Fetal striatal grafts display a striking modularity of composition. With acetylcholinesterase (AChE) histochemistry, the tissue of such grafts can be divided into regions with strong AChE staining of the neuropil and regions in which AChE staining of the neuropil is weak. In the experiments reported here, we reexamined the nature of this modularity. Striatal grafts were made by injecting dissociated cells of E15 ganglionic eminence into the striatum of adult rats, which 7 days before had recived intrastriatal deposits of ibotenic acid. Some donors had been exposed to 3H-thymidine at E11-E15. After 9-17 month survivals, the anatomical organization of the grafts was studied by histochemistry, immunohistochemistry, and autoradiography. In every graft, the AChE-rich regions formed patches (P regions) in a larger AChE-poor surround (NP regions). Neurons labeled with 3H-thymidine appeared in both P and NP regions, suggesting that donor cells were distributed in each type of region and that neither type of tissue, P or NP, was composed exclusively of host tissue. In the AChE-rich P regions, markers characteristic of normal perinatal and mature rat striatum were expressed by medium-sized cells: calcium-binding protein (calbindin D28k) immunostaining, metenkephalin (mENK) immunostaining, and, more rarely, somatostatin (SOM) immunostaining. In the NP regions, however, medium-sized cells expressing calbindin and mENK immunostaining were very rare, and there was an abundance of neuronal types not found in normal mature striatal tissue. These included (1) large, multipolar, calbindin-positive neurons with well-ramified, densely stained dendrites, (2) large, SOM-positive neurons with prominent dendritic trees, and (3) mENK-positive cells smaller than typical striatal, medium-sized, mENK-immunoreactive neurons. In Nissl stains, the AChE-rich P regions resembled the normal striatum of mature animals, whereas the AChE-poor NP regions did not. These findings suggest that the P regions of fetal striatal grafts achieve a phenotypy similar to that of normal striatum at maturity and during much of postnatal development. The dominant expression of perikaryal calbindin-like immunoreactivity in the P regions further suggests that these zones have a high proportion of tissue resembling striatal matrix. By contrast, expression of marker antigens in the NP zones of the grafts suggests that these zones are predominantly composed of nonstriatal tissue or that they have the phenotypy of immature striatum intermixed with some nonstriatal cells.(ABSTRACT TRUNCATED AT 400 WORDS)
By using the developing monkey brain as a model for human development, we investigated the expression pattern of the FOXP2 gene, a member of the FOX family of transcription factors in the developing monkey brain, and compared its expression pattern with transcription factors PBX3, MEIS2, and FOXP1. We observed FOXP2 mRNA expression in several brain structures, including the striatum, the islands of Calleja and other basal forebrain regions, the cerebral cortex, and the thalamus. FOXP2 mRNA was preferentially expressed in striosomal compartments during striatal development. The striosomal expression was transient and developmentally down-regulated in a topographical order. Specifically, during the perinatal state, striosomal FOXP2 expression was detected in both the caudate nucleus and the putamen, although expression was more prominent in the caudate nucleus than in the putamen. Striosomal FOXP2 expression declined during the postnatal period, first in the putamen and later in the caudate nucleus. During the same period, we also detected PBX3 mRNA in the striosomal compartment of the developing monkey striatum. FOXP2, as well as PBX3 and MEIS2, was expressed in the islands of Calleja and other cell clusters of the basal forebrain. FOXP2, in combination with PBX3 and MEIS2, may play a pivotal role in the development of striosomal neurons of the striatum and the islands of Calleja.
