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Dopamine D2 Receptor-Mediated Circuit from the Central Amygdala to the Bed Nucleus of the Stria Terminalis Regulates Impulsive Behavior

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Dopamine D2 Receptor-Mediated Circuit from the Central Amygdala to the Bed Nucleus of the Stria Terminalis Regulates Impulsive Behavior Dopamine D2 receptor-mediated circuit from the central amygdala to the bed nucleus of the stria terminalis regulates impulsive behavior Bokyeong Kima,1, Sehyoun Yoona,1, Ryuichi Nakajimab,1, Hyo Jin Leea, Hee Jeong Lima, Yeon-Kyung Leec, June-Seek Choic, Bong-June Yoona, George J. Augustineb,d,e, and Ja-Hyun Baika,2 aDivision of Life Sciences, School of Life Sciences and Biotechnology, Korea University, 02841 Seoul, Republic of Korea; bCenter for Functional Connectomics, Korea Institute of Science and Technology, 02792 Seoul, Republic of Korea; cDepartment of Psychology, Korea University, 02841 Seoul, Republic of Korea; dLee Kong Chian School of Medicine, Nanyang Technological University, 637553 Singapore; and eInstitute of Molecular and Cell Biology, 138673 Singapore Edited by Richard D. Palmiter, University of Washington, Seattle, WA, and approved September 24, 2018 (received for review July 10, 2018) Impulsivity is closely associated with addictive disorders, and has been suggested that D2Rs in the CeA might modulate such changes in the brain dopamine system have been proposed to behavior (22–24). affect impulse control in reward-related behaviors. However, the In the present study, we aimed to elucidate the role of D2Rs central neural pathways through which the dopamine system within the CeA in the control of impulsive behavior. Our genetic, controls impulsive behavior are still unclear. We found that the anatomical, and optogenetic manipulations reveal that D2R, act- absence of the D2 dopamine receptor (D2R) increased impulsive ing on CeA inhibitory projection neurons, regulates impulsivity. behavior in mice, whereas restoration of D2R expression specifi- −/− cally in the central amygdala (CeA) of D2R knockout mice (Drd2 ) Results normalized their enhanced impulsivity. Inhibitory synaptic output D2R Expression in the CeA Modulates Impulsivity. We examined − − from D2R-expressing neurons in the CeA underlies modulation of impulsive behavior in wild-type (WT) and Drd2 / mice by using − − impulsive behavior because optogenetic activation of D2R-positive a five-choice serial reaction time task (5-CSRTT) (25). Drd2 / inhibitory neurons that project from the CeA to the bed nucleus of mice showed a significantly higher (**P < 0.01) percentage of NEUROSCIENCE the stria terminalis (BNST) attenuate such behavior. Our identifi- premature responses (Fig. 1B), indicative of impulsivity, as well cation of the key contribution of D2R-expressing neurons in the as a higher rate of response omission (Fig. 1B; ***P < 0.001) and CeA → BNST circuit to the control of impulsive behavior reveals a reduced accuracy (Fig. 1B; ***P < 0.001) compared with WT mice pathway that could serve as a target for approaches to the man- (n = 7). These data indicate that the absence of D2R increases agement of neuropsychiatric disorders associated with impulsivity. impulsive behavior but also causes a deficit in attentional performance. Because impulsive behavior is often associated with compul- dopamine receptor | impulsivity | central amygdala | neural circuit | sive behavior (1, 26), we examined whether the high impulsivity of − − optogenetics Drd2 / mice was associated with compulsive eating behavior. Food was offered in the aversive, bright compartment of a light/dark box mpulsive behavior—the tendency to act in premature, risky, or Iinappropriate ways, without consideration of the consequences— Significance is often associated with psychiatric conditions such as drug addic- tion, as well as eating and personality disorders (1–4). Increasing Impulsivity is a tendency to act with little or no forethought or evidence from both human and animal studies suggests the im- consideration of the consequences and is a major component portance of dopaminergic regulation in the pathophysiology of of various psychiatric disorders. However, little is known about impulsive behavior (3, 5–7). Prior human studies indicated that the brain circuits that regulate reward-related impulsivity. Our highly impulsive individuals are characterized by diminished mid- genetic manipulations reveal that dopamine D2 receptors in brain dopamine (DA) D2/D3 autoreceptor availability, which leads to the central nucleus of the amygdala have a crucial role in enhanced DA cell firing and potentiated DA release in terminal fields reward-related impulsive behavior. By using optogenetics to following exposure to novel, salient, or rewarding stimuli (7–9). control the neurons that possess these receptors, we have Moreover, polymorphisms of the D2 DA receptor (DRD2)genein identified elements of a neural circuit that contributes to reg- humans have been linked to impulsivity in association with reward- ulating impulsivity. This information should enable approaches related behavior such as substance abuse and food addiction (10–12). to managing impulsivity associated with neuropsychiatric dis- In rodents, it has been reported that D2/D3 dopamine re- orders such as attention-deficit/hyperactivity disorder, bipolar ceptors (D2/D3Rs) in the nucleus accumbens (NAc) predict trait disorder, and addiction-related disorders. impulsivity and cocaine reinforcement (5). Furthermore, several investigations based on pharmacological manipulations of D2Rs Author contributions: G.J.A. and J.