References

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.

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King CD, Baker B, Gu JG, Vierck CJ, Yezierski RP (2004) Behavioral evidence for a capsaicin-sensitive inhibitory pathway (CSIP): A novel modulatory role for substance P. Neuroscience 2004 Abstracts 292.18. Society for Neuroscience, San Diego, CA.

Summary: Exposure to noxious thermal stimulation or application of capsaicin cream causes the release of SP from capsaicin-sensitive primary afferent terminals that activate neurokinin-1 receptor (NK1R) expressing neurons in the superficial dorsal horn. Recent evidence suggests the existence of a capsaicin-sensitive inhibitory pathway (CSIP), a novel inhibitory mechanism that involves NK1R expressing neurons in laminae III-V. To determine the functional significance of these NK1R expressing neurons, substance P-saporin neurotoxin (SP-SAP) was used to ablate NK1R neurons in the superficial laminae. Elimination of the NK1R neurons in this region made it possible to evaluate the modulatory effects of NK1R expressing inhibitory neurons in deeper laminae. Reflexive responses were evaluated in rats during a 10-minute trial at 44.5°C before (pre-) and 14 days after (post-) intrathecal injection of 350ng SP-SAP. Testing conditions included: 1) baseline; 2) hindpaw application of 1% capsaicin cream; and, 3) intrathecal injection of the NK1 antagonist CP-97,345 following hindpaw application of 1% capsaicin cream. In normal rats, hindpaw application of capsaicin produced thermal hyperalgesia. In contrast, application of capsaicin produced a hypoalgesia in the same rats after treatment with SP-SAP. The capsaicin-induced hyperalgesia in normal rats was blocked by CP-97,345. The antagonist also blocked the capsaicin-induced hypoalgesia in SP-SAP rats. In conclusion, it is suggested that substance P activates inhibitory interneurons in the deep dorsal horn. The inhibitory effect initiated by substance P on pain transmission neurons represents a novel role of substance P in the spinal processing of nociceptive information.

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Abe T, Shimoda T, Sugiyo S, Ohshita N, Takao T, Takemura M (2004) Altered effects of systemic bicuculline on intensity-dependent c-Fos expression in rats ablated with NK-1 receptor-bearing neurons in the trigeminal caudal nucleus. Neuroscience 2004 Abstracts 294.12. Society for Neuroscience, San Diego, CA.

Summary: In rats pretreated with saporin conjugated to substance P (SP-Sap: 5 μM, 5 μl) into cisterna magna, the numbers of neurons-immunoreactive for NK-1 receptor (NK-1R) in laminae I and III of trigeminal caudal nucleus (Vc) were significantly decreased compared with rats similarly treated with saline (Sal; 5 μl) or blank-saporin (Bl-Sap; 5 μM, 5 μl). We examined the effects of selective ablation of NK-1R-bearing neurons and systemic administration of bicuculline (2 mg/kg, i.p.) on the expression of c-Fos induced 2 hr after electrical stimulation (5 Hz, 5 ms) of the trigeminal ganglion (TG) at low (0.1 mA) and high intensities (1.0 mA). In Sal- or Bl-Sap treated rats, 10 min stimulation at 0.1 and 1.0 mA of the TG induced c-Fos-immunoreactive (c-FosIR) cells in the ipsilateral superficial layers of the Vc (VcI/II) in a intensity-dependent manner. In rats treated with SP-Sap, and stimulated at 1.0 mA but not at 0.1 mA, the numbers of c-FosIR cells in the Vc were significantly decreased compared to Sal- or Bl-Sap treated rats. In Sal- or Bl-Sap treated rats preadministed with bicuculline and stimulated at 0.1 mA and 1.0 mA, the numbers of c-FosIR cells in VcI/II were significantly increased and decreased, respectively. However, in SP-Sap treated rats preadministered with bicuculline and stimulated at 0.1 mA and 1.0 mA, the numbers of c-FosIR cells in VcI/II were significantly increased. These results indicate that NK-1R-bearing neurons in the Vc have pivotal role in the modality and/or intensity-dependent sensory (nociceptive) processing in the TSN through GABAA receptors.

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Ralston HJ, Wiley RG, Dougherty PM, Weng HR, Cata J, Chen JH, Hopkins SD, Canchola SA, Galo E, Vierck CJ (2004) The effects of chronic deafferentation and SSP-saporin on pain responses, spinal cord neurons and on the structure and function of the somatosensory thalamus (VPL) in the macaque monkey. Neuroscience 2004 Abstracts 295.1. Society for Neuroscience, San Diego, CA.

Summary: We have used behavioral, physiological and anatomical methods to examine the effects of chronic (> 2 years) lesions of the dorsal column pathway and of the intrathecal administration of the neurotoxin SSP-saporin in adult M. arctoides. Normal animals were evaluated to determine their responses to noxious heat (52 to 58°C) applied to the lower limbs. Subsequently, the monkeys were anesthetized and had unilateral lesions of the dorsal and dorsolateral spinal cord white matter pathways at midthoracic levels. After recovering from the surgery, their pain responses were studied for more than 1 year, following which SSP-saporin was administered to the lumbosacral spinal cord. The animals were found to have a decrease in their responses to noxious heat applied to the lower limbs. Terminal physiological experiments revealed that the neurons within the lower limb representation of VPL on the side contralateral to the thoracic cord lesion did not have normal receptive fields, although some cells responded to stimulation of both upper and lower limbs. Histological sections of lumbar spinal cord were stained for neurokinin 1 receptor (NK-1R) and showed a significant decrease in lamina I NK-1R positive neurons. Electron microscopy of VPL revealed patterns of synaptic terminals that were different than those found in VPL of normal macaques. We will determine whether there is a significant correlation between the altered behaviors and the physiological and anatomical changes in these animals as a consequence of somatosensory deafferentation.

