Amelioration of spatial navigation and short‐term memory deficits by grafts of foetal basal forebrain tissue placed into the hippocampus and cortex of rats with selective cholinergic lesions

Impairments in learning and memory, induced by surgical or excitotoxic lesions of the septo-hippocampal or basalo-cortical pathways, can be ameliorated by grafts of cholinergic-rich foetal basal forebrain tissue into the hippocampus and/or neocortex. However, the effects of such grafts have been only partial, which may be due to the non-specific nature of the lesioning procedures used in these studies, known to destroy both cholinergic and non-cholinergic neuronal projections. In the present study, we have explored the effects of cholinergic-rich grafts in rats subjected to selective cholinergic lesions, induced by intraventricular injections of the immunotoxin 192 IgG-saporin. This lesion, which selectively destroyed 85–95% of the cholinergic neurons in both the septal-diagonal band and nucleus basalis, produced a long-lasting, substantial impairment in both the acquisition of spatial reference memory in the Morris water maze task and delay-dependent short-term memory performance, as seen in a delayed matching-to-position test. Foetal cholinergic grafts (but not control grafts of cerebellar tissue) implanted at multiple sites into both the hippocampus and fronto-parietal neocortex, bilaterally, completely reversed the acquisition deficit in place navigation in the water maze, to an extent that greatly exceeded that previously seen in animals with non-selective lesions. Most notably, however, the impairment in short-term memory was only partially and inconsistently affected, and only at the longest delay times. The morphological analysis, performed at about 7 months after transplantation, showed that the grafts had re-established a close to normal cholinergic innervation in the initially denervated cortical and hippocampal territories. It is proposed that the differential effects of cholinergic-rich transplants on different aspects of cognitive performance may define intrinsic limitations to the functional capacity of the ectopically placed grafts, which may be due to incomplete integration of the grafted cholinergic neurons into functional regulatory circuitries normally available to the basal forebrain cholinergic system.     

Effects of septal and/or raphe cell suspension grafts on hippocampal choline acetyltransferase activity, high affinity synaptosomal uptake of choline and serotonin, and behavior in rats with extensive septohippocampal lesions.

At 31 days of age, Long-Evans female rats sustained aspirative lesions of the septohippocampal pathways and, 14 days later, received intrahippocampal suspension grafts prepared from the region including the medial septum and the diagonal band of Broca (Group S, n = 11), from the region including the mesencephalic raphe (Group R, n = 11) or from both regions together (Group S+R, n = 11). Sham-operated (Group Sham, n = 9) and lesion-only (Group Les, n = 11) rats served as non-grafted controls. Seven Sham, 7 Les and 8 rats from each transplant group were tested for home cage activity (6 months after grafting) and radial maze performance (between 7.5 and 8.5 months post-grafting). One month after completion of behavioral testing, the dorsal hippocampi of these rats were prepared for measuring choline acetyltransferase (ChAT) activity and high affinity synaptosomal uptake of both [3H]choline and [3H]serotonin. The remaining rats were used for histological verifications on brain sections stained for acetylcholinesterase (AChE). The lesions increased locomotor activity, impaired radial maze learning and, in the dorsal hippocampus, reduced AChE positive staining, decreased ChAT activity (-73%) as well as high affinity uptake of both choline (-81%) and serotonin (-82%). Neither type of transplant produced any significant behavioral recovery. However, septal transplants increased hippocampal AChE positivity, restored ChAT activity and enhanced choline uptake to 116% and 70% of the values found in sham-operated rats, respectively; they had no significant effect on uptake of serotonin. Transplants from the raphe region had weak effects on hippocampal AChE positivity, increased both the ChAT activity and the choline uptake to 70% ad 38% of the sham-operated rats, respectively, and produced an (over)compensation of the serotonin uptake which reached 324% of the values found in sham-operated rats. The co-transplantation of both regions resulted in restoration of ChAT activity (113% of sham-operated rats values), choline uptake (83% of sham-operated rats) and serotonin uptake (129% of sham-operated rats). Our neurochemical data show that after extensive denervation of the hippocampus, intrahippocampal grafts of fetal neurons may foster a neurotransmitter-specific recovery which depends upon the anatomical origin of the grafted cells: a graft rich in serotonergic neurons overcompensates the serotonergic deficit, a graft rich in cholinergic neurons attenuates the cholinergic deficit, whereas a mixture of both types of grafts produces recovery from both types of deficits. Thereby, both the feasibility and the interest of the co-grafting technique are confirmed.(ABSTRACT TRUNCATED AT 400 WORDS)     

