Intraseptal tacrine-induced disruptions of spatial memory performance

Behavioural Brain Research 158 (2005) 1–7

Research report

Intraseptal tacrine-induced disruptions of spatial memory performance Helen R. Sabolek, Jamie G. Bunce, James J. Chrobak∗ Department of Psychology, University of Connecticut, Storrs, CT 06269, USA Received 19 January 2004; received in revised form 18 July 2004; accepted 19 July 2004 Available online 8 January 2005

Abstract The medial septal nucleus regulates the physiology and emergent functions (e.g., memory formation) of the hippocampal formation. This nucleus is particularly rich in cholinergic receptors and is a putative target for the development of cholinomimetic cognitive enhancing drugs. Several studies have examined the direct effects of intraseptal cholinomimetic treatments and the results have been somewhat conflicting with both promnestic and amnestic effects. Several variables (e.g., age, task difficulty, timing of drug administration) may influence treatment outcome. The present study examined the effects of intraseptal infusion of the acetylcholinesterase inhibitor tacrine (0–25 ␮g/0.5 ␮l) on spatial memory performance. Tacrine was infused into the medial septum just prior to testing. Tacrine infusions did not significantly affect the number of correct choices in the first eight entries, or the number of correct choices until an error. This treatment did not alter the angle of arm entries, or impair the animals’ ability to complete the task (enter all baited arms). However, tacrine produced a linear dosedependent increase in errors, doubling (12.5 ␮g) and tripling (25.0 ␮g) the number of errors made before rats completed the task. The deficit demonstrates that activation of intraseptal cholinergic receptors can disrupt spatial memory performance. These findings are discussed with regards to septohippocampal-dependent memory processes and the development of therapeutic strategies in the treatment of age-related memory disorders. © 2004 Published by Elsevier B.V. Keywords: Medial septum; Cholinomimetic; Cholinesterase inhibitor; Hippocampus; Radial maze; Alzheimer’s dementia

1. Introduction Central cholinergic neurons are an important component of the neural circuits that support learning and memory. Cholinergic antagonists (e.g., the muscarinic drugs scopolamine or atropine) typically disrupt the acquisition of information and the performance of learned tasks, while cholinergic agonists including acetylcholinesterase inhibitors (e.g., physostigmine, tacrine) can enhance acquisition and performance of learned tasks (see for reviews [4,15,21,35]). Attempts to relate central cholinergic function to specific cognitive processes are complicated by the fact that cholinergic neurons innervate, and cholinergic receptors can be found, throughout most of the entire nervous system. ∗

Corresponding author. Tel.: +1 860 4864243; fax: +1 860 4862760. E-mail address: [email protected] (J.J. Chrobak).

0166-4328/$ – see front matter © 2004 Published by Elsevier B.V. doi:10.1016/j.bbr.2004.07.010

One area rich in cholinergic receptors is the medial septal nucleus/vertical limb of the diagonal band (MS) (e.g., [3,31,33,39,40]). MS neurons (GABAergic, cholinergic, glutamatergic, and peptidergic) project to all hippocampal formation subfields [2,26] and serve as a nodal point for subcortical regulation of hippocampal physiology and function [41]. Studies examining the effect of intraseptal infusion of cholinergic agonists (e.g., oxotremorine, carbachol, and tacrine) have produced somewhat inconsistent results with reports of either promnestic or amnestic effects [8–10,18–20,23,27,32,34]. Several variables (e.g., dose, age of animal, integrity of septohippocampal circuits, task difficulty) may influence treatment outcome. Our laboratory has been interested in defining the conditions under which intraseptal cholinergic treatments enhance [34] and/or disrupt [8–10] performance in hippocampal-dependent memory tasks. Typically young rats are either unaffected or impaired

