Changes in brain functional activation during resting and locomotor states after unilateral nigrostriatal damage in rats

Abstract

To evaluate functional neuronal compensation after partial damage to the nigrostriatal system, we lesioned rats unilaterally in the striatum with 6-hydroxydopamine. Five weeks later, cerebral perfusion was mapped at rest or during treadmill walking using [(14)C]-iodoantipyrine. Regional CBF-related tissue radioactivity (CBF-TR) was quantified by autoradiography and analyzed by statistical parametric mapping and region-of- interest analysis. Lesions were confirmed by tyrosine hydroxylase immunohistochemistry and changes in rotational locomotor activity. Functional compensations were bilateral and differed at rest and during treadmill walking. Consistent with the classic view of striatopallidal connections, CBF-TR of lesioned compared to sham-lesioned rats increased in the ipsilateral subthalamic nucleus (STN) and internal globus pallidus, and decreased in the striatum and external globus pallidus. Contrary to the classic view, CBF-TR increased in the ipsilateral ventral lateral, ventral anterior thalamus and motor cortex, as well as in the central medial thalamus, midline cerebellum, and contralateral STN. During walking, perfusion decreased in lesioned compared to sham-lesioned rats across the ipsilateral striato-pallidal-thalamic-cortical motor circuit. Compensatory increases were seen bilaterally in the ventromedial thalamus and red nucleus, in the contralateral STN, anterior substantia nigra, subiculum, motor cortex, and in midline cerebellum. Enhanced recruitment of associative sensory areas was noted cortically and subcortically. Future models of compensatory changes after nigrostriatal damage need to address the effects of increased neural activity by residual dopaminergic neurons, interhemispheric interactions and differences between resting and locomotor states. Identification of sites at which functional compensation occurs may define useful future targets for neurorehabilitative or neurorestorative interventions in Parkinson's disease.

Fig. 1

Lesion development in the striatum and substantia nigra. Coronal brain sections 33 days after unilateral intrastriatal injection of 6-OHDA (n = 18) or vehicle (n = 15) processed with TH-immunohistochemical and hematoxylin staining. The loss of area of TH-positive staining (arrows) on the lesioned side was expressed as a percentage of the total intact area, as measured on the contralateral side, both for the striatum (1C) and substantia nigra (2C). No detectable loss of TH staining was noted in sham-lesioned rats both at the level of the striatum and substantia nigra. Measurements (±S.E.M.) were taken at +1.0 mm and -1.0 mm relative to bregma (striatum) and -5.8 mm relative to bregma (substantia nigra). *p < 0.0001 vs. control.

Fig. 2

Rotational behavior (mean ± S.E.M.) after administration of D-amphetamine (5 mg/kg, i.p.) in rats with unilateral striatal lesions (n = 18) or sham lesions (n = 15). The left figure depicts total rotation; the right figure depicts net rotation (difference between positive clockwise turns and negative counter-clockwise turns). Injection occurs after a 10-min baseline, as indicated by the arrow. *p < 0.005 lesion vs. sham-lesion group.

Fig. 3

Maps of the color-coded average z-scores of regional cerebral blood flow related tissue radioactivity (CBF-TR) on the topographic surface of the flattened cortex. Depicted are average z-score differences between rats with unilateral striatal lesions and sham-lesioned animals either (top) at rest, or (middle) during treadmill walking. The comparison of the functional brain activation in response to treadmill walking is shown for the lesioned animals (bottom). Arrows denote changes in cerebral perfusion of motor cortex. In these two-dimensional maps of the flattened cortex, the x- and y-coordinates are obtained from measures of the anatomical distances within the autoradiographs. The x-axis (locations) represents lateral distance from the midline (in mm) along the cortical rim within a slice. The y-axis (slices) represents coronal slices, numbered from rostral to caudal, with distance relative to bregma in millimeters (positive values being rostral to this landmark). To avoid discontinuities in the graphic representation, the space between each coronal slice and the locations within each slice, for which there were no measurements, was filled with values calculated by linear interpolation. Interpolations were performed separately for each hemisphere with interpolation distances ranging from 300 to 1000 μm. Superimposed on the maps are the borders of the main cortical areas (Paxinos and Watson, 2005): A, amygdala; Au, auditory; FrA, frontal association; I, insular; LEnt, lateral entorhinal; LO, lateral orbital frontal; M1, primary motor; M2, secondary motor; O, olfactory; P, parietal; Pir, piriform; PRh, perirhinal; RS, retrosplenial; primary somatosensory mapping the S1BF, barrel fields; S1FL, forelimbs; S1HL, hindlimbs; S1J, jaw; S1S, shoulder; S1Tr, trunk; S1U, upper lip region; S2, secondary somatosensory; TeA, temporal association; V1, primary visual; V2, secondary visual.

Fig. 4

Regions of statistically significant differences of functional brain activation in rats with unilateral striatal lesions in lesioned and sham-lesioned rats either at rest (Lesion + Rest, n = 9, Sham+ Rest, n = 7) or during a treadmill walking (Lesion+ Locomotor, n = 9, Sham+ Locomotor, n = 8). Depicted is a selection of representative coronal slices (anterior-posterior coordinates relative to bregma). Colored overlays show statistically significant positive (red) and negative (blue) differences (voxel level, p< 0.01). Abbreviations are those from the Paxinos and Watson (2002) rat atlas: 5 (trigeminal nucleus, motor, sensory), A (amygdala), aca (anterior commissures), APT (anterior pretectal nucleus), Cb (cerebellum), CM (central medial thalamic nucleus), CPu (striatum), GPE (external globus pallidus), GPI (internal globus pallidus), I (insular cortex), LP (lateral posterior thalamic nucleus), M1, M2 (primary, secondary motor cortex), MG (medial geniculus), P (parietal cortex), S1BF, S1J, S1U, S1FL, S1HL, S1Tr (primary somatosensory cortex, barrel field, jaw, lip, forelimb, hindlimb, trunk), PH (posterior hypothalamus), Pir (piriform cortex), Re (thalamic reuinens nucleus), RLi (rostral linear raphe), SC (superior colliculus), SN (substantia nigra), STN (subthalamic nucleus), SuM (supramammillary nucleus), V1, V2 (primary and secondary visual cortex), VM (ventromedial thalamic nucleus), VL/VA (ventral lateral, ventral anterior thalamic nucleus), VPL/VPM (ventral posterolateral, ventral posteromedial thalamus), ZI (zona inserta).

Fig. 5

Striato-pallidal circuits. Shown is the classic view of the indirect pathway (gray shading) and direct pathway (stipled box), as well as their net inhibitory (-) or excitatory (+) effects. STN (subthalamic nucleus), GPE (external globus pallidus), GPI/SNr (Internal globus pallidus/substantia nigra reticulate), ventrolateral/ventral anterior thalamus (VL/VA). Adapted from DeLong and Wichmann (2007).