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Impairments of working memory processes on a model of Alzheimer’s disease in monkeys
Dudkin KN, Chueva IV, Makarov FN, Beach TG, Roher AE (2003) Impairments of working memory processes on a model of Alzheimer’s disease in monkeys. Neuroscience 2003 Abstracts 626.8. Society for Neuroscience, New Orleans, LA.
Summary: We have investigated the characteristics of visual working memory in a delayed-discrimination task in a model of Alzheimer’s disease (AD) in rhesus monkeys. Three animals received unilateral stereotaxic intracerebroventricular injection of the nucleus basalis of Meynert and three monkeys received sterile saline injections and thus served as controls. The lesioning agent consisted of a ribosomal toxin, saporin, conjugated to monoclonal antibodies against (the nbM lesion) the p75 neurotrophin receptor (p75NTR), which is expressed almost exclusively on cholinergic neurons of the nbM. The rationale for the model is the same as for a rabbit model of AD (Roher et al, Ann. NY Acad Sci. 2000). The monkeys were trained to discriminate stimuli with different types of visual information (spatial frequency gratings, color, spatial choice, spatial relationships between components of objects). The data obtained demonstrate that the nbM lesioning agent had a weak effect on visual differentiation without delay (long-term memory), but significantly decreased the duration of information storage (by a factor of 2 – 3) in working memory later two months after injection. These changes depended on temporal stage after injection and stimulus properties, and were accompanied by increase of motor reaction time and of refusal of task decision. In monkeys that were sham injected, there were no alterations in working memory characteristics. The results suggest that considerable worsening of the working memory characteristics for monkeys after lesion of the nbM reflects the formation of an AD model in these monkeys. The principles of functional organization of working memory and role of pathology of the cortical mechanisms in an impairment of memory characteristics are discussed.
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[Interaction between sensory and cognitive processes in visual recognition: the role of the associative areas of the cerebral cortex] Russian
Dudkin KN, Chueva IV, Makarov FN (2003) [Interaction between sensory and cognitive processes in visual recognition: the role of the associative areas of the cerebral cortex] Russian. Ross Fiziol Zh Im I M Sechenova 89(10):1226-1239.
Summary: The authors used ME20.4-SAP(Cat. #IT-15).
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Featured Article: Subplate neurons and functional maturation of thalamocortical synapses
Kanold PO (2003) Featured Article: Subplate neurons and functional maturation of thalamocortical synapses. Targeting Trends 4(4)
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Read the featured article in Targeting Trends.
See Also:
Targeted toxins in pain.
Wiley RG, Lappi DA (2003) Targeted toxins in pain. Adv Drug Deliv Rev 55(8):1043-1054. doi: 10.1016/s0169-409x(03)00102-9
Summary: The authors discuss the use of ‘molecular neurosurgery’ in the study of nociception. Applications using targeted toxins, which include immunotoxins, protein-toxin conjugates, or peptide-toxin conjugates, are illustrated. The authors describe the use of these molecules as research tools, as well as their potential for therapeutics. A helpful table is included that lists neuronal surface markers and class of cells targeted for each targeted toxin. Reagents discussed: CTB-SAP (Cat. #IT-14), IB4-SAP (Cat. #IT-10), OX7-SAP (Cat. #IT-02), 192-Saporin (Cat. #IT-01), ME20.4-SAP (Cat. #IT-15), Anti-DBH-SAP (Cat. #IT-03), Anti-DAT-SAP (Cat. #IT-25), SP-SAP (Cat. #IT-07), Dermorphin-SAP (Cat. #IT-12), Orexin-SAP (Cat. #IT-20), CRF-SAP (Cat. #IT-13), and acetylated LDL-SAP (Cat. #IT-08).
Related Products: CTB-SAP (Cat. #IT-14), IB4-SAP (Cat. #IT-10), OX7-SAP (Cat. #IT-02), 192-IgG-SAP (Cat. #IT-01), ME20.4-SAP (Cat. #IT-15), Anti-DBH-SAP (Cat. #IT-03), Anti-DAT-SAP (Cat. #IT-25), SP-SAP (Cat. #IT-07), Dermorphin-SAP / MOR-SAP (Cat. #IT-12), Orexin-B-SAP (Cat. #IT-20), CRF-SAP (Cat. #IT-13), Acetylated LDL-SAP (Cat. #IT-08)
Role of subplate neurons in functional maturation of visual cortical columns.
