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Sex steroid hormones such as 17β-estradiol (estradiol) regulate neuronal function by binding to estrogen receptors (ERs), including ERα and GPER1, and through differential production via the enzyme aromatase. ERs and aromatase are expressed across the nervous system, including in the striatal brain regions. These regions, comprising the nucleus accumbens core, shell, and caudate-putamen, are instrumental for a wide-range of functions and disorders that show sex differences in phenotype and/or incidence. Sex-specific estrogen action is an integral component for generating these sex differences. A distinctive feature of the striatal regions is that in adulthood neurons exclusively express membrane but not nuclear ERs. This long-standing finding dominates models of estrogen action in striatal regions. However, the developmental etiology of ER and aromatase cellular expression in female and male striatum is unknown. This omission in knowledge is important to address, as developmental stage influences cellular estrogenic mechanisms. Thus, ERα, GPER1, and aromatase cellular immunoreactivity was assessed in perinatal, prepubertal, and adult female and male rats. We tested the hypothesis that ERα, GPER1, and aromatase exhibits sex, region, and age-specific differences, including nuclear expression. ERα exhibits nuclear expression in all three striatal regions before adulthood and disappears in a region- and sex-specific time-course. Cellular GPER1 expression decreases during development in a region- but not sex-specific time-course, resulting in extranuclear expression by adulthood. Somatic aromatase expression presents at prepuberty and increases by adulthood in a region- but not sex-specific time-course. These data indicate that developmental period exerts critical sex-specific influences on striatal cellular estrogenic mechanisms., (© 2020 Wiley Periodicals LLC.)

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 T 2 *-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., (© 2018 International Society for Magnetic Resonance in Medicine.)

Neurogenesis in the subependymal zone (SEZ) declines across the human lifespan, and reduced local neurotrophic support is speculated to be a contributing factor. While tyrosine receptor kinase B (TrkB) signalling is critical for neuronal differentiation, maturation and survival, little is known about subependymal TrkB expression changes during postnatal human life. In this study, we used quantitative PCR and in situ hybridisation to determine expression of the cell proliferation marker Ki67, the immature neuron marker doublecortin (DCX) and both full-length (TrkB-TK+) and truncated TrkB receptors (TrkB-TK-) in the human SEZ from infancy to middle age (n = 26-35, 41 days to 43 years). We further measured TrkB-TK+ and TrkB-TK- mRNAs in the SEZ from young adulthood into ageing (n = 50, 21-103 years), and related their transcript levels to neurogenic and glial cell markers. Ki67, DCX and both TrkB splice variant mRNAs significantly decreased in the SEZ from infancy to middle age. In contrast, TrkB-TK- mRNA increased in the SEZ from young adulthood into ageing, whereas TrkB-TK+ mRNA remained stable. TrkB-TK- mRNA positively correlated with expression of neural precursor (glial fibrillary acidic protein delta and achaete-scute homolog 1) and glial cell markers (vimentin and pan glial fibrillary acidic protein). TrkB-TK+ mRNA positively correlated with expression of neuronal cell markers (DCX and tubulin beta 3 class III). Our results indicate that cells residing in the human SEZ maintain their responsiveness to neurotrophins; however, this capability may change across postnatal life. We suggest that TrkB splice variants may differentially influence neuronal and glial differentiation in the human SEZ., (© 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Caudate nucleus volume is enlarged in autism spectrum disorder (ASD) and is associated with restricted and repetitive behaviors (RRBs). However, the trajectory of caudate nucleus volume in RRBs of young children remains unclear. Caudate nucleus volume was measured in 36 children with ASD and 18 matched 2-3-year-old subjects with developmentally delayed (DD) at baseline (Time 1) and at 2-year follow-up (Time 2). The differential growth rate in caudate nucleus volume was calculated. Further, the relationships between the development of caudate nucleus volume and RRBs were analyzed. Our results showed that caudate nucleus volume was significantly larger in the ASD group at both time points and the magnitude of enlargement was greater at Time 2. The rate of caudate nucleus growth during this 2-year interval was faster in children with ASD than DD. Right caudate nucleus volume growth was negatively correlated with RRBs. Findings from this study suggest developmental abnormalities of caudate nucleus volume in ASD. Longitudinal MRI studies are needed to explore the correlation between atypical growth patterns of caudate nucleus and phenotype of RRBs., (Copyright © 2016. Published by Elsevier Ltd.)

Trait positive affect (PA) in childhood confers both risk and resilience to psychological and behavioral difficulties in adolescence, although explanations for this association are lacking. Neurodevelopment in key areas associated with positive affect is ongoing throughout adolescence, and is likely to be related to the increased incidence of disorders of positive affect during this period of development. The aim of this study was to prospectively explore the relationship between trait indices of PA and brain development in subcortical reward regions during early to mid-adolescence in a community sample of adolescents. A total of 89 (46 male, 43 female) adolescents participated in magnetic resonance imaging assessments during both early and mid-adolescence (mean age at baseline = 12.6 years, SD = 0.45; mean follow-up period = 3.78 years, SD = 0.21) and also completed self-report measures of trait positive and negative affect (at baseline). To examine the specificity of these effects, the relation between negative affect and brain development was also examined. The degree of volume reduction in the right caudate over time was predicted by PA. Independent of time, larger hippocampal volumes were associated with higher PA, and negative affect was associated with smaller left amygdala volume. The moderating effect of negative affect on the development of the left caudate varied as a function of lifetime psychiatric history. These findings suggest that early to mid-adolescence is an important period whereby neurodevelopmental processes may underlie key phenotypes conferring both risk and resilience for emotional and behavioral difficulties later in life.

Importance: The very early postnatal period witnesses extraordinary rates of growth, but structural brain development in this period has largely not been explored longitudinally. Such assessment may be key in detecting and treating the earliest signs of neurodevelopmental disorders., Objective: To assess structural growth trajectories and rates of change in the whole brain and regions of interest in infants during the first 3 months after birth., Design, Setting, and Participants: Serial structural T1-weighted and/or T2-weighted magnetic resonance images were obtained for 211 time points from 87 healthy term-born or term-equivalent preterm-born infants, aged 2 to 90 days, between October 5, 2007, and June 12, 2013., Main Outcomes and Measures: We segmented whole-brain and multiple subcortical regions of interest using a novel application of Bayesian-based methods. We modeled growth and rate of growth trajectories nonparametrically and assessed left-right asymmetries and sexual dimorphisms., Results: Whole-brain volume at birth was approximately one-third of healthy elderly brain volume, and did not differ significantly between male and female infants (347 388 mm3 and 335 509 mm3, respectively, P = .12). The growth rate was approximately 1%/d, slowing to 0.4%/d by the end of the first 3 months, when the brain reached just more than half of elderly adult brain volume. Overall growth in the first 90 days was 64%. There was a significant age-by-sex effect leading to widening separation in brain sizes with age between male and female infants (with male infants growing faster than females by 200.4 mm3/d, SE = 67.2, P = .003). Longer gestation was associated with larger brain size (2215 mm3/d, SE = 284, P = 4×10-13). The expected brain size of an infant born one week earlier than average was 5% smaller than average; at 90 days it will not have caught up, being 2% smaller than average. The cerebellum grew at the highest rate, more than doubling in 90 days, and the hippocampus grew at the slowest rate, increasing by 47% in 90 days. There was left-right asymmetry in multiple regions of interest, particularly the lateral ventricles where the left was larger than the right by 462 mm3 on average (approximately 5% of lateral ventricular volume at 2 months). We calculated volume-by-age percentile plots for assessing individual development., Conclusions and Relevance: Normative trajectories for early postnatal brain structural development can be determined from magnetic resonance imaging and could be used to improve the detection of deviant maturational patterns indicative of neurodevelopmental disorders.

