Selective Immunolesions of Hippocampal Cholinergic Input Fail to Impair Spatial Working Memory

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1 Selective Immunolesions of Hippocampal Cholinergic Input Fail to Impair Spatial Working Memory Robert W. McMahan, 1 Thomas J. Sobel, 1 and Mark G. Baxter 2 * 1 Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 2 Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina HIPPOCAMPUS 7: (1997) ABSTRACT: The septo-hippocampal cholinergic pathway has traditionally been thought of as essential for spatial memory. Recent studies have demonstrated intact spatial learning following removal of this pathway with an immunotoxin selective for cholinergic neurons. In the present experiment, rats with selective removal of hippocampal cholinergic input were tested in a delayed nonmatching-to-position task in a water version of the radial arm maze. This allowed us to increase and parametrically vary the memory load compared with the standard Morris water maze (by varying the delay between the initial four choices and the final four choices) to determine if this would reveal a deficit in rats with lesions of septo-hippocampal cholinergic projections. Male Long-Evans rats were given injections of 192 IgG-saporin, a selective immunotoxin for cholinergic neurons, into the medial septum/vertical limb of the diagonal band (MS/VDB) to remove cholinergic projections to the hippocampus, or a control surgery. The rats were trained on the radial maze task following surgery. An escape platform was located at the end of each arm of the maze and was removed after an arm was utilized for escape. After initial training, a delay was interposed between the first four trials and the second four trials. Errors during the second four-trial component were scored in two categories: retroactive (reentering an arm chosen before the delay) and proactive (reentering an arm chosen after the delay). Retroactive errors increased as delay increased (from 60 s to 6 h) but were equivalent in control and MS/VDB-lesion groups. Proactive errors did not vary with delay and were also unaffected by the lesion. Radioenzymatic assays for choline acetyltransferase activity in the hippocampus of lesioned rats confirmed a significant loss of cholinergic input from the MS/VDB. These results indicate that normal spatial working memory is possible after substantial loss of septo-hippocampal cholinergic projections. Hippocampus 7: , r 1997 Wiley-Liss, Inc. KEY WORDS: acetylcholine; 192 IgG-saporin; medial septum; hippocampus; spatial learning INTRODUCTION Interest in the mnemonic functions of the basal forebrain cholinergic system (BFCS) has been stimulated primarily by the suggestion that it is Contract Grant sponsor: NIA; Contract Grant number P01-AG *Correspondence to: Dr. Mark G. Baxter, Laboratory of Neuropsychology, National Institute of Mental Health, Building 49 Room 1B80, Bethesda, MD baxter@ln.nimh.nih.gov Accepted for publication 3 December 1996 dysfunction of this system that is responsible (wholly or partially) for cognitive deficits observed in normal aging and pathological conditions such as Alzheimer s disease (Bartus et al., 1982; Coyle et al., 1983). Experimental studies of the types of cognitive function subserved by the BFCS have suggested that BFCS damage results in deficits in learning, memory, and attention (Hepler et al., 1985; Whishaw et al., 1985; Dunnett et al., 1987; Muir et al., 1994). In particular, the suggestion has been made that cholinergic projections to the hippocampus originating in the medial septum/vertical limb of the diagonal band (MS/VDB) are important in regulating aspects of hippocampal physiology that are central to its normal function in learning and memory (Stewart and Fox, 1990; Givens and Olton, 1995; Markowska et al., 1995). However, the interpretation of experimental studies seeking to relate BFCS damage to cognitive dysfunction has been uncertain, because damage to cholinergic basal forebrain neurons occurs in conjunction with damage to noncholinergic basal forebrain neurons with similar projection patterns, following injections of neurotoxins into the basal forebrain. Thus, it has not been possible to determine whether BFCS damage or damage to noncholinergic basal forebrain neurons (or a combination) is responsible for behavioral deficits observed following basal forebrain lesions. The recently developed immunotoxin 192 IgGsaporin selectively destroys cholinergic neurons in the basal forebrain (Wiley et al., 1991; Heckers et al., 1994), permitting a direct test of the hypothesis that loss of cholinergic projections to the hippocampus produces deficits in learning and memory. Surprisingly, spatial learning, which is disrupted following lesions of the hippocampus or less selective neurotoxic lesions of the MS/VDB (Morris et al., 1982; Hagan et al., 1988; Marston et al., 1993), is largely or completely unimpaired following 192 IgG-saporin lesions of the MS/ VDB (Berger-Sweeney et al., 1994; Torres et al., 1994; Baxter et al., 1995a). However, working memory for multiple spatial locations may rely more critically on cholinergic input to the hippocampus than memory for r 1997 WILEY-LISS, INC.

