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.2014 Jun 3;111(22):8245-50.
doi: 10.1073/pnas.1407395111. Epub 2014 May 19.

Differential roles of the dopamine 1-class receptors, D1R and D5R, in hippocampal dependent memory

Affiliations

Differential roles of the dopamine 1-class receptors, D1R and D5R, in hippocampal dependent memory

Joshua Sariñana et al. Proc Natl Acad Sci U S A..

Abstract

Activation of the hippocampal dopamine 1-class receptors (D1R and D5R) are implicated in contextual fear conditioning (CFC). However, the specific role of the D1R versus D5R in hippocampal dependent CFC has not been investigated. Generation of D1R- and D5R-specific in situ hybridization probes showed that D1R and D5R mRNA expression was greatest in the dentate gyrus (DG) of the hippocampus. To identify the role of each receptor in CFC we generated spatially restricted KO mice that lack either the D1R or D5R in DG granule cells. DG D1R KOs displayed significant fear memory deficits, whereas DG D5R KOs did not. Furthermore, D1R KOs but not D5R KOs, exhibited generalized fear between two similar but different contexts. In the familiar home cage context, c-Fos expression was relatively low in the DG of control mice, and it increased upon exposure to a novel context. This level of c-Fos expression in the DG did not further increase when a footshock was delivered in the novel context. In DG D1R KOs, DG c-Fos levels in the home cage was higher than that of the control mice, but it did not further increase upon exposure to a novel context and remained at the same level upon a shock delivery. In contrast, the levels of DG c-Fos expression was unaffected by the deletion of DG D5R neither in the home cage nor upon a shock delivery. These results suggest that DG D1Rs, but not D5Rs, contribute to the formation of distinct contextual representations of novel environments.

Keywords: Pavlovian fear conditioning; dopamine 1 receptor; dopamine 5 receptor; memory generalization.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Characterization of forebrain D1R/5R KO mice. (A andB) D1R mRNA expression in flx mice. (C andD) D5R mRNA expression in flx mice. (E andF) D1R mRNA expression in D1R/5R KO mice. (G andH) D5R mRNA expression in D1R/5R KO mice. (I andJ) Quantification of the D1R (DG flx and KO,n = 8; basal ganglia flx and KO,n = 5;I) and D5R mRNA (flx and KO,n = 8 for all subregions;J) signal in D1R/5R KO mice. (K) mPP-DG input–output curve (flx,n = 6; KOn = 9). (L)l-LTP at the mPP-DG synapse (flx,n = 6; KO,n = 8). (M) The 24-h contextual fear memory test (flx,n = 10; KO,n = 11). (N) Average ofL. CP, caudate/putamen; CTX, cortex; NAcc, nucleus accumbens; OLB, olfactory bulb; OT, olfactory tubercle.
Fig. 2.
Fig. 2.
Characterization of DG-specific D1R and D5R KO lines. (A andB) D1R mRNA expression in D1 KO line. (C) D5R mRNA expression in D1 KO line. (D andE) Quantification of D1R (flx,n = 4; KO,n = 4;D) and D5R mRNA (flx,n = 4; KO,n = 3;E) expression in the DG. (F andG) D5R mRNA expression in D5 KO line. (H) D1R mRNA expression in D5 KO line. (I andJ) Quantification of D5R (flx and KO,n = 4 for all subregions;I) and D1R mRNA (flx,n = 4; KO,n = 4;J) expression in the DG. (K) D1R KO line, contextual fear memory test (flx,n = 51; KO,n = 40). (L andM) D1R KO line, quantification of c-Foc+ neurons in the DG (L) and CA3 (M) neurons (DG and CA3; HC flx and KO,n = 3; CTX flx and KO,n = 5; FC flx and KO,n = 4). (N) DG D5R KO line, contextual fear memory test (flx,n = 9; KO,n = 11). (O andP) D5R KO line, quantification of c-Foc+ neurons in the DG (O) and CA3 (P) neurons (DG and CA3; HC flx,n = 3; KO,n = 2; FC flx and KO,n = 3). CTX, context exposure; FC, fear conditioning; HC, home cage.
Fig. 3.
Fig. 3.
Contextual shift design task. (A) Schematic of training and testing schedule. (B) Contextual fear memory test in training context and nontraining context (flx = 20, KO = 17).
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