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HGG Advances May 2024Expression quantitative trait locus (eQTL) analysis is a popular method of gaining insight into the function of regulatory variation. While cis-eQTL resources have been...
Expression quantitative trait locus (eQTL) analysis is a popular method of gaining insight into the function of regulatory variation. While cis-eQTL resources have been instrumental in linking genome-wide association study variants to gene function, complex trait heritability may be additionally mediated by other forms of gene regulation. Toward this end, novel eQTL methods leverage gene co-expression (module-QTL) to investigate joint regulation of gene modules by single genetic variants. Here we broadly define a "module-QTL" as the association of a genetic variant with a summary measure of gene co-expression. This approach aims to reduce the multiple testing burden of a trans-eQTL search through the consolidation of gene-based testing and provide biological context to eQTLs shared between genes. In this article we provide an in-depth examination of the co-expression module eQTL (module-QTL) through literature review, theoretical investigation, and real-data application of the module-QTL to three large prefrontal cortex genotype-RNA sequencing datasets. We find module-QTLs in our study that are disease associated and reproducible are not additionally informative beyond cis- or trans-eQTLs for module genes. Through comparison to prior studies, we highlight promises and limitations of the module-QTL across study designs and provide recommendations for further investigation of the module-QTL framework.
PubMed: 38773772
DOI: 10.1016/j.xhgg.2024.100311 -
Journal of Affective Disorders Reports Apr 2024Trait rumination is a habitual response to negative experiences that can emerge during adolescence, increasing risk of depression. Trait rumination is correlated with...
State rumination predicts inhibitory control failures and dysregulation of default, salience, and cognitive control networks in youth at risk of depressive relapse: Findings from the RuMeChange trial.
BACKGROUND
Trait rumination is a habitual response to negative experiences that can emerge during adolescence, increasing risk of depression. Trait rumination is correlated with poor inhibitory control (IC) and altered default mode network (DMN) and cognitive control network (CCN) engagement. Provoking state rumination in high ruminating youth permits investigation of rumination and IC at the neural level, highlighting potential treatment targets.
METHODS
Fifty-three high-ruminating youth were cued with an unresolved goal that provoked state rumination, then completed a modified Sustained Attention to Response Task (SART) that measures IC (commissions on no-go trials) in a functional MRI study. Thought probes measured state rumination about that unresolved goal and task-focused thoughts during the SART.
RESULTS
Greater state rumination during the SART was correlated with more IC failures. CCN engagement increased during rumination (relative to task-focus), including left dorsolateral prefrontal cortex and dorsalmedial prefrontal cortex. Relative to successful response suppression, DMN engagement increased during IC failures amongst individuals with higher state and trait rumination. Exploratory analyzes suggested more bothersome unresolved goals predicted higher left DLPFC activation during rumination.
LIMITATIONS
The correlational research design did not permit a direct contrast of causal accounts of the relationship between rumination and IC.
CONCLUSIONS
State rumination was associated with impaired IC and disrupted modulation of DMN and CCN. Increased CCN engagement during rumination suggested effortful suppression of negative thoughts, and this was greater for more bothersome unresolved goals. Relative task disengagement was observed during rumination-related errors. DMN-CCN dysregulation in high-ruminating youth may be an important treatment target.
PubMed: 38769946
DOI: 10.1016/j.jadr.2024.100729 -
BioRxiv : the Preprint Server For... May 2024The parabrachial nucleus (PB), located in the dorsolateral pons, contains primarily glutamatergic neurons which regulate responses to a variety of interoceptive and...
