Increased wiring cost during development is driven by long-range cortical, but not subcortical connections.

The brain undergoes a protracted, metabolically expensive maturation process from childhood to adulthood. Therefore, it is crucial to understand how network cost is distributed among different brain systems as the brain matures. To address this issue, here we examined developmental changes in wiring cost and brain network topology using resting-state functional magnetic resonance imaging (rsfMRI) data longitudinally collected in awake rats from the juvenile age to adulthood. We found that the wiring cost increased in the vast majority of cortical connections but decreased in most subcortico-subcortical connections. Importantly, the developmental increase in wiring cost was dominantly driven by long-range cortical, but not subcortical connections, which was consistent with more pronounced increase in network integration in the cortical network. These results collectively indicate that there is a non-uniform distribution of network cost as the brain matures, and network resource is dominantly consumed for the development of the cortex, but not subcortex from the juvenile age to adulthood.

Loss-of-Huntingtin in Medial and Lateral Ganglionic Lineages Differentially Disrupts Regional Interneuron and Projection Neuron Subtypes and Promotes Huntington's Disease-Associated Behavioral, Cellular, and Pathological Hallmarks.

Emerging studies are providing compelling evidence that the pathogenesis of Huntington's disease (HD), a neurodegenerative disorder with frequent midlife onset, encompasses developmental components. Moreover, our previous studies using a hypomorphic model targeting huntingtin during the neurodevelopmental period indicated that loss-of-function mechanisms account for this pathogenic developmental component (Arteaga-Bracho et al., 2016). In the present study, we specifically ascertained the roles of subpallial lineage species in eliciting the previously observed HD-like phenotypes. Accordingly, we used the Cre-loxP system to conditionally ablate the murine huntingtin gene (Httflx) in cells expressing the subpallial patterning markers Gsx2 (Gsx2-Cre) or Nkx2.1 (Nkx2.1-Cre) in Httflx mice of both sexes. These genetic manipulations elicited anxiety-like behaviors, hyperkinetic locomotion, age-dependent motor deficits, and weight loss in both Httflx;Gsx2-Cre and Httflx;Nkx2.1-Cre mice. In addition, these strains displayed unique but complementary spatial patterns of basal ganglia degeneration that are strikingly reminiscent of those seen in human cases of HD. Furthermore, we observed early deficits of somatostatin-positive and Reelin-positive interneurons in both Htt subpallial null strains, as well as early increases of cholinergic interneurons, Foxp2+ arkypallidal neurons, and incipient deficits with age-dependent loss of parvalbumin-positive neurons in Httflx;Nkx2.1-Cre mice. Overall, our findings indicate that selective loss-of-huntingtin function in subpallial lineages differentially disrupts the number, complement, and survival of forebrain interneurons and globus pallidus GABAergic neurons, thereby leading to the development of key neurological hallmarks of HD during adult life. Our findings have important implications for the establishment and deployment of neural circuitries and the integrity of network reserve in health and disease.SIGNIFICANCE STATEMENT Huntington's disease (HD) is a progressive degenerative disorder caused by aberrant trinucleotide expansion in the huntingtin gene. Mechanistically, this mutation involves both loss- and gain-of-function mechanisms affecting a broad array of cellular and molecular processes. Although huntingtin is widely expressed during adult life, the mutant protein only causes the demise of selective neuronal subtypes. The mechanisms accounting for this differential vulnerability remain elusive. In this study, we have demonstrated that loss-of-huntingtin function in subpallial lineages not only differentially disrupts distinct interneuron species early in life, but also leads to a pattern of neurological deficits that are reminiscent of HD. This work suggests that early disruption of selective neuronal subtypes may account for the profiles of enhanced regional cellular vulnerability to death in HD.

Agenesis of the putamen and globus pallidus caused by recessive mutations in the homeobox gene GSX2.

Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans.

Spatiotemporal variations of magnetic susceptibility in the deep gray matter nuclei from 1 month to 6 years: A quantitative susceptibility mapping study.

