Local accumbens in vivo imaging during deep brain stimulation reveals a strategy-dependent amelioration of hedonic feeding

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Significance

Impulsive overeating is a common, disabling feature of eating disorders. Calcium imaging using fiber photometry has emerged as an in vivo methodology to measure neuronal population activity immune to electrical stimulation artifact from deep brain stimulation (DBS). Thus, when used simultaneously, calcium imaging can elucidate poorly understood DBS mechanisms. We show that nucleus accumbens D1 medial spiny calcium signaling increases in preparation of hedonic feeding of high-fat food. Further, responsive, over continuous, DBS strategies effectively disrupt this activity leading to decreased consumption. Implementation of this methodology to better understand mechanisms of these and other forms of neuromodulation for various indications may help advance the field to identify novel therapeutic targets with applications extending beyond obesity.

Abstract

Impulsive overeating is a common, disabling feature of eating disorders. Both continuous deep brain stimulation (DBS) and responsive DBS, which limits current delivery to pathological brain states, have emerged as potential therapies. We used in vivo fiber photometry in wild-type, Drd1-cre, and A2a-cre mice to 1) assay subtype-specific medium spiny neuron (MSN) activity of the nucleus accumbens (NAc) during hedonic feeding of high-fat food, and 2) examine DBS strategy-specific effects on NAc activity. D1, but not D2, NAc GCaMP activity increased immediately prior to high-fat food approach. Responsive DBS triggered a GCaMP surge throughout the stimulation period and durably reduced high-fat intake. However, with continuous DBS, this surge decayed, and high-fat intake reemerged. Our results argue for a stimulation strategy-dependent modulation of D1 MSNs with a more sustained decrease in consumption with responsive DBS. This study illustrates the important role in vivo imaging can play in understanding effects of such novel therapies.

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Most cited references 46

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (hwp): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Electronic): 17 December 2021

Publication date (Print): 4 January 2022

Publication date PMC-release: 17 December 2021

Volume: 119

Issue: 1

Electronic Location Identifier: e2109269118

Affiliations

[1] ^aDepartment of Neurosurgery, Stanford University School of Medicine , Stanford, CA 94305;

[2] ^bNancy Pritzker Laboratory, Department of Psychiatry and Behavioral Science, Stanford University School of Medicine , Stanford, CA 94305;

[3] ^cDepartment of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine , Stanford, CA 94305;

[4] ^dRichards Medical Research Laboratories, Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104

Author notes

²To whom correspondence may be addressed. Email: casey.halpern@ 123456pennmedicine.upenn.edu .

Edited by Donald Pfaff, Laboratory of Neurobiology and Behavior, Rockefeller University, New York, NY; received May 19, 2021; accepted October 28, 2021

Author contributions: H.W., B.K., D.J.C., B.D.H., R.C.M., and C.H.H. designed research; H.W., B.K., and S.N. performed research; H.W., B.K., S.N., D.J.C., B.D.H., R.C.M., and C.H.H. contributed new reagents/analytic tools; H.W., B.K., and S.N. analyzed data; and H.W., B.K., D.J.C., B.D.H., R.C.M., and C.H.H. wrote the paper.

¹H.W. and B.K. contributed equally to this work.

Author information

Bina Kakusa https://orcid.org/0000-0003-0907-2505

Daniel J. Christoffel https://orcid.org/0000-0002-6303-5134

Robert C. Malenka https://orcid.org/0000-0002-5428-5211

Article

Publisher ID: 202109269

DOI: 10.1073/pnas.2109269118

PMC ID: 8740575

PubMed ID: 34921100

SO-VID: df5f0e6e-ca19-47e4-bf02-b74a7148a8aa

License:

This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

History

Date accepted : 28 October 2021

Page count

Pages: 8

Funding

Funded by: Brain and Behavior Research Foundation (BBRF) 100000874

Award ID: N/A

Award Recipient : Daniel J Christoffel Award Recipient : Casey H Halpern

Funded by: Neurosurgery Research and Education Foundation (NREF) 100005351

Award ID: N/A