Escalated aggression in animal models: shedding new light on mesocorticolimbic circuits

Abstract

Recent developments promise to significantly advance the understudied behavioral and neurobiology of aggression: (1) Animal models that capture essential features of human violence and callousness have been developed. These models range from mice that have been selectively bred for short attack latencies, monogamous prairie voles, and glucocorticoid-compromised rats to rodents and non-human primates that escalate their aggression after consuming or when withdrawing from alcohol. (2) Optogenetic stimulation and viral vector-based approaches have begun to identify overlapping and distinctive neural microcircuits and intracellular molecules for adaptive vs. excessive, maladaptive aggressive behavior in several rodent models. Projections from hypothalamic and mesencephalic neurons to the medial prefrontal cortex contain microcircuits that appear pivotal for the escalation of aggression.

Abstinence from prolonged ethanol exposure affects plasma corticosterone, glucocorticoid receptor signaling and stress-related behaviors

“…GR function in the mPFC can regulate response to stressors via modulation of glutamatergic projections to the VTA (Butts and Phillips, 2013; Gourley et al, 2012). These results suggest that mPFC, in part via GR signaling, can modulate the mesocorticolimbic pathway and thereby regulate anxiety-like and aggression-like negative affect symptoms (Butts and Phillips, 2013; Miczek et al, 2015b). Previous research shows that acute withdrawal (2-10 h) from ethanol in CIE rats altered structural neuroplasticity in the mPFC pyramidal neurons (Kim et al, 2014) and decreased expression of GR mRNA in the mPFC without altering GR protein expression and signaling, among other regions (Navarro and Mandyam, 2015; Vendruscolo et al, 2012).…”

“…For example, Addison's disease and adrenal insufficiency are associated with increased irritability, which is mitigated typically by hydrocortisone replacement therapy (Bender et al, 2013; Hahner et al, 2007; Tiemensma et al, 2014). Preclinical research also supports a relation of low corticosterone (CORT, the predominant glucocorticoid in rats) to high aggression (Haller et al, 2001; Miczek et al, 2015b). Particularly, high aggression-like behavior was observed in adrenalectomized rats and was mitigated by CORT replacement prior to testing behavior in a resident-intruder paradigm (Haller et al, 2001).…”

Mad men, women and steroid cocktails: a review of the impact of sex and other factors on anabolic androgenic steroids effects on affective behaviors

“…While there is some divergence in brain regions implicated in offensive versus defensive aggression, these regions are rich in the expression of androgen and estrogen receptors (Sar et al 1990; Apostolinas et al 1999; Mitra et al 2003; Sarkey et al 2008; Oberlander and Henderson 2012a; Miczek et al 2015a). Moreover, these circuits overlap with each other and with brain regions that play key roles in the expression of anxiety-like behaviors (Figure 2).…”

“…The co-occurrence of AAS and alcohol use is particularly germane as both influence anxietylike behaviors and aggression, and both alter signaling along critical pathways in the extended amygdala and associated projection regions (Rashid 2000; Miczek et al 2015a,b; Pagonis et al 2006; Morrow et al 2009; Costine et al 2010; Oberlander and Henderson 2012a, b; Table 1). Of particular note, both alcohol and AAS converge on key molecular components of anxiety and aggression circuits, including CRF 1 -, GABA A receptor- and serotonin-mediated signaling (Lindqvist et al 2002; Nie et al 2004, 2009; Bajo et al 2008; Sommer et al 2008; Roberto et al 2010; Ambar and Chiavegatto 2009; Chiavegatto et al 2010; Costine et al 2010; Gilpin et al 2012, 2015; Oberlander and Henderson 2012b; Onakomaiya et al 2014; Miczek et al 2015a,b; Pleil et al 2015; Quadros et al 2015; Table 1).…”

“…Of particular note, both alcohol and AAS converge on key molecular components of anxiety and aggression circuits, including CRF 1 -, GABA A receptor- and serotonin-mediated signaling (Lindqvist et al 2002; Nie et al 2004, 2009; Bajo et al 2008; Sommer et al 2008; Roberto et al 2010; Ambar and Chiavegatto 2009; Chiavegatto et al 2010; Costine et al 2010; Gilpin et al 2012, 2015; Oberlander and Henderson 2012b; Onakomaiya et al 2014; Miczek et al 2015a,b; Pleil et al 2015; Quadros et al 2015; Table 1). …”