Comparison of the spatial-cognitive functions of dorsomedial striatum and anterior cingulate cortex in mice

<div><p>Neurons in anterior cingulate cortex (aCC) project to dorsomedial striatum (DMS) as part of a corticostriatal circuit with putative roles in learning and other cognitive functions. In the present study, the spatial-cognitive importance of aCC and DMS was assessed in the hidden-platform version of the Morris water maze (MWM). Brain lesion experiments that focused on areas of connectivity between these regions indicated their involvement in spatial cognition. MWM learning curves were markedly delayed in DMS-lesioned mice in the absence of other major functional impairments, whereas there was a more subtle, but still significant influence of aCC lesions. Lesioned mice displayed impaired abilities to use spatial search strategies, increased thigmotaxic swimming, and decreased searching in the proximity of the escape platform. Additionally, aCC and DMS activity was compared in mice between the early acquisition phase (2 and 3 days of training) and the over-trained high-proficiency phase (after 30 days of training). Neuroplasticity-related expression of the immediate early gene <i>Arc</i> implicated both regions during the goal-directed, early phases of spatial learning. These results suggest the functional involvement of aCC and DMS in processes of spatial cognition that model associative cortex-dependent, human episodic memory abilities.</p></div

Development of repetitive looping strategies over the course of training.

<p>Development of repetitive looping strategies over the course of training.</p

Spatial learning in the Morris water maze test.

<p>Animals with lesions in DMS (n = 9; filled circles, black bar) (A) required significantly more time to locate the hidden platform, (B) spent more time along the walls of the pool, (C) searched further away from the location of the hidden, and (D and E) swam slower from the second day of training compared to sham control group (n = 12; filled squares, grey bar). No overall differences between aCC (n = 11; empty circles, white bar) and sham control group were reported. Represented data are expressed as means ±SEM. * indicates significant differences between the sham control and lesion groups: *<i>p</i> < 0.05, **<i>p</i> < 0.01, ***<i>p</i> < 0.001.</p

Histological verification and lesion size determination.

<p>Representative coronal sections of bilateral (A) aCC and (B) DMS lesions. The left, middle and right pictures represent small, big and sham control lesions, respectively. All lesions were restricted to the region of interest. The bilateral lesions are encircled by a dotted line.</p

Employment of search strategies to locate the hidden platform.

<p>The strategy to search for the hidden platform location changed over the course of training and differed between lesion groups. The DMS group (black bar) failed to deploy a preference for the spatial search strategy, and instead relied on a repetitive search strategy. Represented data are expressed as means ±SEM. * indicates significant differences between the sham control and lesion groups: *<i>p</i> < 0.05, **<i>p</i> < 0.01, ***<i>p</i> < 0.001.</p

Learning-dependent changes in <i>Arc</i> expression.

<p>(A) Learning curves, demonstrating task acquisition as a decrease in latency (s) before reaching the hidden platform, of 2 days (2d_T), 3 days (3d_T) and 30 days (30d_T) trained mice are light grey, medium grey and black, respectively. Heat plots (blue and red indicating minimum and maximum search time spent, respectively) during early learning in the 2d_T and 3d_T group indicate that the overall search area remains variable and covers most of the environment with some focus towards the platform quadrant after 3 days of learning. During the late learning phase search patterns in the 30d_T group are highly focused on the hidden platform. Black circle represents the hidden platform. (B) Coronal sections displaying <i>Arc</i> expression in trained mice during early learning (2d_T and 3d_T) and late learning (30d_T) group. The left hemisphere shows the original autoradiogram in grey scale and the right hemisphere shows its matched pseudo-colour counterpart (dark green to white indicating no signal to maximum signal, respectively). (C) <i>Arc</i> expression in aCC increased from 2-day to 3-day trained group and decreased upon overtraining. In free-swimming controls, a reduction in <i>Arc</i> expression was present from the early to the late phase. At 3 days, trained mice demonstrated significantly higher <i>Arc</i> expression compared to free-swimming controls. (D) During the early learning phase <i>Arc</i> expression in DMS of trained mice was upregulated, albeit borderline significant, while extensive training resulted in a decreased <i>Arc</i> expression level. Free-swimming controls only showed a reduction in <i>Arc</i> expression from the early to the late phase. At 3 days, <i>Arc</i> expression in trained mice was significantly higher than in free-swimming controls. Dotted line represents baseline <i>Arc</i> expression level of cage control animals. Black and grey bars represent experimental (trained, T) and free-swimming control (SC) groups, respectively. Represented data are expressed as means ±SEM. * indicates significant differences between groups: **<i>p</i> < 0.01, ***<i>p</i> < 0.001.</p

Motor performance and working memory.

<p>(A) Average fall latencies over 4 consecutive trials on the accelerated rotarod in aCC- (n = 11; white bar), DMS- (n = 9; black bar) and sham control-lesioned mice (n = 12; grey bar) indicated no motor deficits. (B) Percentage of spontaneous alternations in the y-maze showed no differences in spatial working memory between the groups, and (C) total number of arm entries showed unchanged spontaneous locomotor activity.</p

Search strategies to locate the hidden platform.

<p>Search strategies to locate the hidden platform.</p