Figure 5. Acute manipulation of activity of vHIP-mPFC projection neurons regulates social memory in a task- and projection-specific manner.

(A) Experimental timeline for acute DREADD manipulation of the vHIP-mPFC projection. (B) Time spent following either familiar or novel mice in unrestricted social interaction, scored by JAABA (n = 8 vHIP-mPFC mCherry WT mice, p=0.0135 Student’s paired t-test; n = 10 vHIP-mPFC hM3Dq WT mice, p=0.6052 Student’s paired t-test; n = 10 vHIP-mPFC mCherry Mecp2 KO mice, p=0.9219 Wilcoxon paired test; n = 8 vHIP-mPFC hM4Di Mecp2 KO mice, p=0.0469 Wilcoxon paired test). (C) Schematic of novel object recognition test. (D) Time spent sniffing either the familiar or novel object, scored by JAABA (n = 8 vHIP-mPFC mCherry WT mice, p=0.006 Student’s paired t-test; n = 10 vHIP-mPFC hM3Dq WT mice, p=0.0266 Student’s paired t-test). (E) Schematic of CAV2-Cre and DREADD injections to manipulate the vHIP-NAc projection. Injection sites show sparse mCherry labeling of vHIP neurons with identifiable axons in the NAc. Time spent following either familiar or novel mice in unrestricted social interaction, scored by JAABA (n = 10 vHIP-NAc mCherry WT mice, p=0.0391 Wilcoxon paired test; n = 11 vHIP-NAc hM3Dq WT mice, p=0.0189 Student’s paired t-test). Mean ± SD; *p<0.05, **p<0.01. Figure 5—source data 1. See also Figure 5—figure supplement 1.

Figure 5—figure supplement 1. Lack of effects of Acute DREADD stimulation by CNO on anxiety and general (non-social memory) behaviors.

(A and C) Total times spent following novel vs.familiar sentinels in DREADDs expressed in mPFC-projecting vHIP neurons (A) or NAc-Projecting vHIP neurons (C). (B) Total times spent for sniffing novel vs. familiar objects in DREADDs expressed in mPFC-projecting vHIP neurons. (D) Representative tracks of individual trajectories of test mice during social encounters in an open field. (E) Average time spent in the center of the open field, as a measure of anxiety (mCherry mPFC vs. mPFC hM3Dq WT, p>0.9999; mCherry mPFC WT vs. Mecp2 KO, p=0.9937; hM3Dq WT mPFC vs. mCherry mPFC Mecp2 KO, p=0.9718; mCherry vs. hM4Di mPFC Mecp2 KO, p=0.8502; hM4Di mPFC Mecp2 KO vs. mCherry mPFC WT, p=0.9916; One-Way ANOVA). (F–H) Time spent engaging in social, aggressive, general, and locomotor behaviors during the unrestricted social interaction assay in (F) vHIP-mPFC DREADD-expressing WT mice, (G) and vHIP-mPFC Mecp2 KO mice (n = 10 vHIP-mPFC mCherry WT mice; n = 10 vHIP-mPFC hM3Dq WT mice; n = 11 vHIP-mPFC mCherry Mecp2 KO; n = 8 vHIP-mPFC hM4Di Mecp2 KO mice). (H) Time spent engaging in social, aggressive, general, and locomotor behaviors during the unrestricted social interaction assay in DREADD-expressing vHIP-NAc WT mice after acute CNO treatment (n = 8 vHIP-NAc mCherry WT mice; n = 10 vHIP-NAc hM3Dq WT mice; mCherry NAc vs. mCherry mPFC WT, p=0.9492; mCherry vs. hM3Dq NAc WT, p=0.9952; hM3Dq NAc WT vs. mCherry mPFC WT, p=0.9982; hM3Dq NAc WT vs. mCherry mPFC Mecp2 KO, p=0.9009; Student’s t-test or Mann-Whitney Test dependent on Normalcy). Mean ± SD; *p<0.05, **p<0.01.