sfn2001

Zambon NJ, Nagle R, Pokala V, Gibbs RB, Johnson DA (2001) Low dose 192 IgG-saporin selectively destroys basal forebrain cholinergic neurons and impairs acquisition of a spatial memory task. Neuroscience 2001 Abstracts 534.13. Society for Neuroscience, San Diego, CA.

Summary: We previously showed that a high dose (1 μg) of the selective cholinergic immunotoxin 192 IgG-saporin (SAP), injected into the medial septum (MS) of Sprague-Dawley rats, impeded acquisition of a delayed matching-to-position (DMP) spatial memory task, whereas injections of ibotenate (5 μg in 1 μL) did not. The present study examined the effects of lower doses of SAP (0.22 and 0.45 μg in 1 μl) on DMP acquisition. Animals received either SAP or vehicle injected directly into the MS. Two weeks later, animals were food deprived and trained to the DMP task. Rats received 8 trial pairs/day until they reached a criterion of 15/16 correct choices. Seven days later, post-criteria testing for retention was performed. Brain tissues were analyzed for choline acetyltransferase (ChAT) activity, or were processed for immunohistochemical detection of ChAT and parvalbumin. Control rats required significantly fewer days (13.1) to reach criterion than rats that received 0.22 (22.0 days) or 0.45 (20.1 days) μg SAP. There was no effect of SAP treatment on post-criteria testing. Injections of SAP produced marked depletion of ChAT-positive cells and ChAT activity, but no apparent depletion of parvalbumin staining in the MS. In contrast, ibotenate injections used in the previous study were shown to produce marked depletion of parvalbumin staining in the MS, but no significant cognitive impairment. The data suggest that selective destruction of cholinergic neurons in the MS significantly impairs acquisition of the DMP task.

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Chou TC, Gerashchenko D, Saper CB, Shiromani PJ (2001) Loss of histaminergic neurons does not produce hypersomnolence. Neuroscience 2001 Abstracts 522.21. Society for Neuroscience, San Diego, CA.

Summary: Electrolytic lesions of the posterior hypothalamus (PH) produce long-lasting hypersomnolence (1,2). The PH contains histaminergic neurons in the tuberomammillary nucleus (TMN) that project diffusely throughout the brain. Because histamine promotes wakefulness while antihistamines are sedating, the TMN is thought to be critically involved in maintaining wakefulness. To test this hypothesis, we placed cell-specific lesions in the PH and TMN of rats and measured sleep-wake behavior. Lesions were produced using either the conventional excitotoxin ibotenic acid, or the novel toxin orexin (hypocretin) conjugated to the ribosomal toxin saporin (ORX/HCRT-SAP). Ibotenic acid injections were ineffective at lesioning the TMN; most histaminergic neurons were selectively spared while neurons in surrounding regions such as the mammillary bodies and supramammillary area were completely lesioned. In contrast, ORX/HCRT-SAP injections into the TMN lesioned up to 95% of histaminergic neurons, as determined by adenosine-deaminase immunostaining, with a similar loss of neurons in adjacent areas. Surprisingly, neither group of rats showed changes in NREM or REM sleep time or circadian distribution of sleep relative to saline-injected controls for up to 2 weeks after surgery. Thus, the waking state may not be critically dependent on the PH or TMN in rats. Further research is needed to reconcile the sedating effects of antihistamines with the current findings. 1. Ranson 1939, Archiv Neurol and Psychiatry 41(1):1-23. 2. Swett and Hobson 1968, Arch Ital Biol 106(3):283-293.

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Sherren N, Pappas BA (2001) Behavioural and neurochemical changes associated with single and combined acetylcholine and dopamine lesions in neonatal rats. Neuroscience 2001 Abstracts 539.5. Society for Neuroscience, San Diego, CA.