The amygdala is vulnerable to stress-dependent disruptions in neural development. Animal models have shown that stress increases dendritic arborization leading to larger amygdala volumes. Human studies of early stress and amygdala volume, however, remain inconclusive. This study compared amygdala volume in adults with childhood maltreatment to that in healthy controls. Eighteen participants from a longitudinal cohort and 33 cross-sectional controls (17 M/34 F, 25.5±3.1 years) completed a structural magnetic resonance imagining scan and the Maltreatment and Abuse Chronology of Exposure scale. Random forest regression with conditional trees was used to assess relative importance of exposure to adversity at each age on amygdala, thalamic or caudate volume. Severity of exposure to adversity across age accounted for 27% of the variance in right amygdala volume. Peak sensitivity occurred at 10-11 years of age, and importance of exposure at this time was highly significant based on permutation tests (p=0.003). The regression model showed that exposure during this sensitive period resulted in steep dose-response function with maximal response to even modest levels of exposure. Subjects in the highest exposure quartile (MACE-11, range=11-54) had a 9.1% greater right amygdala volume than subjects in the lowest exposure quartile (MACE-11, ≤3.5). No associations emerged between age of exposure and volume of the left amygdala or bilateral caudate or thalamus. Severity of adversity experienced at age 10-11 contributed to larger right but not left amygdala volume in adulthood. Results provide preliminary evidence that the amygdala may have a developmental sensitive period in preadolescence., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Purpose: This study aims to investigate the high-resolution 3-T MRI appearance and morphological variation of the temporal part of the caudate tail in pediatric subjects with normal brain MR examinations., Patients and Methods: One hundred pediatric patients were retrospectively evaluated using a high-resolution 3-T imaging protocol. Different morphological parameters including shape, size, and symmetry were evaluated. The appearance and shape of the caudate tail were classified into nodular, linear, or imperceptible. The location and relation of the caudate tail to the temporal horn and adjacent brain parenchyma were categorized. Relationships between age, gender, shape, location, side, and the cross-sectional area of the caudate tail were investigated., Results: The caudate tail was imperceptible in 22 %, had a nodular shape in 66.5 %, and was flat in 11.5 %. There was asymmetry of the caudate tail between the two sides in 37 % of subjects. The caudate tail was completely embedded within the temporal lobe parenchyma in 8.3 %, completely protruding into the temporal horn in 27.5 %, or intermediate in 64.1 %. The mean cross-sectional area of the caudate tail was constant across ages despite the varied age range of the subjects. There was no difference in overall mean cross-sectional area of the caudate tail between the two sides., Conclusion: There is a wide variation in the appearance of the caudate tail adjacent to the temporal horn of the lateral ventricle. Identification of anatomical variation of the caudate tail may prevent potential diagnostic pitfalls, especially with respect to subependymal heterotopia.

Rationale: Inactivating dopamine (DA) receptors in the caudate-putamen (CPu) attenuates basal and DA agonist-induced behaviors of adult rats while paradoxically increasing the locomotor activity of preweanling rats., Objective: The purpose of this study was to determine (a) whether D1 or D2 receptor inactivation is responsible for the elevated locomotion shown by preweanling rats and (b) whether DA receptor inactivation produces a general state in which any locomotor-activating drug will cause a potentiated behavioral response., Methods: Dimethyl sulfoxide (DMSO) or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was bilaterally infused into the CPu on postnatal day (PD) 17. In experiment 1, DA receptors were selectively protected from EEDQ-induced alkylation by pretreating rats with D1 and/or D2 antagonists. On PD 18, rats received bilateral microinjections of the DA agonist R(-)-propylnorapomorphine into the dorsal CPu, and locomotor activity was measured for 40 min. In subsequent experiments, the locomotion of DMSO- and EEDQ-pretreated rats was assessed after intraCPu infusions of the selective DA agonists SKF82958 and quinpirole, the partial agonist terguride, or after systemic administration of nonDAergic compounds., Results: Experiment 1 showed that EEDQ's ability to enhance the locomotor activity of preweanling rats was primarily due to the inactivation of D2 receptors. Consistent with this finding, only drugs that directly or indirectly stimulated D2 receptors produced a potentiated locomotor response in EEDQ-treated rats., Conclusions: These results show that DA receptor inactivation causes dramatically different behavioral effects in preweanling and adult rats, thus providing additional evidence that the D2 receptor system is not functionally mature by the end of the preweanling period.

Previous studies of early life trauma suggest that in addition to its emotional impact, exposure to early life stress (ELS) is associated with alterations in brain structure. However, little attention has been devoted to the relationship between emotional processing and brain integrity as a function of age of ELS onset. In the present study we examined whether ELS onset in older ages of youth rather than younger ages is associated with smaller limbic and basal ganglia volumes as measured by magnetic resonance imaging (MRI). We hypothesized that later age of manifestation during youth is associated with smaller volumetric morphology in limbic and basal ganglia volumes in adulthood. A total of 173 individuals were divided into three groups based on the age of self-reported ELS. The three groups included individuals only experiencing early childhood ELS (1 month-7 years, n = 38), those only experiencing later childhood ELS (8 years -17 years, n = 59), and those who have not experienced ELS (n = 76). Anterior cingulate cortex (ACC), hippocampus, amygdala, insula and caudate volumes were measured using a T1-weighted MRI. Analyses confirmed that later childhood ELS was associated with volumetric reductions in the ACC and insula volumes, while ELS experienced between the ages of 1 month and 7 years was not associated with lower brain volumes in these regions. The results may reflect the influence of more fully developed emotional processing of ELS on the developing brain and reinforce a body of research implicating both the ACC and insula in neuropsychiatric disorders and emotional regulation.

It is well known that stressful experiences may shape hippocampus-dependent learning and memory processes. However, although most studies focused on the impact of stress at the time of learning or memory testing, very little is known about how stress during critical periods of brain development affects learning and memory later in life. In this study, we asked whether prenatal stress exposure may influence the engagement of hippocampus-dependent spatial learning strategies and caudate nucleus-dependent response learning strategies in later life. To this end, we tested healthy participants whose mothers had experienced major negative life events during their pregnancy in a virtual navigation task that can be solved by spatial and response strategies. We found that young adults with prenatal stress used rigid response learning strategies more often than flexible spatial learning strategies compared with participants whose mothers did not experience major negative life events during pregnancy. Individual differences in acute or chronic stress do not account for these findings. Our data suggest that the engagement of hippocampal and nonhippocampal learning strategies may be influenced by stress very early in life., (Copyright © 2012 Wiley Periodicals, Inc.)

A growing body of evidence suggests that mitochondrial function may be important in brain development and psychiatric disorders. However, detailed expression profiles of those genes in human brain development and fear-related behavior remain unclear. Using microarray data available from the public domain and the Gene Ontology analysis, we identified the genes and the functional categories associated with chronological age in the prefrontal cortex (PFC) and the caudate nucleus (CN) of psychiatrically normal humans ranging in age from birth to 50 years. Among those, we found that a substantial number of genes in the PFC (115) and the CN (117) are associated with the GO term: mitochondrion (FDR qv <0.05). A greater number of the genes in the PFC (91%) than the genes in the CN (62%) showed a linear increase in expression during postnatal development. Using quantitative PCR, we validated the developmental expression pattern of four genes including monoamine oxidase B (MAOB), NADH dehydrogenase flavoprotein (NDUFV1), mitochondrial uncoupling protein 5 (SLC25A14) and tubulin beta-3 chain (TUBB3). In mice, overall developmental expression pattern of MAOB, SLC25A14 and TUBB3 in the PFC were comparable to the pattern observed in humans (p<0.05). However, mice selectively bred for high fear did not exhibit normal developmental changes of MAOB and TUBB3. These findings suggest that the genes associated with mitochondrial function in the PFC play a significant role in brain development and fear-related behavior.

