Samuel P. Hicks

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

Abstract 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.

Locating corticospinal neurons by retrograde axonal transport of horseradish peroxidase

Abstract 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.

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

Abstract 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.

EFFECTS OF LOW LEVELS OF IONIZING RADIATION ON THE DEVELOPING CEREBRAL CORTEX OF THE RAT

THE EFFECTS of low levels of radiation on mammalian development have been little studied in contrast to those following exposures to hundreds of roentgensl-5 whose mechanisms are beginning to be understood.F-ll Various recent reports have made low-level irradiation a matter of interest, and sometimes concern, and they raise questions about mechanisms of action, especially persistent and delayed effects. For example, the incidence of certain skeletal anomalies in a strain of mice disposed to develop them sporadically was increased by exposing them to as little as 25 R during stages of embryonic life when the body axis and early skeleton was being established.12 When mice were exposed to fast neutrons continuously from the time they were conceived until they were adults, at a rate of a little less than 1 rad daily, their growth was impaired and their lifespans shortened more than if the irradiation was begun in adolescence.l3 Children exposed to diagnostic X-rays-even a few roentgenswhen they were fetuses showed a slightly but significantly increased incidence of childhood cancer.14 Retarded development of normal conditioned reflexes, and persistent difficulty in retaining these reflexes, was described in rats exposed to 1 R daily for twenty days during intrauterine life.lG Abnormalities of development at both the cytologic and cytoarchitectural level in the cortex and cerebellum of rats that had been exposed to 20 to 40 R during fetal or newborn stages were reported recently.16 In some of these, there is the problem of whether the consequences were secondary to acute brief injury, analogous to some of the

Low Dose Radiation of the Developing Brain

X-irradiation administered in single doses of 10 to 40 r has a widespread effect on the developing rat brain. It first diminishes the formation of cytoplasmic basophilic material in the nerve cells and inhibits their growth. Single doses of 20 to 40 r cause permanent alterations of individual nerve cells, and interfere with their organization into neuronal assemblies, such as layers of the cerebral cortex.

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

Abstract 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.

Mannosidosis: Two brothers with different degrees of disease severity

Two siblings with different degrees of mental retardation, skeletal dysplasia, coarse facies, delayed speech, motor incoordination, recurrent respiratory infections, and immunological abnormalities, were found to have deficient alpha‐mannosidase activity. Cultured skin fibroblasts in one sib were markedly deficient in alpha‐mannosidase while all other lysosomal enzymes tested were within the normal range. The more severely affected sib came to autopsy and was found to have “washed‐out” appearing cortical neurons and marked histiocytosis effacing lymph node architecture and partially replacing the bone marrow. The post‐mortem brain and liver samples demonstrated a deficiency in alpha‐mannosidase relative to the elevations of other lysosomal enzymes. Although the patterns of abnormalities in the two cases closely match those of descriptions of “type II” and “type I” mannosidosis respectively, the variation should be due to genetic modifiers or environmental effects since the brothers must have shared similar alpha‐mannosidase mutations. Immunologic abnormalities present in the more severely affected sib suggest that the differential survival seen in mannosidosis types I and II may be due to differences in their immune systems.

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

Abstract 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 Rexeds 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.

Genetic prenatal aqueductal stenosis with hydrocephalus in rat

A recessive mutation which arose in Wistar albino rats was variably expressed in the homozygous state as prenatal stenosis of the aqueduct with resultant hydrocephalus. The condition was often compatible with survival to adulthood and with successful reproduction. Mildly sparse hair was the constant gene marker. Eye defects and sometimes foot deformities occurred. The first observable ultrastructural alteration was a disruption of the integrity of the neuroepithelial basal lamina in the cephalic neural tube of affected embryos as early as the 11th fetal day (16–24 somite pairs). The hydrocephalic syndrome closely resembled that produced by giving folic acid analogs to, or producing vitamin B12 deficiency in, pregnant rats in the period including the 11th day. Neither vitamin B12 nor folate, nor certain metabolites closely related to their metabolism, prevented the genes expression. Homozygote mutants mated with homozygote mutants produced 70% hydrocephalic (dome-shaped heads) offspring, but if the mother was heterozygote, there was a “protective” effect and the number of hydrocephalic young was disproportionately smailer.

Vascular malformation of the brainstem: Report of a case with long duration and fluctuating course

We studied a patient with a vascular malformation within the pons and medulla, affecting the cranial nerve nuclei, ascending and descending pathways, and cerebellar peduncles and adjoining structures. The symptoms had been present for more than 50 years. They were fluctuating in the beginning but later were progressive. The malformation probably had its origin during the first month of embryonic life.