Kanold PO, Kara P, Reid RC, Shatz CJ (2003) Role of subplate neurons in functional maturation of visual cortical columns. Science 301(5632):521-525. doi: 10.1126/science.1084152
Summary: Subplate neurons play a role in the development of connections between the thalamus and cerebral cortex. The authors used 0.5-µl injections of 0.25-1.0 mg/ml of ME20.4-SAP (Cat. #IT-15) to eliminate p75 receptor-positive neurons in the subplate of cats to investigate whether these neurons are involved in the organization and maturation of the visual cortex. This study also uses mouse IgG-saporin (Cat. #IT-18) as a control.
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Cerebral abeta deposition induced by cortical cholinergic deafferentation is reduced by cholinergic therapy
Beach TG, Potter PE, Sue LI, Fisher A, Scott S, Layne KJ, Newell AJ, Roher AE, Walker DG (2002) Cerebral abeta deposition induced by cortical cholinergic deafferentation is reduced by cholinergic therapy. Neuroscience 2002 Abstracts 722.9. Society for Neuroscience, Orlando, FL.
Summary: We have previously shown that cortical cholinergic deafferentation in rabbits results in cerebral Abeta deposition (Neurosci Lett 283:9-12, 2000). We have also shown that cholinergic therapy with acetylcholinesterase inhibitors and muscarinic agonists reduces Abeta concentrations in the CSF and cortex of normal rabbits (Neurosci Lett 310:21-24, 2001; Brain Res 905:220-223, 2001). Here we show that the histologic deposition and biochemical elevations of Abeta induced by cholinergic immunotoxin are reduced by systemic therapy with AF267B, an M1-selective muscarinic agonist, and physostigmine, an acetylcholinesterase inhibitor. Rabbits received i.c.v. injections of an immunotoxin composed of the p75 NTR-directed monoclonal antibody ME20.4 conjugated to saporin, a ribosomal toxin. One group of animals received s.c. AF267B (2 mg/kg/day) while another group received s.c. physostigmine (3 mg/kg/day). Control groups received either i.c.v. immunotoxin or sham lesion (i.c.v. saline) and no treatment. Four weeks after surgery, imunohistochemical staining for Abeta showed frequent positive blood vessels and perivascular diffuse plaques in the control group which received immunotoxin injection and no treatment. This was significantly reduced in animals which received either AF267B or physostigmine. Cerebrospinal fluid Abeta concentrations were also reduced significantly by both drug treatments. These results are directly relevant to humans since cortical cholinergic deafferentation is part of normal human aging.
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Developmental regulation of GABA Receptor subunits requires subplate neurons.
Kanold PO, Shatz CJ (2002) Developmental regulation of GABA Receptor subunits requires subplate neurons. Neuroscience 2002 Abstracts 530.11. Society for Neuroscience, Orlando, FL.
Summary: Subplate neurons (SP) are required for formation and patterning of thalamocortical connections. In visual cortex, SP ablation before the onset of the critical period, but when LGN axons are already in layer 4, prevents segregation into ocular dominance columns (ODCs) and emergence of functional orientation columns. Recent studies have linked ODC plasticity with maturation of inhibitory circuitry, which requires the appropriate expression and developmental regulation of GABA receptor subunits. We therefore wondered if SP ablation alters GABA-R subunit expression. Focal injections of kainic acid or immunotoxin were made into cat SP between P7-P10, just prior to the onset of ODC formation. 3 weeks later, in situ hybridization revealed that expression of several subunits of the GABA-A receptor was reduced in the ablated region, especially in layer 4. Other genes involved in synaptic function such as Homer and mGluR subunits also decreased in expression. These changes in gene expression suggest that the efficacy of inhibition in layer 4 is reduced. A reduction in postsynaptic GABA receptors is consistent with previously observed increases in BDNF and GAD expression after SP ablation. These observations imply that SP neurons are essential for the maturation of cortical inhibition, which in turn may be needed for the formation of ODCs and for the functional maturation of thalamocortical connections.
