Aggression and Anxiety: Social Context and Neurobiological Links

Psychopathologies such as anxiety- and depression-related disorders are often characterized by impaired social behaviours including excessive aggression and violence. Excessive aggression and violence likely develop as a consequence of generally disturbed emotional regulation, such as abnormally high or low levels of anxiety. This suggests an overlap between brain circuitries and neurochemical systems regulating aggression and anxiety. In this review, we will discuss different forms of male aggression, rodent models of excessive aggression, and neurobiological mechanisms underlying male aggression in the context of anxiety. We will summarize our attempts to establish an animal model of high and abnormal aggression using rats selected for high (HAB) vs. low (LAB) anxiety-related behaviour. Briefly, male LAB rats and, to a lesser extent, male HAB rats show high and abnormal forms of aggression compared with non-selected (NAB) rats, making them a suitable animal model for studying excessive aggression in the context of extremes in innate anxiety. In addition, we will discuss differences in the activity of the hypothalamic–pituitary–adrenal axis, brain arginine vasopressin, and the serotonin systems, among others, which contribute to the distinct behavioural phenotypes related to aggression and anxiety. Further investigation of the neurobiological systems in animals with distinct anxiety phenotypes might provide valuable information about the link between excessive aggression and disturbed emotional regulation, which is essential for understanding the social and emotional deficits that are characteristic of many human psychiatric disorders

Immunohistochemical double-labeling of OXT and pERK.

<p><b>A–C:</b> Illustrations of OXT (green) and pERK (red) IF in the PVNlm of a non-aggressive female. Total area of A, B and C corresponds to the size of the analyzed area; <b>D:</b> Higher magnification of the white square in C, white asterisks signify double-labeled neurons; <b>E:</b> Density of single- and double-labeled neurons as well as the percentage of OXT-IR neurons that also showed pERK-IR in non-aggressive (white bars, n = 7) and aggressive (grey bars, n = 7) adolescent female NAB rats. Data are means ± s.e.m; *P<0.05.</p

Behavioral profile of adult (10–11 week old) virgin female NAB residents (n = 69) during their first 10-min female intruder test (FIT), and adult (16–22 week old) male NAB residents (n = 108) during their first 10-min resident-intruder test (RI-test).

<p><b>A:</b> attack frequency distribution; <b>B:</b> aggressive, social and non-social behavior as percentage of total behavior; <b>C:</b> different types of offensive behavior as percentage of total aggressive behavior. Data are medians and quartiles. A statistical comparison of the sexes was not performed.</p

Effect of innate anxiety levels on behavior in the FIT.

<p>Overall effects (Kruskal-Wallis) and Mann-Whitney pair-wise comparisons for experiment 2 (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091701#pone-0091701-g003" target="_blank">Fig. 3</a>).</p><p>***P<0.001,</p><p>**P<0.01,</p><p>*P<0.05.</p

Neuropeptide Y, calcitonin gene-related peptide, and neurokinin A in brain regions of HAB rats correlate with anxiety-like behaviours

Anxiety disorders are pervasive psychiatric disorders causing great suffering. The high (HAB) and low (LAB) anxiety-related behaviour rats were selectively bred to investigate neurobiological correlates of anxiety. We compared the level of neuropeptides relevant for anxiety- and depression-related behaviours in selected brain regions of HAB and LAB rats. Increased anxiety and depression-like behaviours of male and female HAB rats in the elevated plus-maze and forced swim tests were accompanied by elevated levels of neuropeptide Y (NPY) in the prefrontal (PFC), frontal (FC) and cingulate cortex (CCx), the striatum, and periaqueductal grey (PAG). Moreover, HAB rats displayed sex-dependent, elevated levels of calcitonin gene-related peptide (CGRP) in PFC, FC, CCx, hippocampus, and PAG. Higher neurokinin A (NKA) levels were detected in CCx, striatum, and PAG in HAB males and in CCx and hypothalamus in HAB females. Increased neurotensin was detected in CCx and PAG in HAB males and in hypothalamus in HAB females. Elevated corticotropin-releasing hormone (CRH) levels appeared in female HAB hypothalamus. Significant correlations were found between anxiety-like behaviour and NPY, CGRP, NKA, and neurotensin, particularly with NPY in CCx and striatum, CGRP in FC and hippocampus, and NKA in entorhinal cortex

