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Peer-reviewed journal article

A Hypothalamic Circuit Underlying the Dynamic Control of Social Homeostasis

Ding LiuiD, Mostafizur Rahman, Autumn JohnsoniD, Ryunosuke AmoiD, Iku Tsutsui‐KimuraiD, Zuri A. SullivaniD, Nicolai Pena, Mustafa TalayiD, Brandon L. LogemaniD, Samantha FinkbeineriD, Lechen QianiD, Seungwon ChoiiD, Athena Capo-Battaglia, Ishmail Abdus-SabooriD, David D. GintyiD, Naoshige UchidaiD, Mitsuko Watabe‐UchidaiD, Catherine G. DulaciD

Abstract

Social grouping increases survival in many species, including humans1,2. By contrast, social isolation generates an aversive state (loneliness) that motivates social seeking and heightens social interaction upon reunion3-5. The observed rebound in social interaction triggered by isolation suggests a homeostatic process underlying the control of social drive, similar to that observed for physiological needs such as hunger, thirst or sleep3,6. In this study, we assessed social responses in multiple mouse strains and identified the FVB/NJ line as exquisitely sensitive to social isolation. Using FVB/NJ mice, we uncovered two previously uncharacterized neuronal populations in the hypothalamic preoptic nucleus that are activated during social isolation and social rebound and that orchestrate the behavior display of social need and social satiety, respectively. We identified direct connectivity between these two populations of opposite function and with brain areas associated with social behavior, emotional state, reward, and physiological needs, and showed that animals require touch to assess the presence of others and fulfill their social need, thus revealing a brain-wide neural system underlying social homeostasis. These findings offer mechanistic insight into the nature and function of circuits controlling instinctive social need and for the understanding of healthy and diseased brain states associated with social context.

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Claude Sonnet 4.6 · xhigh effort · 8 Nov 2026 · from the full text of version 1 (19 May 2023) · CC BY 4.0

Opposing glutamatergic MPN Isolation and mostly GABAergic MPN Reunion neurons in the mouse preoptic hypothalamus encode social need and satiety, with touch as a likely cue.

Social isolation drives a rebound in interaction that resembles hunger or thirst, yet the brain response to isolation and the circuits behind this rebound were unresolved. This work identifies genetically defined hypothalamic populations, maps their brain-wide connectivity, and implicates touch as a likely sensory cue.

Key results

  1. ShownFVB/NJ females showed the strongest social rebound among six strains tested. Rebound grew with isolation duration and did not track reported stress sensitivity of each strain.

    Rebound was absent or weak in BALB/c and DBA, moderate in C57BL/6J, C3H/HeJ and SWR/J. Group sizes were 4 to 7 mice per strain (FVB/NJ n=7); Friedman test against baseline. · Social rebound as a behavioral manifestation of…; Figure legends

  2. ShownMicroendoscopy and Fos mapping defined two largely non-overlapping MPN populations: glutamatergic Isolation neurons (matched to MERFISH cluster E8) and mostly GABAergic Reunion neurons (cluster I11, Trhr-enriched).

    Isolation 26 ± 4% and Reunion 74 ± 4% of responsive neurons; Mc4r+ neurons 67 ± 8% reunion-inhibited (~2.5-fold enrichment); 78 modulated neurons pooled from 3 mice; ~80% of Reunion neurons Slc32a1+. · Identification of candidate neurons underlying…; Figure legends

  3. ShownOptogenetic activation of MPN Isolation neurons drove social interaction in group-housed mice and place avoidance, while inhibition reduced social rebound and preference after isolation.

    Activation n=10 (real-time interaction), n=8 (three-chamber, place preference), n=11 (pre-reunion); inhibition n=8 (reunion), n=7 (three-chamber); the legend lists Wilcoxon signed-rank tests for panels e to i, with *P<0.05, **P<0.01. · Functional characterization of MPNIsolation…; Figure legends

  4. SuggestedMPN Reunion neurons appear to act as a satiety signal: tracing and Fos overlap suggest they synapse onto Isolation neurons, their activation lowers rebound and is rewarding, and reunion elicits dopamine release in NAc.