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Cholinergic neurons in the rabbit forebrain: Chemoarchitecture, in vivo labeling, immunolesions
Varga C, Grosche J, Brauer K, Seeger J, Harkany T, Hartig W (2002) Cholinergic neurons in the rabbit forebrain: Chemoarchitecture, in vivo labeling, immunolesions. Neuroscience 2002 Abstracts 35.3. Society for Neuroscience, Orlando, FL.
Summary: While the rabbit basal forebrain and its cholinergic components became useful targets for modeling of neuropathological changes associated with Alzheimer’s disease, their neuroanatomical organization is still largely elusive. Hence, we focused on (i) the number of cholinergic basal forebrain neurons (CBFN)in the major nuclei based on choline acetyltransferase (ChAT) immunoperoxidase labeling, (ii) the density of ChAT-immunoreactive fibers in distinct neocortical and hippocampal areas, (iii) mapping of projecting CBFN by low-affinity neurotrophin receptor p75 (p75NTR ) staining and (iv) the double fluorescence labeling of ChAT and the neuronal markers p75NTR, nitric oxide synthase (NOS), calbindin, calretinin, parvalbumin, tyrosine hydroxylase and substance P. While cholinergic interneurons were found in the hippocampus, they were not detectable in the neocortex. CBFN were shown to abundantly co-express p75NTR, except in the substantia innominata and ventral pallidum. Whereas cholinergic neurons were devoid of most investigated markers, a subset also contained calbindin or NOS. The selective in vivo labeling of CBFN was achieved with intracerebroventricularly (i.c.v.) injected carbocyanine 3-conjugated ME20.4IgG that recognizes an extracellular epitope of p75NTR. Parallel experiments revealed that the i.c.v. injection of ME20.4IgG-saporin conjugates led to the specific immunolesion of cholinergic cells in about one week, whereas long-term effects of the immunotoxin remain to be further elucidated.
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Effects of cholinergic deafferentation of rhinal cortex on visual recognition in monkeys
Turchi JN, Saunders RC, Mishkin M (2002) Effects of cholinergic deafferentation of rhinal cortex on visual recognition in monkeys. Neuroscience 2002 Abstracts 82.5. Society for Neuroscience, Orlando, FL.
Summary: Excitotoxic lesions of the rhinal (perirhinal/entorhinal) cortices yield substantial deficits in visual recognition (Baxter and Murray, 2001; Malkova et al., 2001). To evaluate the mnemonic role of cholinergic inputs to this region, we compared the visual recognition performance of untreated monkeys with that of monkeys given rhinal cortex infusions of the selective cholinergic immunotoxin ME20.4-SAP. This toxin binds to the p75 receptor, borne by corticopetal cholinergic neurons of the basal forebrain, and is retrogradely transported to the cell body where it permanently destroys ribosomal function. Both groups were first trained to criterion in the rule for delayed nonmatching-to-sample (DNMS) with trial-unique stimuli at a 10-s delay in a Wisconsin General Testing Apparatus. This was followed by treatment and recovery for the experimental group (n=3) and an equivalent rest period for the control group (n=4), after which both groups were retrained on the DNMS rule and then given a memory performance test with increasing delays (30, 60, and 120 s) and list lengths (3, 5, 10, and 20 stimuli). The experimental group relearned the DNMS rule without significant impairment but then demonstrated robust deficits when tested with increasing delays (a mean of 83% vs 95% for controls) and list lengths (67% vs 86% for controls). The findings complement results obtained in a study of muscarinic receptor blockade in the perirhinal cortex (Tang et al., 1997) and indicate that cholinergic integrity of the rhinal cortex is critical for visual recognition memory.
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Unilateral lesions of the cholinergic Basal forebrain and fornix in one hemisphere and inferior temporal cortex in the opposite hemisphere produce severe learning impairments in rhesus monkeys.
Easton A, Ridley RM, Baker HF, Gaffan D (2002) Unilateral lesions of the cholinergic Basal forebrain and fornix in one hemisphere and inferior temporal cortex in the opposite hemisphere produce severe learning impairments in rhesus monkeys. Cereb Cortex 12(7):729-736. doi: 10.1093/cercor/12.7.729
Summary: The authors used a combination of basal forebrain lesioning using ME20.4-SAP (Cat. #IT-15) and surgery to isolate the inferior temporal cortex and medial temporal cortex from cholinergic afferents in rhesus monkeys. Testing of the treated animals demonstrated severe impairments in learning visual scenes and object-reward associations.
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