This study identified structural changes in the caudate nucleus in offspring of mothers who drank moderate levels of alcohol during pregnancy. In addition, the effect of duration of alcohol use during pregnancy was assessed. Young adults were recruited from the Maternal Health Practices and Child Development Project. Three groups were evaluated: prenatal alcohol exposure (PAE) during all three trimesters (3T), PAE during the first trimester only (1T), and controls with no PAE (0T). Magnetic resonance images were processed using the automated labeling pathway technique. Volume was measured as the number (gray+white) and relative percentage (caudate count/whole brain count x 100) of voxels. Asymmetry was calculated by subtracting the caudate volume on the left from the right and dividing by the total (L-R/L+R). Data analyses controlled for gender, handedness, and prenatal tobacco and marijuana exposures. There were no significant differences between the groups for whole brain, left, or right volumes. There was a dose-response effect across the three exposure groups both in terms of magnitude and direction of asymmetry. In the 3T group, the left caudate was larger relative to the right caudate compared to the 0T group. The average magnitude of caudate asymmetry for the 1T group was intermediate between the 0T and 3T groups. Subtle anatomical changes in the caudate are detected at the moderate end of the spectrum of prenatal alcohol exposure., (Copyright © 2010 Elsevier Inc. All rights reserved.)

kappa-Opioid receptor stimulation attenuates psychostimulant-induced increases in extracellular dopamine in the caudate-putamen (CPu) and nucleus accumbens of adult rats, while reducing cocaine-induced locomotor activity and stereotyped behaviors. Because kappa-opioid receptor agonists (e.g., U50,488 or U69,593) often affect the behavior of preweanling rats in a paradoxical manner, the purpose of the present study was to determine whether kappa-opioid receptor stimulation differentially affects dopaminergic functioning in the CPu depending on age. In vivo microdialysis was used to determine whether U50,488 (5 mg/kg) attenuates cocaine-induced dopamine overflow in the dorsal CPu on postnatal day (PD) 17 and PD 85. In the microinjection experiment, cocaine-induced stereotyped behaviors were assessed in adult and preweanling rats after bilateral infusions of vehicle or U50,488 (1.6 or 6.4 microg per side) into the CPu. Results showed that U50,488 attenuated the cocaine-induced increases in CPu dopamine overflow on PD 85, while the same dose of U50,488 did not alter dopamine dialysate levels on PD 17. Cocaine also increased stereotyped behaviors (repetitive motor movements, behavioral intensity scores, and discrete behaviors) at both ages, but adult rats appeared to exhibit more intense stereotypic responses than the younger animals. Consistent with the microdialysis findings, bilateral infusions of U50,488 into the dorsal CPu decreased the cocaine-induced stereotypies of adult rats, while leaving the behaviors of preweanling rats unaffected. These results suggest that the neural mechanisms underlying kappa-opioid/dopamine interactions in the CPu are not fully mature during the preweanling period. This lack of functional maturity may explain why kappa-opioid receptor agonists frequently induce different behavioral effects in young and adult rats., (Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

The basal ganglia are subcortical structures involved in the planning, initiation and regulation of movement as well as a variety of non-motor, cognitive and affective functions. Capuchin monkeys share several important characteristics of development with humans, including a prolonged infancy and juvenile period, a long lifespan, and complex manipulative abilities. This makes capuchins important comparative models for understanding age-related neuroanatomical changes in these structures. Here we report developmental volumetric data on the three subdivisions of the basal ganglia, the caudate, putamen and globus pallidus in brown capuchin monkeys (Cebus apella). Based on a cross-sectional sample, we describe brain development in 28 brown capuchin monkeys (male n=17, female n=11; age range=2months-20years) using high-resolution structural MRI. We found that the raw volumes of the putamen and caudate varied significantly with age, decreasing in volume from birth through early adulthood. Notably, developmental changes did not differ between sexes. Because these observed developmental patterns are similar to humans, our results suggest that capuchin monkeys may be useful animal models for investigating neurodevelopmental disorders of the basal ganglia., (Copyright 2010 Elsevier B.V. All rights reserved.)

Manganese (Mn) is an essential trace element, but overexposure is characterized by Parkinson's like symptoms in extreme cases. Previous studies have shown that Mn accumulation is exacerbated by dietary iron deficiency (ID) and disturbances in norepinephrine (NE) have been reported. Because behaviors associated with Mn neurotoxicity are complex, the goal of this study was to examine the effects of Mn exposure and ID-associated Mn accumulation on NE uptake in synaptosomes, extracellular NE concentrations, and expression of NE transport and receptor proteins. Sprague-Dawley rats were assigned to four dietary groups: control (CN; 35 mg Fe/kg diet), iron-deficient (ID; 6 mg Fe/kg diet), CN with Mn exposure (via the drinking water; 1 g Mn/L) (CNMn), and ID with Mn (IDMn). (3)H-NE uptake decreased significantly (R=-0.753, p=0.001) with increased Mn concentration in the locus coeruleus, while decreased Fe was associated with decreased uptake of (3)H-NE in the caudate putamen (R=0.436, p=0.033) and locus coeruleus (R=0.86; p<0.001). Extracellular concentrations of NE in the caudate putamen were significantly decreased in response to Mn exposure and ID (p<0.001). A diverse response of Mn exposure and ID was observed on mRNA and protein expression of NE transporter (NET) and alpha(2) adrenergic receptor. For example, elevated brain Mn and decreased Fe caused an approximate 50% decrease in NET and alpha(2) adrenergic receptor protein expression in several brain regions, with reductions in mRNA expression also observed. These data suggest that Mn exposure results in a decrease in NE uptake and extracellular NE concentrations via altered expression of transport and receptor proteins.

Dopamine afferent islands were observed in rodent caudate-putamen only during development, whereas patches with intense mu-opioid receptor (MOR) immunoreactivity were seen throughout the life. We performed direct comparison between MOR patches and dopamine islands in the caudate-putamen of rat pups, by double immunofluorescence labeling for MOR and tyrosine hydroxylase. MOR patches were included in dopamine islands at postnatal day (P) 0 to P8, although the patches occupied the same region as the islands at P12-16. Furthermore, the regions of glutamatergic afferents with intense vesicular glutamate transporter 1 and vesicular glutamate transporter 2 immunoreactivities well corresponded to those of dopamine islands at P4. These results suggest that the striatal 'afferent islands' are larger than MOR patches in the early postnatal life.

Early nutrition in animals affects both behavior and brain structure. In humans, randomized trials show that early nutrition affects later cognition, notably in males. We hypothesized that early nutrition also influences brain structure, measurable using magnetic resonance imaging. Prior research suggested that the caudate nucleus may be especially vulnerable to early environment and that its size relates to IQ. To test the hypothesis that the caudate nucleus could be a neural substrate for cognitive effects of early nutrition, we compared two groups of adolescents, assigned a Standard- or High-nutrient diet in the postnatal weeks after preterm birth. Groups had similar birth status and neonatal course. Scans and IQ data were obtained from 76 adolescents and volumes of several subcortical structures were calculated. The High-nutrient group had significantly larger caudate volumes and higher Verbal IQ (VIQ). Caudate volumes correlated significantly with VIQ in the Standard-nutrient group only. Caudate volume was influenced by early nutrition and related selectively to VIQ in males, but not in females. Our findings may partly explain the effects of early diet on cognition and the predominant effects in males. They are among the first to show that human brain structure can be influenced by early nutrition.

Human total brain size is consistently reported to be approximately 8-10% larger in males, although consensus on regionally specific differences is weak. Here, in the largest longitudinal pediatric neuroimaging study reported to date (829 scans from 387 subjects, ages 3 to 27 years), we demonstrate the importance of examining size-by-age trajectories of brain development rather than group averages across broad age ranges when assessing sexual dimorphism. Using magnetic resonance imaging (MRI) we found robust male/female differences in the shapes of trajectories with total cerebral volume peaking at age 10.5 in females and 14.5 in males. White matter increases throughout this 24-year period with males having a steeper rate of increase during adolescence. Both cortical and subcortical gray matter trajectories follow an inverted U shaped path with peak sizes 1 to 2 years earlier in females. These sexually dimorphic trajectories confirm the importance of longitudinal data in studies of brain development and underline the need to consider sex matching in studies of brain development.

