Regeneration and recovery in the fetal nervous system after radiation injury

Previous studies showed that recovery from destructive injury in 12-day fetal rats (23 to 34 somite pairs) exposed to 150 R appeared to be remarkably good except for minor abnormalities of the brain and spinal cord in some animals and occasionally microphthalmia. Nothing more was known of the morphogenesis of this restitution. A series of rats irradiated on the 12th fetal day was studied histologically and in other ways from a few hours after exposure to adulthood. Five to eight hours after 150 R there was widespread necrosis of certain classes of primitive proliferative cells in the nervous system and other tissues, but residual cells had resumed proliferative activity. By 24 h regeneration of the proliferative cells was advanced and most necrotic cells had disappeared, and at 48 h the irradiated fetus closely resembled the normal. There were very few residual dead cells, and minute foci of proliferative cell rosettes were present in the midline of the ventral spinal cord and brain stem. Seventy-two and ninety-six hours after irradiation the fetuses looked like their normal counterparts except for persistent or resolving minute rosettes. At later stages to adulthood, effects of the rosette formation were not visible. In some individuals the spinal cords were reduced slightly in overall cross-sectional area and the pallium was shorter than normal. Other irradiated animals could not be distinguished from normals.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23969/1/0000218.pd

Normal development and post-traumatic plasticity of corticospinal neurons in rats

Corticospinal (CS) neurons projecting to the spinal cord in the adult rat, identified by retrograde axonal transport of horseradish peroxidase (HRP), formed a caudal band in areas 3, 4, and 6 and a rostral band in area 10, separated by a gap. In the infant the gap was filled with CS neurons. The problem: What happened to the transient infant neurons as the mantle expanded, and would they persist if other CS neurons were destroyed in infancy? Identification of CS neurons by HRP and measurements of the growth of the mantle and cortical areas 3, 4, and 6 showed that CS neurons were scattered widely in the cortex as well as in the gap and future bands at 2 to 10 days. By about 2 weeks, CS neurons labeled from the cervical cord were limited to the "adult" bands. The greatest mantle expansion postnatally was in the occipital and bregma regions, including the anterior, but not the posterior, part of area 3, 4, and 6. Thus, expansion of the mantle, growth of areas 3, 4, and 6, and axonal growth of transient and permanent CS neurons did not parallel each other closely. When one or both caudal band regions were ablated at 5, 7, or 10 days, the gap CS neurons persisted bilaterally to adult life. No necrosis of layer V neurons was observed between 10 days and 2 weeks. It was assumed that the gap neurons and other extraneous CS neurons generated exploratory axons which normally disappeared, but when caudal band neurons were destroyed the transient axons attempted to fill the pathway.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22586/1/0000134.pd

Motor-sensory and visual behavior after hemispherectomy in newborn and mature rats

Immature mammals are widely believed to compensate functionally for nervous system alterations better than adults with comparable disorders. Embryos restitute huge losses, but plasticity, remodeling, or use of alternate mechanisms said to underly compensation in injured infants are not understood. Toward understanding these, the effects of ablating or altering parts of the nervous system in infant and mature rats are being studied. In these experiments one lateral half of the forebrain and diencephalon was largely removed at birth or maturity and the consequences to nervous system structure and motor-sensory and visual behavior were observed. Similarities between animals operated on as adults or infants were loss of tactile placing opposite the ablation, ability to discriminate visual patterns, and gauge variable jumping distances visually. Some subjects performed the visual tasks using the eye opposite the hemispherectomy alone, which was exclusively supplied with uncrossed retinogeniculate fibers. Differences were: loss of tactile placing after operation in infants was delayed until the seventeenth day; stride was impaired in animals operated on as adults but was spared in infant subjects; with appropriate ablations, Fink-Heimer-Nauta stains showed that after hemispherectomy, infants, but not adults, developed a small, uncrossed corticospinal tract. The stride component in locomotion seemed dependent on the corticospinal tract system, and was partially dissociated from the placing reaction essential for locomotion on rough terrain. The possibility was considered that the small remodeled corticospinal tract spared the stride component.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32648/1/0000012.pd