Summary: The functional outcomes of neonatal ACh or DA lesions are frequently less severe or qualitatively different from those seen in adult rats, and may be due to compensatory neurochemical changes. Given that these transmitter systems interact in the adult brain and that ACh and DA hypofunction may underlie the cognitive and motor disabilities seen in Rett syndrome, we hypothesized that combined neonatal ACh/DA lesions may produce a profile of neurochemical changes and behavioural impairments which are more severe or distinct from that caused by either lesion alone. Rats were lesioned at postnatal day 7 with 192 IgG-saporin (ACh rats), 6-OHDA with NE receptor blockade (DA rats), or both (ACh/DA rats). Behavioural testing occurred at 4 months of age. In the open field, only ACh/DA rats exhibited locomotor hyperactivity whereas all lesioned groups exhibited reduced exploratory behaviour. Neither DA nor ACh/DA rats were able to solve the Morris water maze, however ACh rats were indistinguishable from controls. 192 IgG-saporin treatment produced a 75% decrease in hippocampal ChAT activity, and cortical decreases of 30%, 70% and 40% in the frontal/cingulate (FC), retrosplenial (RS) and partietotemporal (PT) regions respectively. 6-OHDA treatment produced a 90% decrease in striatal DA levels and a 75% decrease in FC cortex. Interestingly PT DA levels were 68% higher in ACh rats but 47% lower in ACh/DA rats compared to control, while DA rats showed a decrease which was not significantly different from control. Thus sparing of spatial learning ability in ACh rats may be mediated by increases in PT DA levels, whereas combined ACh/DA lesions exacerbate DA loss in this region.

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Pau K (2001) Immunolesioning of brainstem DBH neurons on the mating-induced LH and prolactin surge in the rabbit. Neuroscience 2001 Abstracts 466.7. Society for Neuroscience, San Diego, CA.

Summary: Coitus induces a surge release of norepinephrine (NE) that is accompanied by a preovulatory gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) surge. Prazosin, an alpha-1 adrenergic antagonist, attenuates the GnRH/LH surge, and tyrosine hydroxylase (TH) gene expression in brainstem NE areas increases within 30 min after coitus. Here, we determined the coitus-induced LH/prolactin surge after specific lesioning of dopamine beta-hydroxylase (DBH) neurons in the brainstem with monoclonal anti-DBH sera conjugated with the ribosomal cytotoxin saporin (DBH-SAP). Female NZW rabbits received 3rd cerebroventricular injection (Day 0) of either DBH-SAP (20 µg, n=4) or SAP (3 µg, n=4). On day 14, the four DBH-SAP females were paired with stud males, but none of them mated. After daily injection of estradiol benzoate (EB, 3 µg) for 3 days, all eight females mated. Blood samples were taken once before, and at 10-min intervals for 4 hours after, coitus. Brainstems were prepared for immunocytochemical detection of DBH and TH. Coitus increased both LH and prolactin release in either DBH-SAP or SAP animals. However, postcoital LH and prolactin levels were 55% lower and 50% higher, respectively, in DBH-SAP rabbits than in SAP animals. The number of DBH neurons was near zero in the A6 and reduced by 80% in the A1 and 70% in the A2 noradrenergic areas in DBH-SAP animals. The number of TH neurons was reduced by 95% and 30% in the A6 and A1 areas, respectively, and did not change in the A2 area. The results suggest that the presence of intact brainstem NE neurons are critical for sexual performance and production of normal LH/prolactin surge after coitus in female rabbits.

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Ricceri L, Scattoni ML, Calamandrei G (2001) Neonatal cholinergic lesions alter reactivity to a GABAergic agonist in 18-day-old rats. Neuroscience 2001 Abstracts 541.14. Society for Neuroscience, San Diego, CA.