2 CHOLINERGIC MS/VDB LESIONS AND WORKING MEMORY 131 a single spatial location. We noted a very mild (but reliable) delay-independent impairment on a spatial match-to-position task in the water maze following 192 IgG-saporin lesions of the MS/VDB (Baxter et al., 1995a). Another investigation found a very mild delay-dependent deficit in an operant two-choice delayed non-matching to position task following 192 IgG-saporin lesions of the MS (Torres et al., 1994). The present study was designed to characterize further spatial memory deficits following immunotoxic lesions of the cholinergic input from the MS/VDB to the hippocampus. We trained rats with immunolesions of the MS/VDB in a radial maze task set in the water maze, using escape from water as the motivating factor (Buresova et al., 1985). The basic principle of the task was the same as the standard win-shift spatial radial maze task: a visit to an arm of the maze resulted in escape from the water but repeated visits within a session did not provide escape. The rats were trained on the task postoperatively, and data were collected from a final test phase in which a delay was interposed between the first and second sets of four choices. By varying the delay between sets of choices, we were able to increase the number of spatial locations and parametrically vary the duration of time that information had to be retained, to determine if this would reveal a deficit in MS/VDB-lesioned rats that was not apparent in simpler place learning tasks in the water maze. MATERIALS AND METHODS Subjects Twenty male Long-Evans rats (Charles River, Raleigh, NC), 3 months old, were housed singly in the vivarium beginning 1 week prior to surgery and throughout testing. Food and water were available ad libitum during this experiment, and the colony was maintained on a 12-h light-dark cycle. Surgery and behavioral testing occurred during the light cycle. The initial number of subjects in each group were: control, n 5 8; MS/VDB-lesion, n Surgery Surgical procedures, as described in Baxter et al. (1995a), were identical for each group, except that sterile phosphate-buffered saline was microinjected into control rats, whereas 192 IgGsaporin was microinjected into lesion rats. All surgeries were performed under pentobarbital (Nembutal, 55 mg/kg i.p.) anesthesia, supplemented with additional injections of pentobarbital as needed. The anesthetized rat was placed in a stereotaxic apparatus (Kopf Instruments, Tujunga, CA). The skin over the rat s skull was shaved and cleansed with Betadine, an incision was made through the skin and muscle to expose the skull, and the skin was retracted. Two holes were drilled at stereotaxic coordinates AP mm and ML mm referenced to Bregma, based on the Paxinos and Watson (1986) brain atlas. Injections were made at two depths for each site: one at DV mm and one at DV mm from the surface of the skull referenced to Bregma. A 28-gauge Hamilton syringe filled with either phosphate-buffered saline or 192 IgG-saporin (0.506 mg/ml, Chemicon, Temecula, CA) was lowered to the specific coordinates and left in place for 30 s before beginning the infusion. A total volume of 0.3 ml was infused into the sites at DV mm, and a total volume of 0.2 ml was infused into the sites at DV mm, at a rate of 0.05 ml/min. The syringe was left in place for 9 min following the 0.3 ml injections and 6 min following the 0.2 ml injections to limit diffusion up the needle track. After surgery, the wound was cleaned, closed with sterile wound clips, and treated with a topical antibiotic (Neosporin). The rats were allowed to recover from anesthesia before being placed back in the vivarium. Apparatus Testing took place in a water version of an eight-arm radial maze. The maze was placed in a tank 181 cm in diameter and filled to a depth of 58 cm with tepid (277C) water made opaque by the addition of white tempera paint. The maze was surrounded by white curtains on which black cloth visual cues were placed. A camera connected to a videocassette recorder was located above the center of the tank. The radial maze was made of clear Plexiglas and had removable hidden platforms (12 cm 3 18 cm) at the end of each of the eight arms. The open center of the maze was 45 cm in diameter. Each of the eight arms radiating out from the center of the maze was 18 cm wide and 50 cm long. The walls of each arm extended 25 cm above and 10 cm below the surface of the water. The platforms at the end of each arm were located 1 cm below the surface of the opaque water. There were also clear Plexiglas barricades (blocks) that could be placed at the opening of an arm to occlude the opening and keep the rat from entering the arm (used only in later phases of testing). Behavioral Testing The behavioral experiment began approximately 2 months after surgery. (This group of rats was first tested in an appetitive conditioning procedure to assess attentional processing.) Rats were tested in a delayed nonmatching-to-place radial arm task. At the beginning