A new cell surface relationship between neuroepithelial cells during rat neural tube development

Electron microscopic examination of the developing neural tube in 11th to 13th day rat fetuses revealed a new cell surface relationship between differentiating neuroepithelial cells. Cytoplasmic projections possessing terminal dilations were observed extending from neuroepithelial cells through cytoplasmic furrows into large coated pits at the surface of adjacent cells. This cell-to-cell relationship provides a mechanism for the internalization of surface molecules and possibly even cytoplasmic constituents. Communication between donor and recipient cells mediated in this way suggests a route for the sharing of macromolecules, including cytoplasmic fragments, which could function as regulators in embryonic development and differentiation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24985/1/0000412.pd

Loss of hippocampal [3H]TCP binding in Alzheimer's disease

We have previously demonstrated a marked loss in (NMDA) receptors in the hippocampus and cerebral cortex of patients dying with dementia of the Alzheimer type (DAT). In addition, we have found that the dissociative anesthetic N-(1-[2-thienyl]cyclohexyl)3,4-piperidine ([3H]TCP) binds to a site whose regional distribution is highly correlated with that of NMDA receptor sites. We studied the binding of [3H]TCP to sections of hippocampi from 8 controls, 12 patients with DAT and 7 patients with other dementias. [3H]TCP binding was significantly reduced in strata pyramidalia of CA1/CA2, CA3 and subiculum of DAT hippocampal formation compared to that of control. Labelled dissociative anestheties could potentially be used with positron emission tomography in the diagnosis of DAT.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26773/1/0000325.pd

Development of the motor system: Effects of radiation on developing corticospinal neurons and locomotor function

Corticospinal (CS) neurons demonstrated by retrograde axonal HRP from the cord in adult rats were concentrated in a minor rostral band in area 10, projecting to the cervical cord, and a major caudal band, areas 3, 4, and 6, projecting as far as lumbar levels. The gap between the bands contained CS neurons projecting to the cervical cord only until age 2 weeks, but if the caudal band was ablated, the projections persisted. The problems investigated were (i) How would CS neurons develop postnatally and be distributed in rats prenatally irradiated on the 12th, 14th, 15th (150 R), or 17th day (150 or 200 R)? and (ii) Would answers to the foregoing help establish correlations between the development of structural and motor abnormalities? Most 12th-day-irradiated rats showed normal locomotion on difficult paths and nearly normally developing brain and cord structure, but rare CS neurons had bifurcated apical dendrites. Fourteenth and 15th-day rats had a thin cortex, a large subcortical ectopia, a malformed spinal cord, and a hopping gait. They showed diminished numbers of CS neurons in the cortex with persistent gap CS neurons, and CS neurons in the ectopia that mirrored those in the cortex. Hopping seemed to be generated in the cord, but supraspinal influences require further study. Seventeenth-day rats usually showed disordered locomotor rhythm and inability to adapt it to difficult paths, suggesting impairment of corticostriatal circuits. Some rats also showed inability to place limbs and feet during locomotion on difficult terrain, which resembled that following ablation of areas 3, 4, and 6. Dorsal cortex, including area 10, the chief source of corticostriatal projections in the rat, and areas 3, 4, and 6, was most severely malformed. Discrepancies between functional results of ablating area 10 and malforming it with radiation led us to suggest that abnormal thalamocortical and cortical wiring, for which there was evidence, as well as deficits, might be responsible for the abnormal locomotion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23124/1/0000048.pd

Cell migrations to the isocortex in the rat This work was supported by USPHS grant NB03861 and AEC Contract AT (11-1) 1201.

