Genetic background determines behavioral responses during fear conditioning.

Freezing behavior is used as a measure of a rodent's ability to learn during fear conditioning. However, it is possible that the expression of other behaviors may compete with freezing, particularly in rodent populations that have not been thoroughly studied in this context. Rearing and grooming are complex behaviors that are frequently exhibited by mice during fear conditioning. Both behaviors have been shown to be stress-sensitive, and the expression of these behaviors is dependent upon strain background. To better understand how genetic background impacts behavioral responses during fear conditioning, we examined freezing, rearing, and grooming frequencies prior to fear conditioning training and across different stages of fear conditioning testing in male mice from eight inbred mouse strains (C57BL/6J, DBA/2J, FVB/NJ, SWR/J, BTBR T + ltpr3Tf/J, SM/J, LP/J, 129S1/SvlmJ) that exhibited diverse freezing responses. We found that genetic background determined rearing and grooming expression throughout fear conditioning, and their patterns of expression across stages of fear conditioning were strain dependent. Using publicly available SNP data, we found that polymorphisms in Dab1, a gene that is implicated in both grooming and learning phenotypes, separated the strains with high contextual grooming from the others using a hierarchical clustering analysis. This suggested a potential genetic mechanism for the observed behavioral differences. These findings demonstrate that genetic background determines behavioral responses during fear conditioning and suggest that shared genetic substrates underlie fear conditioning behaviors.

Joint Position Sense Testing in Young Children.

The standard physical examination evaluation for a proprioception abnormality depends upon the patient's ability to follow directions and respond to the examiner, a skill not yet developed in toddlers. This study demonstrates a new proprioception examination method that may allow for better localization of lesions and determines whether healthy toddlers would cooperate with this test. By placing stickers on children's hands, covering their eyes, and then moving their hands, the examiner can see whether the children reach for where their hands and stickers were previously located or to their new location, which serves as an indicator of proprioception ability. When tested on 12- to 36-month-old children without known neurologic issues, we found that older children were more cooperative during the test but that the ability to successfully find the sticker did not depend on age. We have optimized the test for efficient usage in a clinic setting and propose that this is a useful test that can be applied in children, with no change in confidence based on age. No children with known deficits in proprioception were tested, so sensitivity could not be assessed.

Elevated stress hormone levels and antidepressant treatment starting before pregnancy affect maternal care and litter characteristics in an animal model of depression.

Many women who take antidepressant medications become pregnant while taking their medication; however, the impact of depression and antidepressant medication on fetal development is not well understood. This study used a translational animal model of maternal depression to investigate the consequences of discontinuing antidepressant medication during pregnancy. First, rats received corticosterone (CORT; 40 mg/kg, s.c.) or vehicle to induce a depressive-like phenotype. After 16 days of treatment with CORT or vehicle, animals were treated with sertraline (a selective serotonin reuptake inhibitor, SSRI; 20 mg/kg) or vehicle via gavage. Following 21 days of CORT or oil treatment, rats were mated. One group receiving sertraline was discontinued from treatment on gestational day 16, and another group continued sertraline treatment throughout pregnancy to assess the effects of discontinuation. After weaning, dams were sacrificed via perfusion to investigate neurogenesis. As intended, CORT administration created a depressive-like phenotype with increased immobility in the Forced Swim Test and reduced body weight. Interestingly, sertraline treatment could not rescue these altered features. Pre-conceptional CORT exposure resulted in smaller litters and CORT dams that received sertraline until the end of gestation spent more time off of the nest compared to CORT dams that received vehicle or discontinued sertraline during gestation. There was no difference in hippocampal neurogenesis between any of the groups. Our results suggest that treatment with antidepressants may have different effects in healthy or depressed dams, however, we need more research to investigate the detailed and long-term effects of maternal depression and its treatment in translational animal models.

Effectiveness of different corticosterone administration methods to elevate corticosterone serum levels, induce depressive-like behavior, and affect neurogenesis levels in female rats.