of a test session, all eight arms of the maze contained hidden escape platforms. After an arm was chosen for escape, the platform was removed so subsequent visits to that arm would not provide escape from the water tank. Initial phases of training acclimated the rats to aspects of the task prior to testing of working memory. Working memory was tested by introducing a variable delay between the first four trials and the last four trials. During the first four trials, four of the arms were blocked (to prevent the rats from adopting a response strategy of making the same choices on the first four trials from day to day). All eight arms were available for escape on the remaining four trials, but only the four arms that had not yet been chosen (i.e., the previously blocked ones) contained escape platforms. Performance was based on the arm choices made during the last four trials. Rats entering arms that had been chosen before the delay demonstrated

3 132 MCMAHAN ET AL. poor memory, whereas those avoiding these arms and utilizing the previously blocked arms only for escape showed good memory. Each daily test session consisted of eight trials per rat. A trial began when the rat was placed in the center of the maze, at pseudorandomly assigned start positions (facing the junction of two arms). The rat was allowed to swim down the arms until he escaped on a platform; the rat was guided to a platform if one was not located within 120 s. The rat was allowed to remain on the platform for 15 s and then removed to a holding cage, where he remained for 30 s. The end of a session occurred when the rat had escaped from all eight arms. All trials were video recorded for subsequent scoring. The phases of testing were conducted as follows. Phases one and two were designed to acquaint the rat with the procedural aspects of the task (swim to the end of an arm to escape the water) and to teach the rat the win-shift principle: once a location is utilized for escape, a return visit within a session does not provide escape. In phase one (1 day), all the arms were baited with a platform, and none were blocked. The platform at the end of an arm was removed only if a rat chose that arm twice (to encourage the rat to learn to swim to the ends of the arms and escape onto the platforms, but to prevent the development of perservative strategies). Phase two (6 days) was identical to phase one except that each platform was removed once the rat had used it for escape. In all subsequent phases the platform was removed after the rat chose an arm for escape. In phase three (3 days) four of the arms were occluded with blocks during the first four trials. (These arms were never all adjacent or nonadjacent.) The arms that were blocked varied each day; at least two of the four blocked arms were different on successive days of testing. Once the rat had completed four trials, the blocks were removed. The rat remained in the holding cage in the testing room while the blocks were removed. Phase four (2 days) was identical to phase three except that the rat was taken outside the testing room and left for 60 s in a holding cage before beginning the last four trials. This was done to acclimate the rat to being removed from the testing room before formal working memory testing began. Phase five (11 days) was the testing phase. It was identical to phase four except, when the rat was removed from the room, the delay before beginning the remaining four trials was varied. The delay was either 60 s, 1 h, 3 h, or 6 h. The delay schedule was as follows: 60 s, 60 s, 3 h, 60 s, 6 h, 1 h, 3 h, 6 h, 1 h, 3 h, and 1 h. Each rat remained in a separate holding cage outside the test room during the delay period. Neurobiological Analysis At the completion of testing, rats were killed by decapitation, and the hippocampi were rapidly dissected from the brain and frozen on dry ice, before being transferred to microcentrifuge tubes for storage in a freezer at 2707C until neurobiological analysis. Both hippocampi were processed for determination of choline acetyltransferase (ChAT) activity, to verify the presence of a lesion. ChAT activity was measured by the formation of [ 3 H]acetylcholine formed from [ 3 H]acetylcoenzyme-A and choline (Fonnum, 1969). A 300 ml aliquot of tissue (homogenized in 0.32 M sucrose) was combined with 75 ml of a solution containing 2% Triton X-100 and 50 mm EDTA (ph 7.4). Three 40 ml aliquots of this homogenate were each combined with 40 ml of reaction substrate, and incubation was carried out for 15 min at 377C in a shaking water bath. The incubation mixture (final volume, 80 ml) contained: sodium chloride, 200 mm; sodium phosphate (ph 7.4), 50 mm; EDTA, 10 mm; eserine, mm; choline chloride, 6 mm; acetylcoenzyme-a, 0.09 mm; [ 3 H]acetylcoenzyme-A, 0.01 mm; and bovine serum albumin, 0.5 mg/ml. The newly formed [ 3 H]acetylcholine was extracted into a mixture of toluene and acetonitrile (85/15 v/v) containing sodium tetraphenylboron (5 mg/ml). Protein content of the homogenates