Developmental Brain Research最新文献

In mammals, most of the twenty SOX (SRY HMG box) transcription factors are expressed during embryogenesis and play an important role in cell fate determination. We show here that SOX13 is expressed in the developing mouse brain and spinal cord from E12.5 to E15.5, where it is largely confined to the differentiating zone rather than to the proliferating zone. In particular, we found that SOX13 expression was activated in a subset of neural progenitors as they exit the cycle of mitosis, migrate away from the ventricular zone, and start to differentiate into neurons. The SOX13 protein always localized to the nuclei of the differentiating neuronal cells, consistent with a role for SOX13 as a transcription factor during neurogenesis. Our data suggest a role for SOX13 in the specification and/or differentiation of a specific subset of neurons in the developing central nervous system.

During early postnatal development, afferent neurons of the cochlear (spiral) ganglion progressively refine their projections to auditory hair cells so that, by hearing onset, most cochlear nerve fibers innervate a single hearing receptor. One mechanism that might contribute to these changes in cochlear innervation is the programmed cell death (apoptosis) of developing neurons within the spiral ganglion. In the present study, we used the TUNEL method and morphological criteria to identify apoptotic cells within the spiral ganglion of the Mongolian gerbil during the first week of postnatal life when afferent projections to the cochlea are actively refined in this species. The locations of individual apoptotic spiral ganglion cells were mapped onto three-dimensional reconstructions of the entire ganglion for an age-graded series of gerbils to produce the first high-resolution, spatiotemporal maps of apoptotic ganglion cell death for the postnatal cochlea. We observed a significant increase in apoptosis in the spiral ganglion from postnatal day (P) 4 through P6. During this time, the most intense apoptotic activity occurred in regions of the spiral ganglion providing innervation to the lower middle and apical turns of the cochlea. The time course and regional variation of programmed cell death within the developing gerbil spiral ganglion are discussed in terms of the postnatal refinement of cochlear innervation and its possible functional significance for hearing in gerbils.

Cholinergic axons originating from the septum form a characteristic layer of preterminal axons and apparent termination in the molecular layer of the hippocampal dentate gyrus. The present study explored the specificity of this characteristic axonal pattern, through the use of organotypic slice co-cultures. Slices of hippocampus were co-cultured with a slice from one of a variety of other potential sources of afferents, and the afferent axons were labeled histochemically or immunocytochemically to determine which afferents distribute within the dentate molecular layer in a pattern similar to that formed by septal cholinergic projections. Acetylcholinesterase (AChE) histochemistry demonstrated that cholinergic axons from septum, substantia innominata, and striatum all consistently targeted the inner molecular layer of the dentate gyrus. AChE-labeled cholinergic axons from dorsal lateral pontine tegmentum and from spinal cord sometimes formed this pattern, while axons from the habenula failed to extend into the dentate gyrus. Immunocytochemically identified monoaminergic axons from the substantia nigra, locus coeruleus, and raphe extended into co-cultured hippocampus; each of these afferent systems displayed a prominent axonal plexus within the hilus of the dentate, but only the raphe axons projected prominently to the molecular layer. These data demonstrate that the molecular layer of the dentate gyrus provides an attractive target zone for some cholinergic and monoaminergic afferents, but not all. Commonalities between neuronal populations that preferentially project to the molecular layer in vitro may offer clues regarding the axon guidance mechanisms that normally direct cholinergic axons to target sites in the dentate gyrus molecular layer.