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Wei F, Zou S, Robbins MT, Ren K, Dubner R (2004) Mu-opioid receptor-expressing neurons in the nucleus reticularis gigantocellularis contribute to descending facilitation during the development of inflammatory pain. Neuroscience 2004 Abstracts 297.3. Society for Neuroscience, San Diego, CA.

Summary: We have previously shown that nucleus reticularis giangocellularis (NGC) is involved in descending facilitation of inflammatory hyperalgesia. The cellular mechanisms of descending facilitation from the NGC are unknown. The targeted destruction of the mu-opioid receptor-containing neurons in the rostral ventromedial medulla (RVM) by a dermorphin-saporin conjugate prevents nerve injury-induced hyperalgesia in rats (Porreca et al., J. Neurosci. 21:5281, 2001). We examined the effects of selective deletion of the mu-opioid receptor-expressing neurons in the sub-regions of RVM on nocifensive behaviors in rats. After microinjection of dermorphin-saporin conjugate (1.5 pmol/500 nl) into the RVM, there were no changes in baseline thermal and mechanical sensitivity to noxious stimuli. However, the injection of dermorphin-saporin conjugate into bilateral NGC (n=7) significantly attenuated the thermal hyperalgesia and mechanical allodynia at 30 min to 1 d after hindpaw inflammation produced by injection of complete Freund’s adjuvant, compared to sham (blank-saporin or dermorphin) groups (n=3-6). The lesion of the nucleus raphe magnus (NRM) (n=3) only slightly reduced hyperalgesia at 3 h after inflammation. The loss of NGC mu-opioid receptor-containing neurons also decreased nocifensive behaviors only in phase II of the formalin model. In contrast, NRM lesions were without an effect on formalin-induced phase I/II responses. These findings indicate that selective deletion of the mu-opioid receptor-containing neurons in the nucleus reticularis giangocellularis attenuates inflammatory hyperagesia and allodynia.

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Fargo KN, Sengelaub DR (2004) Prevention of depletion-induced motoneuron dendritic atrophy requires testosterone effects on target musculature. Neuroscience 2004 Abstracts 310.10. Society for Neuroscience, San Diego, CA.

Summary: Motoneurons in the spinal nucleus of the bulbocavernosus (SNB) in male rats project to the penile muscles bulbocavernosus (BC) and levator ani (LA). These motoneurons share a midline location, have intermingled somata, extensive dendritic overlap, and common afferents, and organize coordinated contractions of the penile musculature. Unilateral depletion of BC-projecting motoneurons causes marked dendritic atrophy in contralateral BC-projecting motoneurons, and this atrophy can be prevented with testosterone (T) treatment. In this experiment, we test whether the depletion-induced atrophy is related to the innervation of homotypic muscles. BC-projecting motoneurons were depleted by unilateral injection with saporin conjugated to the cholera toxin B subunit (SAP); some animals were simultaneously treated with T. Four weeks later, a period demonstrated to be sufficient to observe dendritic atrophy in remaining motoneurons, HRP conjugated to the cholera toxin B subunit (BHRP) was injected into the ipsilateral LA. SAP injection into the BC muscle killed over 40% of ipsilateral SNB motoneurons. Dendritic length in LA-projecting motoneurons was reduced by almost 60%. Because the SAP-induced depletion of motoneurons and the resultant dendritic atrophy occurred across motor populations, this result indicates that the dendritic atrophy we have observed previously is not restricted to motoneurons projecting to homotypic muscles. In previous studies, prevention of dendritic atrophy by T treatment in BC-projecting motoneurons was accompanied by a marked hypertrophy of the BC muscle. In the present experiment, T treatment failed to prevent dendritic atrophy in LA-projecting motoneurons, and further did not result in hypertrophy of the LA ipsilateral to the SAP-injected BC. Thus, it appears the neuroprotective effect of T treatment on SNB motoneurons may be dependent on T effects in the target musculature.

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Broussard JI, Sarter M, Givens B (2004) Neuronal correlates of signal detection in rat posterior parietal cortex. Neuroscience 2004 Abstracts 331.6. Society for Neuroscience, San Diego, CA.

Summary: The posterior parietal cortex (PPC) has been shown to be involved in the attentional processing of visual stimuli. Recent evidence has indicated that neuronal activity in the PPC is increased during the detection of signals, and this activation is modulated by visual distractors. We tested the hypothesis that detected signals are associated with increased PPC unit activity. Animals were trained in a sustained attention task using signal and nonsignal trials. After training to criterion (>75% accuracy), we implanted moveable stereotrodes into the PPC. A visual distractor was presented in a block of trials during testing sessions and effects on performance and single unit activity were examined. We also evaluated the effects of varying signal duration on performance and single unit activity. PPC neurons (39/111) exhibited a significantly greater response during signal trials than during nonsignal trials. The presentation of visual signals produced a robust increase in neuronal activity prior to the performance of a hit, but not prior to a miss, both of which required a lever press. Analysis of signal duration indicated that shorter signals resulted in fewer hits. PPC neurons became active when the signal was accurately detected, independent of signal duration. Shorter signals activated the PPC on fewer trials, which was associated with a lower likelihood for detection. The visual distractor reduced both the signal-driven unit activity and the relative number of hits. These findings suggest that activation of the PPC is associated with the detection of visual signals. We are currently investigating the effects of local cholinergic deafferentation (via 192 IgG saporin) on signal driven neuronal activity in the PPC. These studies will elucidate the contribution of basal forebrain cholinergic innervation to attentional processing in the PPC.

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