Dissecting the functional contributions of different neuronal subtypes in the dorsal striatum to perseverative behaviour in ephrin-A2/A5-/- mice

Abstract

Overreliance on habit is linked with disorders such as drug addiction and obsessive-compulsive disorder and there is increasing interest in the use of repetitive transcranial magnetic stimulation (rTMS) to alter neuronal activity in the relevant pathways and reduce relapse or accelerated shift towards habit formation. Here we studied the brains of ephrin-A2A5-/- mice, which previously showed perseverative behaviour in progressive-ratio tasks, associated with low cellular activity in nucleus accumbens. We investigated if rTMS treatment had altered the hierarchical recruitment of brain regions from ventral to dorsal striatum associated with abnormal habit formation in these mice. Brain sections of mice that underwent progressive-ratio tasks with and without low intensity rTMS (LI-rTMS) were taken from a previous study. We take advantage of the previous characterisation of perseverative behaviour to investigate the contribution of different neuronal subtypes and striatal regions. Striatal regions were stained for neuronal activation with c-Fos and for medium spiny neurons with DARPP32. Qualitative analysis was carried out for other neuronal subtypes in the striatum - GABAergic, parvalbumin-expressing and cholinergic interneurons. Contrary to our hypothesis, we found neuronal activity in ephrin-A2A5-/- mice still reflected goal-directed behaviour. However, we saw that the dorsolateral striatum contributed more to total striatal activity in untreated ephrin-A2/A5-/- mice. This supported our hypothesis that ephrin-A2/A5-/- mice have greater c-Fos activity in habit-associated striatal regions. LI-rTMS in ephrin-A2A5-/- mice also appeared to delay the shift from goal-directed to habitual behaviour as suggested by increased activation in dorsomedial striatum and nucleus accumbens.