sfn2004

Arshad S, Li P, Fitz NF, Johnson DA (2004) Effect of dehydroepiandrosterone sulfate on retention in passive avoidance in septal hippocampal cholinergic lesioned rats. Neuroscience 2004 Abstracts 436.11. Society for Neuroscience, San Diego, CA.

Summary: Infusions of 192 IgG-saporin (SAP) into the medial septum (MS) selectively destroys cholinergic neurons projecting to the hippocampus. Our previous study demonstrated that this lesion impairs retention but not acquisition of a passive avoidance (PA) task in rats. The present study determined whether the neurosteroid Dehydroepiandrosterone sulfate (DHEAS) (0, 1, 3, 10, 30 mg/ml) could reverse SAP induced impairments of PA retention. Male Sprague-Dawley rats were administered either SAP (.22μg/μl) or vehicle directly into the MS. Passive Avoidance training began 2 weeks later. Training consisted of placing the animal into the lighted chamber of the apparatus and then delivering a foot shock (.75mA, 1 sec), when the animal moved into the adjacent darkened chamber. Training was repeated until the animal avoided the dark chamber for 2 consecutive trials of 2 minutes duration. Retention (latency to crossover to the dark chamber) was tested after seven days. DHEAS was administered one hour prior to retention testing. Results showed a dose dependent increase in crossover latency in SAP treated animals. DHEAS treatment in control animals, however, resulted in a dose dependent decrease in crossover latency. Thus, DHEAS attenuated the impairment in retention in SAP treated animals with hippocampal cholinergic hypofunction, but impaired retention in cholinergically intact rats in PA.

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

Fitz NF, Li P, Johnson DA (2004) Effects of dehydroepiandrosterone sulfate on delayed match to position T-maze task performance in 192- IgG saporin lesioned rats. Neuroscience 2004 Abstracts 436.2. Society for Neuroscience, San Diego, CA.

Summary: Prior studies have shown that infusion of 192 IgG-saporin (SAP), a cholinergic neurotoxin, into the media septum (MS) of rats selectively lesions cholinergic neurons that project to the hippocampus, resulting in impaired acquisition of a delayed matching to position (DMP) T-maze task. Since the neurosteriod dehydroepiandrosterone sulfate (DHEAS), displayed memory enhancing properties in rodents, the present study investigated the effects of DHEAS administration on MS SAP lesioned animals. Male Sprague-Dawley rats received intraseptal infusions of either cerebrospinal fluid or SAP (0.22 μg/μl). Fourteen days later, the rats were administered IP injections of either DHEAS (20mg/ml) or vehicle one hour prior to DMP testing. During the acquisition phase of testing, each rat completed 8 trial pairs per day until reaching criterion (15 of 16 correct choices). Treatment with DHEAS resulted in a 10% shortening of the number of days to reach criterion in the SAP treated animals compared to SAP non-treated animals.

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

Fletcher BR, Guzowski JF, Baxter MG, Shapiro ML, Rapp PR (2004) Hippocampal Arc and Homer 1a expression in behaviorally characterized 192 IgG-saporin lesioned rats. Neuroscience 2004 Abstracts 436.4. Society for Neuroscience, San Diego, CA.

Summary: Fornix lesions impair hippocampal dependent learning and block behavioral induction of the immediate-early gene Arc. The present experiment tested the role of cholinergic innervation in the transcriptional induction of the activity related immediate-early genes Arc and Homer 1a. 192 IgG-saporin or vehicle was injected into the medial septal nucleus and vertical diagonal band. Behavioral characterization on cued and spatial delayed match-to-place tasks in a radial arm water maze revealed an impairment in cognitive flexibility, but not spatial memory in lesioned animals. Immediately after animals explored two novel environments their brains were processed for fluorescence in situ hybridization with probes for Arc and Homer 1a to reveal the recent activation history of individual neurons. Confocal stereological quantification of labeling in the CA1 and CA3 cell fields of the hippocampus revealed no dramatic difference in number of positive cells between groups. These results show that, unlike fornix lesions, cholinergic denervation of the hippocampus is not sufficient to block behavioral activation of Arc or Homer 1a transcription. Therefore, cholinergic innervation is not required for Arc or Homer 1a expression.

