Inducing Partner Preference in Mice by Chemogenetic Stimulation of CA2 Hippocampal Subfield

Abstract

Social recognition is fundamental for social decision making and the establishment of long-lasting affiliative behaviors in behaviorally complex social groups. It is a critical step in establishing a selective preference for a social partner or group member. C57BL/6J lab mice do not form monogamous relationships, and typically do not show prolonged social preferences for familiar mice. The CA2 hippocampal subfield plays a crucial role in social memory and optogenetic stimulation of inputs to the dorsal CA2 field during a short memory acquisition period can enhance and extend social memories in mice. Here, we show that partner preference in mice can be induced by chemogenetic selective stimulation of the monosynaptic projections from the hypothalamic paraventricular nucleus (PVN) to the CA2 during the cohabitation period. Specifically, male mice spend more time in social contact, grooming and huddling with the partner compared to a novel female. Preference was not induced by prolonging the cohabitation period and allowing more time for social interactions and males to sire pups with the familiar female. These results suggest that PVN-to-CA2 projections are part of an evolutionarily conserved neural circuitry underlying the formation of social preference and may promote behavioral changes with appropriate stimulation.

Keywords: PVN; chemogenetic; dCA2; mice; partner preference.

Figure 1

Representative viral labeling. (A) Diagram illustrating the viral delivery to dorsal CA2 and subsequent expression in CA2 fibers and paraventricular hypothalamic nucleus (PVN) cells and then their fibers with cannulation for CNO delivery into PVN. (B) Coronal section showing the expression of immunoreactive fibers in the hippocampus projecting to dorsal CA2 (scale bar 200 μm). (C) Sixteen micrometer coronal section showing sparse cell labeling in the PVN (scale bar 20 μm).

Figure 2

Partner preference induced by CNO treatment. (A) Schematic illustration of partner preference test. Tested mice freely explored the chambers while stimulus females were tethered (PVN^Gq+CNO mice = 8, PVN^mCherry+CNO mice = 9). (B) PVN^mCherry+CNO mice spent equal time in contact with their partner or the stranger, while PVN^Gq+CNO mice demonstrated a significantly longer time in contact with their partner (*P < 0.02). (C) PVN^Gq+CNO mice spent significantly longer time allogrooming their partners, while the PVN^mCherry+CNO group did not (**P < 0.0045). (D) PVN^Gq+CNO mice spent significantly longer in side-by-side contact (“huddling”) with their partners, while the PVN^mCherry+CNO did not (**P < 0.002).

Figure 3

Social behaviors are unchanged by CNO treatment. (A) Sniffing duration of either the partner or stranger were similar within and across the tested groups. (B) Mice spent similar times in the chambers of the partner or the stranger conspecific in both groups as well as extensive time in the empty center chamber.

Figure 4

The extended cohabitation period did not induce partner preference. Mice (n = 6) did not show preference in sniffing (A), proximity (B) or side-by-side contact (C).