Potentiation of Divergent Medial Amygdala Pathways Drives Experience-Dependent Aggression Escalation

Abstract

Heightened aggression can be serious concerns for the individual and society at large and are symptoms of many psychiatric illnesses, such as post-traumatic stress disorder. The circuit and synaptic mechanisms underlying experience-induced aggression increase, however, are poorly understood. Here we find that prior attack experience leading to an increase in aggressive behavior, known as aggression priming, activates neurons within the posterior ventral segment of the medial amygdala (MeApv). Optogenetic stimulation of MeApv using a synaptic depression protocol suppresses aggression priming, whereas high-frequency stimulation enhances aggression, mimicking attack experience. Interrogation of the underlying neural circuitry revealed that the MeApv mediates aggression priming via synaptic connections with the ventromedial hypothalamus (VmH) and bed nucleus of the stria terminalis (BNST). These pathways undergo NMDAR-dependent synaptic potentiation after attack. Furthermore, we find that the MeApv-VmH synapses selectively control attack duration, whereas the MeApv-BNST synapses modulate attack frequency, both with no effect on social behavior. Synaptic potentiation of the MeApv-VmH and MeApv-BNST pathways contributes to increased aggression induced by traumatic stress, and weakening synaptic transmission at these synapses blocks the effect of traumatic stress on aggression. These results reveal a circuit and synaptic basis for aggression modulation by experience that can be potentially leveraged toward clinical interventions.

The Dorsal Raphe Regulates the Duration of Attack through the Medial Orbitofrontal Cortex and Medial Amygdala

“…MeApv have different effects on aggression (Kollack-Walker and Newman, 1995;Lin et al, 2011;Hong et al, 2014;Miller et al, 2019;Nordman et al, 2020b), it is worth considering that the DR may be shortening an attack through a specific subregion of the MeA. The photostimulation protocol used in this study does not allow for discrimination of these subregions due to their anatomical clustering.…”

“…The three main MeA subregions, MeAa, MeApd, and MeApv, are all involved in aggressive behavior (Kollack-Walker and Newman, 1995;Lin et al, 2011;Hong et al, 2014;Miller et al, 2019;Nordman et al, 2020b). While we observed that photostimulation of the DR can activate all three subregions, since the MeApd and…”

“…All behavioral experiments took place during the dark cycle of the day, as this is the main activity phase of the mouse (Koolhaas et al, 2013 (Hong et al, 2014;Nordman et al, 2020b). Videos of behavioral tests were reviewed and hand scored by a researcher blind to the experimental conditions using a bin size of 0.5 s. Aggressive behaviors were identified as chasing, boxing, pinning, biting and wrestling (Blanchard and Blanchard, 1977;Lin et al, 2011;Koolhaas et al, 2013;Hong et al, 2014;Golden et al, 2016).…”

Experience-dependent plasticity in an innate social behavior is mediated by hypothalamic LTP

“…VMHvl Esr1 neurons receive inputs from neurons in over 30 different structures (50), raising the question of whether other inputs to these cells also display plasticity. Indeed, recently published work has identified synaptic plasticity promoted by foot-shock stress in a medial amygdala projection that primarily targets the central part of VMH (VMHc) (127). Although a causal role in promoting aggression was not directly demonstrated for this input, and the mechanism of potentiation was not established, plasticity at this synapse may regulate stress-induced aggression (127).…”

“…Indeed, recently published work has identified synaptic plasticity promoted by foot-shock stress in a medial amygdala projection that primarily targets the central part of VMH (VMHc) (127). Although a causal role in promoting aggression was not directly demonstrated for this input, and the mechanism of potentiation was not established, plasticity at this synapse may regulate stress-induced aggression (127). The present study demonstrates that AHiPM VMHvl Esr1 synapses can undergo Hebbian LTP, and that potentiation of these synapses occurs during social experience that enhances offensive aggression (47,119).…”