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

Kitto MR, Carbrera S, Corley S, Castillo A, Atkinson M, Andrews C, Casteneda M, Crawford D, Iliscupidez M, Monahan R, Rodriguez D, Salley T, Butt AE (2004) 192 IgG-saporin lesions of the nucleus basalis magnocellularis impair biconditional discrimination learning in rats. Neuroscience 2004 Abstracts 436.5. Society for Neuroscience, San Diego, CA.

Summary: Previous results from our laboratory suggest that the cholinergic nucleus basalis magnocellularis (NBM) is involved in configural association learning but not in simple association learning. In the current experiment, we hypothesized that 192 IgG-saporin lesions of the NBM in rats would impair biconditional visual discrimination learning, which requires configural association learning. In contrast, we hypothesized that NBM lesions would not impair acquisition of a simple visual discrimination, which requires only simple association learning. In Problem 1, rats were trained in a T-maze to solve a simple visual discrimination between a food-reinforced black goal arm (B+) and a non-reinforced white arm (W-), where the start arm of the maze was always striped (S). Next, in Problem 2, the reinforcement contingencies of the goal arms were reversed (W+ vs. B-), and the start arm visual cue was changed to gray (G). Finally, rats underwent biconditional discrimination training where half of the trials were of Problem 1 type and half were of Problem 2 type. Separately, Problems 1 (S: B+ vs W-) and 2 (G: W+ vs B-) can be solved using simple associations. However, in the biconditional discrimination, where Problems 1 and 2 are intermixed, configural association learning is required. Preliminary results supported our hypotheses. Acquisition of Problems 1 and 2, the simple association problems, did not differ between the NBM lesion group and the control group. However, performance in biconditional discrimination was impaired in the NBM lesion group compared to controls. These results are consistent with the argument that the NBM is involved in configural but not simple association learning.

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

Ricceri L, Scattoni ML, Cutuli D, Calamandrei G (2004) Effects of neonatal cholinergic lesions on fear conditioning in 18-day-old rats. Neuroscience 2004 Abstracts 436.9. Society for Neuroscience, San Diego, CA.

Summary: We have previously shown that neonatal intracerebroventricular (icv) injections of the selective cholinergic immunotoxin 192 IgG-saporin on postnatal day (pnd) 7 induces behavioural alterations already detectable in the third postnatal week. In the present study we injected 192 IgG-saporin icv, in the nucleus basalis magnocellularis (nbm) or in the medial septum (ms) in 7-day-old rats and we then analysed fear conditioning on pnd 18. Fear conditioning to both auditory cue and environmental context was evident in both control and lesioned rats on pnd 18. However, conditioning to the environmental context (measured by freezing duration) was significantly more marked in icv and MS lesioned rats, whereas no effect of the cholinergic lesion was evident on conditioning to the auditory cue. These results suggest that neonatal removal of the cholinergic input to the hippocampal region paradoxically facilitates processing of spatial information in young rats.

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

Benassi SK, Blanco MM, Mello LE (2004) Electrophysiological profile of IgG192saporin-lesioned rats in the pilocarpine model of epilepsy. Neuroscience 2004 Abstracts 452.14. Society for Neuroscience, San Diego, CA.

Summary: In order to investigate the importance of the basal forebrain cholinergic reorganization to the epileptogenesis process, adult male Wistar EPM-1 rats (180-220g) were subjected to status epilepticus (SE) induction by pilocarpine injection (320mg/kg, i.p.), after cholinergic lesion through IgG192-saporin (5μg/5μL, i.c.v.). Two months after SE induction animals were deeply anesthetized (choral hydrate 400 mg/kg, i.p.) and subjected to the electrical stimulation of the right CA3 and recorded (3M NaCl, 1MΩ) in the contralateral (left) CA1 region. Histological analysis included Nissl staining for the location of stimulating and recording electrodes and histochemistry for acetylcholinesterase (AChE) for the assessment of IgG192-induced lesions. The administration of the IgG192-saporin consistently and specifically diminished AChE staining in the hippocampus and neocortex while not affecting other brain areas (e.g., amygdala, striatum, etc). As compared to naive control animals, pilocarpine-treated animals generally showed loss of paired-pulse inhibition and the presence of multiple population spikes. Epileptic animals that were pre-treated with the cholinergic toxin did not differ from untreated epileptic animals in terms of paired-pulse inhibition or the presence of multiple population spikes. Large paired-pulse facilitation (P2>10 P1) for interstimulus intervals varying from 20 to 200 ms was encountered for both groups of epileptic animals with no distinction between each other. We suggest that the basal forebrain cholinergic system does not have a major role in defining the hyperexcitability of hippocampal circuits in the pilocarpine model of epilepsy.