BACKGROUND: Quantitative susceptibility mapping (QSM) is emerging as a technique that quantifies the paramagnetic nonheme iron in brain tissue. Brain iron quantification during early development provides insights into the underlying mechanism of brain maturation. PURPOSE: To quantify the spatiotemporal variations of brain iron-related magnetic susceptibility in deep gray matter nuclei during early development by using QSM. STUDY TYPE: Retrospective. SUBJECTS: Eighty-seven infants and children aged 1 month to 6 years. FIELD STRENGTH/SEQUENCE: Enhanced T2 *-weighted angiography using a 3D gradient-echo sequence at 3.0T. ASSESSMENT: QSM was calculated by modified sophisticated harmonic artifact reduction for phase data and sparse linear equations and sparse least squares-based algorithm. Means of susceptibility in deep gray matter nuclei (caudate nucleus, putamen, globus pallidus, thalamus) relative to that in splenium of corpus callosum were measured. STATISTICAL TESTS: Relationships of mean susceptibility with age and referenced iron concentration were tested by Pearson correlation. Differences of mean susceptibility between the selected nuclei in each age group were compared by one-way analysis of variance (ANOVA) and Fisher's Linear Significant Difference (LSD) test. RESULTS: Positive correlations of susceptibility with both referenced iron concentration and age were found (P < 0.0001); particularly, globus pallidus showed the highest correlation with age (correlation coefficient, 0.882; slope, 1.203; P < 0.001) and greatest susceptibility (P < 0.05) among the selected nuclei. DATA CONCLUSION: QSM allows the feasible quantification of iron deposition in deep gray matter nuclei in infants and young children, which exhibited gradual accumulation at different speeds. The fastest and highest iron accumulation was observed in the globus pallidus with increasing age during early development. LEVEL OF EVIDENCE: 4 Technical Efficacy:Stage 2 J. Magn. Reson. Imaging 2018.

Evolutionary and developmental contributions for understanding the organization of the basal ganglia.

Herein we take advantage of the evolutionary developmental biology approach in order to improve our understanding of both the functional organization and the evolution of the basal ganglia, with a particular focus on the globus pallidus. Therefore, we review data on the expression of developmental regulatory genes (that play key roles in patterning, regional specification and/or morphogenesis), gene function and fate mapping available in different vertebrate species, which are useful to (a) understand the embryonic origin and basic features of each neuron subtype of the basal ganglia (including neurotransmitter/neuropeptide expression and connectivity patterns); (b) identify the same (homologous) subpopulations in different species and the degree of variation or conservation throughout phylogeny, and (c) identify possible mechanisms that may explain the evolution of the basal ganglia. These data show that the globus pallidus of rodents contains two major subpopulations of GABAergic projection neurons: (1) neurons containing parvalbumin and neurotensin-related hexapetide (LANT6), with descending projections to the subthalamus and substantia nigra, which originate from progenitors expressing Nkx2.1, primarily located in the pallidal embryonic domain (medial ganglionic eminence), and (2) neurons containing preproenkephalin (and possibly calbindin), with ascending projections to the striatum, which appear to originate from progenitors expressing Islet1 in the striatal embryonic domain (lateral ganglionic eminence). Based on data on Nkx2.1, Islet1, LANT6 and proenkephalin, it appears that both cell types are also present in the globus pallidus/dorsal pallidum of chicken, frog and lungfish. In chicken, the globus pallidus also contains neurons expressing substance P (SP), perhaps originating in the striatal embryonic domain. In ray-finned and cartilaginous fishes, the pallidum contains at least the Nkx2.1 lineage cell population (likely representing the neurons containing LANT6). Based on the presence of neurons containing enkephalin or SP, it is possible that the pallidum of these animals also includes the Islet1 lineage cell subpopulation, and both neuron subtypes were likely present in the pallidum of the first jawed vertebrates. In contrast, lampreys (jawless fishes) appear to lack the pallidal embryonic domain and the Nkx2.1 lineage cell population that mainly characterize the pallidum in jawed vertebrates. In the absence of data in other jawless fishes, the ancestral condition in vertebrates remains to be elucidated. Perhaps, a major event in telencephalic evolution was the novel expression of Nkx2.1 in the subpallium, which has been related to Hedgehog expression and changes in the regulatory region of Nkx2.1.

