sfn2004

Conner JM, Chiba AA, Tuszynski MH (2004) The basal forebrain cholinergic system is essential for cortical plasticity and functional recovery following brain injury. Neuroscience 2004 Abstracts 685.12. Society for Neuroscience, San Diego, CA.

Summary: Localized damage to the motor cortex typically results in impaired motor function. Functional recovery following focal brain injury presumably requires the reorganization of cortical circuitry, enabling undamaged areas remote from the lesion site to take over function. Neuronal mechanisms mediating plasticity of cortical representations are not fully understood, but recent studies have indicated that the basal forebrain cholinergic system may play an essential role. In the present study, we investigated the hypothesis that the basal forebrain cholinergic system is essential for enabling cortical reorganization required for functional recovery following focal motor cortex lesions. Following focal cortical injury, performance in a previously learned skilled reaching task dropped by ~75%. After 5-weeks of rehabilitative training, normal (cholinergically-intact) rats recovered 55.2 ± 4.4% of their pre-lesion reaching performance. Rats with specific lesions of the cholinergic neurons projecting to the cortex showed only 18.1 ± 7.7% recovery (p<0.002). Intracortical mapping revealed that massive reorganization of motor representations had occurred in the cortex following focal cortical injury and rehabilitative training. A significant 48.6 ± 12.2% increase (p=0.001) in the size of the rostral forelimb area (RFA) was seen in cholinergically-intact, functionally recovered, rats. In contrast, the size of the RFA did not change in cholinergic-lesioned animals. Subsequent ablation of the RFA completely disrupted skilled reaching performance, suggesting the RFA was essential to the recovered function. These results demonstrate that functional recovery following discrete cortical injury requires basal forebrain cholinergic mechanisms and suggest that the basis for this recovery is the cholinergic-dependent reorganization of motor representations.

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Tait DS, Brown VJ (2004) Cell-body lesions of basal forebrain impair reversal learning but not attentional set-shifting in rats. Neuroscience 2004 Abstracts 779.12. Society for Neuroscience, San Diego, CA.

Summary: There is considerable evidence for a role of basal forebrain acetylcholine in a wide range of attentional tasks (see Sarter & Bruno, 2000, Neurosci, 95:933-952), but previous work from this laboratory found that basal forebrain cholinergic projections are not critical for the acquisition, maintenance and shifting of attentional set (Tait et al, 2002 SfN abstr 286.2). As GABAergic basal forebrain projections to cortex may be important for “cognitive flexibility” (Sarter & Bruno, 2002, Eur J Nsci, 15:1867-1873), the present study assessed the effects of non-specific basal forebrain lesions. Male Lister hooded rats received infusions of 200nl 0.06M ibotenic acid into basal forebrain, at coordinates: nosebar –3.3; AP –0.9; ML ±2.9; DV –6.9. We used the rat attentional-set shifting task (Birrell & Brown, 2000, JNsci, 20:4320-4324), in which rats forage in digging bowls for food rewards, to assess discrimination learning (based on the odor of the bowls or the medium in which the food was hidden), reversal learning and attentional-set shifting (when the relevant aspect of the stimulus is switched; for example, a rat previously attending to odor, now must attend to digging medium or vice versa). There was no impairment in discrimination acquisition or in shifting of attentional-set. Lesioned rats were impaired only on the first of three discrimination reversals, taking significantly longer to reach criterion than controls. Prior evidence indicating no effect of selective BF cholinergic depletion via 192-IgG-saporin administration on reversal performance (Tait et al, 2002) leads us to conclude that the non-cholinergic neurons – most likely the GABAergic projection to prefrontal cortex and thalamus – have an important role in reversal learning. These data are strikingly similar to the effects of excitotoxic basal forebrain lesions in monkeys (Roberts et al, 1992, NSci, 472:251-264).

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

Cordova CA, Yu AJ, Chiba AA (2004) Attention, uncertainty, and acetylcholine: Effects of nucleus basalis cholinergic lesions on probabilistic inference. Neuroscience 2004 Abstracts 779.13. Society for Neuroscience, San Diego, CA.