The parabrachial nucleus (PB), located in the dorsolateral pons, contains primarily glutamatergic neurons which regulate responses to a variety of interoceptive and cutaneous sensory signals. The lateral PB subpopulation expressing the gene which produces the neuropeptide calcitonin gene-related peptide (CGRP) relays signals related to threatening stimuli such as hypercarbia, pain, and nausea, yet the afferents to these neurons are only partially understood. We mapped the afferent projections to the lateral part of the PB in mice using conventional cholera toxin B subunit (CTb) retrograde tracing, and then used conditional rabies virus retrograde tracing to map monosynaptic inputs specifically targeting the PB neurons. Using vesicular GABA (vGAT) and glutamate (vGLUT2) transporter reporter mice, we found that lateral PB neurons receive GABAergic afferents from regions such as the lateral part of the central nucleus of the amygdala, lateral dorsal subnucleus of the bed nucleus of the stria terminalis, substantia innominata, and the ventrolateral periaqueductal gray. Additionally, they receive glutamatergic afferents from the infralimbic and insular cortex, paraventricular nucleus, parasubthalamic nucleus, trigeminal complex, medullary reticular nucleus, and nucleus of the solitary tract. Using anterograde tracing and confocal microscopy, we then identified close axonal appositions between these afferents and PB neurons. Finally, we used channelrhodopsin-assisted circuit mapping to test whether some of these inputs directly synapse upon the PB neurons. These findings provide a comprehensive neuroanatomical framework for understanding the afferent projections regulating the PB neurons.
PubMed: 38766214
DOI: 10.1101/2024.05.07.593004 -
BioRxiv : the Preprint Server For... May 2024Striatal Cholinergic Interneurons (CIN) are drivers of L-Dopa induced Dyskinesias (LID). However, what signaling pathways elicit aberrant CIN activity remains unclear....
BACKGROUND
Striatal Cholinergic Interneurons (CIN) are drivers of L-Dopa induced Dyskinesias (LID). However, what signaling pathways elicit aberrant CIN activity remains unclear. CIN express D2 and D5 receptors suggesting repeated activation of these receptors in response to L-Dopa could promote LID. While the role of D5 in this process has recently been probed, little is known about the role of D2.
METHOD
Mice with CIN-specific D2 ablation (D2 KO) underwent unilateral 6-OHDA lesion and chronic L-Dopa dosing, throughout which LID severity was quantified. The effect of D2 KO on histological markers of LID severity and CIN activity were also quantified postmortem.
RESULTS
D2 KO attenuated LID across L-Dopa doses, reduced expression of histological LID marker p-ERK, and prevented L-Dopa-induced increases in CIN activity marker p-rpS6 in the dorsolateral striatum.
CONCLUSION
The activation of D2 specifically on CIN is a key driver of LID.
PubMed: 38765986
DOI: 10.1101/2024.05.10.593604 -
Molecular Metabolism Jul 2024Although glucagon-like peptide 1 (GLP-1) is known to regulate feeding, the central mechanisms contributing to this function remain enigmatic. Here, we aim to test the...
OBJECTIVE
Although glucagon-like peptide 1 (GLP-1) is known to regulate feeding, the central mechanisms contributing to this function remain enigmatic. Here, we aim to test the role of neurons expressing GLP-1 receptors (GLP-1R) in the dorsolateral septum (dLS; dLS) that project to the lateral hypothalamic area (LHA) on food intake and determine the relationship with feeding regulation.
METHODS
Using chemogenetic manipulations, we assessed how activation or inhibition of dLS neurons affected food intake in Glp1r-ires-Cre mice. Then, we used channelrhodopsin-assisted circuit mapping, chemogenetics, and electrophysiological recordings to identify and assess the role of the pathway from dLS →LHA projections in regulating food intake.
RESULTS
Chemogenetic inhibition of dLS neurons increases food intake. LHA is a major downstream target of dLS neurons. The dLS→LHA projections are GABAergic, and chemogenetic inhibition of this pathway also promotes food intake. While chemogenetic activation of dLS→LHA projections modestly decreases food intake, optogenetic stimulation of the dLS→LHA projection terminals in the LHA rapidly suppresses feeding behavior. Finally, we demonstrate that the GLP-1R agonist, Exendin 4 enhances dLS →LHA GABA release.
CONCLUSIONS
Together, these results demonstrate that dLS-GLP-1R neurons and the inhibitory pathway to LHA can regulate feeding behavior, which might serve as a potential therapeutic target for the treatment of eating disorders or obesity.