    Activation after isolation n=6 reduced rebound; place preference n=7; rabies tracing found 12 input areas; reunion-Fos overlap with presynaptic cells n=4; NAc dopamine signal n=3. Inhibition did not raise rebound (n=8). · MPNReunion neurons and the modulation of social…; Figure legends

  5. SuggestedTouch emerged as the likely social-context cue. Divider-separated and Trpc2-/- mice still showed rebound, whereas isoguvacine prolonged it and Mrgprb4 ablation slightly reduced it. Cloth-tunnel crossing lowered rebound and modulated both MPN populations.

    Cloth-tunnel crossing n=12 lowered rebound vs naked tunnel; isoguvacine n=7; Trpc2-/- n=5; over 90% of Isolation neurons inhibited and ~35% of Reunion neurons excited during crossing, n=2 mice. · Sensory basis of social need and social satiety; Figure legends

Methods, data and reproducibility

Behavioral screening of six mouse strains for social rebound, then microendoscopy calcium imaging, Fos/TRAP2 activity labeling with in situ hybridization, intersectional optogenetics, viral tracing, fiber photometry and touch manipulations in FVB/NJ females.

  • Isolation/reunion screening of six strains in adult female mice · mouse · n = 4 to 7 mice per strain; FVB/NJ 7
  • Pan-neuronal MPN microendoscopy calcium imaging in FVB/NJ mice · mouse · n = 3 mice
  • MPN Mc4r+ calcium imaging in Mc4r-Cre/FVB mice · mouse · n = 3 mice; 78 modulated neurons
  • Fos in situ hybridization with 20 marker genes defining 14 MPN populations · mouse · n = n=3-6 per marker gene
  • Optogenetic activation/inhibition cohorts for Isolation and Reunion neurons · mouse · n = n=6 to 11 per experiment
  • Monosynaptic rabies input tracing and NAc dopamine photometry (GRABDA2m) · mouse · n = input overlap n=4; photometry n=3
  • Touch assays: cloth vs naked tunnel preference and crossing · mouse · n = n=12
Methods & tools
Inscopix IDPS 1.8.0.3519, CNMFe, DeepLabCut, DeepSqueak, Noldus Observer XT 11, MATLAB, GraphPad Prism 9, QuPath 0.3.2, RNAscope V2, TRAP2/Ai9 activity labeling, GRABDA2m dopamine sensor, MERFISH preoptic atlas
Code
https://github.com/DulacLabHarvard/SocialNeedhttps://github.com/zhoupc/CNMF_E
Data & accessions
https://github.com/DulacLabHarvard/SocialNeed
Software & environment
IDPS 1.8.0.3519, QuPath 0.3.2, GraphPad Prism 9, Observer XT 11, Zen Blue 3.5, MATLAB; CNMFe parameters listed in methods.
Reproducibility gaps
Some data only in figures or on request from the corresponding author; custom MATLAB analysis code also available on request; no raw imaging accession given.
Limitations (5)
  • Inhibiting MPN Reunion neurons did not further raise rebound, possibly from incomplete TRAP capture or other satiation mechanisms. · stated by the authors
  • Mrgprb4 neuron ablation gave only a modest rebound reduction, implicating other mechanosensory populations that were not identified. · stated by the authors
  • Visual cues were not tested because FVB mice go blind, and a single microphone could not attribute ultrasonic vocalizations to a mouse. · stated by the authors
  • Imaging evidence rests on few animals (3 mice for MPN imaging, 2 for tunnel crossing); only adult females were studied, limiting generalization to males. · noted in this summary
  • Touch conclusions rely on a systemic peripherally restricted drug and a partial ablation with F1 hybrid controls; selective, circuit-specific touch manipulation was not performed. · noted in this summary

Who should read:Read this if you study hypothalamic circuits for motivated behavior, social isolation, or the sensory basis of social drive and want circuit-level evidence linking touch to homeostasis.

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