High levels of chronic stress or stress hormones are associated with depressive-like behavior in animal models. However, slight elevations in corticosterone (CORT) - the major stress hormone in rodents - have also been associated with improved performances, albeit in a sex-dependent manner. Some of the discrepancies in the literature regarding the effects of high CORT levels may be due to different administrations methods. The current study aims to compare the effects of ∼40mg/kg given either via subcutaneous injection, through an implanted pellet, or in the drinking water, for ∼21days on CORT serum levels, depressive-like behavior in the forced swim test (FST), and neurogenesis levels in the dentate gyrus (DG) in adult female rats. We found that animals exposed to the daily injections showed elevated CORT levels throughout the administration period, while the pellet animals showed only a transient increase, and drinking water animals revealed no elevation in CORT in serum. In addition, only the injection group exhibited higher levels of immobility in the FST. Interestingly, animals receiving CORT via injection or drinking water had lower numbers of doublecortin-positive cells in the ventral DG one week after the last CORT administration compared to animals implanted with a CORT pellet. These results will contribute to the growing literature on the effects of chronic CORT exposure and may help to clarify some of the discrepancies among previous studies, particularly in females.

Disseminated vaccine strain varicella as the acquired immunodeficiency syndrome-defining illness in a previously undiagnosed child.

The Food and Drug Administration licensed a live-virus varicella vaccine (Varivax; Merck & Co Inc, West Point, PA) in March 1995. Prelicensure adverse events were minimal; however, since licensure and increased vaccine use, rare previously undetected risks have arisen. Presented here is the clinical course of a previously undiagnosed, human immunodeficiency virus-infected boy who developed dissemination of the vaccine strain of varicella zoster after immunization. chickenpox, human immunodeficiency virus, pneumonia, encephalopathy, varicella vaccine, adverse events, dissemination.

Periaxin mutations cause recessive Dejerine-Sottas neuropathy.

The periaxin gene (PRX) encodes two PDZ-domain proteins, L- and S-periaxin, that are required for maintenance of peripheral nerve myelin. Prx(-/-) mice develop a severe demyelinating peripheral neuropathy, despite apparently normal initial formation of myelin sheaths. We hypothesized that mutations in PRX could cause human peripheral myelinopathies. In accordance with this, we identified three unrelated Dejerine-Sottas neuropathy patients with recessive PRX mutations-two with compound heterozygous nonsense and frameshift mutations, and one with a homozygous frameshift mutation. We mapped PRX to 19q13.13-13.2, a region recently associated with a severe autosomal recessive demyelinating neuropathy in a Lebanese family (Delague et al. 2000) and syntenic to the location of Prx on murine chromosome 7 (Gillespie et al. 1997).

Child neurology and the Internet.

The Internet has become available as a tool to disseminate and gain access to information as well as to provide an ease of communication. The current question before us is how will we, as child neurologists, take advantage of this opportunity? This article delineates examples of current useful resources, investigates the potential of the Internet for neurology, and suggests a "vision" for the future of neurology on the Internet.

Infarction of basal ganglia associated with California encephalitis virus.

A child developed acute hemiparesis due to infarction of basal ganglia and internal capsule. Pleocytosis of cerebrospinal fluid and elevated immunoglobulin M antibodies suggest that California encephalitis virus infection caused the stroke.

Migratory paths of neurons and glia in the embryonic chick spinal cord.

