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Anders Bjorklund - One of the best experts on this subject based on the ideXlab platform.
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Intrahippocampal grafts of fetal basal Forebrain Tissue alter place fields in the hippocampus of rats with fimbria-fornix lesions.
Neuroscience, 2003Co-Authors: M. L. Shapiro, Ola G. Nilsson, David S. Olton, David Simon, Fred H. Gage, Anders BjorklundAbstract:Abstract Intrahippocampal grafts of fetal basal Forebrain Tissue have been shown to restore several aspects of neural function, including some degree of behavioral recovery in spatial memory tasks, in rats with fimbria-fornix lesions. Place fields, the behavioral correlates of complex-spike unit activity recorded in the hippocampus of rats, are altered by fimbria-fornix lesions, and provide an important measure of the functioning circuitry of the hippocampus after grafts. To investigate the effects of grafts on hippocampal circuitry, complex-spike units were recorded while the rats traversed a radial maze. Quantitative analyses of spatial activity showed that units in normal rats had spatially clustered, reliable place fields that were stable despite alterations of the maze. In contrast, units in rats with fimbria-fornix lesions had more dispersed, less reliable place fields that were disrupted when the maze was covered or rotated. Compared to rats with fimbria-fornix lesions, rats with grafts had units with more tightly clustered, more reliable, and more stable place fields when the maze was altered. The results suggest that: (1) fimbria-fornix lesions disrupt some aspects of complex-spike place field activity. (2) the functioning of hippocampal circuitry is influenced by fetal basal Forebrain grafts. (3) the grafts may ameliorate the effects of lesions on spatial behaviors by influencing critical aspects of place field activity in the hippocampus.
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amelioration of spatial navigation and short term memory deficits by grafts of foetal basal Forebrain Tissue placed into the hippocampus and cortex of rats with selective cholinergic lesions
European Journal of Neuroscience, 1998Co-Authors: Alberto Martinezserrano, G Leanza, Anders BjorklundAbstract:Impairments in learning and memory, induced by surgical or excitotoxic lesions of the septo-hippocampal or basalo-cortical pathways, can be ameliorated by grafts of cholinergic-rich foetal basal Forebrain Tissue into the hippocampus and/or neocortex. However, the effects of such grafts have been only partial, which may be due to the non-specific nature of the lesioning procedures used in these studies, known to destroy both cholinergic and non-cholinergic neuronal projections. In the present study, we have explored the effects of cholinergic-rich grafts in rats subjected to selective cholinergic lesions, induced by intraventricular injections of the immunotoxin 192 IgG-saporin. This lesion, which selectively destroyed 85-95% of the cholinergic neurons in both the septal-diagonal band and nucleus basalis, produced a long-lasting, substantial impairment in both the acquisition of spatial reference memory in the Morris water maze task and delay-dependent short-term memory performance, as seen in a delayed matching-to-position test. Foetal cholinergic grafts (but not control grafts of cerebellar Tissue) implanted at multiple sites into both the hippocampus and fronto-parietal neocortex, bilaterally, completely reversed the acquisition deficit in place navigation in the water maze, to an extent that greatly exceeded that previously seen in animals with non-selective lesions. Most notably, however, the impairment in short-term memory was only partially and inconsistently affected, and only at the longest delay times. The morphological analysis, performed at about 7 months after transplantation, showed that the grafts had re-established a close to normal cholinergic innervation in the initially denervated cortical and hippocampal territories. It is proposed that the differential effects of cholinergic-rich transplants on different aspects of cognitive performance may define intrinsic limitations to the functional capacity of the ectopically placed grafts, which may be due to incomplete integration of the grafted cholinergic neurons into functional regulatory circuitries normally available to the basal Forebrain cholinergic system.
J D Sinden - One of the best experts on this subject based on the ideXlab platform.
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behavioural specificity of neocortical grafts of fetal basal Forebrain Tissue after unilateral lesion of the nucleus basalis with α amino 3 oh 4 isoxozole propionic acid ampa
Brain Research Bulletin, 1997Co-Authors: Fuad Abdulla, Mariarita Calaminici, J A Gray, John Stephenson, J D SindenAbstract:Abstract The previous articles in this series 4 , 9 have shown that unilateral AMPA lesions of the nucleus basalis magnocellularis (nbm) produced widepread morphological and functional changes to the Forebrain cholinergic projection system that could be reversed by transplants of fetal cholinergic Tissue. At earlier postgraft time points, the effects of cholinergic grafts were specific to the neocortical region (frontal or parietal cortex) into which the grafts were targeted. Here we report that nbm lesion-induced spatial learning and memory deficits in the Morris water maze were reversed at 6–8 weeks postsurgery only by cholinergic grafts placed in the frontal cortex or frontal and parietal cortices combined. Similar grafts to parietal cortex only and noncholinergic fetal transplants to any cortical site were ineffective. In contrast, using separate groups of animals, deficits in sensorimotor function could be reversed in only one measure (open field turning) by cholinergic transplants targeted to the parietal (somatosensory) cortex or frontal and parietal cortex combined. These behavioural dissociations demonstrate that the frontal cortical cholinergic innervation from the nbm is necessary for effective spatial cognitive performance.