was assayed by the method of Bradford (1976) with bovine serum albumin as a protein standard. Analysis of Behavioral Data Errors were scored whenever a rat reentered an arm that had already been entered during a session. In phase two, the total number of errors was scored. In phases three, four, and five, errors were scored separately for the four trials before the delay (pre-delay errors) and the four trials after the delay (post-delay errors). Pre-delay errors occurred during the first four trials when the rat searched an arm that had already been chosen for escape during the first four trials. Post-delay errors were divided into two classes: proactive and retroactive. Retroactive errors occurred when the rat searched an arm that had been chosen for escape before the delay. Proactive errors occurred when the rat searched an arm that had already been chosen for escape during the last four trials (including repeated visits to arms that were chosen for escape before the delay). A rat could make a maximum of four retroactive errors (one visit each to arms utilized for escape before the delay); return visits to arms already visited (unsuccessfully) after the delay were scored as proactive errors. Behavioral data were analyzed separately for phase two, phases three and four combined, and phase five. Nonparametric statistics were used because of the highly skewed distributions of error scores. Friedman nonparametric analysis of variance (two-tailed) was used to test differences in within-subjects factors (errors across sessions of testing); the Page test for ordered alternatives (onetailed) determined if these changes were due to linear trends (increases or decreases). Mann-Whitney U-tests (two-tailed) were used to determine effects of lesion on mean error scores across the days of testing within a phase (Siegel and Castellan, 1988). All analyses were performed with Systat 5.1 for Macintosh. RESULTS Neurobiological Analysis Four lesioned rats had hippocampal ChAT activity within the range of the control rats, and these rats were excluded from

4 CHOLINERGIC MS/VDB LESIONS AND WORKING MEMORY 133 subsequent analysis. Mean ChAT activity for the remaining rats (mean 6 standard error, averaged across left and right hippocampi) was nmol/h/mg protein for control rats, and nmol/h/mg protein for lesioned rats, a statistically significant difference (t(14) , P, ). Behavioral Performance Phase two Rats improved their performance across days of testing in this phase, learning to make fewer errors: within-subject analysis revealed that total errors changed across the 6 days of phase two training (F r , P ). The linear decreasing trend approached significance (Page test: L 5 1,234.5; z L ; P ). There was a significant effect of lesion on total errors (U , P ); however, the lesioned rats actually made fewer errors than the controls (mean total errors: control, 12.54; lesion, 9.69). Phases three and four In this phase, four of the arms were blocked during the first four trials and a delay was introduced after the first four trials, in preparation for working memory testing. Again, rats learned the procedural aspects of the tasks, indicated by decreased errors across days of training in phases three and four: pre-delay errors, F r , P ; proactive errors, F r , P ; retroactive errors, F r , P The linear decreasing trends for all three measures were significant (Page tests, Ls. 764, z L s. 2.2, Ps, 0.014). There were no effects of lesion on any of the three types of errors in phases three and four (33 # U # 33.5, Ps. 0.87). On the final day of phase four testing, all rats were making an average of 1.69 proactive errors and 2.19 retroactive errors in the last four trials. Phase five Working memory performance was tested in phase five by varying the delay between the first four trials and the second four trials. Data were collapsed for analysis across the sessions of testing at each delay. Retroactive errors increased with delay, but proactive and pre-delay errors did not vary with delay: an effect of delay was statistically significant for retroactive errors (F r , P ) but not for proactive errors (F r , P ) or pre-delay errors (F r , P ). A Page test on retroactive errors revealed that errors increased linearly with delay: L , z L , P, Pre-delay, proactive, and retroactive errors at each of the four delays are graphed in Figure 1. The increase in retroactive errors with increasing delay is indicative of the increased working memory load produced by longer delays. Pre-delay errors and proactive errors, which reflect mastery of task performance and on-line working memory for recent choices, are unaffected by delay, as would be expected. There is no effect of lesion on working memory performance, indicated by a lack of effect on retroactive errors: U 5 23, P Similarly, lesion did not affect pre-delay errors (U , P ) or proactive errors (U , P ). It is of note that, within the MS/VDB-lesion group, there was no statistically significant correlation between levels