Summary: Animal investigations suggest that the basal forebrain corticopetal cholinergic system helps to regulate attention to unpredictable events. In light of these findings, computational theorists propose that cholinergic neurons precisely alter the way that sensory stimuli are processed in the cortex in light of how well predicted they are. In an initial test of this theory, two groups of rats were trained to respond to probabilistic stimuli presented serially in one of four spatial locations with varying degrees of predictive uncertainty (arising from a 2-layer Hidden Markov model). Following training, one group of rats was given a selective cholinergic lesion of the nucleus basalis/substantia innominata region of the basal forebrain using 192-IgG Saporin. The lesioned rats were unable to allocate attention appropriately, as evidenced by the decreased accuracy of responses to less probable stimuli. These findings provide support for the notion that the basal forebrain corticoptetal cholinergic system facilitates attention by regulating the balance of learned expectations and sensory processing during stimulus inference.

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Taylor CL, Rostron PR, Latimer MP, Winn P (2004) Behavioral characteristics of pedunculopontine tegmental nucleus lesioned and nucleus basalis magnocellularis lesioned rats in a test of vigilance. Neuroscience 2004 Abstracts 780.4. Society for Neuroscience, San Diego, CA.

Summary: Previous work has shown pedunculopontine tegmental nucleus (PPTg) lesioned rats make more omissions on a vigilance task but improve if the target is longer. We compared vigilance performance of PPTg rats with rats bearing 192 IgG Saporin lesions of the nucleus basalis magnocellularis (NbM). The task involved a period of darkness before a dim light of variable duration, followed by a bright light target. A lever press was required during the target to receive food reward, while failure to press during the target constituted an omission. Rats were pre-trained to a criterion of >70% correct and <20% omissions at 1500ms target duration. Post-lesion, rats were assessed for 10 days at 1500ms, 5 days at 4000ms, and 5 further days at 1500ms target durations. Results showed both groups increased omissions relative to controls but this effect was transient in NbM rats. The percentage of omissions in all groups was sensitive to manipulation of target duration. Because increasing target duration also increased the time allowed to make a correct response we re-coded omissions in the 1500ms task to include only those occurring a further 2500ms following target offset (making the response time frame comparable with the 4000ms task). Again, comparison with omissions from the 4000ms task continued to show target duration sensitivity. This finding lends support to PPTg as well as NbM involvement in attention. In order to address why lesioned rats made more omissions in the task we analyzed video data of behaviour at the time of the dim and bright light. Results suggest increased distraction in PPTg lesioned rats while NbM lesioned rats additionally showed failed attempts to lever press in response to the bright signal. This finding has implications for studies using short response time frames where NbM rats may not have time to recover from a failed lever press attempt.

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Truitt WA, Dietrich AD, Fitz SD, Minick PE, Shekhar A (2004) Neurokinin 1 receptor expressing interneurons of the BLA regulate anxiety-like responses in the rat. Neuroscience 2004 Abstracts 782.5. Society for Neuroscience, San Diego, CA.

Summary: The Basolateral Nucleus of the Amygdala (BLA) has been implicated in the regulation and development of anxiety. In general, regarding BLA projection neurons, excitation tends to increase, while inhibition tends to reduce anxiety-like responses. These projection neurons, which comprise approximately 85% of the BLA neurons, are tightly regulated by the activity of local circuit GABAergic interneurons. To date, at least four distinct interneuronal subpopulations have been identified in the BLA, with characteristic morphological and physiological properties suggestive of functional diversity. Yet the in vivo functional selectivity of these subpopulations has not been critically examined. Here we propose to examine the function of one specific interneuronal subpopulation within the BLA by making selective lesions and monitoring anxiety-like behavior. To accomplish this objective the subpopulation of BLA interneurons expressing NK-1r receptors were ablated with the targeted toxin SSP-saporin (SAP). Lesions were made by a series of 6 bilateral, 500nl injections spread throughout the anterior BLA. Control rats were injected with an equal volume of blank-SAP, which does not enter the cells. SSP-SAP injections significantly reduced the number of NK-1r expressing cells compared to blank-SAP treated rats, with little to no nonspecific damage. Lesioning NK-1r expressing cells resulted in increased anxiety-like responses in the social interaction (SI) and elevated plus maze (EPM) tests. Specifically, SI time compared to pre-surgery value was significantly reduced in lesion rats. Lesion rats also had fewer open arm entries in the EPM compared to control rats. Furthermore, lesioned rats failed to recover from this decrease in SI even after 4 weeks of testing. These results suggest that the subpopulation of interneurons within the BLA that express NK-1r is critical in regulating anxiety-like behavior.

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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.

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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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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.

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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.

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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.

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