Summary: We have shown previously that neonatal intracerebroventricular (icv) injections of the selective cholinergic immunotoxin 192 IgG-saporin on postnatal day (pnd) 7induces learning impairments on pnd 15 and disruption of reactivity to spatial novelty on pnd 54. The same neonatal treatment also induces a permanent cholinergic loss in both hippocampus and neocortex. In the present study we analyzed behavioral effects induced by a GABAergic drug (muscimol, a GABAa receptor agonist) in rats neonatally lesioned with 192 IgG-saporin (icv on pnd 7). On pnd 18 192 IgG-saporin lesioned and sham rats were injected with muscimol (0.1, 0.5 mg/kg ip) and placed in an open field arena for 20 min; locomotion, wall rearing and rearing responses were measured. In sham animals, as expected, 0.1 muscimol decreased locomotion, wall rearing and rearing responses. In saporin lesioned animals 0.1 muscimol increased locomotion, left wall rearing responses unchanged and decreased only rearing responses. In a 60s hot-plate test, 0.1 muscimol induced comparable analgesic responses in both sham and saporin-lesioned animals. The 0.5 muscimol dose resulted cataleptic for both saporin and sham lesioned rats. Neonatal saporin per se also reduced wall rearing and rearing responses. These data suggest that only in selective behavioral patterns — associated with locomotion and exploration of the environment — reactivity to a GABAergic agonist is reduced following neonatal cholinergic lesions, probably because of a decrease of GABAa receptors in the medial septal nucleus.

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Schultz JA, Butt AE, George CL, Garraghty PE (2001) The effects of cortical cholinergic depletion on the performance of adult rats in an appetitive-to-aversive transfer task. Neuroscience 2001 Abstracts 313.3. Society for Neuroscience, San Diego, CA.

Summary: The acetylcholinergic (ACh) projections from the nucleus basalis magnocellularis (NBM) to the neocortex have been implicated in attentional processes. In a test of the hypothesis that only complex learning is affected by damage to this cholinergic system, we examined the effects of NBM lesions in an appetitive-to-aversive transfer learning task. Rats were trained using a tone to signal the availability of food reward for lever-pressing before being transferred to an avoidance learning task where the same tone signaled foot-shock that could be escaped or avoided by lever-pressing. A second experiment examined learning in the aversive context only. For both experiments, male Long-Evans rats received bilateral infusions of the immunotoxin192 IgG saporin into the NBM, sham surgery, or no treatment. Acquisition in the appetitive phase of the appetitive-to-aversive transfer task was normal in the NBM lesion group. However, transfer performance in the aversive task was impaired in NBM lesion group; NBM-lesioned rats acquired the avoidance response more slowly and had lower asymptotic avoidance rates than controls. NBM-lesioned rats tested only in the aversive task performed normally. Thus, the deficit in avoidance learning observed in the NBM-lesioned rats previously trained in the appetitive task was not due simply to an inability to learn in the aversive context. Impairments in transfer learning are instead argued to reflect the relative complexity of the appetitive-to-aversive transfer task as compared to either task alone.

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Yurrita MM, Givens B (2001) Effect of chlordiazepoxide infusions into the basal forebrain on medial prefrontal neural activity of rats during sustained visual attention. Neuroscience 2001 Abstracts 313.4. Society for Neuroscience, San Diego, CA.

Summary: There is extensive evidence suggesting a role for the basal forebrain (BF) cholinergic system in attentional processing. In particular, cortical acetylcholine has been shown to modulate performance in a sustained visual attention task, medial prefrontal cortex (mPFC) neural activity, and distractor-related alterations in mPFC neural activity. In order to further characterize the role of the BF in modulation of attention, the effect of direct infusions of the benzodiazepine receptor agonist chlordiazepoxide (CDP) into the BF was investigated. Specifically, this experiment sought to study the effect of two different doses of CDP (20 and 40µg/hemisphere) on mPFC neural activity of rats performing a task that requires them to discriminate between the presence or absence of short, unpredictable stimuli under testing conditions that vary the level of attentional demand. The overall firing rate of mPFC units recorded during performance in the task was not affected by bilateral infusions of either dose of CDP. There was, however, a differential effect of the two doses on the number of units that show an increase in firing rate during the presentation of the distractor. The high dose of CDP increased the percentage of single units that show a distractor-related increase in firing rate, while the low dose had no effect. In order to determine whether the effect of CDP on mPFC neural activity is mediated via cholinergic projections to cortex, the effect of bilateral CDP infusions into the BF on mPFC neural activity will be studied after local cortical deafferentation of the recording area using 192 IgG-saporin. Supported by: NS37026.

