Functions of medial hypothalamic and mesolimbic dopamine circuitries in aggression

Abstract

Aggression is a crucial survival behavior: it is employed to defend territory, compete for food and mating opportunities, protect kin, and resolve disputes. Although widely differing in its behavioral expression, aggression is observed across many species. The neural substrates of aggression have been investigated for nearly a century and two highly conserved circuitries emerge as critical substrates for generating and modulating aggression. One circuitry centers on the medial hypothalamus. Activity of the medial hypothalamic cells closely correlates with attacks and can bi-directionally modulate aggressive behaviors. The other aggression-related circuit involves the mesolimbic dopamine cells. Dopaminergic antagonists are the most commonly used treatment for suppressing human aggression in psychotic patients. Animal studies support essential roles of dopaminergic signaling in the nucleus accumbens in assessing the reward value of aggression and reinforcing the aggressive behaviors. In this review, we will provide an overview regarding the functions of medial hypothalamus and dopaminergic system in mediating aggressive behaviors and the potential interactions between these two circuitries.

Nucleus Accumbens Drd1-Expressing Neurons Control Aggression Self-Administration and Aggression Seeking in Mice

“…Finally, recent studies reported roles of other cell-typespecific circuits in aggression reward, as assessed in the selfadministration and CPP procedures (Aleyasin et al, 2018a;Yamaguchi and Lin, 2018). These include estrogen-receptor ␣1expressing neurons of ventromedial hypothalamus (Falkner et al, 2016), dopamine transporter-expressing neurons of hypothalamic ventral premammillary nucleus projecting to supramammillary nuclei (Stagkourakis et al, 2018), and GABAergic projections from basal forebrain to lateral habenula (Golden et al, 2016).…”

“…We focused on the nucleus accumbens (NAc), which earlier research has implicated in aggression self-administration and CPP (Couppis and Kennedy, 2008;Golden et al, 2016;Aleyasin et al, 2018b). There has been a recent interest in the role of the mesolimbic dopaminergic circuit in controlling aggression reward (Flanigan et al, 2017;Aleyasin et al, 2018a;Yamaguchi and Lin, 2018), as dopaminergic projections from the ventral tegmental area (VTA) to the NAc modulate both aggression intensity (Yu et al, 2014) and NAc dopamine levels Miczek, 2000, 2007). Additionally, local dopamine receptor blockade decreases aggression-reinforced operant responding (Couppis and Kennedy, 2008).…”

The challenge hypothesis revisited: Focus on reproductive experience and neural mechanisms

“…A number of other brain regions express androgen receptors and are associated with aggression are not included in this review such as the medial amygdala (Clinard et al, 2016) and ventromedial hypothalamus (Falkner et al, 2016). Most work on amygdala and hypothalamic modulation of aggression focuses primarily on intensity of aggression rather than other aspects of territoriality (Kruk et al, 1998;Yamaguchi and Lin, 2018). Below we highlight specific brain regions that link rewarding aspects of T, association of T with site fidelity and the vigilance needed to protect offspring and the territory.…”

Animal Models of (or for) Aggression Reward, Addiction, and Relapse: Behavior and Circuits

“…The hypothalamus is strongly linked with aggression, due to the depth of cross-species experiments and pan-methodological approaches repeatedly attributing the initiation of aggression to its subnuclei. Termed the hypothalamic attack area, this region classically spans the lateral through ventromedial hypothalamus, and has been the focus of aggression research for decades (Siegel et al, 1999;Hashikawa et al, 2017b;Yamaguchi and Lin, 2018). Recent work by Lin and colleagues (Lin et al, 2011;Falkner et al, 2014;Hashikawa et al, 2017a) has more selectively identified Esr1 ϩ neurons within the ventrolateral portion of the ventromedial hypothalamus (VMHvl) as the critical population controlling the initiation of aggression in both male and female mice.…”

“…Due to space limitations, we do not describe results from recent studies in which cell-type and circuit-specific optogenetic and chemogenetic methods were used to elicit unconditioned aggressive behavior in different brain areas. We refer the readers to excellent recent reviews on this topic, which provide overviews summarizing these brain regions and circuits (Miczek et al, 2015;Aleyasin et al, 2018a;Yamaguchi and Lin, 2018;Flanigan and Russo, 2019).…”