Physiological and behavioral consequences of delayed septal grafts in the subcortically denervated hippocampus

The present experiments examined whether cholinergic grafts reverse the physiological and behavioral deficits of the damaged hippocampus. Fimbria-fornix lesions were performed in young rats and 3 months later half of the lesioned rats received cholinergic-rich basal forebrain transplants. Eight months after grafting we tested the animals behaviorally in the water maze. Following the behavioral experiments, the animals were implanted with chronic recording and stimulating electrodes and the electrical properties of the hippocampus, including spontaneous EEG, interictal spikes, evoked responses, long-term potentiation, and sensitivity to induced seizures were examined. Grafted rats did not show statistically reliable behavioral recovery (swim latencies, swim path lengths) and their performance was identical to the lesion-only group. Acetylcholinesterase reinnervation of the host hippocampus in grafted animals was similar to intact rats; the grafts also contained numerous parvalbumin-immunoreactive neurons. The most striking physiological change was the significant elevation of seizure threshold in the grafted group, but other physiological parameters did not improve consistently. The findings suggest that the presence of septal tissue grafts and restoration of cholinergic reinnervation in animals with previous subcortical denervation of the hippocampus are not sufficient to restore normal hippocampal electrical patterns or to improve behavioral performance.     

Habenula and thalamus cell transplants mediate different specific patterns of innervation in the interpeduncular nucleus.

Innervation of specific peptidergic and cholinergic compartments of the interpeduncular nucleus (IPN) was investigated using embryonic cell suspension transplants immunoreactive for substance P (SP) and ChAT. In both neonatal and adult host rats, the IPN was first denervated of its normal SP and cholinergic input from the medial habenula by bilateral lesions of the fasciculi retroflexi (FR). In adult hosts, transplants of embryonic habenular cells placed near the denervated IPN mediated a return of the normal pattern of SP staining restricted to habenula-target subnuclei, plus an increase in staining intensity of SP cells intrinsic to the IPN. There was no recovery of ChAT staining. A similar pattern of SP staining resulted following habenular transplants into neonatal hosts, but in addition there was a partial recovery of normal ChAT staining in cholinergic subnuclei and anomalous ChAT staining in normally peptidergic subnuclei. Control transplants of embryonic thalamus cells placed into adult hosts produced a surprising pattern of ChAT staining in the IPN identical to that seen with habenula transplants placed into neonatal hosts; the adult IPN was thus able to support reinnervation mediated by an aberrant cholinergic source while being refractory to its normal habenular cholinergic afferents. This pattern of results implies regulation by the IPN of habenular SP and cholinergic innervation, and some interaction between the maturing normal cholinergic afferents and their targets that is missing when these afferent sources are abnormal.     

