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Updated: Dec 24, 2025
Assessment of Sexual Behavior of Male Mice
Published on: March 5, 2020
Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior in male mice
Meghan E Flanigan1,2, Hossein Aleyasin1,2, Long Li1,2
1Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Abstract:
Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have various negative effects on patients, their families and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, domination of subordinate social targets is reinforcing. In this study, we showed that, in male mice, orexin neurons in the lateral hypothalamus activated a small population of glutamic acid decarboxylase 2 (GAD2)-expressing neurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) and that activation of these GAD2 neurons promoted male-male aggression and conditioned place preference for aggression-paired contexts. Moreover, LHb GAD2 neurons were inhibitory within the LHb and dampened the activity of the LHb as a whole. These results suggest that the orexin system is important for the regulation of inter-male aggressive behavior and provide the first functional evidence of a local inhibitory circuit within the LHb.
Insights
Orexin neurons activate specific brain cells in male mice, increasing aggression. This research reveals a new inhibitory circuit in the brain that may regulate aggressive behaviors.
Area of Science:
- Neuroscience
- Behavioral Neuroscience
- Neurobiology
Background:
- Aggression is a complex behavior linked to neuropsychiatric disorders.
- Brain reward circuits are implicated in aggression, with social domination potentially being reinforcing.
- The role of specific neural pathways in regulating aggression requires further elucidation.
Purpose of the Study:
- To investigate the role of orexin neurons and lateral habenula (LHb) circuits in regulating male-male aggression.
- To identify the specific neuronal populations and receptors involved in orexin-mediated aggression.
Main Methods:
- Utilized male mice as a model system.
- Investigated the activation of glutamic acid decarboxylase 2 (GAD2)-expressing neurons in the LHb by orexin neurons via orexin receptor 2 (OxR2).
- Assessed the impact of activating LHb GAD2 neurons on aggression and conditioned place preference.
Main Results:
- Activation of LHb GAD2 neurons by orexin neurons promoted male-male aggression.
- Activation of these GAD2 neurons led to conditioned place preference for aggression-associated contexts.
- LHb GAD2 neurons were found to be inhibitory, dampening overall LHb activity.
Conclusions:
- The orexin system plays a significant role in the regulation of inter-male aggressive behavior.
- A novel local inhibitory circuit within the LHb, involving GAD2 neurons, has been identified.
- These findings offer insights into the neural mechanisms underlying aggression and potential therapeutic targets.