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by intraseptal cholinomimetic treatment on spatial (e.g., water maze, T-maze, radial maze) memory tasks, while aged (>17 months) rats exhibit enhanced spatial memory (e.g., water maze) [18–20,27,32]. These studies suggested that age-related changes in septohippocampal neurons could account for the differential sensitivity of young versus aged rats [18,27]. Recently, we have reported that intraseptal tacrine can enhance spatial memory performance in a group of young, cognitively impaired rats [34]. These rats were culled from a delayed-non-match-to-sample (DNMTS) task because they were unable to achieve criterion performance. Given their inability to perform accurately on the DNMTS task, we examined the effects of intraseptal tacrine on their performance of a standard (12) arm maze task. Tacrine was administered just prior to testing, and doses of 2.5 and 12.5 ␮g substantially enhanced performance. This was our first demonstration that any cholinomimetic could enhance performance in a spatial memory task. In contrast to the effects of tacrine on cognitively impaired rats, pilot data indicated that intraseptal tacrine impaired the performance of a “normal” group of young rats. In the present study, we followed up on these results and examined the effect of this treatment in a group of “normal” young rats. 2. Materials and methods 2.1. Subjects Fourteen male Long Evans rats (Charles Rivers, MA) were housed individually in Plexiglas pens in a temperature controlled (22 ◦ C) vivarium on a 12:12 h light–dark cycle (lights on at 7 a.m.). Rats were approximately 2.5 months old at the start of training. Water was available ad lib. Rats were fooddeprived to 85% of their free-feeding weight, after which time, they were weighed daily and allowed to gain 5 g per week until reaching 425 g. During the 1-week pre- and postsurgical periods rats were fed ad lib. 2.2. Apparatus The radial maze consisted of a central base measuring 38 cm in diameter that was elevated 53.3 cm above the floor. Twelve Plexiglas arms measuring 50.8 cm long × 10 cm wide extended from the central platform in a radial, sunburst pattern. A small metal food cup (2 cm in diameter) was located 3 cm from the end of each arm. The maze was located in a small (2.4 m × 1.95 m × 2.6 m), dimly lit room that had high contrast geometric shapes painted on the walls and floor to serve as visual cues. 2.3. Pre-operative standard and modified 12-arm radial maze task Training and testing of animals involved daily trials over the course of several months. Rats were initially habituated

to the maze for 5 min each day for 9 days. During this time, chocolate sprinkles were scattered down each arm to encourage exploration, and each food cup contained sprinkles. Following habituation rats were trained on a standard radial maze task, one session per day, 5 days a week, for 6 weeks. Rats were placed in the center of the maze and removed once one of the following occurred: all 12 arms were entered, 20 total choices were made, or 5 min elapsed. The task required animals to visit each arm once in each daily session. A visit was defined as having all four paws across a line 17.5 cm from the arm entrance. Re-entry into an arm previously visited was considered an error. Following 6 weeks of training the task was modified such that three (non-adjacent) arms were blocked each day with transparent Plexiglas barriers (21 cm × 10 cm × 30.5 cm) in a pseudo-random order. Animals were started from the end of a fourth arm, making this task in effect a difficult eight-arm task. This modified procedure discourages rats from developing an adjacent-arm strategy, in which rats simply select adjacent arms in a clockwise or counter clock-wise manner (see [29]). Animals were placed in a randomly chosen start arm facing the food cup (away from the center of the maze) and then allowed to choose all remaining eight arms to retrieve food rewards. The following parameters were assessed: number of correct choices in the first eight entries, total number of re-entries (errors), number consecutive correct choices until the first error was made, and latency per choice (time to complete the task divided by the number of entries made). Additionally, the pattern of arm entries (percent of 30–180◦ turns) were analyzed to determine if treatment altered the frequency of turning angle. Animals ran on the modified 12-arm task for 10 weeks, and were then surgically implanted with a single guide cannula aimed at the MS. 2.4. Surgery A survival surgery was performed in a conventional laboratory setting using aseptic techniques. Rats were anesthetized with a ketamine cocktail (12.5 mg/ml ketamine, 0.25 mg/ml acepromazine, and 1.25 mg/ml xylazine) at a surgical dose of 4 ml/kg (intramuscular; calf muscle). Supplemental doses of the cocktail were administered at half doses to maintain the total absence of leg withdrawal reflex. The scalp was shaved and a betadine solution was applied. The animal was mounted in a stereotaxic apparatus. Ophthalmic ointment was applied to the eyes, which were occluded with a gauze pad. An incision was made along the midline of the scalp and a small burr hole (1 mm2 ) was drilled in the skull above the septal nucleus (coordinates from Bregma: AP = +0.5 mm, ML = 0.0 mm, DV = −4.0 from dura). A stainless steel guide cannula (26 gauge; PlasticsOne Inc.; Roanoke, VA) was implanted above the septal nucleus and was anchored to the skull using three stainless steel screws and secured with dental acrylic. A 33-gauge stylet (Plastics One Inc.) was inserted into the guide cannula to maintain patency. Silk sutures were applied when necessary. Following surgery

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animals were returned to a clean home cage with a heating pad and acetaminophen (73 mg/kg) was administered orally. Food and water were freely available 1-week pre- and postsurgery. Rats were handled daily and the stylets were periodically replaced during the course of the experiment to ensure patency as well as to habituate the animals to the restraint necessary for removing and inserting the injector. All procedures strictly adhered to the guidelines set forth by the University of Connecticut’s Institutional Animal Care and Use Committee (IACUC).