The effects of ibotenic acid lesions of the nucleus basalis and cholinergic-rich neural transplants on win-stay/lose-shift and win-shift/lose-stay performance in the rat

Rats were trained to criterion performance in 2-lever operant conditional memory tasks that required them to follow either a Win-stay/Lose-shift, or else a Win-shift/Lose-stay response rule. Substantial impairments in performance of both pretrained conditional tasks were seen following ibotenic acid lesions of the nucleus basalis, but not of the globus pallidus. The deficit in both tasks was apparent at all inter-response retention intervals, indicating that nucleus basalis lesions produced a general impairment in the performance of the complex conditional operant tasks, and not a specific deficit in short-term memory. The nucleus basalis lesion rats were then divided into groups matched for equivalent performance. One group was given cell suspension grafts into neocortex of E15 cholinergic-rich forebrain tissue; a second group was given similar grafts of E17 hippocampal tissue; and a third group was given sham transplants. Testing beginning 3 months post-transplant showed that there was no evidence of recovery of performance on these tasks in the cholinergic-rich transplanted groups compared to the controls. However, the rats with cholinergic-rich transplants subsequently showed a significant improvement in retention of a step-through passive avoidance task. The results indicate that either cholinergic deafferentation of the neocortex is not critical for the observed deficits in the operant conditional tasks, or recovery of function following cholinergic-rich transplants is task-specific, in that more complex cognitive tasks may require different levels of graft-host neural integration.     

Intrahippocampal grafts of cholinergic-rich striatal tissue ameliorate spatial memory deficits in rats with fornix lesions.

Previous studies have shown that cholinergic grafts derived from the medial septal nucleus are capable of restoring behavioral function in rats with lesions that sever the cholinergic inputs to the hippocampal formation. In this study, we demonstrate that intrahippocampal grafts of cholinergic-rich striatal tissue also ameliorate spatial memory deficits of rats with fornix lesions. We also found that atropine administration dramatically disrupted spatial navigation performance of rats with striatal grafts and control rats, thus suggesting that the striatal graft effects are mediated by cholinergic mechanisms of action. Measurements of high affinity choline uptake (HACU) and muscarinic receptor binding revealed that intrahippocampal striatal grafts increased HACU and normalized muscarinic receptor binding in animals with fornix lesions. Regression analyses demonstrated significant correlations between the amelioration of spatial memory deficits and hippocampal HACU and receptor binding. We conclude that intrahippocampal grafts of cholinergic-rich striatal tissue can ameliorate spatial memory deficits and that this amelioration is associated with the reinstatement of functional cholinergic terminations.     

Spatial memory deficits in aged rats: contributions of the cholinergic system assessed by ChAT

Activity of choline acetylase (ChAT) was measured in basal forebrain cholinergic nuclei and in projection sites of these cells in the hippocampus and cortex of young rats and of aged rats who showed impaired performance on the radial arm maze. Decreased ChAT activity was found in the vertical diagonal band nucleus, the dentate gyrus and striatum of aged rats.     

碱性成纤维细胞生长因子对血管性痴呆大鼠海马胆碱能神经元的影响

目的皮下注射碱性成纤维细胞生长因子(bFGF)于血管性痴呆大鼠,研究用药前后大鼠海马胆碱能神经元的变化。方法制作血管性痴呆(VD)大鼠模型,随机取用VD大鼠模型12只,分治疗组6只,痴呆组6只。另外,取假手术组6只。皮下注射bFGF于治疗组中血管性痴呆大鼠。治疗5周后,以Morris水迷宫定位航行试验和空间探索试验来检测大鼠的学习记忆能力,乙酰胆碱转移酶(ChAT)免疫组织化学染色观察海马CA1区胆碱能神经元数目的变化。结果治疗组大鼠海马CA1区胆碱能神经元数目较痴呆组明显增多。结论皮下注射bFGF后能迁移至海马,诱导海马产生具有ChAT活性神经元,所产生的ChAT活性神经元可能就是胆碱能神经元。     

Task-dependent memory loss and recovery following unilateral nucleus basalis lesion: behavioral and neurochemical correlation

We found that rats with unilateral AF64A lesions of the nucleus basalis of Meynert (nbM) showed significant impairment of active avoidance and Morris water maze learning. Impairment of active avoidance learning almost subsided within one month but impairment of Morris water maze learning persisted 5 months later. Two weeks after production of the lesion, choline acetyltransferase (ChAT) activity was reduced by 45% in the frontal cortex (FC), but not in the hippocampus or corpus striatum. The decreased ChAT activity in the FC gradually recovered, but it was still reduced by 20% even after 20 weeks. In contrast, ChAT activity on the contralateral side of the FC began to increase from 5 weeks onwards. Histological examination also indicated that loss of cholinergic fibers in the FC gradually recovered with time after induction of the lesion. The results from the present study suggest that specific learning (Morris water maze) tasks involve the cholinergic system and that recovery of cholinergic function (ChAT) may be related to plasticity of the contralateral FC.     

