696. WHOLE BRAIN ACTIVITY MAPPING OF THE EFFECTS OF A NOVEL SMALL MOLECULE ON CHRONIC SOCIAL ISOLATION INDUCED AGGRESSION IN MICE

Abstract Background Agitation and aggression are common across many disorders of the brain, including dementia, where 76% of patients are affected. Currently, the only approved pharmacological treatments are atypical antipsychotics, which carry serious safety risks. KNX100 is a novel, prosocial compound that has been shown to reduce aggression in preclinical models. Aims & Objectives To map whole brain activity during aggression and how it is modulated by KNX100 treatment compared to the atypical antipsychotic risperidone. Method Male Swiss mice were group housed (controls) or socially isolated for 10 weeks to induce aggression. Following isolation, mice were treated (i.p.) with KNX100 (7.38mg/kg), risperidone (1mg/kg) or vehicle (n=10-12 per group) before undergoing a social interaction test in a novel context during which aggression was assessed by measuring the number and duration of fights. Mice were perfused, brains cleared, and c-Fos labelled using iDISCO. Cell counts, atlas alignment, and analysis were performed using custom Python and R pipelines. Results KNX100 and risperidone significantly inhibited hyperaggressive behaviour in chronically socially isolated mice. KNX100 treatment significantly normalised or partially normalised activity associated with aggression in over 100 regions. This included subregions of the hippocampus, amygdala, hypothalamus, thalamus, frontal cortex, basal ganglia, basal forebrain, and midbrain. In contrast, risperidone significantly normalised or partially normalised activity associated with aggression in four brain regions and risperidone treatment was primarily associated with changes in activity in subregions of the cerebellum, brainstem, thalamus, and basal ganglia. Discussion & Conclusions Distinct activity patterns were associated with the anti-aggressive effects of KNX100 and risperidone. KNX100 treatment was associated with circuits heavily implicated in threat detection, emotional regulation, behavioral inhibition, and sensory integration. In contrast, risperidone acted primarily on regions involved in motor control, arousal, and sensory gating. Interestingly, while both compounds normalised aggressive behaviour, KNX100 is efficacious at doses that have no effects on gross locomotor activity, whereas risperidone modulates aggression at doses that have sedative-like effects. The findings of the present study provide important insights into the differing neural substrates of KNX100 and risperidone effects on aggression and suggest KNX100 may act more through circuits more specifically involved in emotional regulation and aggression.