To study the migration of chick spinal cord neurons, we labeled individual cells in the ventricular zone with recombinant retroviruses, then identified their progeny histochemically. First, we analyzed cell mixing in the ventricular zone. Some clones labeled at early neural tube stages spread widely along both the dorsoventral and rostrocaudal axes. However, clones labeled later were confined to narrow domains along both axes. These results imply that displacement of cells within the ventricular zone becomes progressively restricted. Second, we studied the migration of cells out of the ventricular zone by infecting embryos at a fixed stage and varying the time of analysis. At first, most clones consisted of radial arrays of cells, suggesting that the initial migration is predominantly radial. In many clones, however, neurons turned orthogonally from parental radial arrays and migrated along the path of circumferentially oriented axons. By hatching, clonally related cells in the gray matter were usually distributed in narrow transverse slabs, but some white matter glial cells had migrated longitudinally for up to several segments. We conclude that the dispersal of clonally related cells results from (1) early mixing of progenitors within the neural tube; (2) radial stacking of progeny in the ventricular zone; (3) migration of progeny from the ventricular zone in spoke-like routes; (4) circumferential migration of some neurons along axons; (5) short-distance dispersal of differentiating neurons; and (6) a late, longitudinal migration of glia through white matter tracts. Finally, we show that floor plate cells differ from other spinal cord cells in both their lineage and migration patterns.

A light and electron microscopic study of the development of the Mauthner cell and vestibular nerve in the axolotl.

Vestibular axons form synapses on a restricted area of the lateral dendrite of the Mauthner cell, a large, identified brainstem neuron found in fish and amphibians. The differentiation of the vestibular nerve, medullary neuropil, and Mauthner cell of the axolotl (Ambystoma mexicanum) was studied to understand better the means by which this synaptic specificity arises. The Mauthner cell first extends a medial process and then a lateral dendrite. The latter initially elongates as a simple process and later sends out branches. As the lateral dendrite grows, vestibular axons enter the brainstem to form one of the earliest of several discrete axon fascicles that course longitudinally through the neuropil. The fascicles, many of which are identifiable on the basis of their location and axonal morphology, are the precursors of the longitudinal tracts of the mature salamander. The lateral dendrite grows dorsally over the orthogonally oriented fascicles, making contact with each at a characteristic time and place. The first afferents to form synapses do so on the soma and proximal lateral dendrite; subsequent afferent groups terminate more distally. Axons within a given fascicle form synapses with the Mauthner cell in a discrete and initially homogeneous domain. As dendritic branches form and the organization of the longitudinal fascicles becomes more complex, the homogeneity of axons terminating on a given region of the Mauthner cell surface is lost, but no major rearrangement or migration of terminals is apparent. These observations are consistent with both active recognition and passive spatiotemporal models of synaptic site specificity.

Effect of precocious and delayed afferent arrival on synapse localization on the amphibian Mauthner cell.

Afferents often form synapses on restricted regions of their target cells. The connections between vestibular axons and the Mauthner cell are an example of this sort of specificity. The Mauthner cells are a pair of identifiable central neurons in certain fish and amphibians. In the axolotl (Ambystoma mexicanum), the large vestibular axons form club endings on only one portion of one dendrite of the Mauthner cell. During development, this specific distribution might result from nothing more than when and where the growing axons and dendrite meet (spatiotemporal model). Alternatively, the distribution might reflect constraints on where the developing axons may grow (axon segregation model) or form synapses (active recognition model). As a test of the spatiotemporal model, ears and vestibular ganglia from older embryos (Harrison stage 33/34-) were unilaterally grafted in place of prospective ear/ganglion placodes of younger embryos (stage 23). Light and electron microscopic examination revealed that the axons precociously entered the brain and formed synapses on the Mauthner cell. Similarly, grafts from younger to older embryos resulted in a delay. In both situations, mapping the club endings on the mature Mauthner cells of 21-mm larvae revealed a distribution similar to that of the contralateral control cells. Thus precocious and delayed afferent arrival did not alter the eventual localization of the synapses. These results conflict with the spatiotemporal model and imply that the vestibular axons are either restricted to a certain region of the neuropil or capable of recognizing a specific region of the Mauthner cell surface.

Migratory patterns of clonally related cells in the developing central nervous system.