of hippocampal ChAT activity and errors of any type averaged across delay (Pearson product-moment correlation, Ps. 0.28) or retroactive errors at any of the four delays (Ps. 0.19). Chance performance on the four post-delay trials was determined by running 10,000 independent simulations of random sequences of arm choices on the post-delay trials and counting the number of retroactive and proactive errors made in each simulated run. The simulations were generated by a program written in Microsoft BASIC and run on a Gateway PC computer. This produced an expected value of 3.2 retroactive errors and 9.5 proactive errors during the four post-delay trials. Based on these values, the rats made fewer proactive errors than expected by chance at all four delays [ts(15), 211.7, Ps, ]. The rats made fewer retroactive errors than expected by chance at the 60 s [t(15) 526.2, P, ] and 1h[t(15) 522.4, P ] delays, but were not performing significantly better than chance at the 3 h [t(15) , P ] and 6 h [t(15) , P ] delays. This provides additional confirmation that the rats had acquired the basic nonmatching-to-position principle (as they made many fewer proactive errors than expected by chance), and that working memory for the pre-delay arms was present at short delays but decayed with longer delays separating the first and second sets of four trials. DISCUSSION The present experiment indicates, unexpectedly, that rats with substantial loss of cholinergic input to the hippocampus can nevertheless display normal spatial working memory, even across extensive delays that increase memory load, in a complex spatial delayed nonmatching-to-position task. These results are at variance with recent reports by Walsh et al. (1996) that found delay-dependent deficits in spatial working memory in a dry-land radial maze task following injections of 192 IgG-saporin into the MS/VDB, and by Shen et al. (1996) that found delayindependent spatial working memory deficits, but intact spatial reference memory, in a dry-land radial maze task, following similar lesions. One possible explanation for our negative finding is that the extent of ChAT depletion (average of 67%) in our study was not great enough to produce an impairment in spatial working memory. However, several lines of evidence suggest that our lack of effect is not simply due to a partial lesion. First, the two recent reports that find spatial working memory deficits in the radial maze following immunolesions of the MS/VDB report comparable depletion of cholinergic markers in the hippocampus [57 62% in the two groups with delay-dependent deficits in the study by Walsh et al. (1996) and 68% in the study by Shen et al (1996).] Also, in the group of MS/VDB-lesioned rats, there was no statistically significant correlation between any measure of spatial working memory performance in the final test phase with

5 134 MCMAHAN ET AL. FIGURE 1. Retroactive, proactive, and pre-delay errors in working memory testing in phase five, at each of the four delays. Retroactive errors (a return visit to an arm chosen before the delay) increase with delay, indicative of the increasing memory load imposed by longer delays. Proactive errors (a return visit to an arm chosen after the delay) and pre-delay errors do not vary with delay, as expected. None of the errors are affected by the MS/VDB immunolesion. levels of hippocampal ChAT activity, suggesting that even the rats with the most severe loss of hippocampal cholinergic innervation were not differentally impaired. Furthermore, lesions that produced levels of ChAT depletion identical to those in the present study produced a disruption in decremental attentional processing in an appetitive Pavlovian serial conditioning procedure, in which the rats in this study were tested before they began training in the radial water maze (M.G. Baxter, M. Gallagher, and P.C. Holland, unpublished observations). Assuming that cholinergic input to the hippocampus is involved in spatial working memory function, one would expect similar effects of these immunolesions on dry-land and waterbased radial maze tasks, because both tasks assess working memory for spatial locations. This may indicate that the specific function of hippocampal cholinergic input is not to modulate spatial working memory, but does not account for the difference in findings between the present study and the reports by Walsh et al. (1996) and Shen et al. (1996). We now discuss several methodological issues that might contribute to the difference in results. Damage to both cholinergic and noncholinergic components of the septohippocampal projection (e.g., by either electrolytic or neurotoxic lesions of the septum or transection of the fornix) is known to produce deficits in spatial working memory (Olton et al., 1978, 1982; Decker et al., 1992). Hence, confirmation that the lesions produced by 192 IgG-saporin are indeed selective for cholinergic neurons is critical, to attribute the results of these lesions to cholinergic loss independent