Choline acetyltransferase expressed by radial neuroglia cells in the development of telencephalon： A validated study

BACKGROUND： Cholinergic neuron directly participants in human motion, learning and memory and is a target cell for multiple degenerative diseases of central nervous system. OBJECTIVE： To investigate whether the mitotic cell is the radial glial cell expressing choline acetyltransferase （CHAT） in ventricle zone （VZ） of telencephalon and whether cholinergic neuron is derived from radial glial cell in ventricle zone of telencephalon. DESIGN： Observational study. SETTING： Department of Histology and Embryology, Basic Medical College of Jilin University. MATERIALS： Nine healthy Wistar rats included 6 females and 3 male. Male and female rats were mated routinely, and the day when spermatozoa or vaginal plug were found was regarded as embryonic 0 （E0）. Primary monoclonal antibodies ChAT and vimentin were provided respectively by Wuhan Boster Company, and Biogenex Company, USA. METHODS： The experiment was carried out in the Laboratory of Cell Culture and Immunohistochemistry, Department of Histology and Embryology from march 2002 to January 2003. Firstly, fluorescence-activated cell sorting （FACS） was used to confirm the time of generation of cholinergic neuron; secondly, telencephalons of rats at embryonic 14 days （E14） were performed coronary sections, then immunohistochemistry double staining for vimentin （a protein marker of radial neuroglia cell） and ChAT （a protein marker of cholinergic neuron） were used to test whether ChAT was expressed in the radial neuroglia cells. MAIN OUTCOME MEASURES： （1） Fluorescence-activated cell numbers of ChAT in telencephalon; （2） results of immunohistochemistry double staining. RESULTS： It is confirmed using by flow cytometer that embryogenesis time of cholinergic neuron was at E12, and shown the population of cells in VZ of dorsal telencephalon of E14 rat co-expressed vimentin and ChAT through immunohistochemistry double staining. A lot of vimentin-positive cells and ChAT-positive cells respectively were observed in VZ of lateral ganglionic eminence. CONCLUSION： Cholinergic neuron in cerebral cortex is derived from radial glial cells in VZ of dorsal telencephalon; meanwhile, cholinergic neuron of striatum is derived from radial glial cells in VZ of lateral ganglionic eminence.     

Intrahippocampal grafts containing cholinergic and serotonergic fetal neurons ameliorate spatial reference but not working memory in rats with fimbria-fornix/cingular bundle lesions

Three-month-old Long-Evans female rats sustained aspirative lesions of the dorsal septohippocampal pathways and, 2 weeks later, received intrahippocampal suspension grafts containing cells from the mesencephalic raphe, cells from the medial septum and the diagonal band of Broca, or a mixture of both. Lesion-only and sham-operated rats were used as controls. All rats were tested for locomotor activity 1 week, 3 and 5 months after lesion surgery, for spatial working memory in a radial maze from 5 to 9 months, and for reference and working memory in a water tank during the 9th month after lesioning. Determination of hippocampal concentration of acetylcholine, noradrenaline, and serotonin was made after completion of behavioral testing. Compared to sham-operated rats, all rats with lesions, whether grafted or not, exhibited increased levels of locomotor activity and made more errors in the radial maze. The lesioned rats were also impaired in the probe trial (30 first seconds) of the water-tank test made according to a protocol requiring intact reference memory capabilities. While rats with septal or raphe grafts were also impaired, the rats with co-grafts showed performances not significantly different from those of sham-operated rats. With a protocol requiring intact working memory capabilities, all lesioned rats, whether grafted or not, were impaired in the water-tank test. In the dorsal hippocampus of lesion-only rats, the concentration of acetylcholine and serotonin was significantly reduced. In rats with septal grafts or co-grafts, the concentration of acetylcholine was close to normal, as was that of serotonin in rats with raphe grafts or co-grafts. These results confirm previous findings showing that co-grafts enabled the neurochemical properties of single grafts to be combined. Data from the water-tank test suggest that cholinergic and serotonergic hippocampal reinnervations by fetal cell grafts may induce partial recovery of spatial reference, but not working memory capabilities in rats.     

