Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety

Dedic, Nina; Kühne, Claudia; Jakovcevski, Mira; Hartmann, Jakob; Genewsky, Andreas; Gomes, Keila Rejane Oliveira; Anderzhanova, Elmira; Pöhlmann, Max L.; Chang, Shu-Ying; Kolarz, Adam; Vogl, Annette M.; Dine, Julien; Metzger, Michael; Schmid, Bianca; Almada, Rafael Carvalho; Ressler, Kerry J.; Wotjak, Carsten T.; Grinevich, Valery; Chen, Alon; Schmidt, Mathias; Wurst, Wolfgang; Refojo, Damián; Deussing, Jan M.

doi:10.1038/s41593-018-0151-z

Cited by 107 publications

(110 citation statements)

References 52 publications

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“…Considering downstream target areas of BNST SOM and BNST CRF neurons (and BNST vGAT ), we could observe minimal differences between these cell types (Figure 3figure supplement 3 and Figure 2F), which was also highly overlapping with reported CeA projections (Hartley et al, 2019;Li, 2019), and corresponded with previous descriptions of BNST CRF projections (Dabrowska et al, 2016;Dedic et al, 2018). Different impact of SOM and CRF may originate from different contacts with specific cell types, which is to be clarified by future studies.…”

Section: Bnst Som But Not Bnst Crf Neurons Facilitate Fear Memorysupporting

confidence: 85%

Somatostatin neurons of the bed nucleus of stria terminalis enhance associative fear memory consolidation in mice

Bruzsik

Biró

Zelena

et al. 2020

Preprint

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Excessive fear learning and extinction-resistant fear memories are core symptoms of anxiety and trauma-related disorders. Despite significant evidence from clinical studies reporting hyperactivity of the bed nucleus of stria terminalis (BNST) under these conditions, the role of BNST in fear learning and expression is still not clarified. Here, we tested how BNST modulates fear learning in mice using a chemogenetic approach. Activation of GABAergic neurons of BNST during fear acquisition, more specifically the consolidation phase, resulted in enhanced cued fear recall. Importantly, BNST activation had no acute impact on fear expression during conditioning or recalls, but it enhanced cued fear recall subsequently, potentially via altered activity of downstream regions as indicated by c-Fos. Enhanced fear memory consolidation could be replicated by selectively activating somatostatin neurons (but not corticotropin releasing factor neurons), suggesting significant modulation of fear memory strength by specific circuits of BNST.

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Section: Bnst Som But Not Bnst Crf Neurons Facilitate Fear Memorysupporting

confidence: 85%

Somatostatin neurons of the bed nucleus of stria terminalis enhance associative fear memory consolidation in mice

Bruzsik

Biró

Zelena

et al. 2020

Preprint

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“…Pharmacological interventions for anxiety primarily target serotonergic and GABAergic neurotransmitter systems. However, early lines of research emphasized a role of dopamine in the pathophysiology of anxiety (Taylor et al, 1982), which recently have been reinvigorated (Kienast et al, 2008a;Dedic et al, 2018). Here, we measured self-reported trait anxiety in healthy adults, and investigated its relationships with brain dopamine function and functional connectivity within circuits implicated in anxiety regulation to probe the neural substrates of this individual difference.…”

Section: Introductionmentioning

confidence: 99%

“…Accumulating evidence links amygdala and PFC dopamine with both anxiety and modulation of functional magnetic resonance imaging (fMRI) activity within these regions. Reduction in dopamine release in rodent medial PFC increases behavioral measures of anxiety (Refojo et al, 2011;Dedic et al, 2018). More generally, a link between dopamine and anxiety is suggested by the high prevalence of anxiety in Parkinson's disease (Walsh and Bennett, 2001), in which there is decline in dopaminergic input to the amygdala and PFC (Javoy-Agid and Agid, 1980;Ouchi et al, 1999) that accompanies losses of striatal terminals.…”

