sfn2000

Sarter M, Turchi J (2000) Effects of intra-basalis infusion of d-cycloserine upon sustained attention performance in rats. Neuroscience 2000 Abstracts 837.10. Society for Neuroscience, New Orleans, LA.

Summary: As basal forebrain NMDA receptor modulation has been hypothesized to play a significant role in tasks taxing attentional processes (Turchi & Sarter 1999), positive NMDA receptor modulation via the glycine site might attenuate the substantive impairments of sustained attentional processing observed following specific lesions of corticopetal cholinergic neurons (McGaughy, Kaiser & Sarter, 1996). Rats were trained in a sustained attention task (McGaughy & Sarter 1995) requiring animals to discriminate between unpredictably occurring visual signals of varying lengths (25, 50, 500 msec) and non-signal events. Upon attaining stable performance, chronic guide cannula were implanted bilaterally for the infusion of an NMDA receptor glycine site ligand into the SI/NB; one group of these animals also received bilateral infusions of 192 IgG-saporin (0.21μg/μl; 0.5 μl/hemisphere), while the other group received infusions (0.5 μl/hemisphere) of the vehicle for the immunotoxin. The effects of administrations of D-cycloserine (DCS: 0.5 & 5 μg in 0.5 μl/hemisphere) were tested in these two groups of animals (lesioned and sham-lesioned). Administration of the higher dose of DCS partly attenuated the lesion-induced decrease in hits in the sustained attention paradigm. This finding suggests that impairments of sustained attention incurred by damage to the basal forebrain cholinergic system may be effectively ameliorated by positive NMDA receptor modulation via the partial agonism of the glycine site.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Westhead C, Saari RK, Morrison P, Williams PT, Saari MJ (2000) Nucleus basalis magnocellularis and enriched housing: Partners in neural patterns of attention?. Neuroscience 2000 Abstracts 837.3. Society for Neuroscience, New Orleans, LA.

Summary: Diminished levels of cholinergic markers in the brains of Alzheimer’s patients led to the belief that central cholinergic systems play a major role in cognitive processes including attention and memory. Recent evidence from our laboratory suggests that housing rats in a complex environment alters neuronal attentional circuitry. These findings led to the design of the current experiment. After weaning, groups of female Wistar rats received either a bilateral infusion of 192-IgG saporin or vehicle solution into the basal forebrain. Following recovery, rats were either housed in an enriched condition or in isolated housing for two weeks, thus creating four treatment groups. Open field testing revealed the expected Housing by Minute interaction but no lesion related effects. The rats were also tested in an incidental learning paradigm. Briefly, half of the rats were pre-exposed to the testing apparatus in the testing room, whereas the other half were placed in a similar arena but in a separate room without task-specific cues. Analysis of the results revealed a significant interaction between the lesion and housing condition as a function of the pre-exposure. As expected, pre-exposure facilitated learning for all sham operated rats but the lesioned enriched rats performed in a paradoxical manner. These rats appeared to be confused by the pre-exposure to the testing apparatus. The findings suggest an inability of enriched lesioned subjects to distinguish between behaviourally relevant and irrelevant stimuli and are in general agreement with the findings of Kilgard and Merzenich (1998). (Approved by the Animal Care Committee, Nipissing University).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Gill TM, Yurrita MM, Givens B (2000) Attentional demand-related alterations in medial prefrontal neural activity of aged rats during sustained visual attention. Neuroscience 2000 Abstracts 837.6. Society for Neuroscience, New Orleans, LA.

Summary: Neural activity within the medial prefrontal cortex (mPFC) exhibits distinct relationships to sustained visual attentional performance in young male Long-Evans rats. Cortical cholinergic input substantially modulates attentional performance, mPFC neural activity, and attentional-demand related alterations in mPFC neural activity. The present study sought to investigate the relationship between sustained attention, mPFC neural activity, and cholinergic input within aged rats. Rats were operantly trained to discriminate between the presence and absence of brief, unpredictable visual signals under testing conditions that varied the level of attentional demand by the presence of a visual distractor. Aged rats were bilaterally implanted with pairs of stereotrodes into the mPFC at 25 months. The overall firing rate of mPFC units recorded during sustained attention was higher in the aged rats (2.39 spikes/s) relative to young rats (1.65 spikes/s). Moreover, a larger percentage of mPFC units exhibited attentional demand-related increases or decreases in firing rate in the aged rats (29%) relative to young rats (18%). Conversely, the magnitude of attentional demand-related increases in activity was smaller in the aged rats (64% increase) relative to young rats (81% increase). The modulatory role of cortical cholinergic input on the overall firing and attentional demand-related alterations in mPFC activity will also be determined and contrasted to the effects in young rats using 192 IgG-saporin infusions into the mPFC.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Holguin A, Armstrong CB, Twining CM, Milligan ED, Hansen MK, McGorry M, O’Connor KA, Quan N, Martin D, Lappi DA, Maier SF, Watkins LR (2000) Anatomical evidence for glial activation after intrathecal lumbosacral HIV-1 glycoprotein; gp120-induced allodynia. Neuroscience 2000 Abstracts 733.4. Society for Neuroscience, New Orleans, LA.