Improvement of passive avoidance task after grafting of fetal striatal cell suspensions in ischemic striatum in the rat

Behavioral recovery and cell survival/growth after grafting of fetal striatal cell suspensions in the ischemic striatum of rats were investigated. Ischemia was induced by one hour intraluminal occlusion of the right middle cerebral artery under halothane anesthesia. During the ischemia rats usually manifested signs of hemiparesis and sometimes rotations. Behavioral function was measured by a passive avoidance task and radial arm maze test at 1-2 weeks and 6-7 weeks after ischemia. The size of the ischemic lesions depended on each animal, but the ischemic animals showed deficits in both passive avoidance task and radial maze test. Two weeks after ischemia, fetal striatal cells, marked with DiI, were transplanted into the ischemic striatum. The transplantation improved the ischemia-induced deficit in the passive avoidance task but not in radial maze test. Although there were variations in the size of the grafts, many DiI-positive cells with dendritic outgrowth were detected under fluorescent microscopy. Immunohistochemical study revealed that many choline acetyltransferase (ChAT) positive cells and GABA-positive cells survived in the grafts. However, striosome-matrix compartments were not evident inside the grafts. Thus, partial recoveries in both cytoarchitectural and behavioral aspects were obtained by striatal cell grafts, suggesting that neural transplantation could be a useful approach in reconstructing ischemic brain function.     

Development of plasticity of brain function with repeated trainings and passage of time after basal forebrain lesions in rats

Summary Basal forebrain (BF) lesion-induced amnesia in rats is widely used as an animal model of Alzheimer's disease (AD). To study the plasticity of brain function in BF-lesioned rats, we examined the effects of repeated trainings and the passage of time after the lesion on learning ability 3 weeks and 3 months after BF-lesions with ibotenic acid, using an eight-arm radial maze and passive avoidance tasks, and measured choline acetyltransferase (ChAT) activity. Both time and re-training played important roles in the recovery of the ability to learn, as measured with the eight-arm radial maze task, but not the passive avoidance task. In contrast, ChAT activity in the frontal cortex, which was low 3 weeks after the lesion, still low 3 months after lesion, even though the ability to learn had recovered. Recovery of the ability to learn can be attributed to undamaged cholinergic neurons, or to other neuronal systems, or to both. This animal model can be used to demonstrate the plasticity of brain function.     

Neurochemical and behavioral recovery after colchicine lesions of the nucleus basalis magnocellularis in rats