Chronic Subordinate Colony Housing (CSC) as a Model of Chronic Psychosocial Stress in Male Rats

Chronic subordinate colony housing (CSC) is an adequate and reliable mouse model of chronic psychosocial stress, resulting in reduced body weight gain, reduced thymus and increased adrenal weight, long-lasting anxiety-like behaviour, and spontaneous colitis. Furthermore, CSC mice show increased corticotrophin (ACTH) responsiveness to acute heterotypic stressors, suggesting a general mechanism which allows a chronically-stressed organism to adequately respond to a novel threat. Therefore, the aim of the present study was to extend the CSC model to another rodent species, namely male Wistar rats, and to characterize relevant physiological, immunological, and behavioural consequences; placing particular emphasis on changes in hypothalamo-pituitary-adrenal (HPA) axis responsiveness to an acute heterotypic stressor. In line with previous mouse data, exposure of Wistar rats to 19 days of CSC resulted in a decrease in body weight gain and absolute thymus mass, mild colonic barrier defects and intestinal immune activation. Moreover, no changes in stress-coping behaviour or social preference were seen; again in agreement with the mouse paradigm. Most importantly, CSC rats showed an increased plasma corticosterone response to an acute heterotypic stressorv (open arm, 5 min) despite displaying similar basal levels and similar basal and stressor-induced plasma ACTH levels. In contrast to CSC mice, anxiety-related behaviour and absolute, as well as relative adrenal weights remained unchanged in CSC rats. In summary, the CSC paradigm could be established as an adequate model of chronic psychosocial stress in male rats. Our data further support the initial hypothesis that adrenal hyper-responsiveness to ACTH during acute heterotypic stressors represents a general adaptation, which enables a chronically-stressed organism to adequately respond to novel challenges

Immunohistochemical single-labeling of pERK.

<p><b>A–G:</b> schematic drawings of coronal brain sections (derived from the Paxinos rat brain atlas, 63) with grey squares corresponding to the location of the quantified brain areas (<b>A:</b> LSv, bregma +0.20; <b>B:</b> BSTmpm<b>,</b> bregma −0.80; <b>C</b>: PVNm and PVNl, bregma −1.80; <b>D:</b> HAA, bregma −2.80; <b>E:</b> MeApd, CeA, VHMvl<b>,</b> bregma −3.14; <b>F:</b> DRd, bregma −7.80; <b>G:</b> PAGvl, bregma −8.30); <b>H:</b> Average density of pERK-IR in non-aggressive (white bars, n = 7) compared with aggressive (grey bars, n = 7) adolescent (7–8 week old) female NAB rats. Data are means ± s.e.m; *P<0.05; <b>I–J:</b> Illustration of pERK-IR in the PVNmp (“mp”) and PVNlm (“lm”) of non-aggressive (left) and aggressive (right) individuals (3v = third ventricle); <b>K–L:</b> Illustration of pERK-IR in the HAA of non-aggressive (left) and aggressive (right) individuals.</p

Timeline of experiments.

<p>Timeline of experiments.</p

Effect of estrous phase on behavior in the FIT.

<p>The number of females attacking as well as the percentage aggressive, social and non-social behavior of receptive and non-receptive adult (10–11 week old) virgin female NAB residents in response to receptive and non-receptive virgin female intruder rats in a 10-min Female Intruder Test (FIT). Data are medians and quartiles.</p

Behavioral profile of adolescent (7–8 week old) virgin female HAB (n = 12), NAB (n = 23) and LAB (n = 12) rats in the EPM and FIT.

<p><b>A:</b> Percentage of time spent in the open arms of the EPM; <b>B–D:</b> Attack latency, percentage of time displaying aggressive behavior and percentage of time displaying social behavior in a 10-min FIT. Data in <b>A–D</b> are medians and quartiles. <b>E:</b> Spearman’s correlation coefficient between percentage of time spent in the open arms of the EPM and percentage of time spent displaying aggressive behavior in the FIT two days later. *P<0.05; **P<0.01; ***P<0.001.</p