Summary: Intrathecal (IT) HIV-1 glycoprotein, gp120: (a) produces thermal hyperalgesia & low threshold mechanical allodynia, and (b) increases interleukin-1β (IL1β) protein levels in lumbosacral (LS) spinal cord tissue & surrounding cerebrospinal fluid (CSF). Activated astrocytes & microglia (glia) release IL1β in response to gp120, and IT IL1 receptor antagonist or glial metabolic inhibitors prevent IT gp120-induced allodynia and thermal hyperalgesia. We determined whether IT gp120 produces glial activation and increased expression of glial IL1β as well as allodynia. LS spinal cord was collected 1.5 & 3 hrs after IT gp120 injection & verification of allodynia for immunocytochemistry (ICC) & in situ analysis of IL1β protein & mRNA. ICC for glial activation markers was performed 4,8 & 18 hrs after IT gp120 in LS & cervical spinal cords, as upregulation of these markers is delayed relative to behavioral changes. IT gp120 produced allodynia & increased IL1β protein ICC expression in LS spinal white (astrocytes) & gray matter (cells not identifiable) at 1.5 but not 3 hrs after injection. Increases in in situ IL1β mRNA were not detected. RT-PCR analysis of IL1β mRNA is underway. Glial activation (ICC) was observed in LS tissue 8 & 18 hrs after IT gp120. We are examining IT gp120 allodynia & hyperalgesia after an IT microglia-specific toxin (Saporin-linked Mac-1 antibody) injection that disrupts glial function. ICC procedures will verify Mac-1 Saporin microglial toxicity.

Related Products: Mac-1-SAP mouse/human (Cat. #IT-06)

Prakash N, Cohen-Cory SC, Frostig RD (2000) NGF-induced rapid functional plasticity in the adult rat somatosensory cortex is mediated by fibers originating in the basal forebrain cholinergic system. Neuroscience 2000 Abstracts 722.6. Society for Neuroscience, New Orleans, LA.

Summary: We have previously demonstrated, by using intrinsic signal optical imaging in vivo, that topical application of nerve growth factor (NGF) to the somatosensory cortex of an adult rat augments the functional representation of a whisker, within minutes after NGF application (Prakash et al. Nature 381:702-6, 1996). In addition, we have shown that the NGF receptor, TrkA is found on fibers projecting to the cortex. We have now tested the hypothesis that these TrkA-positive fibers originate in basal forebrain cholinergic system (BFCS) and that NGF augments the size and amplitude of a cortical representation by enhancing the release of ACh from these fibers. To this end we demonstrate: 1) that BFCS fibers indeed express TrkA receptors by co-localizing TrkA and ChAT immunostaining to single cortical fibers; 2) that removal of these cortical BFCS-fibers by injection of a specific cytotoxin, 192 IgG-saporin, prevented the NGF-induced augmentation; and 3) that topical application of the ACh agonist carbachol induced a rapid augmentation of the whisker functional representation similar to the one observed with NGF. Thus, these results firmly support our hypothesis that NGF-induced effects on cortical functional representations are mediated by the BFCS projection fibers and provide a mechanism for NGF-induced rapid plasticity in vivo.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Khasabov SG, Rogers SD, Mantyh PW, Simone DA (2000) Responses of spinal dorsal horn neurons to capsaicin following intrathecal pretreatment with substance p-saporin toxin. Neuroscience 2000 Abstracts 635.13. Society for Neuroscience, New Orleans, LA.

