Dataset Information

Lateral habenula perturbation reduces default-mode network connectivity in a rat model of depression.

ABSTRACT: Hyperconnectivity of the default-mode network (DMN) is one of the most widely replicated neuroimaging findings in major depressive disorder (MDD). Further, there is growing evidence for a central role of the lateral habenula (LHb) in the pathophysiology of MDD. There is preliminary neuroimaging evidence linking LHb and the DMN, but no causal relationship has been shown to date. We combined optogenetics and functional magnetic resonance imaging (fMRI), to establish a causal relationship, using an animal model of treatment-resistant depression, namely Negative Cognitive State rats. First, an inhibitory light-sensitive ion channel was introduced into the LHb by viral transduction. Subsequently, laser stimulation was performed during fMRI acquisition on a 9.4 Tesla animal scanner. Neural activity and connectivity were assessed, before, during and after laser stimulation. We observed a connectivity decrease in the DMN following laser-induced LHb perturbation. Our data indicate a causal link between LHb downregulation and reduction in DMN connectivity. These findings may advance our mechanistic understanding of LHb inhibition, which had previously been identified as a promising therapeutic principle, especially for treatment-resistant depression.

SUBMITTER: Clemm von Hohenberg C

PROVIDER: S-EPMC5913319 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Lateral habenula perturbation reduces default-mode network connectivity in a rat model of depression.

Clemm von Hohenberg Christian C Weber-Fahr Wolfgang W Lebhardt Philipp P Ravi Namasivayam N Braun Urs U Gass Natalia N Gass Natalia N Becker Robert R Sack Markus M Cosa Linan Alejandro A Gerchen Martin Fungisai MF Reinwald Jonathan Rochus JR Oettl Lars-Lennart LL Meyer-Lindenberg Andreas A Vollmayr Barbara B Kelsch Wolfgang W Sartorius Alexander A

Translational psychiatry 20180327 1

Hyperconnectivity of the default-mode network (DMN) is one of the most widely replicated neuroimaging findings in major depressive disorder (MDD). Further, there is growing evidence for a central role of the lateral habenula (LHb) in the pathophysiology of MDD. There is preliminary neuroimaging evidence linking LHb and the DMN, but no causal relationship has been shown to date. We combined optogenetics and functional magnetic resonance imaging (fMRI), to establish a causal relationship, using an ...[more]

PMID: 29581421

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Project description:BackgroundFunctional magnetic resonance imaging research suggests that major depressive disorder (MDD) in both adults and adolescents is marked by aberrant connectivity of the default mode network (DMN) during resting state. However, emotional dysregulation is also a key feature of MDD. No studies to date have examined emotion-related DMN pathology in adolescent depression. Comprehensively understanding the dynamics of DMN connectivity across brain states in individuals with depression with short disease histories could provide insight into the etiology of MDD.MethodsWe collected functional magnetic resonance imaging data during an emotion identification task and during resting state from 26 medication-free adolescents (13-17 years old) with MDD and 37 well-matched healthy control subjects. We examined between-group differences in blood oxygenation level-dependent task responses and emotion-dependent and resting-state functional connectivity of the two primary nodes of the DMN: medial prefrontal cortex and posterior cingulate cortex (PCC). Additionally, we examined between-group differences in DMN functional connectivity and its relationship to depression severity and onset.ResultsRelative to healthy control subjects, unmedicated adolescents with MDD demonstrated reduced medial prefrontal cortex and PCC emotion-related deactivation and greater medial prefrontal cortex and PCC emotion-dependent functional connectivity with precuneus, cingulate gyrus, and striatum/subcallosal cingulate gyrus. The PCC-subcallosal cingulate connectivity remained inflexibly elevated in the subjects with MDD versus healthy control subjects during resting state. Stronger PCC emotion-dependent functional connectivity was associated with greater depression severity and an earlier age of depression onset.ConclusionsAdolescent depression is associated with inflexibly elevated DMN connections. Given more recent evidence of DMN maturation throughout adolescence, our findings suggest that early-onset depression adversely affects normal development of functional brain networks.

Project description:IntroductionAspects of the built environment relate to health factors and equity in living conditions, and may contribute to racial, ethnic, or economic health disparities. For example, urbanicity is linked with negative factors including exposure to gray space (e.g., impervious surfaces such as concrete, streets, or rooftops). While there is existing research on access to green space and urbanicity on some mental health and cognitive outcomes, there is limited research on the presence of gray space linked with cognitive functioning in youth. The goal of this study was to investigate the link between gray space and amygdala-default mode network (DMN) connectivity.MethodsThis study used data from the ABCD Study. Participants (n = 10,144; age M = 119.11 months, female = 47.62%) underwent resting-state fMRI acquisition at baseline. Impervious surfaces (gray space) were measured via the Child Opportunity Index (COI). To examine the relationship between presence of gray space and -amygdala-DMN (left/right) connectivity, we employed linear mixed effects models. Correlations were run between amygdala-DMN connectivity and internalizing and externalizing symptoms. Finally, post hoc sensitivity analyses were run to assess the impact of race.ResultsMore gray space, adjusting for age, sex, and neighborhood-level variables, was significantly associated with increased left amygdala-DMN connectivity (p = 0.0001). This association remained significant after sensitivity analyses for race were completed (p = 0.01). No significant correlations were observed between amygdala-DMN and internalizing or externalizing symptoms.DiscussionFindings suggest gray space was linked with increased left amygdala-DMN connectivity, circuits that have been implicated in affective processing, emotion regulation, and psychopathology. Thus gray space may be related to alterations in connectivity that may enhance risk for emotion dysregulation. Future investigation of these relationships is needed, as neuroimaging findings may represent early dysregulation not yet observed in the behavioral analyses at this age (i.e., the present study did not find significant relationships with parent-reported behavioral outcomes). These findings can help to inform future public policy on improving lived and built environments.

Dataset Information

Lateral habenula perturbation reduces default-mode network connectivity in a rat model of depression.

Publications

Lateral habenula perturbation reduces default-mode network connectivity in a rat model of depression.

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