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Series 1500, The Vibratome Co., St. Louis, MO), mounted and Nissl stained using thionin. Photomicrographs of relevant injection sites were captured using a Nikon microscope connected to a Spot RT camera system, digitized, and prepared for presentation using Adobe Photoshop 7.0.

3. Results 3.1. Effects of intraseptal tacrine on spatial memory performance

2.5. Infusion procedures Following cannula implantation rats were allowed 4 weeks to attain pre-surgical levels of performance. Animals received a total of three “sham” infusions in which no fluid was infused to habituate them with the procedure. In the weeks following these sham infusions, each animal received four doses of tacrine (Sigma, St. Louis, MO, USA) (0, 2.5, 12.5, and 25 ␮g in 0.5 ␮l saline). Infusions occurred weekly, on the third day of a 5-day testing week. Seven animals received the doses in an ascending order (0, 2.5, 12.5, and 25 ␮g) and seven received the doses in a descending order (25, 12.5, 2.5, and 0 ␮g) to examine possible order effects. For each infusion, a 33-gauge injector (PlasticsOne Inc., Roanoke, VA) was inserted into the guide cannula. This injector extended 2.5 mm past the end of the guide cannula. The injector was connected by polyethylene tubing (PE 20) to a 10 ␮l Hamilton syringe mounted on a syringe pump (Harvard Apparatus, Holliston, MA). After insertion of the injector into the guide cannula, the rat was placed into its home cage and was free to wander during the infusion. Fluid (drug or vehicle) was infused at a rate of 0.125 ␮l/min for 4 min (total volume = 0.5 ␮l). Following 4 min of infusion, one additional minute was allowed for diffusion of the perfusate away from the injection site. The rat was then briefly held to remove the injector, the stylet was replaced and the rat was returned to its home cage. Five minutes after the end of the infusion the animal was run on the maze. 2.6. Statistical analysis Repeated-measures analyses of variance (RMANOVA) and orthogonal trend analyses were used with order of infusion as a between subjects variable on all dependent measures: correct choices in the first eight entries, number correct until first error, total errors, and latency per choice. Dunnett’s post-hoc t-tests were used to further analyze significant results with saline infusion used as the comparison mean. 2.7. Histology Following the completion of testing, rats were anesthetized and transcardially perfused with ice-cold saline followed by 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.2). Brains were sliced using a vibratome (Vibratome

Tacrine treatment disrupted rats’ performance specifically by increasing the number of errors (Fig. 1; Table 1) on the day of treatment (Wednesday). A repeated-measures ANOVA revealed a significant dose-dependent increase in the number of errors (F3,36 = 7.41, P < 0.001), and a significant linear trend (F1,12 = 31.57, P < 0.001; Fig. 1). Dunnett’s t-tests showed that both 12.5 ␮g (dT3,36 = 3.38, P < 0.05) and 25 ␮g (dT3,36 = 4.59, P < 0.01), significantly increased the number of errors. In fact, 12.5 ␮g doubled, and 25 ␮g tripled, the amount of errors committed when compared to saline. There was no main effect of drug order (ascending versus descending drug series) on errors, and no dose by order interaction (F’s < 2.0, P’s > 0.25). The majority of rats completed the task with only three rats at 12.5 ␮g and four at 25.0 ␮g failing to complete the task (see Table 1). Under these higher doses of tacrine, the

Fig. 1. Intraseptal tacrine dose-dependently increased the number of errors at 12.5 and 25 ␮g (* P < 0.05, ** P < 0.01; Dunnett’s t-test vs. saline). There was no significant effect of treatment on the number of correct choices in the first eight arm selections.

