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Noradrenergic circuits in the forebrain control affective responses to novelty

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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-3,4-dihydroxyphenylserine (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.

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Acknowledgments

We thank Lundbeck for providing the DOPS.

Funding

This work was supported by the National Institutes of Health (AG061175, NS102306, and DA038453 to DW; GM8602-22 to DL; MH116622 to RPT).

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Authors and Affiliations

  1. Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA

    Daniel Lustberg, Rachel P. Tillage, Yu Bai, L. Cameron Liles & David Weinshenker

  2. University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Molly Pruitt

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  1. Daniel Lustberg
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  4. Molly Pruitt
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Correspondence to David Weinshenker.

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All animal procedures and protocols were congruent with the National Institutes of Health guidelines for the care and use of laboratory animals and were approved by the Emory University Animal Care and Use Committee.

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Fig. S1

Compsarison of c-fos induction under naïve conditions and after exposure to novelty. a Under behaviorally naïve conditions, c-fos induction was negligible and did not differ between genotypes any forebrain targets tested, including ventral hippocampal subfield CA1 (vCA1), anterior cingulate cortex (ACC), dorsal bed nucleus of the stria terminalis (dBNST), medial septum/diagonal band complex (MS/DB), and basolateral amygdala (BLA). Representative micrographs show low regional c-fos (green) induction in behaviorally naïve Dbh +/- control mice (top row) and Dbh -/- mice (bottom row). Nuclei were counterstained with DAPI (blue). b Representative micrographs showing c-fos induction in LC, ACC, and vCA1 of Dbh +/- control mice that were behaviorally naïve (top row) compared to those that were euthanized 90 min after exposure to the novel environment in the NIL test (bottom row). The scale bar denotes 100 μM in all micrographs. (PNG 3493 kb)

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Lustberg, D., Tillage, R.P., Bai, Y. et al. Noradrenergic circuits in the forebrain control affective responses to novelty. Psychopharmacology 237, 3337–3355 (2020). https://doi.org/10.1007/s00213-020-05615-8

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