Published October 24, 2024 | Version Published
Journal Article Open

Causal evidence of a line attractor encoding an affective state

  • 1. ROR icon California Institute of Technology
  • 2. ROR icon Howard Hughes Medical Institute
  • 3. ROR icon Stanford University

Abstract

Continuous attractors are an emergent property of neural population dynamics that have been hypothesized to encode continuous variables such as head direction and eye position. In mammals, direct evidence of neural implementation of a continuous attractor has been hindered by the challenge of targeting perturbations to specific neurons within contributing ensembles. Dynamical systems modelling has revealed that neurons in the hypothalamus exhibit approximate line-attractor dynamics in male mice during aggressive encounters. We have previously hypothesized that these dynamics may encode the variable intensity and persistence of an aggressive internal state. Here we report that these neurons also showed line-attractor dynamics in head-fixed mice observing aggression. This allowed us to identify and manipulate line-attractor-contributing neurons using two-photon calcium imaging and holographic optogenetic perturbations. On-manifold perturbations yielded integration of optogenetic stimulation pulses and persistent activity that drove the system along the line attractor, while transient off-manifold perturbations were followed by rapid relaxation back into the attractor. Furthermore, single-cell stimulation and imaging revealed selective functional connectivity among attractor-contributing neurons. Notably, individual differences among mice in line-attractor stability were correlated with the degree of functional connectivity among attractor-contributing neurons. Mechanistic recurrent neural network modelling indicated that dense subnetwork connectivity and slow neurotransmission best recapitulate our empirical findings. Our work bridges circuit and manifold levels, providing causal evidence of continuous attractor dynamics encoding an affective internal state in the mammalian hypothalamus.

Copyright and License

© The Author(s)

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Acknowledgement

We thank B. Yang for help in miniscope imaging and initial construct of the ChRmine plasmid and for his feedback; I. Landau and H. Inagaki for feedback; T. Karigo for help in behavioural experiments; J.-S. Kim for help in stereotaxic surgeries and histology; X. Da for help in histology; Y. Huang for help with genotyping and maxi-prep; the members of the Techlab at Caltech for help with 3D printing; D. Wagenaar for help with hardware; Y. Jung for help securing the funds for the 2P-SLM set-up; staff at Bruker, and especially S. Trier, T. Fothergill and E. Cho, for their help in establishing and maintaining the 2P-SLM set-up; the former Anderson laboratory members B. Weissbourd and A. Kennedy for initial feedback on this work; the current Anderson laboratory members for continuous feedback; the Caltech OLAR staff and especially K. Lee for animal care; and C. Chiu, G. Mancuso and L. Chavarria for laboratory management and administrative assistance. D.J.A. is an investigator of the Howard Hughes Medical Institute. This work was supported by grants from the NIH (RO1MH112593, RO1MH123612 and RO1NS123916) and by the Simons Collaboration on the Global Brain. A.N. is supported by a National Science Scholarship from the Agency of Science, Technology and Research, Singapore; and A.V. by a fellowship from the Human Frontiers Science Program and is a postdoctoral fellow at the Howard Hughes Medical Institute.

Funding

D.J.A. is an investigator of the Howard Hughes Medical Institute. This work was supported by grants from the NIH (RO1MH112593, RO1MH123612 and RO1NS123916) and by the Simons Collaboration on the Global Brain. A.N. is supported by a National Science Scholarship from the Agency of Science, Technology and Research, Singapore; and A.V. by a fellowship from the Human Frontiers Science Program and is a postdoctoral fellow at the Howard Hughes Medical Institute.

Contributions

These authors contributed equally: Amit Vinograd, Aditya Nair

A.V., A.N. and D.J.A. designed the study and wrote the manuscript, with critical input from S.W.L. A.N. and A.V. performed data analysis and data collection with help from J.H.K.

Data Availability

Source data for this Article have been deposited in the DANDI repository with the accession code 001037.

Code Availability

Code for fitting models is available at GitHub (https://github.com/lindermanlab/ssm).

Conflict of Interest

The authors declare no competing interests.

Errata

15 September 2025: This paper was originally published under Creative Commons Attribution 4.0 International license, CC-BY-NC-ND, © The Author(s). It is now available under a Creative Commons Attribution 4.0 International license, CC-BY, © The Author(s). The error has been corrected in the online version of the article.

Supplemental Material

Extended Data Fig. 1 Shared line attractor dynamics in freely behaving mice engaging in or observing aggression

Extended Data Fig. 2 Flow fields from miniscope experiments during engagement and observation of aggression

Extended Data Fig. 3 Comparing neuronal activity of x1 neurons during engaging vs. observing aggression

Extended Data Fig. 4 Single cell comparison of integration neurons across conditions

Extended Data Fig. 5 Readouts of behaviour and motion in head-fixed mice

Extended Data Fig. 6 Controls for off-target effects of 2P photoactivation

Extended Data Fig. 7 Spatial clustering of neurons and activity comparison

Extended Data Fig. 8 Characterization of line attractor properties

Extended Data Fig. 9 Examination of finite nature and stability of line attractor

Extended Data Fig. 10 Impact of functional connectivity measurements on non-targeted neurons

Extended Data Fig. 11 Deriving network time constant for model simulations

Extended Data Fig. 12 Additional quantifications of the correlation between functional connectivity and the stability of the decay and ramp

Reporting Summary

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Additional details

Identifiers

Related works

Describes
Journal Article: https://rdcu.be/eUWlT (ReadCube)
Journal Article: PMC11499281 (PMCID)
Journal Article: 39142337 (PMID)
Is supplemented by
Dataset: https://dandiarchive.org/dandiset/001037 (URL)
Software: https://github.com/lindermanlab/ssm (URL)

Funding

Howard Hughes Medical Institute
National Institutes of Health
RO1MH112593
National Institutes of Health
RO1MH123612
National Institutes of Health
RO1NS123916
Simons Foundation
Agency for Science, Technology and Research
International Human Frontier Science Program Organization

Dates

Submitted
2023-11-05
Accepted
2024-08-06
Available
2024-08-14
Published online
Available
2024-09-18
Version of record

Caltech Custom Metadata

Caltech groups
Division of Biology and Biological Engineering (BBE), Tianqiao and Chrissy Chen Institute for Neuroscience
Publication Status
Published