Frontal Cortex and Striatum

In the striatum, postischemic proliferation was also increased. As in the frontal cortex, the BrdU+ cells were either single cells or doublets, but were not in clusters. Statistical analysis revealed that the density of BrdU+ cells in the monkeys 

Previous studies have reported the generation of neurons in frontal cortex and striatum of normal adult monkeys (Gould et al. 2001 Bedard et al. 2002). We therefore searched for evidence of de novo generation of cells with a neuronal immunophenotype in the striatum and frontal cortex of postischemic monkeys. We first performed double-staining for BrdU and the mature neuronal marker 

NeuN (Eriksson et al. 1998 Gould et al. 1999b, 2001 Kornack and Rakic 1999, 2001b Arvidsson et al. 2002 Parent et al. 2002) in an attempt to identify double-labeled cells whose size and morphology were similar to the surrounding NeuN+ neurons. We indeed found such cells, typically located in layers II-IV of the neocortex (Fig. 59) or lateral putamen in striatum (Fig. 60). Morphologically, BrdU+/NeuN+ cells (Fig. 59, 60 arrows) were similar in size and shape to adjacent BrdU /NeuN+ neurons (Fig. 59,60 arrowheads). Confocal analysis revealed that the NeuN+/BrdU+ constituted about 1% of the BrdU+ cells in either frontal neocortex or striatum (Table 10). 

We provided additional confirmation for the neuronal phenotype of the NeuN+/BrdU+ cells. We found that the NeuN+/BrdU+ cells coexpressed GAD, a marker of GABAergic neurons as well as region-specific neuronal transcription factors (Tonchev et al. 2005). In the sham-operated monkeys, rare BrdU+/NeuN+ cells were observed only in striatum and neocortex of the day-44 brains (Table 10). 

Control Ischemia Control Ischemia Control Ischemia Control Ischemia 

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Fig. 57A, B Quantitative analysis of BrdU+ cells in frontal cortex and striatum. A Frontal cortex. B Striatum. p< 0.001 versus controls t test or one-way ANOVA followed by Tukey-Kramer post hoc...

Table 10 Average percentages of colabeling of BrdU with various cell markers in parenchyma of frontal cortex and striatum. BrdU+ cells were sampled for colabeling with either Musashil or Nestin as described in the text...

HT afferents projecting to individual terminal areas. Thus, the effects of SSRIs in areas with predominate innervation from the dorsal raphe are augmented by 5-HT1A receptor antagonists or in 5-HT1A / mice, such as the frontal cortex and striatum, but are less effective (or not at all) in the median raphe-innervated dorsal hippocampus. 

Calbindin-immunoreactive and calretinin-immunoreactive neurons project to the frontal cortex and striatum (Gerfen et al., 1987). In the rat, the efferents of calbindin-positive neurons take part in the neostriatal mosaic (see Section 5.1), since they project selectively to the matrix compartment of the striatum, whereas calbindin-negative neurons innervate preferentially the patch compartment (Gerfen et al., 1985, 1987). 

To determine whether a relationship between dopamine synthesis and either tyrosine levels or myelination exists, 6-8 week-old male PKU mice were placed on a low Phe diet, and levels of dopamine, tyrosine, Phe, and myelin were measured during a 4-week time course study. In the course of performing this study, several surprising findings were made concerning the differential regulation of Phe, tyrosine, and dopamine levels in frontal cortex and striatum of PKU mouse brain. The differential regulation of the amino acids Phe and tyrosine in brain was not initially... 

To determine if a relationship exists between tyrosine levels and dopamine synthesis in the treated PKU mouse brain, it was necessary to quantify tyrosine in blood and brain tissues in control heterozygous, untreated PKU, and treated PKU mice. On the basis of previous studies showing that high levels of Phe out-compete tyrosine for transport across the blood-brain barrier (Choi and Pardrige, 1986 Brenton and Gardiner, 1988 Pardridge, 1998), it was anticipated that brain tyrosine levels would be less than blood tyrosine levels in the untreated PKU mouse. However, it was unexpectedly found that tyrosine levels in frontal cortex and striatum were approximately 1.2 and 1.4 times, respectively, the level of tyrosine in the blood of untreated PKU mice. Thus, the eightfold elevation in blood Phe levels in the untreated PKU mouse did not appear to interfere with the movement of tyrosine into the brain. 

