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Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit.

ABSTRACT: Kappa opioid receptors (KORs) are involved in a variety of aversive behavioral states, including anxiety. To date, a circuit-based mechanism for KOR-driven anxiety has not been described. Here, we show that activation of KORs inhibits glutamate release from basolateral amygdala (BLA) inputs to the bed nucleus of the stria terminalis (BNST) and occludes the anxiolytic phenotype seen with optogenetic activation of BLA-BNST projections. In addition, deletion of KORs from amygdala neurons results in an anxiolytic phenotype. Furthermore, we identify a frequency-dependent, optically evoked local dynorphin-induced heterosynaptic plasticity of glutamate inputs in the BNST. We also find that there is cell type specificity to the KOR modulation of the BLA-BNST input with greater KOR-mediated inhibition of BLA dynorphin-expressing neurons. Collectively, these results provide support for a model in which local dynorphin release can inhibit an anxiolytic pathway, providing a discrete therapeutic target for the treatment of anxiety disorders.

SUBMITTER: Crowley NA

PROVIDER: S-EPMC4814306 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit.

Crowley Nicole A NA Bloodgood Daniel W DW Hardaway J Andrew JA Kendra Alexis M AM McCall Jordan G JG Al-Hasani Ream R McCall Nora M NM Yu Waylin W Schools Zachary L ZL Krashes Michael J MJ Lowell Bradford B BB Whistler Jennifer L JL Bruchas Michael R MR Kash Thomas L TL

Cell reports 20160317 12

Kappa opioid receptors (KORs) are involved in a variety of aversive behavioral states, including anxiety. To date, a circuit-based mechanism for KOR-driven anxiety has not been described. Here, we show that activation of KORs inhibits glutamate release from basolateral amygdala (BLA) inputs to the bed nucleus of the stria terminalis (BNST) and occludes the anxiolytic phenotype seen with optogenetic activation of BLA-BNST projections. In addition, deletion of KORs from amygdala neurons results in ...[more]

PMID: 26997280

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Project description:Anxiety disorders are debilitating psychiatric diseases that affect ∼16% of the world's population. Although it has been proposed that the central nucleus of the amygdala (CeA) plays a role in anxiety, the molecular and circuit mechanisms through which CeA neurons modulate anxiety-related behaviors are largely uncharacterized. Soluble epoxide hydrolase (sEH) is a key enzyme in the metabolism of polyunsaturated fatty acids (PUFAs), and has been shown to play a role in psychiatric disorders. Here, we reported that sEH was enriched in neurons in the CeA and regulated anxiety-related behaviors in adult male mice. Deletion of sEH in CeA neurons but not astrocytes induced anxiety-like behaviors. Mechanistic studies indicated that sEH was required for maintaining the the excitability of sEH positive neurons (sEHCeA neurons) in the CeA. Using chemogenetic manipulations, we found that sEHCeA neurons bidirectionally regulated anxiety-related behaviors. Notably, we identified that sEHCeA neurons directly projected to the bed nucleus of the stria terminalis (BNST; sEHCeA-BNST). Optogenetic activation and inhibition of the sEHCeA-BNST pathway produced anxiolytic and anxiogenic effects, respectively. In summary, our studies reveal a set of molecular and circuit mechanisms of sEHCeA neurons underlying anxiety.SIGNIFICANCE STATEMENT Soluble epoxide hydrolase (sEH), a key enzyme that catalyzes the degradation of EETs, is shown to play a key role in mood disorders. It is well known that sEH is mostly localized in astrocytes in the prefrontal cortex and regulates depressive-like behaviors. Notably, sEH is also expressed in central nucleus of the amygdala (CeA) neurons. While the CeA has been studied for its role in the regulation of anxiety, the molecular and circuit mechanism is quite complex. In the present study, we explored a previously unknown cellular and circuitry mechanism that guides sEHCeA neurons response to anxiety. Our findings reveal a critical role of sEH in the CeA, sEHCeA neurons and CeA-bed nucleus of the stria terminalis (BNST) pathway in regulation of anxiety-related behaviors.

Dataset Information

Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit.

Publications

Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit.

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