-H.B. designed research; B.K., S.Y., R.N., H. J. Lee, H. J. Lim, Y.-K.L., J.-S.C., and J.-H.B. performed research; H. J. Lee, Y.-K.L., J.-S.C., and demonstrated the control of impulsivity mediated by D2R (13, B.-J.Y. contributed new reagents/analytic tools; B.K., S.Y., R.N., H. J. Lim, B.-J.Y., 14). However, these experiments could not clearly distinguish the G.J.A., and J.-H.B. analyzed data; and B.K., S.Y., R.N., G.J.A., and J.-H.B. wrote effects of stimulation and inhibition of D2R and D3R. More- the paper. over, the complex nature of impulsivity has impeded character- The authors declare no conflict of interest. ization of its neural correlates. This article is a PNAS Direct Submission. The amygdala is implicated in the control of impulsivity, with This open access article is distributed under Creative Commons Attribution-NonCommercial- human brain-imaging studies suggesting that changes to the NoDerivatives License 4.0 (CC BY-NC-ND). amygdala system and its connectivity produce higher impulsivity 1B.K., S.Y., and R.N. contributed equally to this work. (15–17), possibly reflecting a neural mechanism for addictive be- 2To whom correspondence should be addressed. Email: [email protected]. havior. The central nucleus of the amygdala (CeA) plays a key role This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. in the integration of fear- and anxiety-relevant information. This 1073/pnas.1811664115/-/DCSupplemental. nucleus also contributes to reward-related behavior (18–21), and it www.pnas.org/cgi/doi/10.1073/pnas.1811664115 PNAS Latest Articles | 1of10 Downloaded by guest on September 25, 2021 Fig. 1. D2R expression in the CeA modulates impulsivity. (A) Experimental scheme of the 5-CSRTT. BW, body weight; SD, stimulus duration. (B) Percentage − − omission, accuracy, and premature response, respectively, in the 5-CSRTT (ITI, 10 s; SD, 1 s) for WT (n = 7) and Drd2 / (n = 7) mice. (C) Schematic for the lenti- shD2R vector (Top Right); injection site (Left, white rectangle) in the CeA shown in a brain section stained with 4′,6-diamidino-2-phenylindole (DAPI) (blue) and EGFP fluorescence (green) in the CeA of a mouse injected with Lenti-shD2R (Bottom Right, n = 9). U6 and CMV indicate U6 and cytomegalovirus pro- moters, respectively. BLA, basolateral amygdala. (Scale bars, 200 μm.) (D) RT-PCR analysis of Drd2 mRNA in the CeA and dorsal striatum (n = 6) of WT mice injected in the CeA with lenti-shD2R (n = 7) or a control virus (Mock, n = 6) as well as densitometric quantification of the relative amount of the D2R amplicon. ***P < 0.001, One-way ANOVA. (E) Percentage omission, accuracy, and premature response, respectively, in the 5-CSRTT for WT mice injected in the CeA with lenti-shD2R − − (n = 9) or a control virus (n = 9). (F) Immunohistochemical analysis of D2R in the brain of a WT mouse (Left)orofDrd2 / mice injected with AAV-GFP (n = 8) or AAV-D2R (n = 8) into the CeA (Middle and Right, respectively). [Scale bar, 1 mm (black).] [Scale bar, 500 μm(white).](G) RT-PCR analysis of Drd2 mRNA in the CeA − − of Drd2 / mice injected as in D.(H) Percentage omission, accuracy, and premature response, respectively, in the 5-CSRTT for WT mice injected with AAV-GFP (n = 8) or Drd2−/− mice injected with AAV-GFP (n = 8) or AAV-D2R (n = 8). All values are represented as mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001 versus WT with unpaired Student’s t test (B and E)andwith**P < 0.01, ***P < 0.001 versus WT/AAV-GFP; ††P < 0.01 with one-way ANOVA followed by Bonferroni test (H). − − (26, 27) consisting of a large white chamber (∼500 lx) that was pretest without food was performed on WT and Drd2 / mice for connected to a dark (∼5 lx) closed chamber (SI Appendix,Fig.S1A 15 min to determine the time spent in the light and dark chambers. and B). After measuring initial body weight and food intake, a Mice were then divided into two groups: one group was allowed to 2of10 | www.pnas.org/cgi/doi/10.1073/pnas.1811664115 Kim et al. Downloaded by guest on September 25, 2021 eat only normal chow (NC) while the other group was given pal- colocalized with Cre immunoreactivity in the CeA, indicating se- atable food (PF) for 14 d. Mice were then returned to the light/dark lective expression of ChR2 in D2R-expressing neurons (Fig. 2B). box for 15 min to measure compulsive eating behavior by providing We observed that 84.8 ± 2.5% of Cre-positive neurons in the CeA PF in the light compartment (Test, SI Appendix,Fig.S1A and B). also expressed ChR2-eYFP, while 89.5 ± 4.1% of ChR2-expessing Overall, mice spent more time in the light compartment compared neurons in the CeA were also Cre-positive (Fig.
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