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Sarter M, Burk JA, Graf A, Russell J, Bruno JP (2001) Basal forebrain cholinergic and gabaergic neurons mediate different aspects of sustained attention performance in rats. Neuroscience 2001 Abstracts 313.7. Society for Neuroscience, San Diego, CA.

Summary: Several studies have demonstrated that lesions of basal forebrain (BF) corticopetal cholinergic neurons, produced by infusing the cholinotoxin 192IgG-saporin, impair the ability to detect visual signals in an operant sustained attention task but not to reject nonsignals. Information about the functions of BF non-cholinergic, particularly GABAergic neurons has remained scarce. As infusions of the excitotoxic amino acid ibotenic acid (IBO) are known to predominantly destroy non-cholinergic neurons in the BF, the effects of BF IBO lesions on sustained attention performance were assessed. Rats were trained to perform a sustained attention task and then received bilateral infusions of IBO (0.06 M; 0.5 μL / hemisphere) or of saline (N=8 /group) into the basal forebrain. Postsurgically, rats were trained to stable performance on the sustained attention task. Compared to controls, ibotenic acid-lesioned rats more frequently responded to non-signal events by ‘claiming’ a hit, and they exhibited an increase in hits in response to the briefest signals. Immunohistological analyses confirmed the predominant loss of parvalbumin-positive and thus presumably GABAergic neurons in the BF, while ChAT-positive neurons were partially spared. Likewise, IBO-lesioned animals exhibited an only moderate decrease in cortical AChE-positive fiber density. These and additional findings indicate that BF GABAergic neurons contribute to attentional performance by mediating the animals’ ability to switch between the response-rules for signals and non-signals.

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Janczewski WA, Gray PA, Feldman JL (2001) Central origin of ataxic breathing after lesion of preBötzinger complex (preBötc) neurokinin 1 receptor expressing (NK1R+) neurons. Neuroscience 2001 Abstracts 243.2. Society for Neuroscience, San Diego, CA.

Summary: Pathological breathing results from near complete lesions of preBötC NK1R+ neurons in awake adult rats (Gray et al., FASEB J.,15, 2001). To determine whether this ataxic pattern is central in origin, we examined the breathing pattern of rats using combined diaphragmatic EMG (diaEMG) and whole body plethysmography (WBP). Under anesthesia, substance P conjugated to saporin was injected bilaterally into the preBötC (n=7) and EMG electrodes were implanted into the diaphragm (n=10). Up to four days postinjection, all rats breathed normally. DiaEMG postinpiratory activity was evident in all rats and accentuated during brief apnea following spontaneous sighs. After postinjection day 5, injected rats showed a transformation in breathing pattern from normal to ataxic characterized by high frequency breaths of varying amplitude separated by periods of tonic diaphragmatic discharge. There was no lag between the WBP output and diaphragmatic activity (WBP measures virtually paralleled the moving average of diaEMG activity), suggesting the absence of significant flow limitations. During apnea, nonrespiratory movement produced artifacts on WBP signal but did not affect diaEMG. We conclude that ablation of preBötC NK1R+ neurons leads to hypoventilation and apneas of purely central origin without upper airway obstruction or bronchoconstriction.

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Cahill JF, Baxter MG (2001) Cholinergic and noncholinergic septal neurons modulate strategy selection in place learning. Neuroscience 2001 Abstracts 314.14. Society for Neuroscience, San Diego, CA.

Summary: Rats solving a simple spatial discrimination task in a plus-maze initially employ a place learning strategy, then switch to a motor response strategy. The hippocampus is required for the use of a place learning strategy in this task. Rats with 192 IgG-saporin lesions of the medial septum/vertical limb of the diagonal band (MS/VDB), that selectively removed cholinergic neurons projecting to the hippocampus, were significantly facilitated in acquisition of the spatial discrimination, and switched from place to response strategies just as control rats did. Rats with ibotenic acid lesions of the MS/VDB, which produced cell loss in the MS/VDB but little damage to cholinergic neurons, were significantly impaired in acquiring the spatial discrimination and did not reliably employ either a place or response strategy at any point in training. This suggests that the MS/VDB modulates hippocampal involvement in place learning, but that cholinergic MS/VDB neurons are neither necessary nor sufficient for using a place strategy to solve a spatial discrimination.

