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

Aggressive behavior is instinctively driven behavior that helps animals to survive and reproduce and is closely related to multiple behavioral and physiological processes. The dorsal raphe nucleus (DRN) is an evolutionarily conserved midbrain structure that regulates aggressive behavior by integrating diverse brain inputs. The DRN consists predominantly of serotonergic (5-HT:5-hydroxytryptamine) neurons and decreased 5-HT activity was classically thought to increase aggression. However, recent studies challenge this 5-HT deficiency model, revealing a more complex role for the DRN 5-HT system in aggression. Furthermore, emerging evidence has shown that non-5-HT populations in the DRN and specific neural circuits contribute to the escalation of aggressive behavior. This review argues that the DRN serves as a multifaceted modulator of aggression, acting not only via 5-HT but also via other neurotransmitters and neural pathways, as well as different subsets of 5-HT neurons. In addition, we discuss the contribution of DRN neurons in the behavioral and physiological aspects implicated in aggressive behavior, such as arousal, reward, and impulsivity, to further our understanding of DRN-mediated aggression modulation.

Estrogen Receptor ß in the Lateral Septum Mediates Estrogen Regulation of Social Anxiety-like Behavior in Male Mice.

17ß-estradiol (E2) regulates various forms of social behavior through the activation of two types of estrogen receptors, ERα and ERß. The lateral septum (LS) is thought to be one of the potential target sites of E2, but the role played by ERα and ERß in this brain area remains largely unknown. In the present study, we first analyzed the distribution of ERα and ERß with double fluorescent immunohistochemistry in a transgenic mouse line in which red fluorescent protein (RFP) signal has been a reliable marker of ERß expression. The overall number of ERß-RFP-expressing cells was significantly higher (about 2.5 times) compared to ERα-expressing cells. The distribution of the two types of ERs was different, with co-expression only seen in about 1.2% of total ER-positive cells. Given these distinctive distribution patterns, we examined the behavioral effects of site-specific knockdown of each ER using viral vector-mediated small interference RNA (siRNA) techniques in male mice. We found ERß-specific behavioral alterations during a social interaction test, suggesting involvement of ERß-expressing LS neurons in the regulation of social anxiety and social interest. Further, we investigated the neuronal projections of ERα- and ERß-expressing LS cells by injecting an anterograde viral tracer in ERα-Cre and ERß-iCre mice. Dense expression of green fluorescence protein (GFP) in synaptic terminals was observed in ERß-iCre mice in areas known to be related to the modulation of anxiety. These findings collectively suggest that ERß expressed in the LS plays a major role in the estrogenic control of social anxiety-like behavior.

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

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.

Prior stress experience modulates social preference for stressed conspecifics in male rats.

Adult male rats tend to avoid adult conspecifics in distress. In this study, we asked whether prior stress experience would modulate social preference for a stressed conspecific using a social affective preference (SAP) test. Male Long-Evans adult rats were assigned to the shocked and non-shocked groups. In the shocked group, rats were acutely subjected to foot shocks (1.0 mA, 5 s duration × 2) 24 h before the SAP test. During the SAP test, the experimental rats were placed in an arena where two adult conspecific stimuli, one of which received the foot shocks immediately before the SAP test, were presented at both ends and allowed to explore freely for 5 min. We measured sniffing behavior toward each conspecific as an index of social preference. Non-shocked adult rats avoided, while shocked rats approached, the stressed conspecifics more than the non-stressed ones. These results suggest that prior stress promotes social preference for a stressed conspecific in adult male rats.