IntroductionOverreliance 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 for therapeutic outcomes. In this study, we researched the brains of ephrin-A2A5−/− mice, which previously showed perseverative behavior in progressive-ratio tasks, associated with low cellular activity in the nucleus accumbens. We investigated whether rTMS treatment had altered the activity of the dorsal striatum in a way that suggested altered hierarchical recruitment of brain regions from the ventral striatum to the dorsal striatum, which is linked to abnormal habit formation.MethodsBrain sections from a limited number of mice that underwent training and performance on a progressive ratio task with and without low-intensity rTMS (LI-rTMS) were taken from a previous study. We took advantage of the previous characterization of perseverative behavior to investigate the contribution of different neuronal subtypes and striatal regions within this limited sample. Striatal regions were stained for c-Fos as a correlate of neuronal activation for DARPP32 to identify medium spiny neurons (MSNs) and for GAD67 to identify GABA-ergic interneurons.Results and discussionContrary to our hypothesis, we found that neuronal activity in ephrin-A2A5−/− mice still reflected the typical organization of goal-directed behavior. There was a significant difference in the proportion of neuronal activity across the striatum between experimental groups and control but no significant effects identifying a specific regional change. However, there was a significant group by treatment interaction which suggests that MSN activity is altered in the dorsomedial striatum and a trend suggesting that rTMS increases ephrin-A2A5−/− MSN activity in the DMS. Although preliminary and inconclusive, the analysis of this archival data suggests that investigating circuit-based changes in striatal regions may provide insight into chronic rTMS mechanisms that could be relevant to treating disorders associated with perseverative behavior.

Topographic mapping of neural circuits is fundamental in shaping the structural and functional organization of brain regions. This developmentally important process is crucial not only for the representation of different sensory inputs but also for their integration. Disruption of topographic organization has been associated with several neurodevelopmental disorders. The aim of this review is to highlight the mechanisms involved in creating and refining such well-defined maps in the brain with a focus on the Eph and ephrin families of axon guidance cues. We first describe the transgenic models where ephrin-A expression has been manipulated to understand the role of these guidance cues in defining topography in various sensory systems. We further describe the behavioral consequences of lacking ephrin-A guidance cues in these animal models. These studies have given us unexpected insight into how neuronal activity is equally important in refining neural circuits in different brain regions. We conclude the review by discussing studies that have used treatments such as repetitive transcranial magnetic stimulation (rTMS) to manipulate activity in the brain to compensate for the lack of guidance cues in ephrin-knockout animal models. We describe how rTMS could have therapeutic relevance in neurodevelopmental disorders with disrupted brain organization.

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 LI-rTMS were taken from a previous study. 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.