Calbindin-D28k (calbindin) is a member of the superfamily of calcium-binding proteins implicated in the regulation of intracellular calcium. In the mature brain, calbindin is widely expressed in neurons of the forebrain and the hindbrain, and in the telencephalon calbindin-like immunoreactivity is particularly strongly expressed by medium-sized neurons of the striatum and by certain other neurons in the cortex and subcortex. We have traced the development of calbindin expression in the forebrain of the rat, and report here that in addition to the steady development of these calbindin-positive neuronal systems, transient waves of calbindin expression occur in cells of the ventricular zones of the basal ganglia and cortex and in cells of the telencephalic regions derived from these ventricular zones including radial glia of the developing striatum. In the striatum and its ventricular zone (the ganglionic eminence, or GE) we identified four transient calbindin-positive systems in the perinatal period. First, calbindin-immunoreactive cells began to appear in the GE by embryonic day (E)18, and by E20 an extensive dorsal and lateral part of the GE was marked by dense calbindin-like immunoreactivity in the ventricular zone. This calbindin system peaked at postnatal day (P)0-P3 and disappeared by P15. Its presence suggests that the GE is divisible on a molecular basis into lateral and medial districts that may correspond to derivatives of the lateral and medial ventricular ridges. Second, a system of calbindin-positive processes appeared in the dorsal and lateral caudoputamen with temporal and spatial distributions matching the germinal zone system. Many of these processes could be traced from calbindin-positive cells in the ventricular zone of the GE, including processes stretching across the full width of the dorsal caudoputamen. Double-staining experiments demonstrated that these radial processes were Rat.401-positive, suggesting that they form a subset of radial glia in the developing telencephalon. These findings demonstrate that during development calbindin is expressed in glial as well as neural cells. They further suggest that the radial glia associated with the GE form heterogeneous populations, the transient calbindin-positive radial glia being associated with the lateral ridge of the GE and its derivatives. Third, a scattered population of calbindin-positive cells with morphologies different from the common medium-sized calbindin-immunoreactive neurons of the striatum appeared in the dorsal and lateral striatum from about E20 to P15. Some of these cells were close to the transient calbindin-positive radial processes in the same region, but others were not.(ABSTRACT TRUNCATED AT 400 WORDS)
The striatal complex of basal ganglia comprises two functionally distinct districts. The dorsal district controls motor and cognitive functions. The ventral district regulates the limbic function of motivation, reward, and emotion. The dorsoventral parcellation of the striatum also is of clinical importance as differential striatal pathophysiologies occur in Huntington’s disease, Parkinson’s disease, and drug addiction disorders. Despite these striking neurobiologic contrasts, it is largely unknown how the dorsal and ventral divisions of the striatum are set up. Here, we demonstrate that interactions between the two key transcription factors Nolz-1 and Dlx1/2 control the migratory paths of striatal neurons to the dorsal or ventral striatum. Moreover, these same transcription factors control the cell identity of striatal projection neurons in both the dorsal and the ventral striata including the D1-direct and D2-indirect pathways. We show that Nolz-1, through the I12b enhancer, represses Dlx1/2, allowing normal migration of striatal neurons to dorsal and ventral locations. We demonstrate that deletion, up-regulation, and down-regulation of Nolz-1 and Dlx1/2 can produce a striatal phenotype characterized by a withered dorsal striatum and an enlarged ventral striatum and that we can rescue this phenotype by manipulating the interactions between Nolz-1 and Dlx1/2 transcription factors. Our study indicates that the two-tier system of striatal complex is built by coupling of cell-type identity and migration and suggests that the fundamental basis for divisions of the striatum known to be differentially vulnerable at maturity is already encoded by the time embryonic striatal neurons begin their migrations into developing striata.
Patterning centers that produce gradients of morphogenetic molecules, including fibroblast growth factor (FGF), bone morphogenetic proteins (BMP), Wnt, Sonic hedgehog (Shh), and retinoic acid (RA), are located in telencephalic anlage during early stages of development. Genetic evidence based on loss-of-function and gain-of-function studies indicate that they are involved in regional specification of the dorsal, ventral, and lateral telencephalon. For patterning of the dorsal telencephalon, FGF8 controls the anteroposterior patterning, while BMP and Wnt molecules regulate the mediolateral patterning. Shh and retinoic acid regulate patterning of the ventral and the lateral telencephalon. The regionalization of telencephalon is accompanied by expression of region-specific codes of transcription factors, which in turn regulate different phases of neuronal development to generate different cell types in each brain region. Therefore, bioactive signals of morphogenetic molecules are translated into transcription factor codes for regional specification, which subsequently leads to neurogenesis of the diversity of cell types in different regions of the telencephalon.
