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.
Highlights
Anxiety disorders are a major health concern, with 7.3% of the global population suffering from an anxiety disorder at any given time (Baxter et al, 2013; Lepine, 2002)
Kappa opioid receptors (KORs) modulation has been identified in key anxiety-related regions such as the dorsal raphe nucleus (Bruchas et al, 2010; Land et al, 2009), the ventral tegmental area (Spanagel et al, 1992), and the prefrontal cortex (Svingos and Colago, 2002; Tejeda et al, 2013). These regions interact with the bed nucleus of the stria terminalis (BNST), a key region involved in anxiety-related behaviors (Kash, 2012); far investigation of KORs in the BNST has been lacking
KORs Signal via a Presynaptic, p38, and Calcium-Dependent Mechanism to Inhibit Glutamate Release in the BNST An extensive body of literature links glutamate signaling in the BNST to both anxiolytic and anxiogenic behavior (Davis et al, 2010; Hubert and Muly, 2014; Kim et al, 2013)
Summary
Anxiety disorders are a major health concern, with 7.3% of the global population suffering from an anxiety disorder at any given time (Baxter et al, 2013; Lepine, 2002). KOR modulation has been identified in key anxiety-related regions such as the dorsal raphe nucleus (Bruchas et al, 2010; Land et al, 2009), the ventral tegmental area (Spanagel et al, 1992), and the prefrontal cortex (Svingos and Colago, 2002; Tejeda et al, 2013) These regions interact with the bed nucleus of the stria terminalis (BNST), a key region involved in anxiety-related behaviors (Kash, 2012); far investigation of KORs in the BNST has been lacking. The BNST is known to express preprodynorphin (Poulin et al, 2009), and previous work from our lab has demonstrated KOR modulation of GABAergic transmission in the BNST
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