Topics: Animals; Glucagon-Like Peptide-1 Receptor; Mice; Neurons; Male; Hypothalamic Area, Lateral; Eating; Glucagon-Like Peptide 1; Feeding Behavior; Mice, Inbred C57BL
PubMed: 38763494
DOI: 10.1016/j.molmet.2024.101960 -
Scientific Reports May 2024Metacognitive systematic bias impairs human learning efficiency, which is characterized by the inconsistency between predicted and actual memory performance. However,...
Metacognitive systematic bias impairs human learning efficiency, which is characterized by the inconsistency between predicted and actual memory performance. However, the underlying mechanism of metacognitive systematic bias remains unclear in existing studies. In this study, we utilized judgments of learning task in human participants to compare the neural mechanism difference in metacognitive systematic bias. Participants encoded words in fMRI sessions that would be tested later. Immediately after encoding each item, participants predicted how likely they would remember it. Multivariate analyses on fMRI data demonstrated that working memory and uncertainty decisions are represented in patterns of neural activity in metacognitive systematic bias. The available information participants used led to overestimated bias and underestimated bias. Effective connectivity analyses further indicate that information about the metacognitive systematic bias is represented in the dorsolateral prefrontal cortex and inferior parietal cortex. Different neural patterns were found underlying overestimated bias and underestimated bias. Specifically, connectivity regions with the dorsolateral prefrontal cortex, anterior cingulate cortex, and supramarginal gyrus form overestimated bias, while less regional connectivity forms underestimated bias. These findings provide a mechanistic account for the construction of metacognitive systematic bias.
Topics: Humans; Parietal Lobe; Magnetic Resonance Imaging; Male; Dorsolateral Prefrontal Cortex; Female; Metacognition; Young Adult; Adult; Brain Mapping; Memory, Short-Term; Learning; Prefrontal Cortex; Judgment
PubMed: 38762635
DOI: 10.1038/s41598-024-62343-1 -
Nature Communications May 2024The dorsolateral prefrontal cortex (dlPFC) is crucial for regulation of emotion that is known to aid prevention of depression. The broader fronto-cingulo-striatal (FCS)...
The dorsolateral prefrontal cortex (dlPFC) is crucial for regulation of emotion that is known to aid prevention of depression. The broader fronto-cingulo-striatal (FCS) network, including cognitive dlPFC and limbic cingulo-striatal regions, has been associated with a negative evaluation bias often seen in depression. The mechanism by which dlPFC regulates the limbic system remains largely unclear. Here we have successfully induced a negative bias in decision-making in female primates performing a conflict decision-making task, by directly microstimulating the subgenual cingulate cortex while simultaneously recording FCS local field potentials (LFPs). The artificially induced negative bias in decision-making was associated with a significant decrease in functional connectivity from cognitive to limbic FCS regions, represented by a reduction in Granger causality in beta-range LFPs from the dlPFC to the other regions. The loss of top-down directional influence from cognitive to limbic regions, we suggest, could underlie negative biases in decision-making as observed in depressive states.
Topics: Animals; Gyrus Cinguli; Decision Making; Female; Corpus Striatum; Macaca mulatta; Dorsolateral Prefrontal Cortex; Prefrontal Cortex; Electric Stimulation; Nerve Net; Neural Pathways
PubMed: 38760337
DOI: 10.1038/s41467-024-48375-1 -
PLoS Biology May 2024People tend to intervene in others' injustices by either punishing the transgressor or helping the victim. Injustice events often occur under stressful circumstances....
People tend to intervene in others' injustices by either punishing the transgressor or helping the victim. Injustice events often occur under stressful circumstances. However, how acute stress affects a third party's intervention in injustice events remains open. Here, we show a stress-induced shift in third parties' willingness to engage in help instead of punishment by acting on emotional salience and central-executive and theory-of-mind networks. Acute stress decreased the third party's willingness to punish the violator and the severity of the punishment and increased their willingness to help the victim. Computational modeling revealed a shift in preference of justice recovery from punishment the offender toward help the victim under stress. This finding is consistent with the increased dorsolateral prefrontal engagement observed with higher amygdala activity and greater connectivity with the ventromedial prefrontal cortex in the stress group. A brain connectivity theory-of-mind network predicted stress-induced justice recovery in punishment. Our findings suggest a neurocomputational mechanism of how acute stress reshapes third parties' decisions by reallocating neural resources in emotional, executive, and mentalizing networks to inhibit punishment bias and decrease punishment severity.
