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

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.

Keywords: deep brain stimulation; fiber photometry; hedonic feeding; nucleus accumbens; responsive neurostimulation.

Fig. 1.

NAc MSN population activity during limited exposure to HF food. (A) Schematic of the experimental design: virus injection and electrode implantation, followed by a recovery period (14 d) and limited HF access (days 1 to 10). (B) AAV-DJ-hSyn-GCaMP6f was injected into the NAc, followed by implantation of a 430-µm optical fiber in the NAc to allow for measurement of GCaMP6f signals. (C) Representative image of GCaMP6f expression and fiber optic implant in the NAc. (D) Schematic of the fiber photometry configuration and behavioral setup. (E) Hedonic feeding behavior developed and stabilized by day 10 of limited HF exposure (1 h/d), indicated by a significant increase in daily HF intake. (F–H) Average traces and quantification of the peak amplitude of the Ca²⁺ signal from the NAc in the 8-s window during HF food approach and locomotion unrelated to HF food on days 1 and 10. Data represent mean ± SEM. ***P < 0.001.

Fig. 2.

NAc D1-MSN GCaMP response during hedonic feeding. (A) AAV-DJ-hSyn-DIO-GCaMP6f was injected into the NAc in D1-cre mice, followed by implantation of an optetrode, to allow for measurement of GCaMP6f signals in D1 MSNs. (B) Representative image of GCaMP6f expression in D1 MSNs and the optetrode implant in the NAc. (C) Hedonic feeding behavior developed and stabilized by day 10 (1 h/d), indicated by a significant increase in daily HF intake. (D–F) Average traces and quantification of the peak amplitude of the GCaMP fluorescence signal from the D1 MSN in the NAc in the 8-s window during HF food approach and locomotion unrelated to HF food on days 1 and 10. Data represent mean ± SEM. **P < 0.01, ****P < 0.0001.

Fig. 3.

(A) AAV-DJ-hSyn-DIO-GCaMP6f was injected into the NAc in A2A-cre mice, followed by implantation of an optetrode, to allow for measurement of GCaMP6f signals in D2 MSNs. (B) Representative image of GCaMP6f expression in D2 MSNs and the optetrode implant in the NAc. (C) Hedonic feeding behavior developed and stabilized by day 10 (1 h/d), indicated by a significant increase in daily HF intake. (D–F) Average traces and quantification of the peak amplitude of the GCaMP signal from D2 MSNs in the NAc in the 8-s window during HF approach and locomotion unrelated to HF food on days 1 and 10. (G) Representative spontaneous GCaMP fluorescence from D2 MSNs. (H) SD of GCaMP fluorescence of D1 and D2 MSNs during 5 min of the off-stimulation period. Data represent mean ± SEM. ****P < 0.0001. ns, nonsignificant, P > 0.05.

Fig. 4.

NAc GCaMP response to open-loop or cDBS. (A and B) Average GCaMP fluorescence response with cDBS at 3 Hz (A) and 130 Hz (B), at 0.1, 0.2, 0.5, and 1.0 mA. (C) Schematic of the experimental design: virus injection and electrode implantation, followed by a recovery period (14 d), limited HF food access (days 1 to 10), and various paradigms of electrical stimulation. (D–F) Behavioral (D) and GCaMP (E and F) response to off- and 3- and 130-Hz cDBS. Data represent mean ± SEM. *P < 0.05, ***P < 0.001, ****P < 0.0001.

Fig. 5.

(A) Schematic of the experimental design: virus injection and electrode implantation, followed by a recovery period (14 d), limited HF food access (days 1 to 10), and various paradigms of electrical stimulation. (B–D) Behavioral and GCaMP response to open-loop or cDBS applied immediately (cDBS-1h) and 3 h prior to and during (cDBS-3h) exposure to HF food. Time 0 in C represents feeding onset. (E and F) Behavioral and GCaMP response to closed-loop or rDBS applied immediately before (rDBS-1h) and 3 h prior to (rDBS-3h) exposure to HF food. Time 0 in F represents stimulation onset. (G) Success rates of rDBS-1h and rDBS-3h to block hedonic feeding behavior during limited HF food exposure. (H) The number of rDBS stimulation bouts during the 1-h HF exposure and 3-h prior without HF exposure are 74.83 ± 17.53 and 45.33 ± 9.83, respectively (29.00 ± 5.29 and 16.33 ± 4.67 for first and second hours without HF exposure, respectively). Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. ns, nonsignificant, P > 0.05. ¥, partial reinstatement of HF intake and calcium signal with cDBS-3h.