Validation of a brain MRI relaxometry protocol to measure effects of preterm birth at a flexible postnatal age.

BACKGROUND: Magnetic resonance imaging (MRI) is a useful tool to study brain growth and organization in preterm neonates for clinical and research purposes, but its practicality can be limited by time and medical constraints. The aim of this study was to determine if MRI relaxometry of the deep nuclei, as opposed to white matter, would reflect the influence of gestational age at birth on structures essential to motor development, regardless of postnatal age at the time of imaging. RESULTS: This was a prospective observational study of infants without brain injury on conventional neuroimaging who were cared for in the neonatal intensive care unit (NICU) at Vanderbilt. Infants were studied using MRI relaxometry within a 2-month window of postmenstrual term age. In 45 infants, white matter MRI T1 relaxation times were influenced by both gestational age and postnatal age at imaging time (R(2) = 0.19 for gestational age vs. R(2) = 0.34 adjusting for both gestational age and age at imaging; all p < 0.01). Similar results were obtained with T2 relaxation times. In contrast, globus pallidus T1 reflected gestational age but was minimally affected by postnatal age (R(2) = 0.50 vs. 0.57, p < 0.001). CONCLUSIONS: The results obtained using this imaging protocol are consistent with the slow maturation of the globus pallidus, essential to normal development of complex motor programs into adulthood. Globus pallidus MRI relaxometry measures the impact of gestational age at birth on brain development independent of postnatal age in preterm infants and should prove useful for predictive modeling in a flexible time-window around postmenstrual term age.

Differential short-term plasticity at convergent inhibitory synapses to the substantia nigra pars reticulata.

Inhibitory projections from the striatum and globus pallidus converge onto GABAergic projection neurons of the substantia nigra pars reticulata (SNr). Based on existing structural and functional evidence, these pathways are likely to differentially regulate the firing of SNr neurons. We sought to investigate the functional differences in inhibitory striatonigral and pallidonigral traffic using whole-cell voltage clamp in brain slices with these pathways preserved. We found that striatonigral IPSCs exhibited a high degree of paired-pulse facilitation. We tracked this facilitation over development and found the facilitation as the animal aged, but stabilized by postnatal day 17 (P17), with a paired pulse ratio of 2. We also found that the recovery from facilitation accelerated over development, again, reaching a stable phenotype by P17. In contrast, pallidonigral synapses show paired-pulse depression, and this depression could be solely explained by presynaptic changes. The mean paired-pulse ratio of 0.67 did not change over development, but the recovery from depression slowed over development. Pallidonigral IPSCs were significantly faster than striatonigral IPSCs when measured at the soma. Finally, under current clamp, prolonged bursts of striatal IPSPs were able to consistently silence the pacemaker activity of nigral neurons, whereas pallidal inputs depressed, allowing nigral neurons to reinstate firing. These findings highlight the importance of differential dynamics of neurotransmitter release in regulating the circuit behavior of the basal ganglia.

FACS-array profiling of striatal projection neuron subtypes in juvenile and adult mouse brains.

A major challenge in systems neuroscience is to perform precise molecular genetic analyses of a single neuronal population in the context of the complex mammalian brain. Existing technologies for profiling cell type-specific gene expression are largely limited to immature or morphologically identifiable neurons. In this study, we developed a simple method using fluorescent activated cell sorting (FACS) to purify genetically labeled neurons from juvenile and adult mouse brains for gene expression profiling. We identify and verify a new set of differentially expressed genes in the striatonigral and striatopallidal neurons, two functionally and clinically important projection neuron subtypes in the basal ganglia. We further demonstrate that Ebf1 is a lineage-specific transcription factor essential to the differentiation of striatonigral neurons. Our study provides a general approach for profiling cell type-specific gene expression in the mature mammalian brain and identifies a set of genes critical to the function and dysfunction of the striatal projection neuron circuit.