Experimentally-induced lesions of the basal forebrain have been used to test the hypothesis that the cholinergic system plays a critical role in learning and memory. In the present study, a basal forebrain infusion of colchicine, a microtubule assembly inhibitor, was used to characterize the relationship between a cholinergic marker and behavioral function. Bilateral infusions were made in the nucleus basalis magnocellularis (NBM) of male Long-Evans rats. At 4 weeks post-lesion, behavioral assessments were made on half of the rats in each group. These rats were sacrificed 1 week later and regional choline acetyltransferase (ChAT) activity was measured. The remaining rats were behaviorally tested 11 weeks post-lesion and sacrificed 12 weeks post-lesion. The brains of additional rats were studied for Nissl-staining, ChAT-, GAD- and metEnk immunoreactivity (IR) and AChE histochemistry. At 5 weeks after colchicine infusion, there was a significant decrease in parietal and frontal cortical ChAT activity, impaired acquisition of a water maze spatial navigation task and decreased passive avoidance cross-over latency. At 12 weeks after colchicine infusion, ChAT activity was decreased in frontal but not parietal cortex; acquisition of the water maze task was not significantly different from vehicle-infused rats, and a significant deficit was observed in passive avoidance latency. ChAT-IR in the NBM showed a significant decrease at both time points, while changes in AChE-stained cortical fibers paralleled the ChAT activity. GAD- and metEnk-IR were decreased but were not different between the two time points. These data show task-specific behavioral recovery associated in time with recovery of regional cholinergic markers.     

Differential effects of physostigmine and pilocarpine on the spatial memory deficits produced by two septo-hippocampal deafferentations in rats

Rats that had received two kinds of septo-hippocampal deafferentations, medial septum (MS) lesion and fimbria-fornix (FF) transection, were assayed for brain cholineacetyltransferase (ChAT) activity and spatial memory in an 8-arm radial maze task. Both lesions produced profound and long-lasting spatial memory impairments, which were characterized by a reduction in the numbers of correct arm choices and first correct choices, a reduction in the percent of correct choices and an increase in the number of errors. The degree of memory impairment was severer in FF- than in MS-lesioned rats, and paralleled that of decreases in ChAT activity in the hippocampus. MS lesion reduced ChAT activity in the hippocampus by approximately 45%, while FF lesion almost completely depleted the activity. An intraperitoneal injection of physostigmine (0.0032-0.32 mg/kg), an acetylcholinesterase (AChE) inhibitor, significantly ameliorated the spatial memory deficit induced by MS lesion, but hardly affected that by FF lesion. In contrast, intraperitoneal doses (0.032-3.2 mg/kg) of pilocarpine, a muscarinic agonist, showed a significant improvement of both types of memory deficit with bell shaped dose-response curves. The drug was more potent in the FF- than in the MS-lesioned rats. These results suggest that the septo-hippocampal cholinergic system plays a crucial role in the maintenance of spatial memory, and that the degree of septo-hippocampal deafferentation affects the efficacy of cholinergic drugs.     

Graft-induced learning impairment despite graft-enhanced cholinergic functions in the hippocampus of rats with septohippocampal lesions

Effects of aspirative fimbria-fornix lesions and intrahippocampal grafts of fetal septal-diagonal band or hippocampal tissue were examined, in Long Evans female rats, on spontaneous alternation, radial maze learning, hippocampal acetylcholine concentrations and [3H]choline accumulation by hippocampal slices. Septohippocampal damage decreased all of these variables. Septal-diagonal band grafts increased hippocampal acetylcholine levels as well as [3H]choline accumulation of tissue (when incubated for 45 min), but they had no effect on alternation rates and further impaired radial maze performances. No such behavioral and neurochemical effects were observed in rats with hippocampal grafts. Our data suggest that factors other than graft-induced improvement of cholinergic functions in the denervated hippocampus may be involved in the expression of behavioral effects by intrahippocampal acetylcholine-rich grafts.     