Table 1 Effect of intraseptal tacrine on performance of radial maze task 0.0 ␮g Correct in first eight choices Correct until first error Entries between first and repeat entry Total errors Latency per choice a b

2.5 ␮g

12.5 ␮g

25 ␮g

6.8 ± 0.3 6.6 ± 0.2 6.6 ± 0.3

6.1 ± 0.3

5.6 ± 0.6 5.3 ± 0.5 5.3 ± 0.3 5.3 ± 0.4 4.6 ± 0.4 5.0 ± 0.3

4.5 ± 0.4 4.4 ± 0.4

2.1 ± 0.7 3.0 ± 0.6 5.6 ± 1.3a 6.9 ± 1.3b 6.1 ± 0.4 5.5 ± 0.3 5.5 ± 0.3 7.0 ± 0.5

P < 0.05. P < 0.01 (Dunnett’s t-tests).

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rats had difficulty finding the last one or two remaining baited arms. Importantly, even at 12.5 and 25 ␮g, most rats navigated to seven correct arms and there were no significant effects on either the number of correct choices in the first eight entries (F3,36 = 2.165, P = 0.11), or the number correct entries until an error (F3,36 = 1.09, P = 0.37). The pattern of errors made by rats following the higher doses of tacrine (12.5 and 25 ␮g) was not perseverative (repetitively chosing one or two arms over and over) rather rats navigated around the maze choosing sequences of previously chosen arms. In order to examine whether the pattern of errors was different following tacrine treatment, we examined the number of arms chosen between the first entry into any arm and each repeat entry into that arm for all errors. For example, one rat receiving 12.5 ␮g of tacrine chose in the sequence 7, 11, 8, 5, 3, 1, 11, 9, 7, 5, 12, 7, 3, 1, 9, and 6. The repeat occurrence of 11, 7, 5, 7 again, 3, 1, and 9 constitute errors with the number of arm entries between the initial entry and each repeat being 4, 7, 5, 2, 7, 7, and 6 for each error, respectively. The mean number of choices between the initial choice and all repeats were 5.3 ± 0.4 following saline and 4.6 ± 0.4, 5.0 ± 0.3, 4.4 ± 0.4 for 2.5, 12.5, and 25 ␮g. Note that only 9 of 14 rats made any errors following saline, while 13 of 14 made errors following 2.5 and 12.5 ␮g and all made errors following 25 ␮g of tacrine. A RMANOVA on tacrine treatment trials (excluding saline trials because of too few rats making any errors) this measure was not significant [F2,26 = 0.9]. One might suspect that rats might make more perseverative errors near the end of a trial, but this was not the case with the mean number of arm entries between the initial choice and the last error was 4.7 ± 0.4, 4.9 ± 0.5, and 5.0 ± 0.4 for 2.5, 12.5 and 25 ␮g tacrine, respectively. Examining this index for all days just prior and just after the treatment day yielded a range of daily averages from 4.2 to 5.9 for all days when minimally half the rats made an error. As a tentative indices of memory span, both this index as well as the number correct until the first error (see Table 1) indicate that tacrine treatment did not significantly affect memory span. RMANOVA on total errors for the day prior to treatment (Tuesday) and 2 days after treatment (Thursday and Friday) indicated no significant differences in any indices [F’s2,26 < 1.0]. RMANOVA on all other performance indices (e.g., correct until first error) were also not significant. Previously, we have observed that intraseptal treatment with oxotremorine can produced semi-chronic performance disruptions for days following treatment. These day after effects have not been observed following either tacrine or the direct acting agonist carbachol [8]. There was a significant effect of tacrine on latency per choice (F3,36 = 5.42, P < 0.01) and a significant quadratic trend was present (F1,12 = 18.24, P < 0.01). However, Dunnett’s ttests revealed no difference in latencies between saline and any dose of tacrine (dTs3.36 < .99, P > 0.05). The lack of significance is due to the quadratic nature of the response. Mean latencies decreased at lower doses and increased at 25 ␮g by

Fig. 2. The pattern of arm entries did not change as a function of dose of tacrine. Pseudo-randomly blocking three arms each day prevented the animals from using a response strategy to solve the task.