Neural Stem Cells Direct Axon Guidance via Their Radial Fiber Scaffold.

Neural stem cells directly or indirectly generate all neurons and macroglial cells and guide migrating neurons by using a palisade-like scaffold made of their radial fibers. Here, we describe an unexpected role for the radial fiber scaffold in directing corticospinal and other axons at the junction between the striatum and globus pallidus. The maintenance of this scaffold, and consequently axon pathfinding, is dependent on the expression of an atypical RHO-GTPase, RND3/RHOE, together with its binding partner ARHGAP35/P190A, a RHO GTPase-activating protein, in the radial glia-like neural stem cells within the ventricular zone of the medial ganglionic eminence. This role is independent of RND3 and ARHGAP35 expression in corticospinal neurons, where they regulate dendritic spine formation, axon elongation, and pontine midline crossing in a FEZF2-dependent manner. The prevalence of neural stem cell scaffolds and their expression of RND3 and ARHGAP35 suggests that these observations might be broadly relevant for axon guidance and neural circuit formation.

A developmental redox dysregulation leads to spatio-temporal deficit of parvalbumin neuron circuitry in a schizophrenia mouse model.

The fast-spiking parvalbumin (PV) interneurons play a critical role in neural circuit activity and dysfunction of these cells has been implicated in the cognitive deficits typically observed in schizophrenia patients. Due to the high metabolic demands of PV neurons, they are particularly susceptible to oxidative stress. Given the extant literature exploring the pathological effects of oxidative stress on PV cells in cortical regions linked to schizophrenia, we decided to investigate whether PV neurons in other select brain regions, including sub-cortical structures, may be differentially affected by redox dysregulation induced oxidative stress during neurodevelopment in mice with a genetically compromised glutathione synthesis (Gclm KO mice). Our analyses revealed a spatio-temporal sequence of PV cell deficit in Gclm KO mice, beginning with the thalamic reticular nucleus at postnatal day (P) 20 followed by a PV neuronal deficit in the amygdala at P40, then in the lateral globus pallidus and the ventral hippocampus Cornu Ammonis 3 region at P90 and finally the anterior cingulate cortex at P180. We suggest that PV neurons in different brain regions are developmentally susceptible to oxidative stress and that anomalies in the neurodevelopmental calendar of metabolic regulation can interfere with neural circuit maturation and functional connectivity contributing to the emergence of developmental psychopathology.

Substance P effects exclusively on prototypic neurons in mouse globus pallidus.

Previous studies have suggested that the neurokinin-1 receptor (NK-1R) expressing neurons in the globus pallidus (GP) receive substance P (SP), presumably released by axon collaterals of striatal direct neurons. However, the effect of SP on the GP remains unclear. In this study, we identified that the SP-responsive cells comprise a highly specific cell type in the GP with regard to immunofluorescence, electrophysiology, and projection properties. Morphologically, NK-1R-immunoreactive neurons occasionally co-expressed parvalbumin (PV) and/or Lim-homeobox 6 (Lhx6), but not Forkhead box protein P2 (FoxP2), which is mainly expressed by arkypallidal neurons. Retrograde tracing experiments also showed that some of GP neurons projecting to the subthalamic nucleus (namely prototypic neurons) expressed NK-1R as well as Lhx6 and/or PV, but not FoxP2. In vitro electrophysiological study revealed that, among 48 GP neurons, the SP agonist induced inward current in 21 neurons. The response was prevented by bath application of the NK-1R antagonist. Based on the firing properties, 92 recorded GP neurons were classified into three distinct types, i.e., CL1, 2, and 3. Interestingly, all the SP-responsive neurons were found to be in CL2 and CL3 types, but not in CL1. Moreover, active and passive membrane properties of the neurons in those clusters and immunofluorescent identification suggested that CL1 and CL2/3 could be considered as arkypallidal and prototypic neurons, respectively. Therefore, SP-responsive neurons were one of the populations of prototypic neurons based on both anatomical and electrophysiological results. Altogether, the striatal direct pathway neurons could affect the indirect pathway in the way of prototypic neurons, via the action of SP to NK-1R.