No nerve growth factor response to treatment with memantine in adult rats

Summary. Nerve growth factor (NGF) is the most widely examined neurotrophin in the experimental models of Alzheimers disease (AD) and has been shown to prevent the retrograde degeneration of cholinergic neurons. In this study we examined NGF and cholineacetyltransferase (ChAT) changes in several rat brain regions after excitotoxic lesion of the entorhinal cortex with quinolinic acid and tested the effect of memantine on spatial learning in the radial maze after lesion. We observed a significant increase (+26%, p=0.02) of NGF concentrations in the hippocampus of the lesioned rats when compared to sham-lesioned rats. Chronic treatment with memantine showed no significant effect on the NGF increase in the hippocampus (p=0.72). The ChAT activity was significantly increased in the lesioned rats when compared to controls (+16%, p<0.05) and did not depend on treatment with memantine. In spite of this, memantine improved performance of the radial maze. This indicates that memory improving effects of memantine observed in experimental animals and in clinical studies are probably not related to changes in brain NGF content, whereas the observed NGF increase in the denervated hippocampus is probably trauma-related reflecting impaired retrograde transport of hippocampal NGF.Present address: Solvay Pharmaceuticals BV, Weesp, NiederlandePresent address: Institute of Pharmacology PAN, Cracow, Poland     

Differential effects of short- and long-term hyperhomocysteinaemia on cholinergic neurons, spatial memory and microbleedings in vivo in rats

Hyperhomocysteinaemia (HHcy) has been identified as a cardiovascular risk factor for neurodegenerative brain diseases. The aim of the present study was to investigate the effects of short (5 months) or long (15 months) HHcy in Sprague–Dawley rats in vivo. Short- and long-term HHcy differentially affected spatial memory as tested in a partially baited eight-arm radial maze. HHcy significantly reduced the number of choline acetyltransferase (ChAT)-positive neurons in the basal nucleus of Meynert and ChAT-positive axons in the cortex only after short-term but not long-term treatment, while acetylcholine levels in the cortex were decreased at both time points. Nerve growth factor (NGF) was significantly enhanced in the cortex only after 15 months of HHcy. HHcy did not affect cortical levels of amyloid precursor protein, beta-amyloid(1-42), tau and phospho-tau181 and several inflammatory markers, as well as vascular RECA-1 and laminin density. However, HHcy induced cortical microbleedings, as illustrated by intensive anti-rat IgG-positive spots in the cortex. In order to study the regulation of the key enzyme ChAT, organotypic rat brain slices were incubated with homocysteine, which induced a decline of ChAT that was counteracted by NGF treatment. In conclusion, our data demonstrate that chronic short- and long-term HHcy differentially caused memory impairment, cholinergic dysfunction, NGF expression and vascular microbleedings.     

Transplantation of septal cholinergic neurons to the hippocampus improves memory impairments of spatial learning in rats treated with AF64A

Embryonic septal neurons were transplanted into damaged hippocampus in adult rats which had received lateral ventricular administration of AF64A, a cholinergic neurotoxin. About 3 months after transplantation, the rats with bilateral septal grafts showed significant improvement in the radial maze and T-maze tasks. Many ingrowths of acetylcholinesterase (AChE)-positive fibers originating from the grafts were observed in the hippocampus of the rats which showed good performance in these learning tasks. These results indicate that transplantation of septal cholinergic neurons into the AF64A-treated hippocampus may induce at least partial recovery in learning tasks believed to involve the hippocampus.     

Neurochemical, histopathological and mnemonic effects of combined lesions of the medial septal and serotonin afferents to the hippocampus

Male Long-Evans rats received micro-injections of either (NMDA) in the medial septum/vertical diagonal band (MS/DB), 5,7-dihydroxytryptamine (5,7-DHT) in the fimbria/fornix and cingulate bundle or combined NMDA/5,7-DHT micro-injections. NMDA administration caused considerable damage to the MS and enlarged the lateral ventricles. It reduced the activity of choline acetyltransferase as well as the intensity of acetylcholinesterase staining in the hippocampus. 5,7-DHT selectively reduced the concentration of hippocampal serotonin. The rats were assessed for spatial memory in the Morris water maze and the radial arm maze (reference and working memory version). The 5,7-DHT-induced lesion of hippocampal serotonin had no effect by itself on either task. However, it augmented the reference memory impairment caused by the NMDA-induced lesion and delayed the recovery from NMDA-induced impairment of working memory on the radial maze. Combined damage of hippocampal cholinergic and serotonergic afferents did not severely affect spatial memory.