Noradrenergic circuits in the forebrain control affective responses to novelty
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ORIGINAL INVESTIGATION
Noradrenergic circuits in the forebrain control affective responses to novelty Daniel Lustberg 1 & Rachel P. Tillage 1 & Yu Bai 1 & Molly Pruitt 2 & L. Cameron Liles 1 & David Weinshenker 1 Received: 13 April 2020 / Accepted: 17 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Rationale In rodents, exposure to novel environments elicits initial anxiety-like behavior (neophobia) followed by intense exploration (neophilia) that gradually subsides as the environment becomes familiar. Thus, innate novelty-induced behaviors are useful indices of anxiety and motivation in animal models of psychiatric disease. Noradrenergic neurons are activated by novelty and implicated in exploratory and anxiety-like responses, but the role of norepinephrine (NE) in neophobia has not been clearly delineated. Objective We sought to define the role of central NE transmission in neophilic and neophobic behaviors. Methods We assessed dopamine β-hydroxylase knockout (Dbh −/−) mice lacking NE and their NE-competent (Dbh +/−) littermate controls in neophilic (novelty-induced locomotion; NIL) and neophobic (novelty-suppressed feeding; NSF) behavioral tests with subsequent quantification of brain-wide c-fos induction. We complimented the gene knockout approach with pharmacological interventions. Results Dbh −/− mice exhibited blunted locomotor responses in the NIL task and completely lacked neophobia in the NSF test. Neophobia was rescued in Dbh −/− mice by acute pharmacological restoration of central NE with the synthetic precursor L-3,4dihydroxyphenylserine (DOPS), and attenuated in control mice by the inhibitory α2-adrenergic autoreceptor agonist guanfacine. Following either NSF or NIL, Dbh −/− mice demonstrated reduced c-fos in the anterior cingulate cortex, medial septum, ventral hippocampus, bed nucleus of the stria terminalis, and basolateral amygdala. Conclusion These findings indicate that central NE signaling is required for the expression of both neophilic and neophobic behaviors. Further, we describe a putative noradrenergic novelty network as a potential therapeutic target for treating anxiety and substance abuse disorders. Keywords Norepinephrine . Dopamine β-hydroxylase . Neophobia . Neophilia . Novel environment . Novelty suppressed feeding . Guanfacine . C-fos . Locus coeruleus . Anxiety
Introduction A novel environment may represent either an appetitive opportunity or a potential threat; the valence of the context is uncertain because it has never been encountered before (Kafkas and Montaldi 2018). In novel environments, it is Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00213-020-05615-8) contains supplementary material, which is available to authorized users. * David Weinshenker [email protected] 1
Department of Human Genetics, Emory University, Atlanta, GA 30322, USA
2
University of Maryland School of Medicine, Baltimore, MD 21201, USA
adaptive for animals to exhibit initial anxiety-like behavior (neophobia) that gr
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