Subpallial origin of part of the calbindin-positive neurons of the claustral complex and piriform cortex.

The aim of the present study was to investigate whether part of the calbindin-positive neurons of the claustral complex and piriform cortex originate in the subpallium. To that end, we prepared organotypic cultures of embryonic telencephalic slices, and applied the cell tracker CMTMR to the ventricular/subventricular zone of the lateral or medial ganglionic eminence. Following 48 h of incubation, we observed a number of CMTMR-labeled cells (showing red fluorescence) of subpallial origin in the claustral complex and piriform cortex. To know whether some of these cells of subpallial origin were calbindin-positive, we performed immunofluorescence for calbindin using an Alexa 488-conjugated secondary antiserum (green fluorescence). Our results showed that some of the CMTMR-labeled cells of subpallial origin in the claustral complex and piriform cortex are calbindin-positive (and possibly GABAergic). The subpallial origin of part of these cells was confirmed by observation of double labeled neurons in the claustral complex that expressed both Lhx6 mRNA (a marker of cells derived from the medial ganglionic eminence) and calbindin. Future studies will be required to analyze the existence of a subpopulation of non-GABAergic calbindin cells in the claustral complex and piriform cortex, and to know their origin.

Observation and modeling of deep brain stimulation electrode depth in the pallidal target of the developing brain.

OBJECTIVE: It is unclear how brain growth with age affects electrode position in relation to target for children undergoing deep brain stimulation surgery. We aimed to model projected change in the distance between the entry point of the electrode into the brain and target during growth to adulthood. METHODS: Modeling was performed using a neurodevelopmental magnetic resonance imaging database of age-specific templates in 6-month increments from 4 to 18 years of age. Coordinates were chosen for a set of entry points into both cerebral hemispheres and target positions within the globus pallidus internus on the youngest magnetic resonance imaging template. The youngest template was nonlinearly registered to the older templates, and the transformations generated by these registrations were applied to the original coordinates of entry and target positions, mapping these positions with increasing age. Euclidean geometry was used to calculate the distance between projected electrode entry and target with increasing age. RESULTS: A projected increase in distance between entry point and target of 5-10 mm was found from age 4 to 18 years. Most change appeared to occur before 7 years of age, after which minimal change in distance was found. CONCLUSIONS: Electrodes inserted during deep brain stimulation surgery are tethered at the point of entry to the skull. Brain growth, which could result in a relative retraction with respect to the original target position, appears to occur before 7 years of age, suggesting careful monitoring is needed for children undergoing implantation before this age. Reengineering of electrode design could avoid reimplantation surgery in young children undergoing deep brain stimulation.

The autism puzzle: Diffuse but not pervasive neuroanatomical abnormalities in children with ASD.