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Jackson O, Firoz EF, Janisiewicz AM, Baxter MG (2001) Environment-spatial conditional learning: Contribution of medial septal cholinergic neurons. Neuroscience 2001 Abstracts 314.15. Society for Neuroscience, San Diego, CA.

Summary: Visual-spatial conditional discrimination learning is impaired by damage to the cholinergic septohippocampal neurons in marmoset monkeys (Ridley et al., 1999). We sought to explore the generality of this finding by testing rats with selective lesions of cholinergic septohippocampal projections (made with 192 IgG-saporin) on an environment-spatial conditional discrimination task. In this task, one of two sets of local environmental cues (consisting of a unique geometric shape with unique visual stimuli) directed search to a particular goal location in the environment (selected from eight possible locations). Preliminary observations suggest that rats with selective lesions of medial septal cholinergic neurons are impaired on acquiring this conditional discrimination task, but are unimpaired on acquiring a single discrimination problem using the same cues. This finding is consistent with a general role for septohippocampal cholinergic projections in the learning of conditional discrimination problems, suggesting that medial septal cholinergic neurons subserve cognitive functions other than decremental attentional processing (Baxter et al., 1997, 1999).

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Rodefer JS, Jonasson Z, Cahill JF, Tobey RE, Baxter MG (2001) Effects of basal forebrain cholinergic lesions on spatial learning in male and female rats. Neuroscience 2001 Abstracts 314.16. Society for Neuroscience, San Diego, CA.

Summary: Studies with a selective toxin for basal forebrain cholinergic neurons have consistently found little spatial learning impairment in rats with lesions limited to basal forebrain cholinergic neurons. However, the basal forebrain cholinergic system is extensively modulated by estrogen and related sex hormones. Furthermore, female mice are more susceptible than male mice to scopolamine-induced impairments in water maze performance (Berger-Sweeney et al., 1995). Hence, behavioral effects of selective cholinergic lesions may differ between male and female rats, a possibility that has not been directly assessed experimentally. In the present study, male and female Long-Evans rats were given injections of 192 IgG-saporin into the medial septum/vertical limb of the diagonal band (MS/VDB), or a control surgery, and postoperatively tested on several spatial learning tasks in the Morris water maze. On place acquisition, female control rats performed worse than male controls; MS/VDB-lesioned rats performed identically to male controls, regardless of sex. Male rats performed better than female rats on reversal of place discrimination, regardless of lesion status. In a test of place learning strategy, cholinergic lesions appeared to enhance the use of a spatial (vs. a motor response strategy) in rats of both sexes. Hence, female rats are not more susceptible to place learning impairment following loss of cholinergic input to the hippocampus; indeed these lesions seem to enhance place learning in female rats. Furthermore, removal of cholinergic input to the hippocampus seems to enhance the selection of a spatial strategy.

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Bartness TJ, Demas GE (2001) A novel method for localized sympathetic nervous system denervation of peripheral tissue using guanethidine. Neuroscience 2001 Abstracts 309.10. Society for Neuroscience, San Diego, CA.

Summary: A simple technique for the functional deactivation of the sympathetic nervous system innervation of peripheral tissues is described using the local application of guanethidine. Multiple unilateral microinjections of guanethidine were made into one inguinal or epididymal white adipose tissue (IWAT and EWAT) pads of hamsters, whereas the contralateral pad received equivolumetric saline vehicle injections. Guanethidine treatment virtually abolished the sympathetic innervation of both EWAT and IWAT, as measured by the absence of significant norepinephrine (NE) tissue content two weeks later and as suggested by the two-fold increase in IWAT mass characteristic of surgically induced WAT denervation. IWAT and EWAT NE content and mass were unaffected in the contralateral control pads. Guanethidine injections into the spleen also lead to a function sympathectomy as indicated by significant depletions of NE content. Because guanethidine treatment did not decrease body mass nor induce ptosis, no chemical-induced malaise or global sympathetic denervation, respectively, was suggested. We compared the effects of local guanethidine treatment on IWAT NE content and pad mass with the local application of the sympathetic neurotoxin, anti-dopamine beta hydroxylase saporin, and with local surgical IWAT denervation. Guanethidine treatment significantly reduced IWAT NE content to a greater degree than for the alternative sympathectomy methods. These results suggest that locally applied, chemical sympathectomy with guanethidine provides an effective, restricted method for denervating WAT and likely other peripheral tissues.