less than 1 s per choice. We have repeatedly observed that intraseptal treatments modestly alter response latencies in a variety of spatial memory tasks that do not vary with accuracy measures. 3.2. Effects of intraseptal tacrine on turn angle We also examined the turning pattern as rats navigated the maze. Rats may make more errors simply because a treatment alters their sensorimotor abilities in such a way as to preclude 30, 60 or 90◦ turns with respect to the arm they are exiting. McCann et al. [28], for example, demonstrated that peripheral scopolamine (cholinergic antagonist) as well as several serotonergic drugs increase errors in an eightarm maze and shift turn angles progressively toward turns greater than 90◦ . Fig. 2 illustrates that intraseptal tacrine had no effect on the frequency of 30–180◦ turns across all arm choices. Given that three arms of the maze were blocked on any trial, for some arm selections the next adjacent arm was not 30◦ but 60◦ left or right (the pattern of blocked arms never included two adjacent arms). The percentage of adjacent arm selections was also not affected by any treatment [33% (saline), 35% (2.5 ␮g), 29% (12.5 ␮g), and 30% (25 ␮g)]. This turning data indicates that the majority of arm selections were not to adjacent arms and that neither control, nor tacrine treated rats predominantly chose adjacent arms. 3.3. Histology Examination under a light microscope revealed that the guide cannula placements for all 14 rats were located within the dorsal aspect of the septum approximately 3–4 mm deep and injector sites within the MS/VLDB complex approximated 5.5–6.5 mm deep (see Fig. 3). Most of the placements straddled the midline, with the most variability being in the anterior to posterior position.

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Fig. 3. Histology. All 14 rats were found to have guide cannula placements within the dorsal aspect of the septum and injector sites within the MS/VLDB complex (A). A representative example of a placement is shown in (B). Arrow denotes the injector tip.

4. Discussion Medial septal infusions of the cholinesterase inhibitor tacrine disrupted spatial memory performance. Following tacrine treatment, the number of errors increased linearly with increasing dose, with 12.5 ␮g of tacrine doubling and 25 ␮g tripling the number of errors made when compared to saline. Despite the increase in errors, no change was observed in the number of correct choices in the first eight entries, or the number of correct choices until an error was made. Thus, rats performed reasonably well, even at the highest dose (25 ␮g) until they had to navigate to the last one or two arms containing food reward. It is unlikely that the disruption in performance was due to a change in motor function or motivation, even at the highest dose. The majority of rats completed the task at the 25 ␮g dose, and only four did not enter all eight arms within 20 entries. However, these four rats did navigate to seven of the eight baited arms and all rats vigorously navigated the maze and ate the sprinkles located at the end of the arms. Analyses of the error patterns following intraseptal tacrine revealed no decrease in “memory span”. There was no change in the number of correct choices until the first error or in the number of arm entries between the initial and any subsequent repeat entry into any arm (e.g., rat chooses 1, 5, 9, 7, 6, 3, 8, 5, 1, . . ., the second choice of 5 and 1 are errors with 5 and 7 arm entries between the initial and subsequent re-entry).

Thus, the observed deficit was not perseverative nor reflecting any obvious decrease in memory span. The deficit could relate to an increase in proactive interference and/or a spatial discrimination deficit. The multiple choices the rat makes each day, and the progressive decrease in the probability of a correct choice as a function of choice number, make it difficult to distinquish the specific cognitive process(es) disrupted by intraseptal treatments. Currently, we are examining these alternatives in a delayed-match-to-sample, eight-arm, radial water maze task where the rat navigates to a single, new, platform location each day to escape from the water. This task offers the advantage of having a unique location (yesterday’s platform location) as a source of proactive interference for remembering today’s platform location. The spatial relationship between today’s location and yesterday’s location can be systematically manipulated so as to examine how treatments affect proactive interference and spatial discrimination. The present study is the first to demonstrate a disruptive effect of intraseptal tacrine on memory performance. Notably only a few studies have examined the memory effects of intracranial tacrine [34,36]. We have recently shown that intraseptal tacrine can enhance spatial memory performance in cognitively impaired young rats [34]. The rats in that study were culled from a delayed-non-match-to-sample radial maze task because they could not reach criterion performance. Impaired rats also performed very poorly on the standard (nondelay) 12-arm maze (making roughly six errors before com-