Autism Spectrum Disorder (ASD) is a clinically diagnosed, heterogeneous, neurodevelopmental condition, whose underlying causes have yet to be fully determined. A variety of studies have investigated either cortical, subcortical, or cerebellar anatomy in ASD, but none have conducted a complete examination of all neuroanatomical parameters on a single, large cohort. The current study provides a comprehensive examination of brain development of children with ASD between the ages of 4 and 18 years who are carefully matched for age and sex with typically developing controls at a ratio of one-to-two. Two hundred and ten magnetic resonance images were examined from 138 Control (116 males and 22 females) and 72 participants with ASD (61 males and 11 females). Cortical segmentation into 78 brain-regions and 81,924 vertices was conducted with CIVET which facilitated a region-of-interest- (ROI-) and vertex-based analysis, respectively. Volumes for the cerebellum, hippocampus, striatum, pallidum, and thalamus and many associated subregions were derived using the MAGeT Brain algorithm. The study reveals cortical, subcortical and cerebellar differences between ASD and Control group participants. Diagnosis, diagnosis-by-age, and diagnosis-by-sex interaction effects were found to significantly impact total brain volume but not total surface area or mean cortical thickness of the ASD participants. Localized (vertex-based) analysis of cortical thickness revealed no significant group differences, even when age, age-range, and sex were used as covariates. Nonetheless, the region-based cortical thickness analysis did reveal regional changes in the left orbitofrontal cortex and left posterior cingulate gyrus, both of which showed reduced age-related cortical thinning in ASD. Our finding of region-based differences without significant vertex-based results likely indicates non-focal effects spanning the entirety of these regions. The hippocampi, thalamus, and globus pallidus, were smaller in volume relative to total cerebrum in the ASD participants. Various sub-structures showed an interaction of diagnosis-by-age, diagnosis-by-sex, and diagnosis-by-age-range, in the case where age was divided into childhood (age < 12) and adolescence (12 < age < 18). This is the most comprehensive imaging-based neuro-anatomical pediatric and adolescent ASD study to date. These data highlight the neurodevelopmental differences between typically developing children and those with ASD, and support aspects of the hypothesis of abnormal neuro-developmental trajectory of the brain in ASD.

Distinct developmental origins manifest in the specialized encoding of movement by adult neurons of the external globus pallidus.

Transcriptional codes initiated during brain development are ultimately realized in adulthood as distinct cell types performing specialized roles in behavior. Focusing on the mouse external globus pallidus (GPe), we demonstrate that the potential contributions of two GABAergic GPe cell types to voluntary action are fated from early life to be distinct. Prototypic GPe neurons derive from the medial ganglionic eminence of the embryonic subpallium and express the transcription factor Nkx2-1. These neurons fire at high rates during alert rest, and encode movements through heterogeneous firing rate changes, with many neurons decreasing their activity. In contrast, arkypallidal GPe neurons originate from lateral/caudal ganglionic eminences, express the transcription factor FoxP2, fire at low rates during rest, and encode movements with robust increases in firing. We conclude that developmental diversity positions prototypic and arkypallidal neurons to fulfil distinct roles in behavior via their disparate regulation of GABA release onto different basal ganglia targets.

Early postnatal development of the monkey globus pallidus: a Golgi and electron microscopic study.

The globus pallidus of 20 monkeys ranging in age from newborn to 4 months was examined in Golgi-impregnated material and ultrastructurally. There was no discernible difference between the lateral and medial segments of the structure. At the light microscope level, all neuronal types described in the adult are found at birth. The most common, the large fusifom cell, shows initial signs of immaturity such as blunt protrusions and dendritic dilations at bifurcation points, as well as growth cones, filopodia, and filiform processes. These features become more rare with age, and by 4 months, the neurons appear fully mature save for the terminal dendritic arborizations which are still underdeveloped. From the earliest ages examined, the large globular cells and the interneurons are more mature than the previous type. The afferent radial fibers of striatal origin are observed from birth, but they are grouped in bundles only after 8 weeks. The density of their climbing branches increases over time, reaching a mature appearance by 16 weeks. Afferents entering from the ventral surface do not yet show clusters of varicosities at 2 weeks. At the latter age, plexuses of fine beaded fibers are already seen covering large extensions of the nucleus. The fine structure correlates well with the Golgi material. The basic features of the neuropil are present at birth, albeit with immature characteristics such as the incomplete covering of the dendrites with axonal boutons and the low level of myelination of the radial fibers. Growth cones and profiles with signs of degeneration are observed during the first month. In the early ages examined, most dendrites show large varicosities and protrusions, some of which are spinelike and can be postsynaptic to multiple terminals. The other dendritic type, with only an occasional axodendritic synapse, is also seen from birth and increases in size as a function of time. The type I axonal boutons, of probable striatal origin, are quite immature at birth, and their characteristic interdigitations are seen only after the first week. The type II, III, IV, and V boutons appear mature at all ages examined but crest synapses formed by the type III terminals are observed in the later stages of the study. Finally, postsynaptic vesicle-containing profiles are present at 4 weeks, but triadic synaptic arrangements are formed only by 16 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)

Postnatal development of caudate input neurons in the cat.