Heterogeneous spatiotemporal patterns of C57B/L6 murine brain maturation during the first 7 weeks after birth (i.e. P15 to P45) were assessed in vivo by diffusion tensor imaging (DTI) at 9.4 T. Maps of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were used to assess developmental changes. Because directionally encoded color (DEC) maps provide an efficient and straightforward way to visualize anisotropy direction, they were used to highlight the orientation-dominant anisotropic tissues. In the corpus callosum, the increases in FA (approximately 0.4 to approximately 0.6 from P15 to P45) were primarily dominant in the medial-lateral direction, whereas the ADC decreased slightly (approximately 0.8 x 10(-3) to approximately 0.5 x 10(-3) mm(2)/s from P15 to P45). Similar increases in FA (approximately 0.3 to approximately 0.4 from P15 to P45) and decreases in ADC (approximately 0.8 x 10(-3) to approximately 0.5 x 10(-3) mm(2)/s from P15 to P45) were found in the cingulate, but these anisotropic changes were dominant in the anterior-posterior direction. In the caudate putamen, there were significant FA increases (approximately 0.1 to approximately 0.2 from P15 to P45) dominant in the dorsal-ventral and anterior-posterior directions, whereas the ADC increased rapidly early in development (approximately 0.3 x 10(-3) to approximately 0.7 x 10(-3) mm(2)/s from P15 to P17). There were no significant changes in tissue anisotropy in the somatosensory regions (whisker, forelimb), but the ADC decreased slightly (approximately 0.7 x 10(-3) to approximately 0.5 x 10(-3) mm(2)/s from P15 to P45). Although the major differences in DEC values were mainly observed in white matter pathways, other cortical and subcortical regions showed some potential morphological changes that were consistent with classical histological findings. In summary, these results show that high-resolution DTI at high magnetic fields allows detection and quantification of brain structures throughout normal development in C57B/L6 mice in vivo., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Stem cells with the potential to give rise to new neurons reside in different regions of the adult rodents CNS, but in vivo only the hippocampal dentate gyrus and the subventricular zone-olfactory bulb system are neurogenic under physiological condition. Comparative analyses have shown that vast species differences exist in the way the mammalian brain is organized and in its neurogenic capacity. Accordingly, we have demonstrated recently that, in the adult rabbit brain, striking structural plasticity persists in several cortical and subcortical areas. Here, by using markers for immature and mature neuronal and glial cell types, endogenous and exogenously administered cell-proliferation markers, intraventricular cell tracer injections coupled to confocal analysis, three-dimensional reconstructions, and in vitro tissue cultures, we demonstrate the existence of newly formed neurons in the caudate nucleus of normal, untreated, adult rabbit. Our results suggest that neurogenesis in the caudate nucleus is a phenomenon independent from that occurring in the adjacent subventricular zone, mostly attributable to the activity of clusters of proliferating cells located within the parenchyma of this nucleus. These clusters originate chains of neuroblasts that ultimately differentiate into mature neurons, which represent only a small percentage of the total neuronal precursors. These results indicate that striatum of rabbit represents a favorable environment for genesis rather than survival of newly formed neurons.

Background and Purpose: Brain volume and diffusion change during maturation. Quantitation of these changes may be helpful in understanding normal brain development. We used diffusion-weighted imaging to characterize the volumetric and diffusion changes in vivo., Methods: We recruited 30 pediatric volunteers (aged 1 month-17 years; 14 male, 16 female). Diffusion was measured in three orthogonal directions with a b value of 1000 s/mm2. The diffusion parameters from the entire brain were calculated and fitted to a triple gaussian model. In addition, region-of-interest measurements were made in caudate, thalamus, genu and splenium of the corpus callosum, and periventricular white matter (PVWM). The brain volume was measured by counting pixels and by using the model., Results: Water diffusion of the whole brain, caudate, thalamus, genu and splenium of the corpus callosum, and PVWM decreased during maturation, with the most significant change within the first 2 years. Robust negative correlations were found between age and the measured average diffusion constant (Dav) values in each of the measured locations (P <.005). Volumes of different cerebral compartments and the total intracranial volume (ICV) increased rapidly during the first 2 years of life and then had a slower growth process through adolescence. Age was correlated with the ICV and the volume of each brain compartment (P <.005)., Conclusion: Brain diffusion decreases and brain volume increases during maturation, with the most significant changes occurring within the first 2 years of life. The brain model used in this study provides a good estimate of the increasing brain volume.

This study examined the cognitive and neural development of attention switching using a simple forced-choice attention task and functional magnetic resonance imaging Fourteen children and adults made discriminations among stimuli based on either shape or color. Performance on these trials was compared to performance during blocked trials requiring all color or all shape discriminations. Magnetic resonance echo planar images were acquired during performance of the task. Both children and adults showed robust bilateral activity of the caudate nucleus when switching attention between color and shape discriminations that correlated negatively with mean response latency on these trials. However, neither switching costs nor caudate activity correlated with age, suggesting early development of the underlying neural circuitry involved in switching between salient stimulus sets. Overall, children and adults differed in performance and patterns of brain activity on the task, with adults responding more accurately and faster than children, and recruiting more prefrontal and parietal regions. These results suggest an important role of subcortical regions (i.e. caudate nucleus) in non-cued attention switching, with increasing recruitment of cortical regions with age.

Dopaminergic (DA) neurons in the substantia nigra (SN) and ventral tegmental area (VTA) of the midbrain project to the dorsolateral caudate/putamen and to the ventromedially located nucleus accumbens, respectively, establishing the mesostriatal and the mesolimbic pathways. Disruptions in this system have been implicated in Parkinson's disease, drug addiction, schizophrenia, and attention deficit hyperactivity disorder. However, progress in our understanding has been hindered by a lack of knowledge of how these pathways develop. In this study, different retrograde tracers, placed into the dorsolateral caudate/putamen and the nucleus accumbens, were used to analyze the development of the dopaminergic pathways. In embryonic day 15 mouse embryos, both SN and VTA neurons, as well as their fibers, were doubly labeled by striatal injections into the dorsolateral and ventromedial striatum. However, by birth, the SN DA neurons were labeled exclusively by DiA placed in the dorsolateral striatum, and the VTA DA neurons were labeled only by DiI injected into the ventromedial striatum. These data suggest that initial projections from midbrain DA neurons target nonspecifically to both the dorsolateral striatum and the nucleus accumbens. Later during development, the separate mesostriatal and mesolimbic pathways differentiate through the selective elimination of mistargeted collaterals.

Dendritic expression of the activity-regulated cytoskeleton-associated protein (Arc) is dramatically enhanced by increased synaptic activity in adult brain. We used immunocytochemical electron microscopy to determine whether the subcellular localization of Arc in developing dendrites corresponds to the peak period of synaptogenesis in the postnatal rat caudate-putamen nucleus (CPN). The distribution was compared with that of mu-opioid receptors (MORs), whose localization in dendritic spines closely parallels excitatory synapse formation during postnatal development (Wang et al. [2003] Neuroscience 118:695-708). Sections were processed for immunocytochemical detection of antisera against Arc or MORs at the beginning (postnatal day 15; P15) and the end (P30) of the peak period of synaptogenesis in rat CPN. At P15, immunolabeling for Arc showed a punctate distribution in the cytoplasm of dendritic shafts, some of which was associated with polyribosomes. In some spiny dendrites, Arc immunoreactivity was more intensely localized in putative spines than in their parental dendrites, whereas, in other spiny dendrites, Arc labeling was restricted in the shafts. Many dendritic shafts and spines also showed immunoreactivity for MORs, although dually labeled spines were less numerous than the shafts. At P30, the proportion of singly and dually labeled spines significantly increased from 2.0% to 7.5% and from 9.5% to 21%, respectively. Arc labeling in spines was more detectable beneath the postsynaptic density or at extrasynaptic sites on the plasma membrane. Our results suggest a correlation between Arc expression in dendritic spines during postnatal development and the onset of synaptogenesis in opioid-responsive neurons in the rat CPN., (Copyright 2004 Wiley-Liss, Inc.)