The cAMP response element-binding protein (CREB) is an activity-dependent transcription factor that is involved in neural plasticity. The kinetics of CREB phosphorylation have been suggested to be important for gene activation, with sustained phosphorylation being associated with downstream gene expression. If so, the duration of CREB phosphorylation might serve as an indicator for time-sensitive plastic changes in neurons. To screen for regions potentially involved in dopamine-mediated plasticity in the basal ganglia, we used organotypic slice cultures to study the patterns of dopamine-and calcium-mediated CREB phosphorylation in the major subdivisions of the striatum. Different durations of CREB phosphorylation were evoked in the dorsal and ventral striatum by activation of dopamine D1-class receptors. The same D1 stimulus elicited (i) transient phosphorylation (<15 min) in the matrix of the dorsal striatum; (ii) sustained phosphorylation (<2 hr) in limbic-related structures including striosomes, the nucleus accumbens, the fundus striati, and the bed nucleus of the stria terminalis; and (iii) prolonged phosphorylation (up to 4 hr or more) in cellular islands in the olfactory tubercle. Elevation of Ca 2؉ inf lux by stimulation of L-type Ca 2؉ channels, NMDA, or KCl induced strong CREB phosphorylation in the dorsal striatum but not in the olfactory tubercle. These findings differentiate the response of CREB to dopamine and calcium signals in different striatal regions and suggest that dopamine-mediated CREB phosphorylation is persistent in limbic-related regions of the neonatal basal ganglia. The downstream effects activated by persistent CREB phosphorylation may include time-sensitive neuroplasticity modulated by dopamine.Dopamine is a classical neurotransmitter that can influence neurologic functions ranging from movement to emotion, memory, and reinforcement. The behavioral aspects of reward and motivation are known to be modulated by the nigrostriatal and mesolimbic pathways. The primary striatal targets of these dopamine-containing systems are different. The nigrostriatal system primarily innervates the caudoputamen. The mesolimbic system innervates a number of forebrain structures including the ventral striatum, which is formed by the nucleus accumbens and olfactory tubercle. Although both the dorsal and ventral striatum are targets of dopamine-containing afferents from the midbrain and share a striatal architecture, they differ from each other in neurochemical organization and in their connectivity with other brain regions (1, 2). The dorsal striatum is engaged primarily in processing information from the cerebral cortex and thalamus and is involved in motor control, aspects of cognitive control, and some forms of learning and memory. The ventral striatum receives inputs from limbic structures including the amygdala, the hippocampus, and the limbic prefrontal cortex, and projects back to limbic structures via the ventral pallidum. These limbicassociated circuits are thought to underlie motivationa...
Nolz-1, as a murine member of the NET zinc-finger protein family, is expressed in post-mitotic differentiating neurons of striatum during development. To explore the function of Nolz-1 in regulating the neurogenesis of forebrain, we studied the effects of ectopic expression of Nolz-1 in neural progenitors. We generated the Cre-loxP dependent conditional transgenic mice in which Nolz-1 was ectopically expressed in proliferative neural progenitors. Ectopic expression of Nolz-1 in neural progenitors by intercrossing the Nolz-1 conditional transgenic mice with the nestin-Cre mice resulted in hypoplasia of telencephalon in double transgenic mice. Decreased proliferation of neural progenitor cells were found in the telencephalon, as evidenced by the reduction of BrdU−, Ki67− and phospho-histone 3-positive cells in E11.5–12.5 germinal zone of telencephalon. Transgenic Nolz-1 also promoted cell cycle exit and as a consequence might facilitate premature differentiation of progenitors, because TuJ1-positive neurons were ectopically found in the ventricular zone and there was a general increase of TuJ1 immunoreactivity in the telencephalon. Moreover, clusters of strong TuJ1-expressing neurons were present in E12.5 germinal zone. Some of these strong TuJ1-positive clusters, however, contained apoptotic condensed DNA, suggesting that inappropriate premature differentiation may lead to abnormal apoptosis in some progenitor cells. Consistent with the transgenic mouse analysis in vivo, similar effects of Nozl-1 over-expression in induction of apoptosis, inhibition of cell proliferation and promotion of neuronal differentiation were also observed in three different N18, ST14A and N2A neural cell lines in vitro. Taken together, our study indicates that ectopic expression of Nolz-1 in neural progenitors promotes cell cycle exit/premature neuronal differentiation and induces abnormal apoptosis in the developing telencephalon.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology. The core syndromes of ASD are deficits in social communication and self-restricted interests and repetitive behaviors. Social communication relies on the proper integration of sensory and motor functions, which is tightly interwoven with the limbic function of reward, motivation, and emotion in the brain. Monoamine neurotransmitters, including serotonin, dopamine, and norepinephrine, are key players in the modulation of neuronal activity. Owing to their broad distribution, the monoamine neurotransmitter systems are well suited to modulate social communication by coordinating sensory, motor, and limbic systems in different brain regions. The complex and diverse functions of monoamine neurotransmission thus render themselves as primary targets of pathophysiological investigation of the etiology of ASD. Clinical studies have reported that children with maternal exposure to valproic acid (VPA) have an increased risk of developing ASD. Extensive animal studies have confirmed that maternal treatments of VPA include ASD-like phenotypes, including impaired social communication and repetitive behavior. Here, given that ASD is a neurodevelopmental disorder, we begin with an overview of the neural development of monoaminergic systems with their neurochemical properties in the brain. We then review and discuss the evidence of human clinical and animal model studies of ASD with a focus on the VPA-induced pathophysiology of monoamine neurotransmitter systems. We also review the potential interactions of microbiota and monoamine neurotransmitter systems in ASD pathophysiology. Widespread and complex changes in monoamine neurotransmitters are detected in the brains of human patients with ASD and validated in animal models. ASD animal models are not only essential to the characterization of pathogenic mechanisms, but also provide a preclinical platform for developing therapeutic approaches to ASD.
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