Summary: Intrathecal (i.t.) application of the cytotoxic substance P-saporin (SP-SAP) conjugate is internalized by dorsal horn neurons expressing the SP receptor (SPR) and results in loss of SPR-expressing neurons. Loss of SPR+ neurons attenuates the nocifensive behavior and hyperalgesia produced by intraplantar injection of capsaicin (CAP). Here we determined the effect of SP-SAP on CAP-evoked excitation and sensitization of dorsal horn neurons to heat and mechanical stimuli. Separate groups of rats were given i.t. injection of vehicle (VEH) or SP-SAP (5´10-6mM in 10ml) 10 or 30 days prior to electrophysiological experiments. Extracellular recordings were obtained from nociceptive dorsal horn neurons classed as high threshold (HT) or wide dynamic range (WDR). Responses to mechanical (von Frey monofilaments) and heat (35°C-51°C) stimuli were obtained before and after injection of 10 mg CAP into the receptive field. In VEH-treated animals, CAP produced an intense activation of HT and WDR neurons with a mean peak discharge rate of 52.2±11.2 Hz. In addition, the mean number of impulses evoked by mechanical stimuli increased 267±33% following CAP and mean heat thresholds decreased from 44.7±1.6°C to 37.7±0.7°C. In SP-SAP treated animals, however, the peak response evoked by CAP was decreased by 61±11% as compared to control. Moreover, CAP did not significantly alter responses to mechanical or heat stimuli. These data suggest that dorsal horn neurons that possess the SPR play a critical role in the development of sensitization to mechanical and heat stimuli following CAP.

Related Products: SP-SAP (Cat. #IT-07)

Tarpley JW, Martin WJ, Baldwin BS, Forrest MJ, MacIntyre DE (2000) Contribution of IB4-positive sensory neurons to NGF-induced hyperalgesia in the rat. Neuroscience 2000 Abstracts 633.18. Society for Neuroscience, New Orleans, LA.

Summary: Sensory information is transmitted from the periphery to the spinal cord by distinct subsets of primary afferent neurons, including two major classes of C-fibers that are distinguished by their ability to bind the lectin IB4. IB4-positive neurons are primarily non-peptidergic, express the receptor tyrosine kinase, Ret, and are preferentially sensitive to the neurotrophic factor, GDNF. By contrast, the nerve growth factor (NGF) receptor tyrosine kinase, trkA, is predominantly expressed in IB4-negative neurons that contain substance P. Previous work suggested that depletion of IB4-positive neurons increases acute nociceptive thresholds to noxious thermal stimuli. The extent to which these non-peptidergic neurons mediate changes in nociception after injury is unknown. Here, we examined the contribution of IB4-positive, non-peptidergic, neurons to thermal and mechanical sensitivity after acute tissue injury. Baseline thermal (radiant heat) and mechanical (von Frey) thresholds were measured in rats prior to injection of IB4-saporin (5 ug/5 ul) into the left sciatic nerve. By two weeks, IB4-saporin-treated animals exhibited pronounced increases in their nociceptive thresholds to thermal and mechanical stimuli. At this time, treatment with NGF (5 ug/50 ul, i.pl.) increased paw thickness in both control and IB4-saporin-treated rats. However, nociceptive thresholds were significantly lowered in control rats, but not in those treated with IB4-saporin. This suggests that IB4-positive neurons contribute to injury-induced changes in thermal and mechanical sensitivity and provide insight into the function of this unique set of primary afferent neurons.

Related Products: IB4-SAP (Cat. #IT-10)

Yezierski RP, Yu CG, Wiley RG (2000) Prevention and treatment of a spontaneous pain-like behavior following excitotoxic spinal cord injury (SCI) by ablation of neurons expressing the substance P receptor. Neuroscience 2000 Abstracts 733.9. Society for Neuroscience, New Orleans, LA.