Gender differences exist in the development of the nigrostriatal dopamine system, and in the incidence and course of pediatric and adult neuropsychiatric diseases in which this system is implicated. The medium size spiny neuron (MSN) is the major output neuron of the caudate nucleus. It receives a large dopaminergic input from the substantia nigra, and 96% of the MSNs express DARPP-32, a dopamine and cyclic AMP-regulated phosphoprotein and key mediator of dopamine function. There are few examples, however, of direct effects of sex hormones, including 17beta-estradiol (E(2)), on the MSN. We report that in vitro, E(2) (10-50 nM) promotes MSN phenotypic maturation, as determined by increased soma size, neurite length, and DARPP-32 protein levels. Treatment with the 'anti-estrogen' ICI 182,780 or the partial-agonist tamoxifen also increases DARPP-32 levels, but when added to E(2), ICI 182,780 only prevents the increase in DARPP-32 levels and increase in soma size and neurite length. Surprisingly, maturation effects are more robust in cells derived exclusively from female embryos. Western blot analysis of protein lysates and immunocytochemistry of cultured MSNs reveals the presence of the estrogen receptor beta (ERbeta). These data suggest that ERbeta may mediate the differentiating effect of E(2) on embryonic MSNs, and provide new avenues of investigation for the role of sex hormones in the development of the striatum and in diseases affecting the basal ganglia.

During development, delta-opioid receptors (DORs) in the rat caudate-putamen nucleus (CPN) appear later than mu-opioid receptors (MORs), whose developmental pattern specifically relates to synaptogenesis. We used electron microscopic immunocytochemistry to determine whether there are also age-related changes in subcellular localization of DORs in the rat CPN. Sections from postnatal day (P) 0-P30 and adult dorsomedial CPN were immunogold-silver labeled to examine the plasmalemmal and cytoplasmic distribution of these receptors. In addition, immunoperoxidase labeling was used to determine the numerical density of synapses relative to DOR-labeled profiles. Immunolabeling for DOR was undetectable at P0, light at P5, and dense from P10 onward. The labeling during P5-P10 was mainly localized in somatodendritic profiles but also was readily seen in axon terminals, most of which formed asymmetric synapses with dendrites. From P15, a few immunogold particles were seen in contact with postsynaptic densities in spines, and the proportion of these particles significantly increased in P30 and adult CPN. Other particles were localized in the cytoplasm of dendrites and terminals without significant age-related changes. Stereological analysis showed that compared with labeled dendritic shafts and spines, labeled axon terminals have a closer correlation with synapse formation. These results are in marked contrast with MORs, which show an age-related increase in association with dendritic plasma membrane and a good correlation in the developmental pattern of MOR-labeled spines with synapse formation (Wang et al. [2003] Neuroscience 118:695-708). Together, our results suggest receptor-type specific roles for endogenous opioids acting at both pre- and postsynaptic sides in the developing CPN., (Copyright 2003 Wiley-Liss, Inc.)

The mu-opioid receptor (MOR) in the caudate-putamen nucleus (CPN) appears early during prenatal development, and shows a patch-like distribution throughout the postnatal period and adulthood. In the adult rat CPN, neurons in patch compartments receive glutamatergic excitatory input mainly from the cortex through synapses onto spines, many of which express MORs. Thus, MOR expression in spines may be related to corticostriatal synaptogenesis. We used electron microscopic immunocytochemistry to determine potential age-dependent changes in the distribution pattern of MOR during postnatal synaptogenesis in the rat CPN. Immunogold-silver labeling revealed that the dendritic plasmalemmal density of MOR at postnatal day (P) 0 was significantly lower than, but after P10 was similar to, that of adult. In contrast, such age-dependent changes were not observed in axon terminals. Stereological analysis of immunoperoxidase labeling for MOR showed a good correlation in the developmental numerical densities of synapses with MOR-labeled spines and those of total asymmetric axospinous synapses, linear correlation coefficient r=0.99. Synapses with MOR-labeled dendrites, however, had a low correlation with axodendritic synapses (r=0.61), and synapses with MOR-labeled terminals showed no correlation with axospinous and axodendritic synapses (r=0.19). These results provide ultrastructural evidence that the targeting of MOR on the plasma membrane of dendrites and spines parallels the peak period of synaptogenesis during the third postnatal week in the rat CPN. Thus, the postnatal spatiotemporal expression pattern of MOR appears to match the functional maturation of corticostriatal glutamate transmission.

The present study examined the regional differences in dopamine transporter binding sites and NMDA receptor complex binding based on autoradiographic images obtained in postmortem sections of human normal brain tissues. In middle-aged control tissues, high and comparable levels of [(3)H]CFT binding were observed in the caudate nucleus, putamen, and accumbens nucleus without significant alteration along the rostrocaudal axis and ventral and dorsal parts of these nuclei. In aging normal brain tissues, dopamine binding sites for [(3)H]CFT were significantly reduced in the caudate nucleus, putamen, and accumbens nucleus. l-[(3)H]Glutamate, [(3)H]MK-801, and [(3)H]glycine binding to the NMDA receptor complex was lower in aging brain tissues than in middle-aged controls. Significant correlation did occur between age and [(3)H]CFT binding and between age and l-[(3)H]glutamate, [(3)H]MK-801, and [(3)H]glycine binding sites. These results demonstrate that the basal ganglia have age-associated reductions in dopamine transporter uptake and NMDA receptors. These data support hypoactive activity of the NMDA receptor complex system with advancing age. The dopamine transporter uptake and NMDA receptors appear to be vulnerable to the aging process in the basal ganglia., (Copyright 2001 Academic Press.)

Some catecholamines and indolamines inhibit lipid peroxidation. Recent studies indicate that catecholaminergic inhibition of lipid peroxidation may be receptor mediated in vivo and in cell cultures. Because oxidative stress is one of the hypothesized pathogenic mechanisms for neurodegenerative diseases, including Alzheimer's disease (AD), we hypothesized that catecholaminergic and indolaminergic inhibition of lipid peroxidation would be altered in AD as compared to age-matched non-AD. To test this hypothesis we studied the effect of a variety of neurotransmitters and their antagonists on ascorbate-stimulated lipid peroxidation in membrane fragment preparations derived from postmortem human brain. In this in vitro system, the inhibition of lipid peroxidation by dopamine and serotonin did not appear to be receptor mediated. Further, our findings indicate that there is no apparent effect of age or AD on the inhibition of lipid peroxidation by catecholaminergic and indolaminergic agents.

