Hypothalamic-amygdala gating of caregiving-like prosocial behavior in mice
Kai-Wen Geng, Rui-Rui Wang, Yan Yang, Yan Wang, Ting He, Chun-Li Li, Chong-Shun Xu, Jun Chen
Kai-Wen Geng, Rui-Rui Wang, Yan Yang, Yan Wang, Ting He, Chun-Li Li, Chong-Shun Xu, Jun Chen
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Research Article Cell biology Neuroscience

Hypothalamic-amygdala gating of caregiving-like prosocial behavior in mice

Abstract

Distress sharing within an ingroup instinctively motivates caregiving-like prosocial behavior in social animals and humans, yet how aversive social stimuli paradoxically trigger such behavior remains unclear. Here, we show that stress-state matching in observer mice elicits caregiving-like behaviors (allogrooming and injury-targeted allolicking) toward cagemates in pain, resulting in synchronized social buffering. Importantly, we identify that the excitation of vasopressin receptor 1a–expressing (V1aR-expressing) neurons in the central medial amygdala (CeM) underlies both emotional-state matching and subsequent allogrooming/allolicking. This excitation is accomplished by arginine vasopressin (AVP) release from presynaptic terminals of the hypothalamic paraventricular nucleus (PVN) to act specifically on postsynaptic V1aR in the CeM. The CeMV1aR neurons then project to the ventral tegmental area (VTA) to drive caregiving-like actions through positive reinforcement, manifested as prosocial preference and recurrent allogrooming/allolicking, and to produce anxiolysis in the caregiver. Collectively, we unravel a dedicated trisynaptic PVNAVP-CeMV1aR-VTA circuit driving and gating caregiving-like behaviors and advance the mechanistic understanding of AVP-V1aR signaling in prosociality.

Authors

Kai-Wen Geng, Rui-Rui Wang, Yan Yang, Yan Wang, Ting He, Chun-Li Li, Chong-Shun Xu, Jun Chen

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Figure 2

CeM V1aR is essential for caregiving-like behavior.

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CeM V1aR is essential for caregiving-like behavior. (A) Genotyping of V1...
(A) Genotyping of V1aRwt/wt (WT), V1aRnull/wt (HET), and V1aRnull/null (MUT) mice. (B and C) Relative V1aR mRNA expression in the brain (B) and liver (C) of WT, HET, and MUT mice. (D–F) Latency (D), duration (E), and bouts (F) of allogrooming/allolicking toward pain-suffering cagemates in V1aR WT versus V1aR MUT observers. (G) Plasma CORT levels of V1aR WT and V1aR MUT observers after exposure to naive or melittin-treated demonstrator in divider paradigm. (H–J) Heatmaps of locomotor activity (H), exploration time (I), and preference index (J) of both V1aR WT and V1aR MUT mice in social affective preference (SAP) test. (K and L) Schematic of brain c-Fos mapping (K) and heatmap of normalized fold change in c-Fos+ cells across brain regions in observers exposed to melittin-treated versus naive cagemates (L). (M and N) Representative c-Fos images (M) and quantification (N) in the CeA of observers interacting with naive versus melittin-treated cagemates. (O and P) Schematic of CeM injection with scramble or V1aR siRNA (left), followed by measurements of V1aR mRNA expression (O) and statistics (P). (Q–S) Latency (Q), duration (R), and bouts (S) of allogrooming/allolicking in control and CeM V1aR knockdown observers toward pain-suffering cagemates. (T) Plasma CORT levels of control and CeM V1aR knockdown mice after 25–30 minutes social exposure to melittin-treated demonstrators in divider paradigm. (U–W) Heatmaps of locomotor activity (U), exploration time (V), and preference index (W) of control and CeM V1aR knockdown mice in SAP test. Scale bars: 100 μm (original), 50 μm (magnified) in M and O. Data are mean ± SEM. All mice are male. Exact n values are indicated in the figure. Statistical results are included in Supplemental Table 2. ACC, anterior cingulate cortex; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; CeC, central capsular amygdala; CeL, central lateral amygdala; CeM, central medial amygdala; Hippo, hippocampus; IC, insular cortex; NAc, nucleus accumbens; PAG, periaqueductal gray; PrL, prelimbic cortex; PVN, hypothalamic paraventricular nucleus; VTA, ventral tegmental area. M, melittin; N, naive. SAP test, social affective preference test. One-way ANOVA with Tukey test multiple comparisons for B and C; Mann Whitney U test for D and F; 2-way ANOVA with Tukey’s multiple comparisons for G; Paired t test for I and V; Unpaired t test for J, N, P, S, T and W; Unpaired t test with Welch’s correction for E, Q, and R.