Separate proliferation kinetics of fibroblast growth factor-responsive and epidermal growth factor-responsive neural stem cells within the embryonic forebrain germinal zone.

The embryonic forebrain germinal zone contains two separate and additive populations of epidermal growth factor (EGF)- and fibroblast growth factor (FGF)-responsive stem cells that both exhibit self-renewal and multipotentiality. Although cumulative S phase labeling studies have investigated the proliferation kinetics of the overall population of precursor cells within the forebrain germinal zone through brain development, little is known about when and how (symmetrically or asymmetrically) the small subpopulations of stem cells are proliferating in vivo. This has been determined by injecting timed-pregnant mice with high doses of tritiated thymidine ((3)H-thy) to kill any stem cells proliferating within the striatal germinal zone in vivo and then by assaying for neurosphere formation in vitro. Injections of 0.8 mCi of (3)H-thy given every 2 hr for 12 hr to timed-pregnant mice at E11, E14, and E17 resulted in significant depletions in the number of neurospheres generated by FGF-responsive stem cells at E11 and by EGF-responsive and FGF-responsive stem cells at E14 and E17. With increasing embryonic age, the depletions observed in the number of neurospheres generated in vitro in response to FGF2 after exposure to (3)H-thy in vivo decreased, suggesting there is an increase in the length of the cell cycle of FGF-responsive neural stem cells through embryonic development. The results suggest that the FGF-responsive stem cell population expands between E11 and E14 by dividing symmetrically, but switches to primarily asymmetric division between E14 and E17. The EGF-responsive stem cells arise after E11, and their population expands through symmetric divisions and through asymmetric divisions of FGF-responsive stem cells.

Spatio-temporal impairments in limb and body movements during righting in an hemiparkinsonian rat analogue: relevance to axial apraxia in humans.

Humans with Parkinson's disease (PD) often have problems in righting themselves, in that they have difficulty in recruiting their axial musculature to rotate the body to prone. Since this "axial apraxia' is not ameliorated by L-DOPA therapy, it has been concluded that dopamine (DA) does not play a role in recruiting axial rotation of the body [14]. This hypothesis was tested by comparing the righting of rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra (SN) with that of intact rats. Body-on-body righting, where asymmetrical tactile stimulation of the body initiates hindquarter righting, was used to specifically test tactile righting independently of righting triggered or influenced by other sensory systems. In this behavioral test, rats are placed on their sides, their forequarters are held down and their hindquarters released. The DA-depleted rats took longer to begin righting, to complete righting, and used more limb action to right themselves than did control rats. These findings suggest that for this tactile based form of righting, DA-depletion produces axial apraxia. However, frame-by-frame analysis of righting sequences of DA-depleted rats showed that pelvis-led axial rotation could occur, but the spatio-temporal relationship between body and limb movements was disorganized. Therefore, following DA-depletion axial apraxia-like deficits appear to arise from sensorimotor disruption. This raises the issue of whether the axial apraxia in PD patients arises from damage to systems beyond the nigrostriatal DA system, or from interference with sensorimotor integration that is not ameliorated by replacement therapy.

Impairments and compensatory adjustments in spontaneous movement after unilateral dopamine depletion in rats.

Rats with unilateral dopamine (DA) depletions (hemi-Parkinson rats) display directional biases in their locomotion in spontaneous and drug induced tests. These biases have been explained as being due either to changed responsiveness to sensory stimulation, changes in motor ability, or to central changes, but as yet their basis is not fully understood. The purpose of the present experiment is to examine the posture of immobility and the posture and strategies of locomotion in rats with unilateral DA depletions. The rats are found to display impairments in their bad limbs (contralateral-to-lesion limbs) in adjusting posture and moving. They compensate by supporting themselves mainly on their good hindlimb, using the bad hindlimb and tail for balance and by disproportionately relying upon their good limbs to turn and to walk. Thus, their center of gravity is shifted to the good side and movement is preferentially directed toward the good side, in part to maintain equilibrium and in part to remove weight from the bad limbs so that they can enter the swing phase of the stepping cycle. It is proposed that the bad limbs may be unable to apply force to adjust posture and produce movement. These results provide a basis for predicting the movements that the animals will use in various situations and they expand the test repertoire this hemi-Parkinson model provides for studying recovery processes after loss of dopamine.