As a continuation of the morphometric studies on the preceding paper, here we report on the rate of growth of the caudate nucleus (n.), thalamus, red n., and the substantia (s.) nigra using, with few exceptions, the same cohort of cats. The same previously used brains (n=64 cats) were allocated to the following age groups: fetal (E) 59 days, postnatal (P) days 1, 7, 15, 30, 45, 60, 90, 120, and 180. Sixteen additional cats, interspersed within the groups, were substituted for the red n. and s. nigra studies. There were six subjects per group (except for E59, n=4). Using a projection microscope and cytochrome oxidase-stained coronal sections, a combined (left plus right sides) total of 4693, 3822, 1636, and 1180 sections were drawn for the caudate, thalamus, s. nigra, and red n., respectively. With computer assistance, the drawings were digitized to calculate mean cross-sectional areas and then the mean volume of each structure per group. The growth time tables for the caudate n., thalamus and s. nigra were fairly synchronous. In terms of percentage of the adult volume, for the left side (both sides grew at a similar rate), the three structures grew at a fast pace between E59 and P30. Thus, at E59 their respective percentages relative to adult volume were 23.7, 29.8 and 22.6% and by P30 the percentages were within adult range (85.2, 115.1 and 87.5%, respectively). Starting at P30, for the thalamus and at P45 for the caudate n., there was a consistent tendency to an overgrow which ranged between 4.3 and 30.9% (at P180, P<0.5) for the caudate and between 0.3 and 15.1% for the thalamus. In addition, starting at P30, the right thalamus tended to be consistently larger than the left by a margin ranging between 0.5 and 11.2% (P120, P<0.05). The red n. grew at a different, slower pace. Starting from a fetal volume equivalent to an 18.6% of adult size, its volume was only a 61.0% of the adult value at P30 and came within range of adulthood size only by P60 (81. 3%). Neither the s. nigra nor the red n. showed any consistent tendency to overgrow or to asymmetry. These findings are discussed in the context of the literature. Furthermore, we discuss general conclusions and considerations pertaining to both papers as well as draw comparisons with the maturational time tables of other developmental landmarks in cats. Finally, in a comparison with growth of human brain structures, we point at the limitations and complexities involved in studying human material and, noting interspecies similarities, we propose that the present data from an advanced gyrencephalic mammal may form the bases for a model of structures maturation in humans.

Thy-1 is a cell-surface molecule of the immunoglobulin superfamily which is expressed at high levels in the mature nervous system. Thy-1 has been implicated in regulating axonal outgrowth and synaptic function, but little is known regarding its cellular localization and expression in the central nervous system (CNS) during development or in adulthood. In this study, Thy-1 gene expression and protein localization were examined in sensory-motor and related areas of the adult and postnatally developing mouse CNS. Thy-1 mRNA expression was restricted to neurons; immunoreactivity was densely distributed throughout the neuropil of all regions examined, often delineated the neuronal plasmalemma, and labeled axons in white matter tracts of the brain and spinal cord. In adulthood, immunolabeling was regionally widespread and was present relatively homogeneously throughout all cell-dense layers of sensory-motor cortex, throughout most thalamic nuclei, globus pallidus, and spinal cord. Developmentally, however, Thy-1 expression and localization exhibited a spatially and temporally staggered sequence leading to the adult pattern. In sensory-motor cortex, Thy-1 expression in layer V preceded expression in other layers; in the barrel field, labeling of barrel septa preceeded a gradually increasing intensity of immunolabeling of barrel centers; in the thalamus, Thy-1 exhibited a differential onset and temporal pattern of expression across different nuclei associated with motor, sensory, or limbic systems; in the caudate nucleus, Thy-1 expression was greatest during the first postnatal week of life before declining during subsequent development. Taken together, the adult distribution and developmental patterns leading to it form a unique profile in comparison with other structurally related glycosyl-phosphatidylinositol (GPI)-anchored neural cell adhesion molecules. The pattern and timing of Thy-1 expression across layers and nuclei during early postnatal development are more complex than previously recognized, thus perhaps reflecting varied roles for Thy-1 in aspects of structural or functional maturation which proceed independently of the timing of neurogenesis, migration, and dendritic and axonal growth., (Copyright 2000 Wiley-Liss, Inc.)

Perturbations in the developmental regulation of the dopaminergic system have been hypothesized to participate in the age-dependent onset of schizophrenia. Although data from studies of non-human primates suggest that dopamine D1-like receptors decrease during adolescence, less information is available concerning changes in human brain. The present study employed quantitative receptor autoradiography to measure D1-like receptor density and affinity in human caudate and putamen. Samples were obtained postmortem from 15 subjects (9 weeks to 49 years), and grouped a priori into three classes: infants, adolescents, and adults. Receptor density and affinity were assessed by saturation binding with [3H]-SCH23390, a D1 receptor antagonist. A decrease in D1 receptor density was observed from infancy to adulthood, with no change in receptor affinity. The temporal pattern of D1-like receptor expression during maturation may play a role in the interaction of dopamine with other neurotransmitter systems, and in the occurrence and pharmacotherapy of neurological and neuropsychiatric disorders.

We have studied dopamine D2 receptor binding by [11C]raclopride positron emission tomography in 14 patients with dopa-responsive dystonia (DRD). Data were compared with 16 levodopa-treated patients with Parkinson's disease (PD) and 26 healthy controls. The results revealed an elevated [11C]raclopride binding index in the putamen and caudate nucleus of DRD patients compared with controls as well as a significant elevation in the caudate nucleus compared with PD patients. The increase of [11C]raclopride binding may be interpreted either as reduced tracer displacement by endogenous dopamine, or as an alteration of the receptor features due to chronic dopamine deficiency. The difference in [11C]raclopride binding in DRD and PD patients in the caudate nucleus suggests that this structure may be of pathophysiological relevance in the presentation of the clinical features of both diseases.

Density of dopamine transporter (DAT) and serotonin transporter (5-HTT) membrane proteins in the caudate-putamen (CPu) and nucleus accumbens (NAc) of rat brain was assessed at seven ages at postnatal days (PD) 7-60, by in vitro quantitative autoradiography. Binding of [3H]GBR-12935 (to DAT) and [3H]paroxetine (to 5-HTT) increased steadily and very similarly, from low levels at PD-7 to maximal levels, to 6-7-fold higher density at PD-60 in both regions. These findings indicate that DAT and 5-HTT follow a synchronized course of development in rat CPu and NAc. In contrast to reported elimination of excessive receptors in CPu and NAc during maturation, there was no evidence of pruning of DAT or 5-HTT in these regions of rat forebrain.

The pore-forming alpha subunits of voltage-gated potassium channels in neurons and other excitable cells are expressed in association with accessory beta subunits. These subunits both promote insertion of channel complexes into surface membranes and influence their electrophysiological properties. As part of an effort to understand the regulation of voltage-gated potassium channels during development, we cloned the mouse homolog of the rat Kvbeta1 potassium channel subunit. Kvbeta1 subunits are known to associate preferentially with Shaker (Kv1)-related alpha subunits. We then used a digoxigenin-tagged cRNA probe and in situ hybridization techniques to visualize the appearance of Kvbeta1 mRNA transcripts during late embryonic and early neonatal development of the mouse brain. We detected Kvbeta1-specific labeling of cells in hippocampus, cerebral cortex, caudate putamen, colliculus, and cerebellum. In hippocampus, we observed Kvbeta1 mRNA in CA3 pyramidal neurons at the earliest time examined, embryonic day 16 (E16). Between E16 and postnatal day 7 (P7), cell labeling increased uniformly across the pyramidal neurons of Ammon's horn (CA1, CA2, and CA3). Subsequently, between P7 and P22, regional differences characteristic of mature hippocampus appeared-intense labeling of neurons in CA3 and CA1, and less in CA2. In cortex, labeling of cells in the subplate and cortical plate layers was observed at E16. During development, the intensity of this labeling increased, and labeled cells persisted into the adult stage in the deep cortical layer (VIb) formed from subplate neurons. Additional labeling of scattered solitary cells in cortical layers II-VIa emerged between P3 and P7 and was prominent in mature cortex. In caudate putamen, Kvbeta1-labeled cells were observed at P1 and were restricted to the lateral and rostral half of the caudate. During development, labeling expanded caudally and medially and eventually filled the mature caudate putamen. In colliculus, a small population of inferior colliculus cells showed labeling at P7, and additional labeling of scattered cells appeared during development. In superior colliculus, labeling was observed only in the adult deep gray layer. In cerebellum, intense labeling was observed in Purkinje cells at all stages between P1 and adult. Labeling was also seen in granule neurons in the external granule layer at early postnatal stages and in the inner granule layer beginning at P7.