Lectin-bound horseradish peroxidase (WG-HRP) was pressure-injected into the caudate nucleus (Cd) of neonatal (less than 24 hours of age) and adult cats in order to assess the postnatal development of monosynaptic Cd input neurons. Tissue was processed for peroxidase activity with a benzidine dihydrochloride chromagen. The injection of WG-HRP produced relatively similar labelled zones of marker uptake in the caudate nuclei of both neonates and adults. Similar axonal projections were also labelled in both age groups. While many characteristics of retrogradely labelled CD input neurons were apparently constant throughout postnatal life, each of these features had a particular developmental modification. (1) Regardless of age, neuronal somata that projected to the CD were located in the neocortex, thalamus, substantia nigra, mesencephalic raphe nuclei, and globus pallidus. In each of these brain sites, labelled CD input neurons appeared to migrate postnatally. (2) The Cd afferent axons originated from the same neuronal lines in neonates and adults--small-to-medium-sized cortical neurons and medium-sized-to-large fusiform cells in all other brain sites. In each of the brain sites, labelled neurons displayed marked postnatal somatic growth. (3) In both age groups, there was a characteristic intrasomatic reaction product density in the labelled neurons located in each brain site (substantia nigra greater than thalamus = raphe = globus pallidus greater than cortex). In each of these brain sites, the intrasomatic reaction product density was less in neonates than in adults.

NGF receptor (p75)-immunoreactivity in the developing primate basal ganglia.

The distribution of the p75 nerve growth factor receptor (NGFr) was determined within the developing human basal ganglia in specimens between weeks 16 through 40 of gestation, 5 years of age, and adulthood. Although NGFr-immunoreactive neurons were rarely seen in the caudate nucleus, a few such neurons were seen in the putamen between prenatal weeks 16 and 26 of development. At 26 and 40 weeks of gestation, the putamen also displayed NGFr-immunoreactive fibers of putative basal forebrain origin. Some of these fibers coursed through the putamen en route to the cortex while others appeared to remain within the putamen. The external segment of the globus pallidus contained dense collections of NGFr-immunoreactive neurons between 16 and 26 weeks of gestation, whereas the internal segment was devoid of immunoreactive perikarya. A few NGFr-immunoreactive neurons were observed within the globus pallidus at embryonic week 40. The expression of NGFr-immunoreactive neurons within the external segment of the globus pallidus was paralleled by a dense granular NGFr-immunoreactive terminal-like staining pattern within the subthalamic nucleus. This staining pattern was most intense at midgestation (weeks 21-26) and was not observed at 40 weeks of gestation or in adulthood. Interestingly, a similar NGFr-immunoreactive terminal-like pattern was also observed within the monkey subthalamic nucleus at embryonic day 120. These data indicate that NGF receptor mediated mechanisms may underlie developmental processes within the primate basal ganglia. The absence of NGFr-immunoreactive neurons within the caudate nucleus, and the paucity of such neurons in the putamen, suggests that NGF receptors play a limited role in primate neostriatal development. Alternatively, developmental events mediated through NGF receptors may occur prior to embryonic week 16. Furthermore, an NGFr/trophic interaction appears to underlie the development of the pallidal-subthalamic nucleus pathway.

Histogenesis of the striopallidal system in the rat. Neurogenesis of its neurons.

