Lateral habenula glutamatergic neurons projecting to the dorsal raphe nucleus promote aggressive arousal in mice

Abstract

The dorsal raphe nucleus (DRN) is known to control aggressive behavior in mice. Here, we found that glutamatergic projections from the lateral habenula (LHb) to the DRN were activated in male mice that experienced pre-exposure to a rival male mouse (“social instigation”) resulting in heightened intermale aggression. Both chemogenetic and optogenetic suppression of the LHb-DRN projection blocked heightened aggression after social instigation in male mice. In contrast, inhibition of this pathway did not affect basal levels of aggressive behavior, suggesting that the activity of the LHb-DRN projection is not necessary for the expression of species-typical aggressive behavior, but required for the increase of aggressive behavior resulting from social instigation. Anatomical analysis showed that LHb neurons synapse on non-serotonergic DRN neurons that project to the ventral tegmental area (VTA), and optogenetic activation of the DRN-VTA projection increased aggressive behaviors. Our results demonstrate that the LHb glutamatergic inputs to the DRN promote aggressive arousal induced by social instigation, which contributes to aggressive behavior by activating VTA-projecting non-serotonergic DRN neurons as one of its potential targets.

Aggression modulator: Understanding the multifaceted role of the dorsal raphe nucleus

“…Other studies have also shown the contribution of a subset of non-5-HT neurons in the DRN to inter-male aggression. Takahashi et al [77] showed that DRN neurons that receive inputs from the LHb are involved in aggressive arousal induced by social instigation, which causes an increase in aggressive behavior from the basal level. This study showed that DRN-projecting LHb neurons (LHb-DRN projection) were activated during social instigation-heightened aggression, but not during basal resident-intruder aggression without social instigation.…”

“…While various studies indicate that DRN 5-HT neurons contributes both the expression and inhibition of aggressive behavior, [53,[62][63][64][65][66][67] recent optogenetic research has revealed that silencing these neurons does not affect aggressive behavior. [77] DRN 5-HT neurons also have a multifaceted role with respect to reward processing, encoding both reward and aversion signals, [129,130] and there are some contradictory findings about the reward property of the activation of DRN 5-HT neurons. [132][133][134][135][136][137][138] Furthermore, the activity of DRN 5-HT neurons is positively associated with physiological [95][96][97]100] and behavioral arousal levels.…”

“…Indeed, optogenetic and chemogenetic inhibition of the LHb‐DRN projection blocked the escalation of aggressive behavior by social instigation but did not affect basal resident‐intruder aggression. [ 77 ] These results indicate that the LHb‐DRN projection is not necessary for the expression of basal aggressive behavior, but is involved in the escalation of aggressive behavior from its basal level when animals are primed by a rival instigator. To identify the type of neurons responsible for the escalation of aggression within the DRN, DRN cells that received direct input from the LHb were labeled using an AAV1‐Cre strategy.…”

“…Indeed, optogenetic activation of DRN neurons that project to the VTA (DRN‐VTA projection) increases aggressive behavior in male mice. [ 77 ] Therefore, the subpopulation of non‐5‐HT neurons that project to the VTA is involved in the escalation of inter‐male aggressive behavior.…”

Multi-level variations of lateral habenula in depression: A comprehensive review of current evidence

“…Correspondingly, improved depressive-like behavior in rats and higher 5-HT levels in the DRN after intra-LHb microinjection of a substance P receptor antagonist showed antidepressant potentials in this circuit ( 126 ). A recent study showed that one subpopulation of LHb neurons project directly to glutamatergic DRN neurons projecting to VTA dopamine neurons and mediate social instigation-induced aggressive behavior in male mice ( 127 ).…”