There is reason to believe that dopamine is important in developmental programs of the basal ganglia, brain nuclei implicated in motor and cognitive processing. Dopamine exerts effects through dopamine receptors, which are predominantly of the D1 and D2 subtypes in the basal ganglia. Cocaine acts as a stimulant of dopamine receptors and may cause long-term abnormalities in children exposed in utero. Dopamine receptor (primarily D1) stimulation has been linked to gene regulation. Therefore, D1 and D2 receptor densities in perinatal and adult striatum and globus pallidus were examined using quantitative autoradiography. The most striking finding was that pallidal D1 receptor densities were 7-15 times greater in the perinatal cases than in the adult. Pallidal D2 receptor densities were similar at both ages. In both the adult and perinatal striatum, D2 receptor densities were greater in the putamen than in the caudate, and both D1 and D2 receptor densities were modestly enriched in caudate striosomes compared with the matrix. In both caudate and putamen, perinatal D1 receptor levels were within the adult range, whereas D2 receptor levels were only 50% of adult values. The development of D1 and D2 receptors appears to vary across the major subdivisions of the human basal ganglia. The facts that we found such extremely high levels of D1 receptors in the perinatal pallidum, and that D1 receptor activation influences gene regulation, suggest that the globus pallidus could be particularly susceptible to long-term changes with perinatal exposure to cocaine and other D1 receptor agonists or antagonists.

The aim of this study is to describe the vascular characteristics of the nucleus caudatus (NC). This study is performed on 30 human brains by injecting the vascular system with gelatinous Indian ink. Examination of serial slices, 250 microns thickness, made translucent by the Spalteholz method, enabled us to follow the course and behavior of the vessels of the NC. The arteries of the NC belong to the group of the central arteries arising from the anterior and middle cerebral arteries or from the anterior choroidal arteries. Inside the different parts of the NC (head, body and tail) the central arteries and their ramifications give rise to a specific vascular network quite similar to this one of the putamen. This network consists of regular, polygonal, rectangular or square meshes. Each mesh is composed by the juxtaposition of vascular units formed by an arterial ring arranged around a principal vein which is surrounded by a capillary free space. The arterioles of the network of the NC are terminal or side branches of the central arteries. They are characteristic in their course by forming rope-like structures (coils) also described on the ramifications of the putaminal central arteries. Similarities between the vascular networks of the NC and the putamen are in relation with the histological structure, with the morphogenetic evolution, with the functional activity. The specificity and the clear delimitation of the vascular networks of the NC and of the putamen are particularly obvious in cerebral vascular diseases leading to infarcts strictly limited to these two nuclei.

We investigated the nature of cGMP-synthesizing cells in the developing rat forebrain using cGMP-immunocytochemistry in combination with in vitro incubation of brain slices. When brain slices of immature rats, aged between 1 and 4 weeks, were incubated with sodium nitroprusside (SNP), a nitric oxide (NO) donor compound, in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX), small round cells with a few processes in and around the corpus callosum were visualized with the cGMP-antibody. The morphology and the distribution of the cGMP-positive cells were consistent with the criteria for oligodendrocytes. Furthermore, the cGMP-positive cells expressed 2'3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and gelsolin, which are marker proteins for oligodendrocytes. Therefore, we concluded that the cGMP-positive cells were oligodendrocytes. A subpopulation of the oligodendrocyte was found to be cGMP-immunoreactive also when slices were incubated in the absence of SNP. Furthermore, incubation of the slice in the presence of L-NAME, an inhibitor of NO synthase, but in the absence of SNP abolished cGMP immunostaining. In addition, some populations of neurons and astrocytes in restricted brain areas produced cGMP in response to the incubation with SNP as previously reported, whereas both ameboid and ramified microglial cells did not respond to the treatment. Atrial natriuretic peptide, a stimulator of particulate guanylyl cyclase, enhanced cGMP synthesis in astrocytes in some brain regions but not in oligodendrocytes. These findings indicate that oligodendrocytes in the immature rat brain express soluble guanylyl cyclase. No cGMP-positive oligodendrocytes were found in the mature rat brain, suggesting that cGMP may mediate signals related to myelinogenesis in the rat brain.

A substantial decrease in number of striatal dopamine uptake sites is a characteristic finding in aging. This decrease resembles the dopaminergic nigro-striatal degeneration in Parkinson's disease (PD). A dysfunction of cytochrome P450IID6 (debrisoquine-4-hydroxylase) is suggested to be involved in the pathogenesis of PD. In this study, binding sites associated with the neuronal form of P450IID6 were studied in the caudate nucleus from individuals in the age range 20-81 years using [3H]GBR 12935 as a radioligand. No significant changes in binding parameters were obtained, while in the same region a significant decrease in number of dopamine uptake sites occurred. Thus, in aging, P450IID6 and dopaminergic degeneration seem not to be functionally related in this region. Whether such a relation exists in PD is still to be examined.

In the present study a left-right asymmetry in both D1- and D2-receptor density in the caudate-putamen nucleus is shown and a lateralisation of D2-receptor distribution in the accunbens nucleus is also described. In old animals in which D1- and D2-receptors density is decreased, the dopamine receptor asymmetries are lost.

Tissue samples from the caudate nucleus were obtained from eight children (eight to 172 months of age) who underwent hemispherectomies for the relief of intractable seizures. Neurophysiological, pharmacological and morphological properties of caudate neurons were characterized by intracellular recordings in an in vitro slice preparation. These properties were compared with those of tissue obtained from animal studies. Electrophysiological properties of human caudate neurons that were similar to those of cat caudate and rat neostriatal cells included resting membrane potential, input resistance, action potential rise time, fall time, duration and action potential afterhyperpolarization amplitude, as well as the general characteristics of locally evoked synaptic responses. Properties that were different included action potential amplitudes and time-constants. Human caudate neurons also displayed responses similar to those of cat caudate or rat neostriatal cells to manipulation of excitatory amino acid receptor systems and to dopamine application. Kynurenic acid, a broad-spectrum excitatory amino acid receptor antagonist, decreased the amplitude of evoked synaptic responses, indicating that they were partially mediated by excitatory amino acids. In Mg2+ free Ringer's solution, the amplitudes and durations of postsynaptic responses were increased and bursts of action potentials were induced. These effects were mediated by activation of N-methyl-D-aspartate receptors since they were blocked by 2-amino-5-phosphonovalerate, a specific N-methyl-D-aspartate-receptor antagonist. Iontophoretic application of N-methyl-D-aspartate also induced membrane oscillations and bursts in almost all caudate neurons. Dopamine decreased the amplitude of postsynaptic responses, an effect antagonized by domperidone, a selective D2 dopamine receptor antagonist. Developmentally, the greatest change was an increase in action potential amplitude, although input resistance decreased and action potential afterhyperpolarization amplitude increased. Postsynaptic responses were similar across age. All but one of the caudate neurons identified by intracellular injection of biocytin or Lucifer Yellow were medium-sized spiny cells. These experiments show that human caudate neurons display a number of electrophysiological properties similar to rat neostriatal or cat caudate neurons recorded in brain slices. Furthermore, few electrophysiological parameters changed significantly over the age period examined suggesting that the human caudate at eight months displays many of the neuronal functions of the more mature caudate nucleus.

