Lasting changes in neuronal activation patterns in select forebrain regions of aggressive, adolescent anabolic/androgenic steroid-treated hamsters

Abstract

Repeated exposure to anabolic/androgenic steroids (AAS) during adolescence stimulates high levels of offensive aggression in Syrian hamsters. The current study investigated whether adolescent AAS exposure activated neurons in areas of hamster forebrain implicated in aggressive behavior by examining the expression of FOS, i.e., the protein product of the immediate early gene c-fos shown to be a reliably sensitive marker of neuronal activation. Adolescent AAS-treated hamsters and sesame oil-treated littermates were scored for offensive aggression and then sacrificed 1 day later and examined for the number of FOS immunoreactive (FOS-ir) cells in regions of the hamster forebrain important for aggression control. When compared with non-aggressive, oil-treated controls, aggressive AAS-treated hamsters showed persistent increases in the number of FOS-ir cells in select aggression regions, namely the anterior hypothalamus and lateral septum. However, no differences in FOS-ir cells were found in other areas implicated in aggression such as the ventrolateral hypothalamus, bed nucleus of the stria terminals, central and/or medial amygdala or in non-aggression areas, such as the samatosensory cortex and the suprachiasmatic nucleus. These results suggest that adolescent AAS exposure may constitutively activate neurons in select forebrain areas critical for the regulation of aggression in hamsters. A model for how persistent activation of neurons in one of these brain regions (i.e., the anterior hypothalamus) may facilitate the development of the aggressive phenotype in adolescent-AAS exposed animals is presented.

Figure 1

Diagram showing the location of the areas selected to quantify FOS-containing cells (shaded areas). Plates were modified from hamster atlas of Morin and Wood (2001) and reflect specific positions in the rostral-caudal plane (i.e., distance in mm from bregma to the plane of section at the skull surface). Abbreviations: AH, anterior hypothalamus; BNST, medial division of the bed nucleus of the stria terminalis; CeA, central amygdala; LS, intermediate part of the lateral septal nucleus; MeA, medial amygdala; mSON, medial division of the supraoptic nucleus; VLH, ventrolateral hypothalamus; S1, somatosensory neocortex; SCN, suprachiasmatic nucleus.

Figure 2

Adolescent AAS treatment increases offensive aggression. Number of offensive attacks and latency to first attack in AAS- and sesame oil- treated residents. Bars denote SEM. *p<0.05; **p<0.01; Mann-Whitney, two-tailed (number of attacks), Student’s t-test, two-tailed (attack latency).

Figure 3

Brightfield photomicrographs of a coronal section through the Syrian hamster hypothalamus. Shown are FOS-containing cells (arrows) within the anterior hypothalamus (encircled) of (A, C) AAS-treated and (B, D) sesame oil-treated hamsters. High power photomicrographs in C and D represent FOS immunostaining in the ventro-lateral aspects of the anterior hypothalamus delineated below the center dashed line in A and B, i.e., the latero-anterior hypothalamic brain region. oc, optic chiasm; 3V, 3^rd ventricle.

Figure 4

Number of FOS-immunoreactive cells in select brain regions of AAS- vs. sesame oil- treated hamsters. ** p< 0.01; Student's t-test, two-tailed.

Figure 5

A model showing the hypothetical relationship between adolescent AAS-induced neuronal activation and the serotonin (5HT) with the arginine vasopressin (AVP) systems in the AH (adapted from Ferris et al., J. Neurosci. Vol. 17; 4331–4340. 1997). In the first panel (-AAS) a dense plexus of 5-HT afferent fibers originating from neurons in the raphe nucleus innervate AVP neurons localized to the medial supraoptic nucleus (mSON) and nucleus circularis (NC), i.e., vasopressinergic neurons identified as potential sources of AVP innervation to the AH involved in agonistic behavior. These AVP neurons together with 5HT neurons from the raphe nucleus regulate the activity of AH neurons involved in the facilitation of aggression. The identity (?) of these post-synaptic AH neurons is unknown but two potential candidates are glutamate and norepinephrine. 5-HT is inhibitory (−), working through a 5-HT1A/B receptors, whereas AVP is excitatory (+), working through a V1A receptor. In the second panel (+AAS), adolescent AAS exposure markedly enhances AVP and reduces 5HT afferent innervation to the AH and alters the expression of 5HT1A and 1B receptors throughout this brain region (see Refs. [25,26,33,67]), constitutively dis-inhibiting (i.e., activating) non-AVP neurons (? Glutaminergic – see Ref. [21]) in the AH facilitating aggression. Neuronal activation in this model is represented as dark nuclei indicating persistent FOS expression.