Pattern of forebrain activation in high novelty-seeking rats following aggressive encounter

Abstract

We have previously demonstrated that selectively-bred High (bHR) and Low (bLR) novelty-seeking rats exhibit agonistic differences, with bHRs acting in a highly aggressive manner when facing homecage intrusion. In order to discover the specific neuronal pathways responsible for bHRs’ high levels of aggression, the present study compared c-fos mRNA expression in several forebrain regions of bHR/bLR males following this experience. bHR/bLR males were housed with female rats for two weeks, and then the females were replaced with a male intruder for 10 min. bHR/bLR residents were subsequently sacrificed by rapid decapitation, and their brains were removed and processed for c-fos in situ hybridization. Intrusion elicited robust c-fos mRNA expression in both phenotypes throughout the forebrain, including the septum, amygdala, hippocampus, cingulate cortex, and the hypothalamus. However, bHRs and bLRs exhibited distinct activation patterns in select areas. Compared to bHR rats, bLRs expressed greater c-fos in the lateral septum and within multiple hypothalamic nuclei, while bHRs showed greater activation in the arcuate hypothalamic nucleus and in the hippocampus. No bHR/bLR differences in c-fos expression were detected in the amygdala, cortical regions, and striatum. We also found divergent 5-HT1A receptor mRNA expression within some of these same areas, with bLRs having greater 5-HT1A, but not 5-HT1B, receptor mRNA levels in the septum, hippocampus and cingulate cortex. These findings, together with our earlier work, suggest that bHRs exhibit altered serotonergic functioning within select circuits during an aggressive encounter.

High novelty-seeking rats are resilient to negative physiological effects of the early life stress

“…We believe that the bLR rat represents a useful new rodent model of co-morbid anxiety- and depression given their naturally high levels of anxiety- and depressive-like behavior (Kabbaj et al, 2000, White et al, 2007, Flagel et al, 2010, Clinton et al, 2011a, Perez et al, 2009, Clinton et al, 2008, Stedenfeld et al, 2011, Garcia-Fuster et al, 2012), diminished aggression (Kerman et al, 2011) and sexual motivation (McCullumsmith et al, 2007), and reduced responsivity to reward (Kabbaj, 2004, Piazza et al, 1989, Flagel et al, 2011, Davis et al, 2008, Garcia-Fuster et al, 2010, Cummings et al, 2011). The present study together with our earlier work (Clinton et al, 2008, Stedenfeld et al, 2011) also demonstrates bLRs’ high vulnerability to chronic stress whereas bHRs are fairly resilient.…”

The neurobiology of offensive aggression: Revealing a modular view

“…Employing selectively-bred high responder Sprague-Dawley rats (bHR) that are hyperactive and vigorously explore novel environments, exhibit elevated impulsivity and aggression and enhanced psychostimulant self-administration compared to low responder rats (bLR). Clinton et aldemonstrated divergent patterns of c-fos mRNA expression and 5-HT 1A receptor mRNA in the lateral septum, multiple hypothalamic nuclei, hippocampus and some cortical areas following an aggressive encounter [100,102]. Basically, a similar quantitative difference in number of Fos-IR cells between non-aggressive (virgin) and aggressive (lactating) female mice were found in various nodes of the social behavioral neurocircuitry [123].…”

“…Optogenetic activation of these neurons in virgin males suppresses inter-male and pup-directed aggression [98]. The involvement of brain areas like posterior amygdala (PoA) (also described as amygdalo-hippocampal transition area and subiculum has been observed also in neural activation studies [99,100] but the kind of behaviorally relevant information provided has not been elucidated yet.…”

“…Obviously, this picture is too simple and with the subsequent advances in neuroanatomical tracing, lesion, stimulation and imaging techniques, a considerably more complex and refined neuronal circuitry emerged. In particular the recent studies using immediate-early gene protein (e.g., Fos, Jun, and Zenk) expression mapping, have revealed the individual neurons in the entire brain that become activated or inhibited during the expression of different behavioral coping-style reactions [73,100,102]. For example, in the residentintruder paradigm proactive fighting (i.e., aggressive) resident mice in comparison to reactive non-aggressive resident mice show an increased number of Fos-positive neurons in the central and medial amygdala, anterior bed nucleus of the stria terminalis, ventrolateral hypothalamus, nucleus accumbens shell, orbital frontal cortex, lateral/ventrolateral periaqueductal gray and dorsal raphe, while in the vmPFC, lateral septum and dorsolateral periaqueductal gray a reversed pattern was seen [73].…”

Early-life exposure to the SSRI paroxetine exacerbates depression-like behavior in anxiety/depression-prone rats

“…Rats bred for low response to novelty (bLR) display high levels of behavioral inhibition, spontaneous anxiety and depression-like behavior compared to bred High Responder (bHR) rats (Stead et al, 2006a, Clinton et al, 2011b, Garcia-Fuster et al, 2011, Stedenfeld et al, 2011, Cummings et al, 2013). The bHR/bLR rats exhibit 5HT circuit differences that likely contribute to their disparate behavioral phenotypes, with adult bLR rats exhibiting lower Tph2 and Sert mRNA in the dorsal raphe (Kerman et al, 2011) and increased 5HT receptor mRNA levels in multiple limbic brain regions compared to bHRs (Ballaz et al, 2007b, Calvo et al, 2011, Clinton et al, 2011a). …”