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 8

VTA-projecting CeMV1aR neurons promote caregiving-like behavior.

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VTA-projecting CeMV1aR neurons promote caregiving-like behavior. (A) Sch...
(A) Schematic of CeM injections and VTA fiber implantations (left), and a representative image showing eNpHR3.0-mCherry expression (right) in the VTA. (B) Whole-cell voltage clamp showing light-mediated silencing of CeMV1aR neurons by eNpHR3.0. (C) Schematic for opto-inhibition during caregiving-like behavior test. (D–F) Latency (D), duration (E), and bouts (F) of allogrooming/allolicking toward pain-suffering cagemates under opto-inhibition in the VTA of mCherry and eNpHR3.0 mice. (G) Schematic of CeM injections and VTA fiber implantations (left), and a representative image showing ChR2-eYFP expression (right) in the VTA. (H and I) Probability (H) and duration (I) of evoked allogrooming/allolicking toward naive or melittin-treated cagemates during VTA opto-activation (17 s) in eYFP versus ChR2 mice. (J) Percentage of trials in each eYFP and ChR2 mice with evoked allogrooming/allolicking during VTA opto-activation. (K) Schematic and a representative image showing the viral injection, cannula, and fiber implantations in the CeA and VTA, respectively. (L and M) Probability (L) and duration (M) of evoked allogrooming/allolicking toward melittin-treated cagemates during VTA opto-activation (17 s) in ChR2 mice with preapplication of saline or lidocaine in the CeA. (N) Percentage of trials in each ChR2 mouse with evoked allogrooming/allolicking during VTA opto-activation with preapplication of saline or lidocaine in the CeA. (O) Allogrooming/allolicking time toward melittin-treated cagemates with preapplication of saline or lidocaine in the CeA during 60-minute prosocial interaction. (P) The setup of RTPP test. (Q and R) Heatmaps (20 Hz) of locomotor activity (Q) and percentage of time spent in the chamber paired with opto-activation (R) in the RTPP test. (S) Experimental design. Divider paradigm allows visual/olfactory/auditory exposure but bodily untouchable between the observer and demonstrator (which is either naive or melittin-treated). Timeline of the experiment: during the social interaction, CeMV1aR-VTA projection was optogenetically activated (or not activated) in observer mice expressing either ChR2 (experimental group) or eYFP (control group). Following the behavioral test, blood was collected from all observer mice for ELISA measurement. (T) Plasma CORT levels in eYFP and ChR2 observers after 25-minute social interaction in divider paradigm. Observer mice were exposed to either naive or melittin-treated cagemates, and CeMV1aR-VTA projection was optogenetically activated or not activated during the interaction. Scale bars: 100 μm (G), 200 μm (A). All mice are male. n = 48–114 trials from 4–5 mice in H–J and L–O. Other n values are indicated in the figure. Statistical results are included in Supplemental Table 2. Mean ± SEM in D–F, J, N, O, R, and T. Box and whiskers (center line, median; box limits, quartiles; whiskers, 1.5 × interquartile range; points, outliers) in I and M. Unpaired t test for E, F, R, and T (eYFP/Melittin/Laser versus ChR2/Melittin/Laser; eYFP/Naive/No laser versus ChR2/Naive/No laser); Unpaired t test with Welch’s correction for D; Kruskal-Wallis test with Dunn’s multiple comparisons for I; 2-way ANOVA with Tukey’s multiple comparisons for J; Wilcoxon matched-pairs test for M; Paired t test for N, O, and T (ChR2/Melittin/Laser versus ChR2/Naive/No laser).