Refinement of topographic maps during sensitive periods of development is a characteristic feature of diverse sensory and motor circuits in the nervous system. Within the neural system that controls vocal learning and behavior in zebra finches, axonal connections of the cortical nucleus lMAN demonstrate striking functional and morphological changes during vocal development in juvenile males. These circuits are uniquely important for song production during the sensitive period for vocal learning, and the overall size of these brain regions and their patterns of axonal connectivity undergo dramatic growth and regression during this time. Axonal connections to and from lMAN are topographically organized in adult males that have already learned song. We wondered whether the large-scale changes seen in lMAN circuitry during the time that vocal behavior is being learned and refined could be accompanied by the emergence of topographic mapping. However, results presented herein demonstrate that most of these song-control circuits show the same broad patterns of axonal connectivity between subregions of individual nuclei at the onset of song learning as seen in adult birds. Thus, coarse topographic organization is not dependent on the types of experience that are crucial for vocal learning. Furthermore, this maintenance of topographic organization throughout the period of song learning is clearly not achieved by maintenance of static axonal arbors. In fact, because the volumes of song-control nuclei are growing (or regressing), topography must be maintained by active remodeling of axonal arbors to adapt to the changes in overall size of postsynaptic targets. A salient exception to this pattern of conserved topography is the projection from lMAN to the motor cortical region RA: this pathway is diffusely organized at the onset of song learning but undergoes substantial refinement during early stages of song learning, suggesting that remodeling of axonal connections within this projection during the period of vocal learning may signify the production of increasingly refined vocal utterances.

Parkinson's disease (PD), a neurodegenerative disorder, causes severe motor impairment due to loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). MPTP, a neurotoxin that causes dopaminergic cell loss in mice, was used in an animal model to study the pathogenic mechanisms leading to neurodegeneration. We observed the activation of apoptosis signal regulating kinase (ASK1, MAPKKK) and phosphorylation of its downstream targets MKK4 and JNK, 12 h after administration of a single dose of MPTP. Further, Daxx, the death-associated protein, translocated to the cytosol selectively in SNpc neurons seemingly due to MPTP mediated down-regulation of DJ-1, the redox-sensitive protein that binds Daxx in the nucleus. Coadministration of alpha-lipoic acid (ALA), a thiol antioxidant, abolished the activation of ASK1 and phosphorylation of downstream kinases, MKK4, and JNK and prevented the down-regulation of DJ-1 and translocation of Daxx to the cytosol seen after MPTP. ALA also attenuated dopaminergic cell loss in SNpc seen after subchronic MPTP treatment. Our studies demonstrate for the first time that MPTP triggers death signaling pathway by activating ASK1 and translocating Daxx, in vivo, in dopaminergic neurons in SNpc of mice and thiol antioxidants, such as ALA terminate this cascade and afford neuroprotection.

A rapid growth in human cerebellar development occurs in the third trimester, which is impeded by preterm delivery. The goal of this study was to characterize the impact of preterm delivery on the developmental program of the human cerebellum. Still born infants, which meant that all development up to that age had taken place in-utero, were age paired with preterm delivery infants, who had survived in an ex-utero environment, which meant that their development had also taken place outside the uterus. The two groups were assessed on quantitative measures that included molecular markers of granule neuron, purkinje neuron and bergmann glia differentiation, as well as the expression of the sonic hedgehog signaling pathway, that is important for cerebellar growth. We report that premature birth and development in an ex-utero environment leads to a significant decrease in the thickness and an increase in the packing density of the cells within the external granular layer and the inner granular layer well, as a reduction in the density of bergmann glial fibres. In addition, this also leads to a reduced expression of sonic hedgehog in the purkinje layer. We conclude that the developmental program of the cerebellum is specifically modified by events that follow preterm delivery.

Connections of representations of the teeth and tongue in primary somatosensory cortex (area 3b) and adjoining cortex were revealed in owl, squirrel, and marmoset monkeys with injections of fluorescent tracers. Injection sites were identified by microelectrode recordings from neurons responsive to touch on the teeth or tongue. Patterns of cortical label were related to myeloarchitecture in sections cut parallel to the surface of flattened cortex, and to coronal sections of the thalamus processed for cytochrome oxidase (CO). Cortical sections revealed a caudorostral series of myelin dense ovals (O1-O4) in area 3b that represent the periodontal receptors of the contralateral teeth, the contralateral tongue, the ipsilateral teeth, and the ipsilateral tongue. The ventroposterior medial subnucleus, VPM, and the ventroposterior medial parvicellular nucleus for taste, VPMpc, were identified in the thalamic sections. Injections placed in the O1 oval representing teeth labeled neurons in VPM, while injections in O2 representing the tongue labeled neurons in both VPMpc and VPM. These injections also labeled adjacent part of areas 3a and 1, and locations in the lateral sulcus and frontal lobe. Callosally, connections of the ovals were most dense with corresponding ovals. Injections in the area 1 representation of the tongue labeled neurons in VPMpc and VPM, and ipsilateral area 3b ovals, area 3a, opercular cortex, and cortex in the lateral sulcus. Contralaterally, labeled neurons were mostly in area 1. The results implicate portions of areas 3b, 3a, and 1 in the processing of tactile information from the teeth and tongue, and possibly taste information from the tongue.

The initial establishment of topographic mapping within developing neural circuits is thought to be shaped by innate mechanisms and is primarily independent of experience. Additional refinement within topographic maps leads to precise matching between presynaptic and postsynaptic neurons and is thought to depend on experiential factors during specific sensitive periods in the animal's development. In male zebra finches, axonal projections of the cortical lateral magnocellular nucleus of the anterior neostriatum (lMAN) are critically important for vocal learning. Overall patterns of topographic organization in the majority of these circuits are adult-like throughout the sensitive period for vocal learning and remain stable despite large-scale functional and morphological changes. However, topographic organization within the projection from the core subregion of lMAN (lMAN core ) to the motor cortical robust nucleus of the archistriatum (RA) is lacking at the onset of song development and emerges during the early stages of vocal learning. To study the effects of song-related experience on patterns of axonal connectivity within different song-control circuits, we disrupted song learning by deafening juvenile zebra finches or exposing them to loud white noise throughout the sensitive period for song learning. Depriving juvenile birds of normal auditory experience delayed the emergence of topographic specificity within the lMAN core 3RA circuit relative to age-matched controls, whereas topographic organization within all other projections to and from lMAN was not affected. The projection from lMAN core to RA therefore provides an unusual example of experience-dependent modification of large-scale patterns of brain circuitry, in the sense that auditory deprivation influences the development of overall topographic organization in this pathway.