Neurons and glioblasts that arise in the ventricular zone migrate to form discrete nuclei and laminae as the central nervous system develops. By stably labeling precursor cells in the ventricular zone, pathways taken by different cells within an individual clone can be described. We have used recombinant retroviruses to label precursor cells with a heritable marker, the E. coli lacZ gene; clones of lacZ-positive cells are later mapped histochemically. Here we review results from three regions of the chicken central nervous system--the optic tectum, spinal cord, and forebrain--and compare them with previous results from mammalian cortex and other regions of the vertebrate CNS. In particular, we consider the relationship between migratory patterns and functional organization, the existence of multiple cellular sources of migratory guidance, and the issue of whether a cell's choice of migratory pathway influences its ultimate phenotype.

Lineage, arrangement, and death of clonally related motoneurons in chick spinal cord.

We have used recombinant retroviruses as lineage markers to study the genealogy of motoneurons (MNs) in the chick spinal cord. We infected individual progenitors by injecting virions into the neural tube at stages 11-18, a few cell divisions before MNs are born. The descendants of infected cells were subsequently detected with a histochemical stain for beta-galactosidase (lacZ), the product of the retrovirally introduced gene. Clonally related, lacZ-positive cells formed clusters that were usually radial or planar in shape. The cells that comprised these clones were classified by morphology, size, and location. About 15% of the clones in the spinal cord contained MNs, and these were studied further. Multicellular clones that contained only MNs were infrequent. Instead, close relatives of MNs included a variety of other neurons, as well as glia and ependymal cells. Most non-MNs in these clones were found in the ventral and intermediate parts of the spinal cord. Neurons included interneurons and autonomic preganglionic neurons in the column of Terni. Labeled glia were found in both the gray and white matter and included astrocytes and cells tentatively identified as oligodendrocytes. Thus, even shortly before MNs are born, their progenitors are multipotential. Clonally related MNs were not restricted to a single motor pool. Some clones contained MNs in both the medial and lateral parts of the lateral motor column, which are known to innervate distinct groups of limb muscles. Furthermore, some clones contained MNs in the medial motor column (which innervate axial muscles) as well as in the lateral motor column. In contrast, the dispersal of clonally related MNs (and other neurons) was restricted in the rostrocaudal axis; most clones were less than one-quarter segment in length. Thus, MNs derived from a single progenitor are more likely to share rostrocaudal position than synaptic targets. To investigate the fate of clonally related MNs, we counted the number of MNs per clone at times before, during, and after the major period of MN death. The number of MNs per clone declined in precise parallel with the total number of MNs during this period, suggesting that neurons are eliminated without regard to their clone of origin. This result implies that the decision to live or die occurs on a cell-by-cell rather than a clone-by-clone basis.

The paths and destinations of the induced ipsilateral retinal projection in goldfish.

Adult goldfish had one tectal lobe removed surgically, and several months later, the eye contralateral to the missing tectum was injected with radioactive proline. Radioautographs of the brains were studied to trace the paths and termination sites of the optic fibers. The optic tract decussated at the chiasm, as normally, but then ran caudally in a large neuroma on the tectum-less side of the brain. Substantial numbers of fibers left this neuroma to enter two or more of five commissures, through which they recrossed the midline. These commissures: transverse, minor, horizontal, posterior and ansate, ordinarily contain few or no optic fibers. All are normally linked with the tectum. Negligible numbers of aberrant optic fibers recrossed the midline elsewhere. On the intact side of the brain, ipsilateral to the injected eye, the optic fibers innervated some or all of the nuclei and areas normally served by contralateral retinal fibers. An earlier behavioral study of these same fish had shown that some of them made reversed optokinetic nystagmus in response to stripe movement seen by the eye projecting ipsilaterally; others failed to respond to stimuli through this eye. In all the reversed responders, a caudal group of retinal projection sites was labeled ipsilaterally. This included the basal optic nucleus and the caudal portions of nucleus dorsolateralis thalami and area pretectalis. In the non-responders, these targets were not labeled ipsilaterally. Together, these results suggest that one or more of these three sites is or are responsible for optokinetic nystagmus in normal goldfish.