Summary: Intraspinal injection of the AMPA/metabotropic agonist quisqualic acid (QUIS) leads to the onset of excessive grooming behavior with an average onset time of 11-15 days. This behavior has been proposed as a model of chronic central pain following SCI (Yezierski et al., 1998). An important histological correlate of this behavior is a pattern of neuronal loss that includes the neck of the dorsal horn with sparing of the superficial laminae. Previously, we speculated that laminae I projection neurons might be part of the substrate responsible for the onset and progression of injury induced excessive grooming behavior. To test this hypothesis we evaluated the effects of the [Sar9,Met(OH)11]substance P-saporin (SSP-SAP) neurotoxin delivered directly to the dorsal surface of the cord in ‘prevention’ and ‘treatment’ protocols. Two groups of animals were injected with 125mM QUIS. One group received a treatment of SSP-SAP (10μl; 15 or 30ng/μl) for ten minutes immediately after QUIS injection. The second group was treated with 30ng/μl within 5 days after the onset of excessive grooming behavior. The results showed that only 30% (3/10) of the animals receiving SSP-SAP in the prevention protocol developed excessive grooming behavior compared to a norm of 80-90%, and those that developed the behavior had a delayed onset (18-26 days) and small skin area targeted for grooming. Animals receiving SSP-SAP treatment after the onset of grooming had significantly less grooming than animals not receiving treatment. Staining for the NK-1R receptor showed that animals with minimal grooming behavior had a significant decrease in lamina I staining with normal staining around the central canal and IML. In conclusion the results have shown that ablation of lamina I substance P receptive neurons significantly delayed the onset and progression of a spontaneous pain-like behavior induced by excitotoxic SCI.

Related Products: SSP-SAP (Cat. #IT-11)

Mazei MS, Wiley RG, Deutch AY (2000) Intracortical injection of DBH-saporin targets noradrenergic axons in the medial prefrontal cortex of the rat. Neuroscience 2000 Abstracts 639.8. Society for Neuroscience, New Orleans, LA.

Summary: The medial prefrontal cortex (mPFC) is innervated by both dopaminergic and noradrenergic neurons. While the densities of the two types of catecholamine axons are different in subregions of the mPFC, axons of both types are present in most of the mPFC. The goal of this study was to selectively lesion noradrenergic axons in the rat mPFC while sparing dopaminergic axons, using microinjection of the immunotoxin dopamine β-hydroxylase (DBH)-saporin. DBH-saporin (10- 100 ng/μ1) was unilaterally injected into three brain regions, the mPFC, caudate-putamen (CP) and cerebellum. Rats were sacrificed 2-10 days post-injection and the lesion was characterized by tyrosine hydroxylase (TH), DBH, and norepinepherine transporter (NET) immunohistochemistry. DBH-saporin administration resulted in discrete lesions. There appeared to be a decrease in the number of immunoreactive (ir) axons after DGH-saporin infusion into the mPFC: surviving axons were swollen and dystrophic. However, the effect of DBH-saporin appears more pronounced when examining DBH-ir than with NET-ir. Intrastriatal injections of DBH-saporin did not decrease TH-ir, suggesting that dopaminergic axons were spared. Since DBH-saporin acts by entry into DBH-containing vesicles, a longer time course may be necessary to observe loss of the NET marker than DBH. Studies are in progress to examine this possibility.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Ricceri L, Baxter MG, Frick KM, Berger-Sweeney J (2000) Preservation of reactivity to spatial novelty in adult rats after specific basal forebrain 192 IgG-saporin lesions. Neuroscience 2000 Abstracts 563.4. Society for Neuroscience, New Orleans, LA.

Summary: We have shown previously that neonatal intracerebroventricular (icv) injections of the selective cholinergic immunotoxin 192 IgG-saporin induce marked cholinergic loss in both hippocampus and cortex. These lesions also have long-term behavioral effects in adulthood, impairing reactivity to spatial novelty in a spatial open field test with five objects. In the present study, we analyzed behavioral and neurochemical effects of intraparenchymal injections of 192 IgG-saporin in the medial septal area (MS, 175 ng) or nucleus basalis magnocellularis area (nBM, 70 ng per side) of adult Wistar rats. Animals were then tested in the spatial open field test. NBM cholinergic lesions significantly reduced object exploration in the initial phase of the test, whereas locomotor activity, spatial and object novelty responses were unaffected by either the MS or nBM lesion. A loss in cortical (-61%) and hippocampal (-92%) choline acetyl-transferase activity was found following nBM and MS lesions, respectively. These data show that, although interrupting cholinergic basal forebrain innervation of neocortex and hippocampus in the first postnatal week induces long-term deficits in reaction to spatial rearrangement of familiar objects, the removal of the cholinergic inputs in adulthood does not compromise the same behavioral responses. These data suggest that the same MS and nBM neurons play differential roles in regulating reactivity to spatial changes at different maturational stages.

Related Products: 192-IgG-SAP (Cat. #IT-01)