Topics: Humans; Punishment; Male; Stress, Psychological; Female; Adult; Young Adult; Prefrontal Cortex; Emotions; Social Justice; Brain; Magnetic Resonance Imaging
PubMed: 38754078
DOI: 10.1371/journal.pbio.3002195 -
Annals of Indian Academy of Neurology 2024Fibromyalgia syndrome (FMS) is a chronic disease characterized by widespread, persistent musculoskeletal pain in association with impaired health-related quality of...
BACKGROUND AND OBJECTIVE
Fibromyalgia syndrome (FMS) is a chronic disease characterized by widespread, persistent musculoskeletal pain in association with impaired health-related quality of life. Repetitive transcranial magnetic stimulation (rTMS) is an emerging tool for the management of fibromyalgia. There is no standardized protocol of rTMS for the treatment of FMS, and both low- and high-frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) are described in the literature with variable efficacy. The objective of this study was to determine the effectiveness of rTMS in people with fibromyalgia and compare the response of low- and high-frequency stimulation with sham stimulation.
MATERIALS AND METHODS
This study was a single-blinded, randomized, placebo-controlled trial. Ninety patients with the diagnosis of FMS were randomly allocated into one of the following three groups: low-frequency (1 Hz) group, high-frequency (10 Hz) group, and sham group. Pain, depression, anxiety, and quality of life were measured using the Numerical Pain Rating Scale (NPRS), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HDRS), and Revised Fibromyalgia Impact Questionnaire (FIQR) immediately following treatment as well as at 1 and 3 months after treatment. The data was statistically analyzed using Statistical Package for the Social Sciences version 23 software. value < 0.05 was considered statistically significant.
RESULTS
Intergroup analysis revealed a significant improvement in NPRS, HAM-A, HDRS, and FIQR scores in both low- and high- frequency groups immediately following treatment and for 3 months after treatment. No significant difference in the efficacy of low- and high-frequency stimulation was noticed.
CONCLUSIONS
rTMS is an effective mode of treatment in people with FMS. Both low and high frequencies of stimulation at DLPFC are equally effective in reducing pain and associated symptoms.
PubMed: 38751921
DOI: 10.4103/aian.aian_1041_23 -
BioRxiv : the Preprint Server For... May 2024Substance Use Disorders (SUDs) manifest as persistent drug-seeking behavior despite adverse consequences, with Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD)...
Substance Use Disorders (SUDs) manifest as persistent drug-seeking behavior despite adverse consequences, with Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD) representing prevalent forms associated with significant mortality rates and economic burdens. The co-occurrence of AUD and OUD is common, necessitating a deeper comprehension of their intricate interactions. While the causal link between these disorders remains elusive, shared genetic factors are hypothesized. Leveraging public datasets, we employed genomic and transcriptomic analyses to explore conserved and distinct molecular pathways within the dorsolateral prefrontal cortex associated with AUD and OUD. Our findings unveil modest transcriptomic overlap at the gene level between the two disorders but substantial convergence on shared biological pathways. Notably, these pathways predominantly involve inflammatory processes, synaptic plasticity, and key intracellular signaling regulators. Integration of transcriptomic data with the latest genome-wide association studies (GWAS) for problematic alcohol use (PAU) and OUD not only corroborated our transcriptomic findings but also confirmed the limited shared heritability between the disorders. Overall, our study indicates that while alcohol and opioids induce diverse transcriptional alterations at the gene level, they converge on select biological pathways, offering promising avenues for novel therapeutic targets aimed at addressing both disorders simultaneously.
PubMed: 38746311
DOI: 10.1101/2024.04.29.591734