Cells that took up tritiated thymidine (H-3T) at various periods of intrauterine and early infant life in the periventricular proliferative zone and migrated to form the isocortex in the rat were tracked autoradiographically in series of stages to characterize their movements. Cells labeled at any stage soon separated themselves into cohorts, some continuing to proliferate, others migrating at once, and still others delaying before migrating. Migratory cells moved to the developing cortex along the curved and oblique paths of the pallial fibers, whose basic plan was established by the early thalamocortical fibers. Magnitude of speed was 15 to 30 Μ per hour. The primitive neural cells that originated on each of the fourteenth to eighteenth intrauterine days first reached the cortex in about 48 hours, others took two or three days longer. Migrations originating on the nineteenth to twenty-first days continued into the week after birth; as the primitive cells approached the cortex, however, they differentiated into young neurons, and traveled perpendicularly to its outer part. The first cohort of twentieth day labeled cells reached their intracortical destinations in about three days, the last in about ten days. The isocortex was formed essentially from within outward. The first neuroglia destined for the isocortex arose on the twenty-first intrauterine day.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49811/1/1091600311_ftp.pd

Development of the motor system: Hopping rats produced by prental irradiation

Irradiation of prenatal and infant rats resulted in a spectrum of highly reproducible nervous system malformations associated with locomotor abnormalities difficult to correlate with morphologic findings. Fetal rats exposed to 150 R on the 13th, 14th, or 15th day of gestation were born with a hopping gait, paired hind and forelimbs moving in unison instead of the normal alternating mode. Some animals switched partly or completely to an alternating gait of forelimbs, rarely hind limbs. Rats irradiated on the 12th, 16th, or 17th day did not hop. The problem: Was the hopping related to the brain or spinal cord? Hopping rats could jump to a level or tilted landing platform. Their forelimbs tactually placed independently of each other, whether they hopped or not, but the hind limbs scratched synchronously. Thoracic cord transection led to crossed extension hind-limb reflexes in normal rats, and simultaneous withdrawal of hind limbs in hopping rats, in response to bilateral pinprick. The dorsal horns, especially Rexed's laminae I-VI, and sometimes the most dorsal part of VII, which were being formed in the 13- to 15-day period as shown by tritiated thymidine autoradiography, were underdeveloped. This was due to failure to make restitution of residual dorsal proliferative cells remaining after radiation. Some neurons destined for the dorsomedial parts of the ventral horns may have been lost after the 13th- and 14th-day irradiation, but not the 15th. Precisely how dorsal horn deficiencies could affect the spinal locomotor generator, presumed to be more ventrally situated, it is not yet known. Nor has the exact nature of the suprasegmental adaptation to the hopping mechanism and switching to normal forelimb gait been worked out.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23125/1/0000049.pd

Locating corticospinal neurons by retrograde axonal transport of horseradish peroxidase

Different views of the location and organization of corticospinal (CS) neurons in the rat have resulted from fiber degeneration studies, electrophysiologically derived somatotopic maps, studies of CS axonal branching, and functional alterations after ablation of parts of the motor-sensory cortex. To locate more precisely CS neurons that projected to different levels of the spinal cord, and to determine whether or not they were arranged somatotopically, we labeled them with horseradish peroxidase (HRP) from their cut spinal axons. These labeled neurons were arranged in a major caudal band about 4.5 mm long and 3 mm wide corresponding principally to areas 3, 4, and 6, and a minor rostral band in the anterior part of area 10. The caudal band also corresponded to electrophysiologically derived somatotopic hindlimb and forelimb motor areas. The most significant finding was that CS neurons labeled from the lumbar spinal cord and from cervical levels were intermixed generally throughout the caudal band, showing virtually no somatotopic anatomic arrangement. The rostral band, which corresponded to mouth parts in somatotopic maps, was an unexpected finding. Calculations based on estimates of the numbers of CS axons at different cord levels indicated that about 10,000 CS neurons in each cortex projected as far as the rostral cervical cord, and about 2000 continued as far as lumbar levels. The HRP method as used was capable of labeling a majority of the calculated numbers of CS neurons, but showed a large variance in the total numbers of neurons labeled. The distributions of the neurons within the domains of the bands was consistent regardless of the numbers labeled.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22865/1/0000427.pd