Conditional over-and underexpression of genes in specific areas and cell types of the rodent brain have been recently used to model a key mechanism of schizophrenia (i. e. overactivity of dopamine D2 receptors (D2R) in the striatum). For that purpose transgenic mice were generated, which overexpress selectively in the postnatal phase D2 receptors in medium spiny neurons of the striatum. This overexpression can be inactivated by chronic oral treatment with doxycycline¹. In adulthood, these mice exhibit deficits in prefrontal-dependent cognitive tasks and a decrease in incentive motivation². While the latter deficits are reversible upon treatment with doxycycline and subsequent deactivation of the transgene, the prefrontal cognitive deficits remain despite downregulation of striatal D2R to normal levels. The diverse brain regions and networks underlying different behavioral tasks show a various extent of plasticity. However, it is not known how a circumscribed functional or structural alteration in the striatum reversibly or irreversibly influences brain networks responsible for these complex behavioral tasks. The purpose of the present study is to identify brain regions that are changing due to the normalization of striatal D2R.D2R overexpression animals were generated as described before¹. 8 mice with striatal D2R overexpression as well as 8 control animals were administered doxycycline (40 mg/kg food), which was given for two weeks in order to downregulate overexpression. The mice were measured at a 9.4 T animal scanner equipped with a cryogenic mouse brain coil before and after the treatment (3 weeks apart). For the VBM analysis 3D T2-weighted RARE-images (resolution of 78x78x156 μm³) were acquired. The VBM analysis was performed by longitudinal registration (SPM12) of each animal’s second time-point measurement to the first time-point measurement, which generated Jacobian Determinant images depicting the local volumetric differences in the non-linear registration procedure. Mean images of both time-points for each subject were segmented and normalized with DARTEL to a template space as described in (³). Resulting tissue images were multiplied by the Jacobian Determinant images and analyzed in a two-sample t-test in SPM12.While the groups were too small to show cross-sectional differences using standard VBM procedures, the longitudinal registration showed large areas of significant (p<0.05 cluster-corrected) volume gain after the treatment in the animals with D2R overexpression (Fig. 1). The areas with increased volume due to the treatment covered large parts of frontal and prefrontal lobe, striatum, amygdala, frontal parts of the parieto-temporal lobe and inferior colliculus with an asymmetry covering larger areas in the left hemisphere. We did not find any areas with decreased volume over time in the D2R overexpression group.

Our results demonstrate a high structural plasticity in some parts of the brain within three weeks after the onset of downregulation of the D2R overexpression. Particularly the regions showing a volume increase over time, i.e. the frontal, prefrontal and temporal regions correspond to areas with decreased gray matter volume commonly found in VBM studies on schizophrenia patients⁴.

These results also emphasize the high sensitivity of longitudinal VBM since regardless of this outcome we could not find any cross-sectional group differences before or after the treatment.