Ross J Baldessarini - One of the best experts on this subject based on the ideXlab platform.
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enhanced expression of dopamine d 1 and glutamate nmda receptors in dopamine d 4 receptor knockout mice
Journal of Molecular Neuroscience, 2004Co-Authors: Lu Gan, Ross J Baldessarini, Tomas L Falzone, Kehong Zhang, Marcelo Rubinstein, Frank I TaraziAbstract:Expression of dopamine ([DA] D1 and D2) and glutamate ([Glu]), (N-methyl-d-aspartic acid [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kanaic acid [KA]) receptor types were analyzed autoradiographically in Forebrain regions of D4 receptor knockout mice and their wild-type controls. Selective radioligand binding to D4 receptors was virtually absent in D4 receptor knockout mouse brain in contrast to significant specific D4 binding in Forebrain Tissue of wild-type controls. Labeling of D1 receptors was significantly increased in nucleus accumbens (NAc; 39%) and caudate putamen (CPu; 42%) of D4-knockout mice vs wild-type controls. In addition, NMDA receptor labeling was significantly increased in NAc (31%), CPu (40%), and hippocampal CA1 (21%) and CA3 (25%) regions of D4 knockouts vs wild-type controls. No changes in D2, AMPA or KA receptors were found. The findings suggest that D1, D4, and NMDA receptors might interact functionally and that developmental absence of D4 receptors might trigger compensatory mechanisms that enhance expression of D1 receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of specific genes, as complex adaptive changes not directly related to the missing gene might contribute to physiological and behavioral responses.
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lack of effect of chronic clorgyline or selegiline on dopamine and serotonin transporters in rat caudate putamen or nucleus accumbens septi
Neuroscience Letters, 1997Co-Authors: Sylva K Yeghiayan, Susan L Andersen, Ross J BaldessariniAbstract:Abstract Rats were injected intraperitoneally thrice weekly for 4 weeks with doses of selective inhibitors of monoamine oxidase type A (clorgyline, 1 mg/kg) or B ((−)-selegiline, 10 mg/kg), or saline. Both treatments produced sustained elevations of concentrations of dopamine and serotonin, and decreased their deaminated metabolites in Forebrain Tissue. Nevertheless, no change in binding of [ 3 H]GBR-12935 to the dopamine transporter or of [ 3 H]paroxetine to the serotonin transporter in caudate-putamen or nucleus accumbens septi was found with quantitative autoradiography. These results support the impression that transporter proteins for these monoamines are not regulated by increased ligand abundance.
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prolonged d2 antidopaminergic activity of alkylating and nonalkylating derivatives of spiperone in rat brain
Molecular Pharmacology, 1992Co-Authors: Ross J Baldessarini, N S Kula, Alexander Campbell, Venkatesalu Bakthavachalam, Jun Yuan, John L NeumeyerAbstract:Alkyl and arylalkyl derivatives of the dopamine (DA) D2 antagonist spiperone were prepared and characterized chemically and pharmacologically. They included the N-methyl, N-phenethyl (NPS), and N-p-aminophenethyl (NAPS) derivatives, as well as the alkylating isothiocyanato (NIPS), bromacetamido, and ethylfumaramido p-substituted N-phenethylspiperones. These compounds showed high lipophilicity (log P up to 6.0 with NIPS), as well as very high in vitro D2 affinity (Ki = 35-280 pM) and D2 versus D1 selectivity (540-9000-fold) in radioreceptor assays with corpus striatum of rat brain. Of the alkylating series, NIPS showed the highest D2 affinity (57 pM) and D2 versus D1 selectivity (2040-fold) and so was selected for further evaluation. NPS, NAPS, and NIPS showed little or no affinity for 34 non-DA binding sites defined by radioligand assays for monoamine, amino acid, and peptide neurotransmitters, ion channels, peptide growth factors, and transmission mediators but did show low alpha 2 and moderate alpha 1 and 5-hydroxytryptamine (5-HT2) affinity with rat Forebrain Tissue in vitro; NIPS showed a marked gain in D2 versus 5-HT2 selectivity, compared with spiperone (1520- versus 26-fold). Systemic injections of NIPS induced marked decreases in rat striatal D2 binding sites 24 hr later, with little effect on D1, 5-HT2, or alpha 1 sites; NIPS and NAPS lowered apparent Bmax values at D2 receptors with little change in ligand affinity, ex vivo as well as in vitro. NPS, NAPS, and NIPS all induced dose-dependent lowering of D2 binding ex vivo (ID50 = 1-9 mumol/kg, intraperitoneally) and blocked the behavioral effects of the DA agonist apomorphine (0.9 mumol/kg) potently (ID50 = 0.3-0.5 mumol/kg) at 24 hr. Recovery from these anti-DA actions required about 1 week after equimolar (15 mumol/kg) and similarly effective doses of NPS and NAPS, as well as NIPS. Thus, highly selective and avidly bound lipophilic D2 affinity ligands with similarly avid in vitro and prolonged in vivo anti-DA activities can be derived from N-phenethylspiperones with or without an alkylating moiety present. Such affinity ligands may represent useful additions to previously used, generally less selective, D2 affinity ligands.
