Traumatic Stress Induces Prolonged Aggression Increase through Synaptic Potentiation in the Medial Amygdala Circuits

Abstract

Traumatic stress can lead to heightened aggression which may be a symptom of psychiatric diseases such as PTSD and intermittent explosive disorder. The medial amygdala (MeA) is an evolutionarily conserved subnucleus of the amygdala that regulates attack behavior and behavioral responses to stressors. The precise contribution of the MeA in traumatic stress-induced aggression, however, requires further elucidation. In this study, we used foot shock to induce traumatic stress in mice and examine the mechanisms of prolonged aggression increase associated with it. Foot shock causes a prolonged increase in aggression that lasts at least one week. In vivo electrophysiological recordings revealed that foot shock induces potentiation of synapses formed between the MeA and the ventromedial hypothalamus (VmH) and bed nucleus of the stria terminalis (BNST). This synaptic potentiation lasts at least one week. Induction of synaptic depotentiation with low-frequency photostimulation (LFPS) immediately after foot shock suppresses the prolonged aggression increase without affecting non-aggressive social behavior, anxiety-like and depression-like behaviors, or fear learning. These results show that potentiation of the MeA-VmH and MeA-BNST circuits is essential for traumatic stress to cause a prolonged increase in aggression. These circuits may be potential targets for the development of therapeutic strategies to treat the aggression symptom associated with psychiatric diseases.

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

“…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 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, 2020a ), 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 because of their anatomic clustering.…”

“…3 F–M , 4 F–U ). The MeA can be divided into three main subdivisions: the anterior MeA (MeAa), the posteriordorsal MeA (MeApd), and the posteriorventral MeA (MeApv), all of which are involved in aggressive behavior ( Kollack-Walker and Newman, 1995 ; Lin et al, 2011 ; Hong et al, 2014 ; Miller et al, 2019 ; Nordman et al, 2020a ). Analysis of c-Fos expression in the MeA revealed that all three regions are activated by photostimulation of the DR ( Fig.…”

“…Stimulation of dopamine D1 receptor (D1R)-expressing neurons within the MeApv projecting to the bed nucleus of the stria terminalis increases aggression, while stimulation of those projecting to the ventromedial hypothalamus decreases aggression ( Miller et al, 2019 ). Potentiation of synapses between the MeApv and the ventromedial hypothalamus and bed nucleus of the stria terminalis underlies aggression priming and heightened aggression induced by traumatic stress ( Nordman et al, 2020a , b ). Notably, dysfunction within the OFC and MeA is associated with excessive and impulsive aggression in mice and humans ( Grafman et al, 1996 ; Blair, 2004 ; New et al, 2004 ; Shalom et al, 2004 ; Coccaro et al, 2007 ; Mpakopoulou et al, 2008 ; Buades-Rotger et al, 2017 ; Herpertz et al, 2017 ).…”

“…If excessive tissue damage occurred, the test was prematurely terminated and not analyzed. Excessively aggressive mice, as determined by total attack time >40% during the RI test, were eliminated from further analysis ( Hong et al, 2014 ; Nordman et al, 2020a ). 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 ).…”

Amygdala Circuit Substrates for Stress Adaptation and Adversity

“…The CeA also makes reciprocal connections with regions such as the locus coeruleus and BNST, which, as discussed below, are critically engaged in regulating the stress response. Although not a focus of this review [refer to several excellent reviews on the topic (27,28)], it should be noted that the BNST (part of the extended amygdala) plays an increasingly appreciated role in stress responsivity through connections with both the CeA and MeA (29).…”