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

Bailey AL, Bennett G, Ribeiro-da-Silva A (2004) Investigation of the functional role of non-peptidergic primary afferent sensory fibres in the transmission of pain related information. Neuroscience 2004 Abstracts 484.1. Society for Neuroscience, San Diego, CA.

Summary: It is well established that small diameter, unmyelinated, primary afferent C-fibres can be divided into two neurochemically defined populations, one that contains neuropeptides such as Substance P (SP) and Calcitonin-gene related peptide (CGRP) and the other which binds Isolectin B4 (IB4) and is relatively peptide negative. A great deal of circumstantial evidence indicates that the non-peptidergic afferents play a functionally distinct role in pain transmission compared to peptidergic afferents. Indeed, the concept of two distinct subpopulations of C-fibres would indicate the occurrence of parallel processing in pain pathways. However, the functional role of non-peptidergic afferents in the transmission of pain-related information is still unclear. In an attempt to clarify their functional role, we decided to study the development of hyperalgesia and allodynia in adult male Sprague-Dawley rats with selective ablation of IB4-binding, non-peptidergic afferent input to the dorsal horn. To achieve this, we injected IB4 conjugated to Saporin (SAP) into the left sciatic nerve and examined both neurochemical and behavioural changes over a month’s time. Our data show that following injection of the toxin conjugate, IB4-labelling, P2X3-immunopositive fibre terminals disappear from a band in the superficial dorsal horn that expands over a two week period until it comprises most of the mediolateral extent of the dorsal horn. Behavioural data indicates that there are transient changes in acute pain thresholds to mechanical and thermal stimuli. Changes in pain thresholds in animals lacking non-peptidergic input into the spinal dorsal horn in an animal model of Complete Freund’s Adjuvant (CFA) induced inflammation will also be presented.

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

McGaughy JA, Koene R, Eichenbaum HB, Hasselmo ME (2004) Effects of cholinergic deafferentation of prefrontal cortex on working memory: A convergence of behavioral and modeling results. Neuroscience 2004 Abstracts 551.7. Society for Neuroscience, San Diego, CA.

Summary: In humans, the prefrontal and medial temporal lobe areas are differentially activated during working memory dependent upon the whether stimuli are familiar or novel. Prefrontal activation occurs with highly familiar stimuli whereas the medial temporal lobe is activated by novel stimuli (Stern, et al. Hippocampus v. 11, 2001). The maintenance of novel information in the entorhinal cortex (EC) is hypothesized to depend upon self-sustained spiking activity in single neurons produced by cholinergic activation of muscarinic receptors (Klink and Alonso, J. Neurophys. 77, 1997). The current study investigated whether cholinergic modulation of the prefrontal cortex regulates sustained spiking activity for familiar stimuli. Rats were trained in an odor-cued delayed non-matching to sample task. After reaching asymptotic performance, rats were infused bilaterally with either 192 IgG-saporin (SAP) or its vehicle into the prefrontal cortex(PFC;0.01μg/μl;1.0μl/injection). Following PFC-SAP lesions,rats were impaired in working memory with highly familiar odors when choice stimuli were probed sequentially but not simultaneously. Though PFC-SAP rats reliably sampled both choices, they failed if the first cup probed matched the sample. PFC-SAP rats were also unable to maintain multiple items in memory. These impairments cannot be explained by the loss of response inhibition, the conditional response rule, attentional or sensory abilities. It is hypothesized that in the absence of a functional frontal cortex, the PFC-SAP rats relied on the EC. Computational modeling of EC suggests repetitions of an odor or the presentations of multiple odors disrupt the pattern of self-sustained spiking in this area and, thus, the representation of the stimulus. These data elucidate the interplay between the PFC and EC during a working memory task.