The homozygous knockout mouse for the β3 subunit of the GABA_A receptor has been proposed as a model for the neurodevelopmental disorder, Angelman syndrome, based on phenotypic similarities of craniofacial abnormalities, cognitive defects, hyperactivity, motor incoordination, disturbed rest–activity cycles, and epilepsy. Since most children with Angelman syndrome are autosomal heterozygotes of maternal origin, apparently through genomic imprinting, we used gabrb3-deficient heterozygote mice of defined parental origin to investigate whether this phenotype is also maternally imprinted in mouse. Whole brain extracts showed greatly reduced β3 subunit levels in male mice of maternal origin but not in male mice of paternal origin. Females of both parental origin showed greatly reduced β3 subunit levels. Heterozygotes did not exhibit hyperactive circling behavior, convulsions, or electrographically recorded seizures. EEGs showed qualitative differences among heterozygotes, with male mice of maternal origin demonstrating more abnormalities including increased theta activity. Ethosuximide inhibited theta bursts, suggesting an alteration in the thalamocortical relay. Carbamazepine induced EEG slowing in males and EEG acceleration in females, with a larger effect in paternal-origin heterozygotes. Evidence thus suggests both parent-of-origin and gender-related components in developmental regulation of β3 expression, in particular, that the maternally-derived male heterozygote may carry a developmental modification resulting in less β3 protein, which may reflect partial genomic imprinting of the gabrb3 gene in mice.

The developmental neurotoxicity of chlorpyrifos (CPF) involves mechanisms other than inhibition of cholinesterase. In the current study, we examined the ability of CPF to evoke lipid peroxidation in the developing brain of fetal and neonatal rats. CPF given to pregnant rats on gestational days 17–20 or to neonatal rats on postnatal days 1–4, failed to elicit increases in thiobarbituric acid-reactive species (TBARS) in brain regions even when the dose was raised above the threshold for systemic toxicity and hepatic damage. In contrast, CPF administration during the second postnatal week, the peak period of neuronal cell differentiation and synaptogenesis, did evoke significant increases in TBARS even at a dose devoid of systemic toxicity. Terbutaline, which is chemically unrelated to CPF and which stimulates neuronal cell metabolism through direct actions on β-adrenoceptors, also elicited oxidative damage in the developing brain with greater sensitivity in the second postnatal week. These results indicate that diverse compounds can exert convergent effects on brain development through their shared potential to elicit oxidative stress, and that the net outcome is dependent upon specific developmental stages in which metabolic demand is especially high. Furthermore, given the common use of terbutaline in the therapy of preterm labor, and the nearly ubiquitous exposure of the human population to organophosphorus pesticides, the combined oxidative burden of exposure to both agents may contribute to the worsened neurodevelopmental outcomes noted in animal models of such dual exposures.

To examine whether lighting conditions during the development of the rat circadian system affect the morphology of the suprachiasmatic nucleus (SCN), three groups of rats were born and maintained until they were 24 days old under constant light (LL), constant darkness (DD) or 24-h light–dark cycles (LD, 12-h light and 12-h darkness). We applied a stereological method to study whether these conditions lead to alterations in the volume of the SCN and changes in the total number of neurons and glial cells. While lighting conditions did not induce differences in the SCN volume, the number of both neurons and glial cells did differ between groups. The DD rats showed the lowest number of neurons. Glial cells were also lower in this group than in the other two groups; however the number of glial cells in LL rats was lower than in LD rats. Moreover, females had more glial cells than males but males and females showed a similar number of neurons. These findings indicate the plasticity of the SCN in response to lighting conditions during the developmental stage.

To understand thermal regulation of neonatal chicks, the contribution of thyrotropin-releasing hormone (TRH), a key regulator of the hypothalamus–pituitary–thyroid axis, was investigated. Intracerebroventricular (i.c.v.) injection of TRH (5 and 20 μg) increased body temperature, but did not change plasma T₃ and T₄ concentrations. Intraperitoneal (i.p.) injection of triiodothyronine (T₃) and thyroxine (T₄) did not influence body temperature.

Thereafter, the relationships between TRH and the hypothalamus–pituitary–adrenal axis and sympathetic nervous system were further investigated. Central TRH stimulated both corticosterone and epinephrine release. The i.c.v. injection of a corticotropin-releasing factor receptor antagonist attenuated the change in body temperature and corticosterone concentration caused by TRH, but did not influence plasma T₃ and T₄ concentrations. The i.p. injection of epinephrine did not induce hyperthermia. Therefore, the thermoregulatory response to TRH may differ in neonatal stages being dependent upon the stimulation of the hypothalamus–pituitary–adrenal axis rather than the hypothalamus–pituitary–thyroid axis.