Preoptic Hypothalamic Neurons Promote Social Behavior in Mice Following Short-term Social Isolation in a Sex- and Context-Dependent Manner

Core Concepts

A population of preoptic hypothalamic neurons, termed POAiso neurons, increases its activity in single-housed female and male mice following same-sex and opposite-sex social interactions, respectively, and this neuronal activity contributes to the effects of short-term social isolation on social behaviors in a sex- and context-dependent manner.

Abstract

The study identifies a population of neurons in the preoptic area (POA) of the hypothalamus, termed POAiso neurons, that increase their activity in single-housed female mice following same-sex social interactions. Chemogenetic silencing of these POAiso neurons attenuates the effects of short-term social isolation on female social behaviors, reducing social investigation, ultrasonic vocalizations (USVs), and mounting. In contrast, permanent ablation of POAiso neurons selectively reduces mounting behavior in single-housed females without affecting social investigation or USVs. Optogenetic activation of POAiso neurons in group-housed females promotes USV production, but does not recapitulate the full effects of short-term isolation on female social behaviors. The study further extends these findings to male mice, showing that a similar population of POA neurons increases its activity in single-housed males following opposite-sex, but not same-sex, social interactions. Chemogenetic silencing of these POAiso neurons in single-housed males tends to reduce mounting, but does not affect social investigation or USV production. These results identify a population of hypothalamic neurons that promote social behavior following short-term isolation in a sex- and social context-dependent manner. The POA appears to play a key role in regulating various aspects of social behavior, including social investigation, vocalizations, and mounting, with distinct subsets of POA neurons potentially contributing to the regulation of these different social behaviors.

Stats

Single-housed female mice spent more time investigating female visitors compared to group-housed females. Single-housed female mice exhibited more mounting behavior towards female visitors, which was never observed in group-housed females. Pairs containing single-housed female residents produced higher rates of ultrasonic vocalizations (USVs) compared to pairs with group-housed female residents. Single-housed males spent more time investigating both female and male visitors compared to group-housed males. Single-housed males spent more time mounting female visitors compared to group-housed males, but there was no difference in mounting during same-sex interactions. Pairs containing single-housed male residents produced higher rates of USVs compared to pairs with group-housed male residents, but only during interactions with female visitors.

Quotes

"Humans and other social mammals find social interactions rewarding and are highly motivated to seek out social connections. Consequently, the experience of social isolation is aversive and impacts both our brains and our behaviors." "Beyond its effects on mesolimbic circuits, whether social isolation acts on additional neuronal populations to promote social interaction is unknown." "Optogenetic activation of POAiso neurons elicits USV production in group-housed females, particularly when female subjects are engaged in interactions with female visitors, but otherwise fails to recapitulate the effects of short-term isolation on the social behaviors of female mice."

Key Insights Distilled From

Short-term social isolation acts on hypothalamic neurons to promote social behavior in a sex- and context-dependent manner

by Zhao,X., Cha... at www.biorxiv.org 11-21-2023

https://www.biorxiv.org/content/10.1101/2023.11.20.567901v2

Deeper Inquiries

How do the POAiso neurons identified in this study interact with and influence other brain regions and circuits known to regulate social behavior, such as the mesolimbic dopamine system

In the study, the POAiso neurons identified play a crucial role in regulating social behavior by interacting with and influencing other brain regions and circuits, such as the mesolimbic dopamine system. The mesolimbic circuits are known to be involved in the regulation of social motivation and social reward during social interactions. These circuits, including the ventral tegmental area (VTA) and the nucleus accumbens (NAc), are key components of the brain's reward system and play a significant role in processing social stimuli and reinforcing social behaviors. The POAiso neurons likely interact with the mesolimbic dopamine system by sending projections to these regions or receiving inputs from them. Activation of POAiso neurons may lead to the release of neurotransmitters or neuromodulators that modulate the activity of dopaminergic neurons in the VTA, thereby influencing social motivation and reward processing. Additionally, the POAiso neurons may also communicate with other brain regions involved in social behavior, such as the amygdala and prefrontal cortex, to coordinate social responses and behaviors.

What are the molecular and genetic signatures of the POAiso neurons, and how do they compare to other genetically-defined subsets of POA neurons that have been implicated in the regulation of social and sexual behaviors

The molecular and genetic signatures of the POAiso neurons identified in the study provide insights into their identity and potential functions compared to other genetically-defined subsets of POA neurons implicated in the regulation of social and sexual behaviors. The POAiso neurons are characterized by their increased activity following same-sex social interactions in single-housed female mice. They are predominantly GABAergic neurons, as indicated by the co-expression of vesicular GABA transporter (VGAT) mRNA. This neurotransmitter phenotype suggests that POAiso neurons utilize GABA as their primary neurotransmitter to modulate neural activity and communication within neural circuits regulating social behavior. In comparison to other genetically-defined subsets of POA neurons, such as Esr1+ neurons or Calcr-expressing neurons, the POAiso neurons exhibit a distinct pattern of activation and functional effects on social behavior. While Esr1+ neurons have been implicated in the regulation of male mounting behavior and USV production, and Calcr-expressing neurons have been associated with social-seeking behaviors in females, the POAiso neurons identified in this study specifically promote social investigation, mounting, and USV production in single-housed female mice following short-term isolation. This suggests that the POAiso neurons represent a unique population within the POA that plays a specialized role in mediating the effects of social isolation on female social behavior.

Given the context-dependent effects of short-term social isolation on male social behavior, what are the underlying neural mechanisms that allow the POA to differentially regulate social behaviors in males depending on the sex of the social partner

The context-dependent effects of short-term social isolation on male social behavior, as observed in the study, highlight the underlying neural mechanisms that allow the POA to differentially regulate social behaviors in males based on the sex of the social partner. The POAiso neurons identified in the study exhibit increased activity in single-housed males following interactions with female visitors but not with male visitors. This differential activation pattern suggests that the POAiso neurons are sensitive to the social context and the presence of opposite-sex conspecifics, leading to changes in male social behavior. The underlying neural mechanisms that enable the POA to regulate social behaviors in males depending on the sex of the social partner may involve the integration of sensory information, hormonal signals, and social cues. The POAiso neurons likely receive inputs from sensory pathways conveying information about the sex and identity of social partners, as well as hormonal signals that fluctuate in response to social interactions. By integrating these inputs and modulating their activity, the POAiso neurons can selectively influence male social behaviors, such as social investigation, mounting, and USV production, in a context-specific manner. Additionally, the interactions between the POAiso neurons and other brain regions involved in social behavior, such as the amygdala and hypothalamus, may further contribute to the regulation of male social behaviors in response to social isolation and social interactions with different sexes.