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

Stead S, Doering LC (2004) A novel mouse model for Parkinson’s disease using an immunotoxin directed at the dopamine transporter. Neuroscience 2004 Abstracts 563.1. Society for Neuroscience, San Diego, CA.

Summary: Current laboratory models of Parkinson’s disease utilize neurotoxins directed at midbrain dopamine neurons to mimic nigro-striatal dopaminergic neuron degeneration. To date, however, there is no single model that accurately simulates the pathogenic, histological, biochemical and clinical features relevant for the investigation of PD. The most common laboratory rodent model of Parkinson’s uses the neurotoxin 6-hydroxydopamine (6-OHDA) to cause relatively acute degeneration of the dopamine neurons in the substantia nigra (Schwarting RKW and Huston JP, 1996, Prog Neurobiol., 50:275-331). Axonally transported toxins can be used to make selective lesions in the central nervous system. We have found that a slower degeneration of the SN can be achieved with an immunotoxin directed against the dopamine transporter (DAT). This immunotoxin, consisting of the highly active ribosome inactivating protein Saporin linked to an antibody to the dopamine transporter, was recently reported to cause selective degeneration of the SN in rats (Wiley RG et al., 2003, Cell Mol Neurobiol., 23:839-850.). We have shown that unilateral stereotaxic injection of the Anti-DAT-Saporin into the striatum of female C57BL6 mice causes a progressive reduction in the numbers of DA neurons in the SN in comparison to the non-lesioned hemisphere, and sham controls. Furthermore, in parallel to the immunohistochemical dopamine neuron death, the animals display a pronounced circling behaviour when challenged with apomorphine (6mg/kg). This model is akin to the gradual deterioration of the nigro-striatal system that occurs in Parkinson’s Disease and provides a system to intervene at various stages of dopamine neuron loss and evaluate the effectiveness of stem cell therapy.

Related Products: Anti-DAT-SAP (Cat. #IT-25)

Leung LS, Petropoulos S, Ma J, Shen B (2004) Cholinergic neurons in the basal forebrain participate in consciousness and general anesthesia. Neuroscience 2004 Abstracts 565.4. Society for Neuroscience, San Diego, CA.

Summary: Acetylcholine (Ach) in the brain has long been associated with consciousness. In this study, we assessed consciousness in rats by their EEG and behavioral responses to a general anesthetic. Cholinergic neurons in the nucleus basalis of Meynert (NbM) were lesioned by bilateral injection of toxin IgG192-saporin (0.15 μg at P1.4, L2.7, 7.7 mm below dura) in 10 adult male rats. Control (5 rats) had saline injected into the NbM. EEGs were recorded by electrodes placed in layer V of the frontal cortex (FC) and visual cortex (VC). Spectral analysis of the spontaneous EEGs in FC and VC during awake-immobility indicated that lesioned animals showed higher delta (0.8 to 4 Hz) and lower gamma (30- 58 Hz) power as compared to controls. Subsequent acetylcholinesterase staining (optical density) confirmed significant Ach depletion in both FC and VC, in the lesion as compared to the control group (P<0.002, Wilcoxon). When challenged with a normally subanesthetic dose of general anesthetic, the lesioned rats showed, as compared to controls, significantly longer durations of loss of righting and tail-pinch response after 5 mg/kg i.v. propofol (P<0.001), but not after 20 mg/kg i.p. pentobarbital or 2% halothane. In correspondence with the deep behavioral anesthesia, delta power at FC after propofol was significantly larger in lesioned than control rats. Lesioned rats, as compared to controls, also showed decreased locomotion (behavioral excitation) when given 2% halothane in a large chamber. In summary, a loss of Ach in the neocortex decreases the level of consciousness as indicated by increased delta and decreased gamma EEG, and by an increased sedative/ anesthetic response to propofol i.v. We suggest that patients with Alzheimer disease may show altered response to some general anesthetics.

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