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Butt AE, Noble MM, Barrett H, Brinegar S, Hixon A, Kester B, Levey D, Rea T, Ryan M, Schulze S, Vogel L (2001) 192 IgG saporin lesions of the nucleus basalis magnocellularis impair working but not reference memory in a delayed non-match-to-position y-maze task. Neuroscience 2001 Abstracts 314.17. Society for Neuroscience, San Diego, CA.

Summary: The current experiment tests the hypothesis that the cortically projecting cholinergic neurons of the nucleus basalis magnocellularis (NBM) are selectively involved in working and not reference memory. Male Long-Evans rats received extensive pre-operative training in a delayed non-match-to-position (DNMTP) task in a Y-maze. In this task, 0-s, 1-min, or 2-min delays were interposed between consistently food-reinforced “sample runs”, where rats were allowed access to only one arm of the maze, and “choice runs”, where rats were allowed access to both arms of the maze but were reinforced only for entering the arm opposite that entered on the previous sample run. Upon completion of pre-operative training, rats were matched for performance and were randomly assigned to a sham lesion group or to the NBM lesion group, which received bilateral infusions of the cholinergic immunotoxin 192 IgG-saporin into the NBM. As predicted, post-operative performance in the NBM lesion group was normal at the 0-s delay but was severely impaired at the 1-min and 2-min delays. Results suggest that the NBM is critically involved in supporting normal spatial working memory but that previously acquired reference memory for the non-matching rule remains intact following selective NBM lesions.

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Estacio MA, Tsukamura H, Reyes BA, Maeda KI (2001) Noradrenergic inputs to the paraventricular nucleus (PVN) is involved in estrogen receptor α expression in the PVN of 48-h fasted and 2DG-injected female rats. Neuroscience 2001 Abstracts 409.6. Society for Neuroscience, San Diego, CA.

Summary: Involvement of noradrenergic inputs to the paraventricular nucleus (PVN) in estrogen receptor α (ERα) expression in the PVN during 48-h fasting and 2DG-induced glucoprivation in female rats was determined by examining the effect of destroying the noradrenergic inputs to the PVN using the saporin-conjugated anti-dopamine-β-hydroxylase (anti-DBH-saporin). Ovariectomized rats were injected bilaterally with anti-DBH-saporin in the PVN. After two weeks, animals were either fasted for 48 hours or injected intravenously with 2DG, then perfused with 4% paraformaldehyde. Brain sections were processed for ERα and DBH immunocytochemistry. Forty-eight-hour fasting or 2DG injection siginificantly increased the number of ERα-immunoreactive (ERα-ir) cells in the PVN in control animals. Anti-DBH-saporin injection prevented fasting- or 2DG-induced increase in ERα-ir cells in the PVN. The DBH-ir axons in the parvocellular PVN were severely reduced following anti-DBH-saporin injection in both fasted and 2DG injected rats. Among the brainstem noradrenergic cell groups examined, there was a significant decrease in the number of DBH-ir cells in the A2 region of both fasted and 2DG injected rats treated with anti-DBH-saporin. There was no obvious reduction in the number of DBH-ir cells in the A1 and A6 regions in the anti-DBH-saporin-injected fasted- or 2DG-injected rats. The results suggest that the A2 noradrenergic input to the PVN plays a major role in increasing ERα expression in the PVN in response to 48-h fasting or 2DG-induced glucoprivation.