Significant increases in myelin-bound protein (MBP) and dopamine levels were observed in the frontal cortex and striatum during the first week the PKU mice were placed on diet. The approximate levels of Phe and tyrosine at the 1-week time point, then, should be good estimates for the concentrations of Phe and tyrosine that were conducive to the observed recovery in these brain structures. In striatum at the 1-week time point, levels of Phe fell to about 240 m j, (about 1.8-fold above control), and in frontal cortex Phe decreased to about 225 J, (about a threefold elevation above control), lyrosine only rose to 53 and 58% of control in frontal cortex and striatum, respectively, during the first week of the study. These data re-emphasize the point that low brain tyrosine levels do not impede MBP/myelination and dopamine synthesis in the treated PKU brain. 

McQuade Sharp (1997) tested whether electrical stimulation of the DRN or the MRN releases 5-HT in rat forebrain regions in a pattern that correlates with the distribution of 5-HT projections from the serotonergic nuclei. Stimulation of the DRN evoked the release of 5-HT in the frontal cortex, dorsal striatum, globus pallidus, and ventral hippocampus. Conversely, 5-HT release in dialysates collected from the dorsal and ventral hippocampus and the medial septum was increased in response to MRN stimulation. Thus, the functional mapping of DRN... 

Nyberg and colleagues (72) were the first to demonstrate that risperidone induces marked occupancy of central 5-HT2 and D2 receptors in vivc. About 60% (range, 45% to 68%) of the 5-HT2 receptors in the frontal cortex and about 50% (range, 40% to 64%) of the D 2 receptors in the striatum were occupied 4 and 7 hours, respectively, after a single oral dose of 1 mg. These results indicate that 5-HT 2 receptor occupancy should be very high at doses of 4 to 10 mg daily. 

In old rats (26 months old), oral administration of EGb (10 mg/kg and 30 mg/kg, for 7 days) produces elevations of 5-HT in the frontal cortex, hippocampus, striatum and hypothalamus, and of dopamine levels in the hippocampus and hypothalamus compared with controls. On the other hand, EGb decreases the 5-HT level in the pons, and those of norepinephrine in the hippocampus and hypothalamus [157]. In this connection, Racagni et al. [158] showed that the O-methylated amine metabolite of norepinephrine, normetanephrine, was markedly elevated (+500%) in the cerebral cortex by chronic oral administration of EGb (100 mg/kg, for 14 days), suggesting an increase of norepinephrine turnover. In addition, treatment with EGb (50 or 100 mg/kg/day, for 20 days) diminished the increased plasma levels of epinephrine, norepinephrine, and corticosterone induced by acute auditory stress in young and old rats [113]. 

Fig. 56 Representative composite micrographs of BrdU immunostaining spanning all neo-cortical layers of the frontal cortex of control and postischemic day-9 monkeys. The position of the visual field is depicted as a frame on the schematic map (upper right). Note the increased number of positive cells after ischemia. F, frontal cortex S, striatum. Scale bar = 200 pm...

Fig. 59A, B Neuronal production in postischemic frontal cortex. A Double-staining for NeuN and BrdU on postischemic day 44. The depicted region corresponds to the frame on the schematic map (lower left). A frame in layer IV focuses on the region magnified in B. B Note that the BrdU+/NeuN+ cell (arrows), which is similar in size and shape to adjacent BrdU /NeuN+ neurons, extends processes toward them (arrowheads). The BrdU+/NeuN+ cell is shown with channel separation and 3D reconstructions in insets. A BrdU+/NeuN cell is depicted by arrowheads. F, frontal cortex S, striatum. Scale bars = 200 pm (A) 20 pm (B)...

The histamine system has been implicated in the pathophysiology of schizophrenia by several observations, including evidence for increased CNS metabolism of histamine (Prell et al., 1995), lower levels of H1 receptor expression in the frontal cortex, the striatum, and the thalamus as evaluated by positron emission tomography (Iwabuchi et al., 2005 Yanai and Tashiro, 2007), and the therapeutic efficacy of H3 antagonists on cognitive symptoms in patients with schizophrenia (Vohora, 2004 Esbenshade et al., 2006). Functionally, this... 

With regard to neurotransmitters, we found no significant difference in the levels of norepinephrine, 3,4-dihydrophenylacetic acid, dopamine, 5-hydroxyindoleacetic acid, homovanilinic acid, and serotonin in the frontal cortex, the hippocampus, and the striatum between conventional rats fed the safflower-oil diet and those fed the perilla-oil diet. The acetylcholine (Ach) level was very high in the striatum, but these diets had no effect on the Ach levels in brain regions (Fig. 6). In stroke-prone spontaneously hypertensive rats, DHA supplementation increased Ach levels in the frontal cortex and the hippocampus compared with those fed the safflower-oil diet (Minami, 1997a,b). 

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