This study discusses the histogenesis of the structures of the extrapyramidal system. The first part based on [3H]thymidine autoradiography provides data on the time of origin of the various neuronal populations that characterize different structures of the extrapyramidal system. Such data are essential to any further study dealing with the localization of the different sites of origin of the neurons along the ependymal matrix and with their migration during the histogenetic sequences leading to their definitive pattern of adult distribution. The neurons of globus pallidus and of the entopeduncular nucleus are generated on days 12-15 and days 11-14, respectively. A peak of neurogenesis occurs on day 12 for the entopeduncular nucleus and on day 14 for the globus pallidus. In the pallidum, the first neurons to form on day 12 settle caudally, while neurons generated on day 15 settle in the rostral extremity. The genesis of the medium-sized neurons of the neostriatum extends from day 12 to at least postnatal day 2. A peak is obvious on day 15. Although the neurogenesis of these neurons follows a mild caudorostral gradient, a more careful examination reveals four different patterns of settlement according to the area involved and the period of gestation. At the level of the caudal neostriatum, the neurons display a clear mediolateral spatiotemporal gradient. More rostrally, the neurons generated on days 13, 14 and 15 show two patterns of settlement. On the one hand, many neurons settle rather densely along the external capsule on day 13, occupying more rostral levels on days 14 and 15. On the other hand, in the body of the neostriatum, clusters of isochronically generated neurons are obvious. Later, newly generated neurons display a rather homogeneous distribution in the structure. A parallel is drawn between these patterns of development and the patterns of distribution of afferent terminals or neurotransmitters. The large chromophilic neurons of the neostriatum appear exclusively during the early period. Two peaks of neurogenesis are apparent. The one on day 13 comprises neurons that settle caudally. It is contemporaneous to the neurogenesis of the adjacent basal nucleus. The second peak occurs on day 15 and corresponds to that of the medium-sized neurons.

Spatiotemporal expression gradients of the carbohydrate antigen (CD15) (Lewis X) during development of the human basal ganglia.

The developmental expression pattern of the carbohydrate epitope CD15 (Lewis X, Le X) (alpha1-->3-fucosyl-N-acetyl-lactosamine) has been immunocytochemically evaluated in paraffin sections within the human basal ganglia from 10 weeks gestation to three years after birth. At 11 weeks of gestation, CD15 (Le X) positive radial glial cells were located in the anterior and dorsal parts of the lateral ganglionic eminence. Their processes ran from the subventricular zone radially in a highly ordered fashion to the dorsolateral margin of the caudate nucleus and further to the lateral rim of the putamen. At 12 weeks of gestation, strands of CD15 (Le X) material continued to the pial surface, forming a continuous CD15 (Le X) positive borderline separating the accumbens nucleus and olfactory tubercle from the piriform cortex. At 13 weeks of gestation the dorsal putamen was completely CD15 (Le X) immunoreactive along its perimeter and CD15 (Le X) patches, consisting of fine granular material, appeared at the dorsolateral margin of the putamen at this age; while the first CD15 (Le X) patches in the caudate nucleus were observed four weeks later. The matrix compartment of the caudate and dorsal putamen became gradually stained by granular CD15 (Le X) positive material into which CD15 (Le X) immunoreactive somata were embedded. The striking contrast in staining between patch and matrix compartments disappeared shortly after birth. The ventral striatum did not become immunoreactive until the last few weeks before birth. After the formation of CD15 (Le X) positive patches in the striatum (from 12 weeks of gestation), delicate CD15 (Le X) fibres, often accumulated in bundles and related to the striatal patches, became apparent coursing towards the external pallidal lamina and the globus pallidus. Immunoreactivity in the globus pallidus itself was transient, emerging from 16 weeks of gestation, reaching a peak at 21 weeks of gestation and disappearing by birth. Both processes, i.e. the occurrence of CD15 (Le X) striatopallidal fibres and the emerging immunoreactivity in their pallidal target, may be interrelated, so that ingrowing CD15 (Le X) positive axons from the striatum provoke CD15 (Le X) expression in the external and internal pallidum. The variable patterns and intensities of CD15 (Le X) expression are possibly related to periods of maturation of the striatum and the establishment of functional interactions within the basal ganglia. Differential staining of patch and matrix in the developing neostriatum suggests that a distinct phase of cellular adhesion or dishesion mediated by the CD15 (Le X) epitope occurs during establishment of the patch and matrix regions.