Section: Introductionmentioning

confidence: 99%

Dopaminergic Mechanisms Underlying Normal Variation in Trait Anxiety

et al. 2019

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Trait anxiety has been associated with altered activity within corticolimbic pathways connecting the amygdala and rostral anterior cingulate cortex (rACC), which receive rich dopaminergic input. Though the popular culture uses the term "chemical imbalance" to describe the pathophysiology of psychiatric conditions such as anxiety disorders, we know little about how individual differences in human dopamine neurochemistry are related to variation in anxiety and activity within corticolimbic circuits. We addressed this issue by examining interindividual variability in dopamine release at rest using [ 11 C]raclopride positron emission tomography (PET), functional connectivity between amygdala and rACC using resting-state functional magnetic resonance imaging (fMRI), and trait anxiety measures in healthy adult male and female humans. To measure endogenous dopamine release, we collected two [ 11 C]raclopride PET scans per participant. We contrasted baseline [ 11 C]raclopride D2/3 receptor binding and D2/3 receptor binding following oral methylphenidate administration. Methylphenidate blocks the dopamine transporter, which increases extracellular dopamine and leads to reduced [ 11 C]raclopride D2/3 receptor binding via competitive displacement. We found that individuals with higher dopamine release in the amygdala and rACC self-reported lower trait anxiety. Lower trait anxiety was also associated with reduced rACC-amygdala functional connectivity at baseline. Further, functional connectivity showed a modest negative relationship with dopamine release such that reduced rACC-amygdala functional connectivity was accompanied by higher levels of dopamine release in these regions. Together, these findings contribute to hypodopaminergic models of anxiety and support the utility of combining fMRI and PET measures of neurochemical function to advance our understanding of basic affective processes in humans.It is common wisdom that individuals vary in their baseline levels of anxiety. We all have a friend or colleague we know to be more "tightly wound" than others, or, perhaps, we are the ones marveling at others' ability to "just go with the flow." Although such observations about individual differences within nonclinical populations are commonplace, the neural mechanisms underlying normal variation in trait anxiety have not been established. Using multimodal brain imaging in humans, this study takes initial steps in linking intrinsic measures of neuromodulator release and functional connectivity within regions implicated in anxiety disorders. Our findings suggest that in healthy adults, higher levels of trait anxiety may arise, at least in part, from reduced dopamine neurotransmission.

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“…Wir konnten zeigen, dass das CRH in weiten Teilen des Gehirns von Neuronen synthetisiert wird, die den Neurotransmitter γ-Aminobuttersäure (GABA) als Botenstoff verwenden. Ausnahmen sind CRH + -Neurone des piriformen Cortex, verschiedene Kerne des Hirnstamms sowie jene Neurone im PVN, die die HHN-Achse aktivieren, die allesamt glutamaterg sind [10]. Bei GABAergen CRH + -Neuronen im Hippocampus und Cortex handelt es sich um Interneurone, die -mehr oder weniger räumlich begrenzt -Neurone in der unmittelbaren Umgebung inhibieren.…”

Section: Inhibitorische Projektionsneurone Der Erweiterten Amygdala Sunclassified

“…Im Gegensatz dazu hat eine verstärkte Aktivierung des CRHR1 im VTA durch eine lokale Applikation von CRH oder die gezielte Aktivierung von CRHR1-abhängigen Signalwegen eine Reduktion der Ängstlichkeit zur Folge (Abb. 3, [10]).…”

Section: Crh Und Crhr1 Kontrollieren Ein Angstlösendes Netzwerkunclassified

Regulation des Angstverhaltens — zur Rolle neuronaler Netzwerke

Dedic

Deussing

2019

Biospektrum

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The corticotropin-releasing hormone (CRH) system orchestrates the organism’s stress response including the regulation of adaptive be haviours. Here we describe a novel neuronal circuit, which acts anxiety suppressing and positively modulates dopamine release. This anxiolytic circuit comprises inhibitory CRH-expressing, long-range projection neurons within the extended amygdala. These neurons innervate the ventral tegmental area, a prominent brain reward center that expresses high levels of CRH receptor type 1.

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Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety

Cited by 107 publications

References 52 publications

Somatostatin neurons of the bed nucleus of stria terminalis enhance associative fear memory consolidation in mice

Somatostatin neurons of the bed nucleus of stria terminalis enhance associative fear memory consolidation in mice

Dopaminergic Mechanisms Underlying Normal Variation in Trait Anxiety

Regulation des Angstverhaltens — zur Rolle neuronaler Netzwerke

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