G Leanza - One of the best experts on this subject based on the ideXlab platform.
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amelioration of spatial navigation and short term memory deficits by grafts of foetal basal Forebrain Tissue placed into the hippocampus and cortex of rats with selective cholinergic lesions
European Journal of Neuroscience, 1998Co-Authors: Alberto Martinezserrano, G Leanza, Anders BjorklundAbstract:Impairments in learning and memory, induced by surgical or excitotoxic lesions of the septo-hippocampal or basalo-cortical pathways, can be ameliorated by grafts of cholinergic-rich foetal basal Forebrain Tissue into the hippocampus and/or neocortex. However, the effects of such grafts have been only partial, which may be due to the non-specific nature of the lesioning procedures used in these studies, known to destroy both cholinergic and non-cholinergic neuronal projections. In the present study, we have explored the effects of cholinergic-rich grafts in rats subjected to selective cholinergic lesions, induced by intraventricular injections of the immunotoxin 192 IgG-saporin. This lesion, which selectively destroyed 85-95% of the cholinergic neurons in both the septal-diagonal band and nucleus basalis, produced a long-lasting, substantial impairment in both the acquisition of spatial reference memory in the Morris water maze task and delay-dependent short-term memory performance, as seen in a delayed matching-to-position test. Foetal cholinergic grafts (but not control grafts of cerebellar Tissue) implanted at multiple sites into both the hippocampus and fronto-parietal neocortex, bilaterally, completely reversed the acquisition deficit in place navigation in the water maze, to an extent that greatly exceeded that previously seen in animals with non-selective lesions. Most notably, however, the impairment in short-term memory was only partially and inconsistently affected, and only at the longest delay times. The morphological analysis, performed at about 7 months after transplantation, showed that the grafts had re-established a close to normal cholinergic innervation in the initially denervated cortical and hippocampal territories. It is proposed that the differential effects of cholinergic-rich transplants on different aspects of cognitive performance may define intrinsic limitations to the functional capacity of the ectopically placed grafts, which may be due to incomplete integration of the grafted cholinergic neurons into functional regulatory circuitries normally available to the basal Forebrain cholinergic system.
Fuad Abdulla - One of the best experts on this subject based on the ideXlab platform.
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behavioural specificity of neocortical grafts of fetal basal Forebrain Tissue after unilateral lesion of the nucleus basalis with α amino 3 oh 4 isoxozole propionic acid ampa
Brain Research Bulletin, 1997Co-Authors: Fuad Abdulla, Mariarita Calaminici, J A Gray, John Stephenson, J D SindenAbstract:Abstract The previous articles in this series 4 , 9 have shown that unilateral AMPA lesions of the nucleus basalis magnocellularis (nbm) produced widepread morphological and functional changes to the Forebrain cholinergic projection system that could be reversed by transplants of fetal cholinergic Tissue. At earlier postgraft time points, the effects of cholinergic grafts were specific to the neocortical region (frontal or parietal cortex) into which the grafts were targeted. Here we report that nbm lesion-induced spatial learning and memory deficits in the Morris water maze were reversed at 6–8 weeks postsurgery only by cholinergic grafts placed in the frontal cortex or frontal and parietal cortices combined. Similar grafts to parietal cortex only and noncholinergic fetal transplants to any cortical site were ineffective. In contrast, using separate groups of animals, deficits in sensorimotor function could be reversed in only one measure (open field turning) by cholinergic transplants targeted to the parietal (somatosensory) cortex or frontal and parietal cortex combined. These behavioural dissociations demonstrate that the frontal cortical cholinergic innervation from the nbm is necessary for effective spatial cognitive performance.