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Wiley RG, Kline IV RH, Lappi DA (2001) Dose-dependent effects of intrathecal substance P-saporin and SSP-saporin. Neuroscience 2001 Abstracts 281.11. Society for Neuroscience, San Diego, CA.

Summary: Selective destruction of lamina I dorsal horn neurons expressing the neurokinin-1 receptor (NK-1R) can attenuate responses to capsaicin injection and thermal hyperalgesia/mechanical allodynia in models of inflammatory, persistent or neuropathic pain. In the present study, we sought to determine the relationships between spinal intrathecal dose of substance P-saporin or the related toxin, SSP-saporin, the loss of NK-1R neurons and reduction of phase II formalin responses. Rats were injected intrathecally with 10 ul of either vehicle, 175 ng, 350 ng or 700 ng of SP-sap. Others were injected with either vehicle, 25 ng, 50 ng or 100 ng of SSP-sap. After 2 weeks, nocifensive behavior was scored for 90 min after a unilateral hindpaw injection of dilute formaldehyde. The amount of phase II nocifensive behavior from 20-90 min post injection was totaled for each animal. Rats were sacrificed and transverse lumbosacral spinal cord sections were stained for NK-1R using indirect immunoperoxidase technique. Digital micrographs of the superficial dorsal horn were captured and the number of pixels in the darkest intensity values were expressed as percent of the analysis area for each dorsal horn. Significant correlations were noted for dose vs dark pixel percentage and for dark pixel percentage vs phase II formalin behavior. The greater the toxin dose the greater the loss of NK-1R staining and the greater the attenuation of phase II formalin behavior. These results indicate that the toxin effects on pain behavior are proportional to the degree of loss of lamina I NK-1R expressing neurons.

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Savage LM, Buzzette R, Ramirez D (2001) The role of the cholinergic basal forebrain in learning, memory and reward expectancies. Neuroscience 2001 Abstracts 314.18. Society for Neuroscience, San Diego, CA.

Summary: The cholinergic basal forebrain degenerates in Alzheimer’s Disease and the degree of this degeneration correlates with a decline in cognitive processing. In the present study we have modeled this degeneration in the rat by the selective immunotoxin 192 IgG-Saporin. This immunotoxin destroys cholinergic neurons in the basal forebrain nuclei in rats and thus allows for the study of the impact of cholinergic deafferentation on learning, memory, and other cognitive processes without direct effects on other neuronal systems. After intracerebroventricularly infusions of the immunotoxin or vehicle solution, male rats were allowed to recover for three weeks before being tested in a matching-to-position task. The matching-to-position task was altered to influence the type of cognitive strategies a subject would use to solve the task. The main behavioral manipulation was the use of the differential outcome procedure (DOP). The DOP involves correlating each to-be-remembered event with a distinct reward condition. We found that cholinergic lesions did not dramatically impair learning the matching rule. However, the memory performance of subjects with cholinergic lesions was dramatically impaired – if subjects were not trained with the DOP. When subjects were trained with the DOP, and relied on reward expectancies to solve the delayed-matching-to-position task the cholinergic lesion had little effect. These findings demonstrate that cholinergic immunolesions by 192IgG-saporin induce specific cognitive impairments—dependent on task demand characteristics.

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Hamaue N, Yamazaki Y, Ohmori H, Sumikawa K (2001) Nicotine enhances N-methyl-D-aspartate receptor responses and facilitates long-term potentiation in the hippocampus from rats with cholinergic lesions. Neuroscience 2001 Abstracts 376.5. Society for Neuroscience, San Diego, CA.