Transforming growth factor alpha (TGF alpha) is a mitogenic polypeptide which acts at the epidermal growth factor receptor to produce its biologic effects. Recent studies have demonstrated that TGF alpha may act as a neurotrophic factor. Cerebral hemispherectomy (hemidecortication) is performed on some children with intractable epilepsy. Prior studies have demonstrated improved functional recovery in both children and animals when the surgery is performed at a very early age. In order to test whether TGF alpha may be involved in the functional recovery of the neostriatum following cerebral hemidecortication, we performed in situ hybridization for TGF alpha mRNA on brains of rats which underwent hemispherectomy at postnatal day (P) 6 or P12 or in adulthood, and sacrificed one, 7, or 30 days following surgery. Normal striatal expression in control animals was very high at P6 and then decreased throughout development. In animals undergoing lesion at earlier ages (P6 and P12), TGF alpha mRNA expression was first depressed in the ipsilateral neostriatum one day after surgery and then elevated to supranormal levels 7 and 30 days after surgery. Maximal decreases (40% below contralateral neostriatum) were seen in animals lesioned at P12 and sacrificed the next day. Maximal elevations (60% greater than opposite neostriatum) were seen in animals operated on at P6 and sacrificed 30 days post surgery. Expression in the adult animal was only mildly affected, with a 20% increase found in the ipsilateral caudate 7 days after the lesion, but no significant changes after one or 30 days survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Forebrain nuclei that control learned vocal behavior in zebra finches are anatomically distinct and interconnected by a simple pattern of axonal pathways. In the present study, we examined afferent regulation of neuronal survival during development of the robust nucleus of the archistriatum (RA). RA projection neurons form the descending motor pathway of cortical vocal-control regions and are believed to be directly involved in vocal production.RA receives afferent inputs from two other cortical regions, the lateral magnocellular nucleus of the anterior neostriatum (lMAN) and the higher vocal center (HVC).However, because the ingrowth of HVC afferent input is delayed, lMAN projection neurons provide the majority of afferent input to RA during early vocal learning. lMAN afferent input to RA is of particular interest because lMAN is necessary for vocal learning only during a restricted period of development. By making lesions of lMAN in male zebra finches at various stages of vocal development (20-60 days of age) and in adults (>90-days old), we asked whether the survival of RA neurons depends on lMAN afferent input, and if so whether such dependence changes over the course of vocal learning. The results showed that removal of lMAN afferent input induced the loss of over 40% of RA neurons among birds in early stages of vocal development(20 days of age). However, lMAN lesions lost the ability to induce RA neuron death among birds in later stages of vocal development (40 days of age and older). These findings indicate that many RA neurons require lMAN afferent input for their survival during early vocal learning, whereas the inability of lMAN lesions to induce RA neuron death in older birds may indicate a reduced requirement for afferent input or perhaps the delayed ingrowth of HVC afferent input (at approx. 35 days of age)provides an alternate source of afferent support. Removal of lMAN afferent input also dramatically increased the incidence of mitotic figures in RA, but only among 20-day-old birds at 2 days post-lesion. The early, acute nature of the mitotic events raises the possibility that cell division in RA may be regulated by lMAN afferent input.

The glycoprotein 5'-nucleotidase is a cell surface phosphatase and represents a new marker for striosomes in the adult rat caudoputamen. We report here on its developmental expression in the rat and mouse striatum, and show an unexpected converse 5'-nucleotidase chemoarchitecture of the caudoputamen in these closely related species. In the rat, 5'-nucleotidase activity was first visible as neuropil staining in tyrosine hydroxylase-positive dopamine islands of the midstriatum on postnatal day 1, and by the end of the first postnatal week, 5'-nucleotidase-positive dopamine islands also appeared rostrally. This compartmental pattern persisted thereafter, so that in adult animals, in all but the caudal caudoputamen, zones of enhanced 5'-nucleotidase staining were restricted to calbindin-D28k-poor striosomes. Weak 5'-nucleotidase activity also emerged in the matrix. In striking contrast, in the mouse striatum, enhanced 5'-nucleotidase activity was preferentially associated with extrastriosomal tissue. Enzymatic reaction first appeared on embryonic day 18, and developed over the first postnatal week into a mosaic pattern in which the matrix was stained but the dopamine islands were unstained. The matrix staining itself was heterogeneous. After the second postnatal week, most of the caudoputamen was stained, and in adult mice only rostral striosomes expressed low 5'-nucleotidase activity. We conclude that in rats, 5'-nucleotidase represents one of the few substances that maintains a preferential dopamine island/striosome distribution during striatal development. In mice, 5'-nucleotidase activity is expressed preferentially in the matrix during development, and its compartmental pattern is gradually lost with maturation, except very rostrally. These findings do not suggest an instructive role of the enzyme in striatal compartment formation in either species, but do suggest the possibility that 5'-nucleotidase contributes to the differentiation of striatal compartments during development.

In order to study the influence of prenatal developmental factors upon reaction of the brain to injury, fetal kittens (E43-48) were lesioned in the frontal or parietal cortex unilaterally and maintained into young adulthood. The animals were sacrificed by perfusion with an aldehyde fixative or by an overdose of pentobarbital. Frozen sections were cut and stained with thionin. These sections were used for calculation of caudate nuclei volumes and for measurements of neuronal and glial cell packing density and neuronal cell body size. Island and matrix compartments were sampled separately. We found that the volume of the ipsilateral caudate nucleus had significantly increased as compared to (a) the volume of the corresponding nucleus in intact cats (mean, 15%) and (b) the nucleus contralateral to the lesion (mean, 7.6%). The latter nucleus also tended to a volume increase (mean, 8.1%). The cytoarchitecture of the caudate nuclei was essentially unchanged with two exceptions. The neuronal cell packing density in the matrix compartment of the contralateral side was decreased (mean, 14.9%) while the size of neuronal cell bodies in the island compartment of the nucleus ipsilateral to the lesion was smaller (mean, 5%) relative to controls. These findings suggest that the number of neurons in the caudate of lesioned animals was larger than in intact controls, particularly on the lesioned side of the brain. This might be due to a reduction of naturally occurring cell death during development.

We have studied by both qualitative and quantitative methods the subependymal cells in the caudato-pallial angle (CPA) of the lateral ventricle from 1, 2, 6 and 18 month-old rats. We have chosen the CPA, among other zones, because it is an easily delimited glial proliferative zone. The qualitative analysis was carried out using both Klüver-Barrera and Luxol-Fast-Blue stains. The quantitative study was carried out by a semiautomatized image analysis system. Three types of subependymal nuclei were classified by Klüver-Barrera stain, according to the following parameters: staining intensity, morphology and size. Each of the three type groups was found at different frequency depending of rat age. Luxol-Fast-Blue stained mitotic images in metaphase or anaphase: n = 38 in the 1 month, n = 49 in 2 months, n = 12 in the 6 months, and n = 5 in the 18 month-old rats. The quantitative analysis (length, areas and volume of CPA) were in agreement with the above data, showing a more subependymal activity in the 2 month-old animals than in the 1, 6 and 18 month-old rats.

The regional and cellular ontogeny of the mRNA encoding the dopamine- and cAMP-regulated phosphoprotein, DARPP-32, has been studied in rat striatum by quantitative in situ hybridization histochemistry. The mRNA for DARPP-32 exhibited a characteristic developmental profile. The hybridization signal was first visible on the day of birth, at which time DARPP-32 mRNA was concentrated in patches in the caudate-putamen. By the end of the first postnatal week, the majority of neurons in the caudate-putamen expressed the DARPP-32 message. Levels of mRNA per cell increased markedly during the second postnatal week, and peaked around the beginning of the third week. The adult level of DARPP-32 mRNA was lower than that observed at the apex of mRNA expression, on a per cell basis, while the proportion of neurons expressing detectable levels of message remained relatively constant. In the nucleus accumbens and olfactory tubercle, DARPP-32 mRNA development lagged somewhat behind that observed in the caudate-putamen, but was similar in other respects. A non-quantitative study employing an oligonucleotide probe complementary to the mRNA encoding another cAMP-regulated phosphoprotein, ARPP-21, revealed a similar developmental sequence to DARPP-32. The present results suggest that for DARPP-32 mRNA, genetic and, possibly, environmental factors play a role in determining the developmental patterns observed.