of any effect on noncholinergic projections. We have previously shown that the lesion protocol used in the present study does not result in damage to a major population of septohippocampal projection neurons that are noncholinergic. These GABAergic neurons, which may compose as much as 50% of the septohippocampal projection (Köhler et al., 1984; Wainer et al., 1985), are localized along the midline and exhibit immunostaining for parvalbumin (Freund, 1989; see histological material presented in Baxter et al., 1995a). In the absence of immunohistochemical evidence that noncholinergic neurons are still present at the lesion site, the possibility remains that a less selective lesion, damaging both cholinergic and noncholinergic neurons, could account for any behavioral effects produced by intraseptal infusions of immunotoxin. A suppression of parvalbumin immunostaining was noted after a single large-volume injection of 192 IgG-saporin into the midline of the MS (Torres et al., 1994), raising the possibility that midline injections of 192 IgG-saporin in the MS/VDB could produce damage to both cholinergic and noncholinergic neurons. In this context, it is important to note that in the other two recent studies examining radial maze performance after 192 IgG-saporin lesions of the MS/VDB, a single injection of 192 IgG-saporin was placed directly on the midline. It is not known if this surgical protocol spared the noncholinergic neurons located on the midline, because no data demonstrating sparing of these neurons were presented in these studies. Other differences in protocols between studies should be considered. The radial maze task in the studies by Walsh et al. (1996) and Shen et al. (1996) used food as a motivating stimulus; in the present study, escape from water was the motivating stimulus. It is possible that submersion in water is more aversive to rats than food restriction, and that additional stress in the water maze task may recruit neuromodulatory systems that could compensate for a mild spatial working memory deficit. For example, stress is known to activate catecholaminergic systems

6 CHOLINERGIC MS/VDB LESIONS AND WORKING MEMORY 135 (e.g., Mabry et al., 1995). By this view, stress-induced activation of catecholamines might compensate for a cholinergic deficit. As reported elsewhere, the deleterious effects of muscarinic receptor blockade on spatial working memory are exacerbated by noradrenergic depletion (Decker and Gallagher, 1987) and adrenergic enhancement can reverse spatial working memory impairments induced by cholinergic blockade (Stone et al., 1991). Another procedural difference of potential importance is that the rats in the other two studies were trained before the lesions were made; ours were trained and tested postoperatively. Preoperative learning in the presence of an intact septohippocampal cholinergic projection may have interfered with postoperative performance; however, preoperative training might be expected to facilitate post-lesion performance rather than exacerbate a deficit. Finally, it is possible that the different surgery-testing intervals contributed to the difference in results. Postoperative testing began 10 or 14 days after surgery in the studies of Shen et al. (1996) and Walsh et al. (1996), respectively; training on the radial water maze in the present study did not begin until several months post surgery. It is possible that working memory ability recovered in the rats in our study during this extended surgery-test interval. However, this difference is unlikely to account fully for the difference in findings: we have shown elsewhere that 192 IgGsaporin lesions of the MS/VDB disrupt decremental attentional processing of conditioned stimuli in a latent inhibition (LI) paradigm. In the LI procedure, normal rats demonstrate a reduction in conditioning to a preexposed conditioned stimulus (CS) compared to a novel CS, an effect not seen after 192 IgG-saporin lesions of the MS/VDB (Baxter et al., 1995b). This lesion effect was observed after the completion of spatial learning and match-to-place memory testing (Baxter et al., 1995a), several months after surgery. Hence, a behavioral effect of these lesions can be observed even after an extended post-surgical interval. The possibility remains open that other differences between dry-land and water maze versions of the radial maze task may account for differences in findings between these two studies. A potential direction for future research is to determine if differences in the nature of environmental cues available for spatial navigation in the two different test settings is an important factor in whether or not deficits are observed following selective removal of hippocampal cholinergic input. Acknowledgments The authors gratefully acknowledge Michela Gallagher for supporting this project, as well as Michela Gallagher and Paul Colombo for their comments on an earlier version of this manuscript. 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