Summary: Nicotine reverses cognitive impairments caused by lesion of the cholinergic system and improves performance of Alzheimer’s patients. The mechanisms underlying these effects of nicotine, however, are unknown. Because nicotine facilitates the induction of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) in the hippocampal CA1 region, we examined whether nicotine enhances NMDAR responses and facilitates LTP induction in the hippocampus from rats with cholinergic lesions. Selective cholinergic denervation of rat hippocampus was performed by the immunotoxin 192 IgG-saporin. We then recorded burst NMDAR responses in hippocampal slices prepared from 192-IgG-saporin-treated rats and found that nicotine (1 μM) enhanced burst NMDAR responses. When GABAergic transmission was completely blocked by picrotoxin, nicotine had no effect on burst NMDAR responses. We also monitored the induction of LTP in 192-IgG-saporin-treated hippocampi and found that a weak tetanus (20 pulses at 100 Hz), which induced LTP in PBS-treated hippocampi, failed to induced LTP. However, in the presence of nicotine (1 μM), a same weak tetanus induced LTP in 192-IgG-saporin-treated hippocampi. Our results suggest that nicotine potentiates NMDAR responses by disinhibition of pyramidal cells and facilitates LTP induction in the hippocampus from animals with cholinergic lesions. The observed nicotine effects may represent the cellular mechanism underlying the compensatory action of nicotine in the presence of cholinergic deficits.

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Yoder RM, Reuss SA, Pang KC (2001) Maze strategy in rats with GABAergic or cholinergic lesions of medial septum. Neuroscience 2001 Abstracts 418.7. Society for Neuroscience, San Diego, CA.

Summary: Cholinergic and GABAergic neurons are the two major cell types that project from medial septum to hippocampus. Although complete lesions of hippocampus or medial septum impair spatial memory, selective lesions of cholinergic or GABAergic neurons do not impair spatial abilities on an 8-arm radial or Morris water maze. Control and lesion rats possibly use different strategies to solve these tasks. Previous studies show that normal rats initially use a place strategy, then switch to a response strategy. In contrast, rats with hippocampus inactivated rely on a response strategy. Our preliminary results suggest that rats with GABAergic lesions of medial septum preferentially use a response strategy. The present study assessed whether rats with cholinergic (192-IgG saporin) or GABAergic (kainic acid) lesions of the medial septum preferentially use a place, response, or cue strategy to solve a plus maze task. During training, one arm contained food (goal) and an adjacent arm served as the starting location. The room contained distal cues and a proximal cue near the food. Probe trials were used every 4th day to assess the maze strategy used by the rat. During probe trials, the start location was located on the arm opposite the original start arm, and the proximal cue was located in the original start location. This study determines whether rats with loss of cholinergic or GABAergic medial septal neurons preferentially use different strategies to solve maze tasks.

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de Butte M, Fortin T, Sherren N, Pappas BA (2001) Selective neonatal neurochemical lesions persist into old age and cause Alzheimer-like pathology. Neuroscience 2001 Abstracts 426.8. Society for Neuroscience, San Diego, CA.

Summary: There is a strong negative correlation between forebrain acetylcholine (ACH) function and the depth of Alzheimer’s dementia (AD). Forebrain norepinephrine (NE) is also frequently reduced in AD. However, it is not clear when these neurochemical abnormalities begin. Since there is some evidence to suggest that the AD begins early in life but fulminates with aging, it may also be the case that ACH and/or NE dysfunction occurs early and participates in the slide towards dementia in old age. To shed light on this possibility, we created lesions of forebrain ACH and NE in the neonatal rat by intracranial injection of 192 IgG saporin and systemic injection of 6-OHDA respectively, allowing the animals to reach old age. Massive ACH and NE lesions were evident at 22 months of age as reflected by immunohistochemical probes for p75 low affinity nerve growth factor and dopamine beta hydroxylase immunoreactive axons respectively. Morris water maze testing showed that surprisingly, the NE but not the ACH lesioned rats were impaired on this reference memory task. Typically, young NE lesioned rats are not impaired on it. The ACH lesion did not exacerbate the consequences of the NE lesion. On the other hand, unbiased stereological counts of hippocampal CA1 pyramidal cells indicated that the ACH lesion caused a significant loss of cells whereas the NE lesion had no effect by itself nor did it exacerbate the effects of the ACH lesion. These results indicate that selective NE and ACH lesions inflicted at birth, persist into old age. Furthermore, the NE lesion seemingly impairs memory in old age while the ACH lesion causes a loss of CA1 cells reminiscent of that which is a hallmark of AD.

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