A hypothalamus-habenula circuit controls aversion

Iakovos Lazaridis,Karl Deisseroth,Yvonne Johansson,Moritz Weglage,Yang Xuan,Ourania Tzortzi,Daniel Fürth,Marie Carlén,Janos Fuzik,Marc Parent,Lief E Fenno,Gilad Silberberg,Charu Ramakrishnan,Konstantinos Meletis,Antje Märtin

doi:10.1038/s41380-019-0369-5

Iakovos Lazaridis, Karl Deisseroth + Show 13 more

Open Access

https://doi.org/10.1038/s41380-019-0369-5

Copy DOI

Journal: Molecular psychiatry	Publication Date: Feb 12, 2019
Citations: 120	License type: open-access

Affiliation: Karolinska Institutet, Stanford University

Abstract

Encoding and predicting aversive events are critical functions of circuits that support survival and emotional well-being. Maladaptive circuit changes in emotional valence processing can underlie the pathophysiology of affective disorders. The lateral habenula (LHb) has been linked to aversion and mood regulation through modulation of the dopamine and serotonin systems. We have defined the identity and function of glutamatergic (Vglut2) control of the LHb, comparing the role of inputs originating in the globus pallidus internal segment (GPi), and lateral hypothalamic area (LHA), respectively. We found that LHb-projecting LHA neurons, and not the proposed GABA/glutamate co-releasing GPi neurons, are responsible for encoding negative value. Monosynaptic rabies tracing of the presynaptic organization revealed a predominantly limbic input onto LHA Vglut2 neurons, while sensorimotor inputs were more prominent onto GABA/glutamate co-releasing GPi neurons. We further recorded the activity of LHA Vglut2 neurons, by imaging calcium dynamics in response to appetitive versus aversive events in conditioning paradigms. LHA Vglut2 neurons formed activity clusters representing distinct reward or aversion signals, including a population that responded to mild foot shocks and predicted aversive events. We found that the LHb-projecting LHA Vglut2 neurons encode negative valence and rapidly develop a prediction signal for negative events. These findings establish the glutamatergic LHA-LHb circuit as a critical node in value processing.

Highlights

The neural circuits responsible for encoding predictions of upcoming rewards and negative events are central to motivated behaviors and the survival of animals
We focused the analysis on regions in the basal ganglia and the hypothalamus, and we found that the lateral hypothalamic area (LHA) was the most prominent input region to lateral habenula (LHb) in terms of absolute numbers of Rb-EGFP labeled neurons (Fig. 1e)
We have in this study presented evidence for the central role of a subtype of LHA Vglut2 neurons in mediating aversive signals through projections to LHb

Summary

Introduction

The neural circuits responsible for encoding predictions of upcoming rewards and negative events are central to motivated behaviors and the survival of animals. Limbic and basal ganglia circuits have been extensively linked to motivation, action-selection, and aversion [1]. In this context, LHb, an evolutionarily conserved epithalamic nucleus, is especially interesting due to its control over the neuromodulators dopamine and serotonin [2]. Rewards, and the LHb circuitry has been proposed to play an important role in signaling reward and punishment prediction errors [3, 4]. Defining the mechanisms underlying LHb activity, and the role of the different inputs that modulate LHb activity, are important aspects in deciphering how aversive and rewarding events are represented

Objectives

Results

Conclusion