Whole-brain circuit dissection in free-moving animals reveals cell-specific mesocorticolimbic networks
Michael Michaelides, Sarah Ann R. Anderson, Mala Ananth, Denis Smirnov, Panayotis K. Thanos, John F. Neumaier, Gene-Jack Wang, Nora D. Volkow, Yasmin L. Hurd
Michael Michaelides, Sarah Ann R. Anderson, Mala Ananth, Denis Smirnov, Panayotis K. Thanos, John F. Neumaier, Gene-Jack Wang, Nora D. Volkow, Yasmin L. Hurd
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Technical Advance

Whole-brain circuit dissection in free-moving animals reveals cell-specific mesocorticolimbic networks

Abstract

The ability to map the functional connectivity of discrete cell types in the intact mammalian brain during behavior is crucial for advancing our understanding of brain function in normal and disease states. We combined designer receptor exclusively activated by designer drug (DREADD) technology and behavioral imaging with μPET and [18F]fluorodeoxyglucose (FDG) to generate whole-brain metabolic maps of cell-specific functional circuits during the awake, freely moving state. We have termed this approach DREADD-assisted metabolic mapping (DREAMM) and documented its ability in rats to map whole-brain functional anatomy. We applied this strategy to evaluating changes in the brain associated with inhibition of prodynorphin-expressing (Pdyn-expressing) and of proenkephalin-expressing (Penk-expressing) medium spiny neurons (MSNs) of the nucleus accumbens shell (NAcSh), which have been implicated in neuropsychiatric disorders. DREAMM revealed discrete behavioral manifestations and concurrent engagement of distinct corticolimbic networks associated with dysregulation of Pdyn and Penk in MSNs of the NAcSh. Furthermore, distinct neuronal networks were recruited in awake versus anesthetized conditions. These data demonstrate that DREAMM is a highly sensitive, molecular, high-resolution quantitative imaging approach.

Authors

Michael Michaelides, Sarah Ann R. Anderson, Mala Ananth, Denis Smirnov, Panayotis K. Thanos, John F. Neumaier, Gene-Jack Wang, Nora D. Volkow, Yasmin L. Hurd

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Figure 2

Validation of HSV vector selectivity and infusion sites.

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Validation of HSV vector selectivity and infusion sites. (A) Representat...
(A) Representative images from the NAc of rats injected with HSV-Pdyn-GFP (A) or HSV-Penk-GFP (B) and assessed for substance P (SP) (which coexpresses with Pdyn and not Penk) or enkephalin (Enk) immunoreactivity. In rats injected with Pdyn-GFP, 100% of cells were positive for both GFP and SP (arrowheads) and 4.5% were positive for GFP and Enk (arrows). In rats injected with Penk-GFP, we found that 6.7% of cells were positive for both GFP and SP (arrows) and 76.7% were positive for GFP and Enk (arrowheads). Original magnification, ×20. (C) Schematic image of injection sites and viral spread of HSV-Pdyn-hM4Di and HSV-Penk-hM4Di vectors. Mean diameter (d) of area surrounding each injection site was measured at 0.51 ± 0.03 mm (SEM).