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pleting the standard 12-arm task). The results of our present study are consistent with pilot data from our lab showing that doses of tacrine higher than 12.5 ␮g disrupt performance on a standard 12-arm maze task in normal young rats. Previous studies have shown that young rats are either unaffected or impaired by intraseptal cholinomimetic treatment on spatial (e.g., water maze, T-maze, radial maze) memory tasks while aged (>17 months) rats exhibit enhanced spatial memory (e.g., water maze) [18–20,27,32]. These findings suggested that age-related changes in the activity of septohippocampal, and particularly septohippocampal cholinergic neurons, could account for the differential sensitivity of young versus aged rats [18,27]. The rats in the present study, and those in our initial report of tacrine-induced enhancement, were less than 1-year-old at the time of infusions. While age may be an intervening variable that affects septohippocampal circuits, individual differences in the functional integrity of hippocampal and/or septohippocampal circuits, as expressed in spatial memory performance, may exist within young rats (see e.g., [37]). Importantly, such differences may render rats differentially sensitive to the effects of intraseptal cholinomimetic drug treatments. The nature of these differences is an open question. Focus on the role of septohippocampal cholinergic neurons in hippocampal-dependent memory function has not yielded obvious answers (e.g., [5,6,14]). Levels of cholinergic neurochemical indices do correlate with cognitive performance in aged rats (>20–22 months, e.g., [6]). However, no clear relationship exists between regional age-related changes in hippocampal cholinergic markers and memory performance at earlier ages (e.g., [7,18]). Thus extremely low levels of septohippocampal cholinergic activity likely relate to dysfunctional hippocampal circuits. What is optimal above those low levels likely depends upon a more complex set of factors. Attempts have also been made to demonstrate that increased hippocampal acetylcholine indices (e.g., acetylcholine release using microdialysis) are related to enhanced learning and memory performance [11,22]. While this may be true under certain conditions, it is not likely the case under all or most conditions (see [1,13,15,16] for extended discussions). A variety of evidence suggests that there exists a limited range of acetylcholine release that optimizes the cognitive functions subserved by hippocampal circuits [16,38]. Focus, on the septohippocampal cholinergic neurons and their regulation by cholinergic receptors may obscure the greater complexity of intrinsic septal and septohippocampal circuits. MS neurons (including cholinergic, GABAergic, and glutamatergic afferents) participate in the generation of the well-described theta (6–12 Hz) rhythm and theta-associated gamma (40–100 Hz) patterns among hippocampal neurons (e.g., [7,12,20,27]). Intraseptal cholinomimetic treatments, as a consequence of altering the pattern of activity among septohippocampal cholinergic, GABAergic, and glutamatergic neurons, can produce an increase in the amplitude of hippocampal theta [19,24,27,30]. Theta is a rhythmic pattern

among hippocampal neurons that while dependent upon MS input more directly reflects their periodic excitation by entorhinal cortical inputs. This pattern appears anytime a rat moves, whisks, attends to their sensory environ and during REM sleep [7,12]. We suggest that the effect of intraseptal cholinomimetic treatment may depend upon their ability to optimize or enhance theta as suggested by Givens and colleagues [19,20,27]. Intraseptal cholinomimetic treatments have only been successful in enhancing memory performance in either aged and cognitively impaired rats [18,27,34]. These rats may have sub-optimal septohippocampal circuits and the intraseptal cholinomimetic treatment may boost the signaling capability of these circuits. In normal young rats, it may be very difficult to increase the signaling capacity of the septohippocampal input and increasing doses of intraseptal cholinomimetics may transform the synchronizing theta rhythmicity of hippocampal networks into epileptiform behavior [38]. It is important to recognize that hippocampal theta reflects a state of controlled hyperexcitability within hippocampal circuits. In normal young rats, treatments that increase theta (e.g., intraseptal carbachol) may yield epileptiform activity in HF circuits and lead to seizures (see [17,25]). Clearly many more studies need to be done to (1) determine under what conditions intraseptal cholinomimetics actually either enhance/impair memory and (2) to assess the electrophysiological and other neurobiological correlates of promnestic and amnestic treatments. While the present findings are limited, they point to the fact that activation of septal cholinergic receptors in young rats can produce memory impairments when administered just prior to task performance. The need for cognitive enhancers in the treatment of age-related cognitive decline and Alzheimer’s dementia necessitates basic information about the systems level effects of acute/chronic cholinomimetic treatment. To date animal findings have not thoroughly documented the consequences of short-/long-term cholinomimetic therapy. Our recent findings indicate that activation of septal cholinergic receptors can impair (present findings) or enhance performance [34] on a spatial memory task. Understanding more clearly how and when modulation of septohippocampal circuits alters the information processing capability of hippocampal formation is critical to the development of treatments for cognitive dysfunction associated with septohippocampal insult.

Acknowledgments This work is supported by NSF #0090451.

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