Linking Inattention To Aggression - Data From The BALB/CJ Mouse Model of Aggression

Abstract

Abstract Current studies of aggression in heterogenous cohorts often display considerable genetic and phenotypic variance. The study of inbred mouse strains with reduced genetic variability between sub-strains and more amenable control of the environment enables a platform for the dissection of genetic and epigenetic moderators of aggression and it s cognitive and emotional underpinnings. Comparison of the BALB/cJ and BALB/cByJ sub-strains is one approach to utilise this method which has been deployed in the EU FP7 Aggressotype and MATRICS consortia. The BALB/cJ mouse model compared to its BALB/cByJ control shows increased aggression (reduced latency to attack; increased number of bites and atypical bite pattern) coupled to increased anxiety-like behaviour as demonstrated in the elevated plus maze. MRI studies of these mice using an 11.7T Bruker Biospec MRI scanner demonstrates reduced white matter integrity in the anterior cingulate cortex (ACC) and dorsomedial striatum (DMS) and increased brain gray matter volume coupled to lower body weight. In high resolution ex vivo MRI studies of these sub-strains, marked volumetric increases are seen in the striatum, hypothalamus, hippocampus. Decreases in the volume are apparent in the frontal, insular and sensory cortices. Furthermore, 1H-MRS of the aggressive BALB/cJ mouse model demonstrates no change in anterior cingulate cortex (ACC) excitatory glutamate but a reduction in ACC GABA levels compared to the BALB/cByJ control strain. Realtime quantitative polymerase chain reaction (qPCR) estimates of GABA related gene expression demonstrates no change in ACC expression of the GABA synthetic enzymes GAD1 or GAD2 (coding for glutamate decarboxylase (GAD)67 and GAD65 respectively) but a 20 fold increase in the mRNA expression of the GABA catabolic enzyme 4-Aminobutyrate aminotransferase (ABAT) in the ACC. Furthermore, 1H-MRS estimates of total ACC choline levels (which may reflect intrinsic choline tone at nicotinic alpha7 receptors as well as excitatory acetylcholine and phosphocholine concentrations) are decreased in the aggressive BALB/cJ strain. Taken together, this suggests a dysregulation in the BALB/cJ mice of excitatory / inhibitory balance within the ACC, a crucial prefrontal cortical control region involved in the regulation of both cognitive and emotional processing. Causal modelling in human childhood and adolescent ADHD cohorts has suggested a causative role for inattention in mediating aggressive responses. Interestingly, BALB/cJ mice also demonstrate decreased attention performance (increased omissions) compared to BALB/cByJ mice in the 5-choice serial reaction time task. Indications that this might result from altered (threat) sensitivity to their environment is underlined by behavioural data showing that BALB/cJ fail to learn to punishment and demonstrate altered fear conditioning. Reduced cortisol levels are seen in blood samples from aggressive BALB/cJ mice both before and following the resident intruder task compared to their BALB/cByJ controls; this is linked to reduced ACC expression of corticotrophin-releasing hormone (Crh) mRNA in BALB/cJ mice. Finally, the psycho-stimulant methylphenidate (which is effective in the clinic) normalises aggressive behaviour and aberrant fear conditioning in BALB/cJ mice suggesting that methylphenidate s blockade of dopamine and norepinephrine uptake may regulate stress sensitivity and inhibitory control in these mice.