groups, chandelier and basket neurons, with very similar electrophysiological properties but significantly different horizontal spread of the axonal arborization. In paired cell recordings, unitary inhibitory postsynaptic potentials (IPSPs) elicited by FS neurons in pyramidal cells had rapid time course, small amplitude at resting membrane potential, and were mediated by GABAA receptors. Repetitive FS neuron stimulation, partially mimicking the sustained firing of interneurons in vivo, produced short-term depression of the unitary IPSPs, present at connections made by both basket and chandelier neurons and due at least in part to presynaptic mechanisms. These results suggest that FS neurons and their synaptic connections with pyramidal cells have homogeneous physiological properties. Thus different functional roles of basket and chandelier neurons in the DLPFC in vivo must arise from the distinct properties of the interneuronal axonal arborization or from a different functional pattern of excitatory and inhibitory connections with other components of the DLPFC neuronal network.

scholarly journals The hidden cost of receiving favors: A theory of indebtedness

2020 ◽  
Author(s):  
Xiaoxue Gao ◽  
Eshin Jolly ◽  
Hongbo Yu ◽  
Huiying Liu ◽  
Xiaolin Zhou ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Theoretical Model ◽  
Dorsolateral Prefrontal Cortex ◽  
Large Scale ◽  
Brain Activity ◽  
Ventromedial Prefrontal Cortex ◽  
Utility Model ◽  
Dorsomedial Prefrontal Cortex ◽  
Dorsolateral Prefrontal ◽  
Hidden Cost

AbstractReceiving help or a favor from another person can sometimes have a hidden cost. In this study, we explore these hidden costs by developing and validating a theoretical model of indebtedness across three studies that combine large-scale experience sampling, interpersonal games, computational modeling, and neuroimaging. Our model captures how individuals infer the altruistic and strategic intentions of the benefactor. These inferences produce distinct feelings of guilt and obligation that together comprise indebtedness and motivate reciprocity. Altruistic intentions convey care and concern and are associated with activity in the insula, dorsolateral prefrontal cortex and ventromedial prefrontal cortex, while strategic intentions convey expectations of future reciprocity and are associated with activation in the temporal parietal junction and dorsomedial prefrontal cortex. We further develop a neural utility model of indebtedness using multivariate patterns of brain activity that captures the tradeoff between these feelings and reliably predicts reciprocity behavior.

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