In order to study the effects of differential housing conditions on recovery from damage to different components of the hippocampal formation, 85 rats received bilateral lesions of the hippocampus, entorhinal cortex, or subiculum or sham surgery and then were housed for 30 days in either an enriched environment or an impoverished environment. Rats were subsequently tested on a battery of tasks for assessing locomotor activity in their home cage, reactivity to novelty, spatial working and reference memory in the Morris water maze, and learning in the Hebb–Williams maze. Rats with the hippocampus removed showed impairments in most of the tasks we used (home-cage and novelty-induced locomotor activity, water maze, and Hebb–Williams maze). Most of the deficits induced by lesions to the entorhinal cortex were similar to those induced by the removal of the hippocampus. Some differences appear to be among the deficits induced by the lesions of these structures when assessing the home-cage locomotor activity, the reactions to novelty, and one aspect of the Hebb-Williams maze learning. Lesions to the subiculum induced only an impairment in the probe trial of the water-maze task. Confirming and extending previous findings in rats with various (but nonexcitotoxic) lesions of the hippocampus, an enriched environment had a beneficial effect on several of the deficits observed in the tasks we used. Further, only the rats with hippocampal lesions benefitted from having been housed in the enriched environment. However, their facilitated recovery was not observed in all tasks. After damage to different components of the hippocampal formation, the beneficial effects induced by the enriched housing conditions were shown to be both lesion-locus- and task-dependent.

This longitudinal study, extending over 12 months, assessed the behavioural and biochemical effects of hippocampal sympathetic ingrowth (HSI) into the partially denervated hippocampus. Male Long-Evans rats received fimbria-fornix lesions (FIFO) or sham operations at 90 days of age. At the same time half of the rats from each group sustained bilateral ablation of the superior cervical ganglia (SCGX). A battery of behavioural tests, measuring spontaneous alternation, activity in the open field and home cage, and radial-maze performance, were employed, starting after one very short (16 days) and one extended (216 days) post-operative delay. Neurochemical analyses measuring choline acetyltransferase (ChAT) activity, high-affinity choline (HACU) and noradrenaline uptake by hippocampal synaptosomes (HANU), hippocampal noradrenaline ([NA]), serotonin ([5-HT]) and 5-hydroxyindoleacetic acid ([5-HIAA]) concentrations were carried out in a dorsal, a "middle" and a ventral region of the hippocampus. Lesion of the FIFO induced a significant and enduring deficit in radial-maze performance, in addition to a persistent locomotor hyperactivity. ChAT and HACU were significantly depleted in all three regions of the hippocampus at 12 months, and these deficits were negatively correlated with maze performance. SCGX in the presence of the FIFO lesion significantly reduced [NA] in the middle region of the hippocampus, as compared to SCGX rats, and contributed to a restoration of lesion-induced depletions in [5-HT] and [5-HIAA] in the middle and ventral hippocampal regions, whilst failing to elicit any behavioural changes at either time point. It is concluded that if lesion-induced HSI indeed occurred, as is suggested by neurochemical evidence, it had no effect upon the observed behavioural deficits elicited by transection of the FIFO in the rat.

We examined the effects in young adult female Long-Evans rats of single or combined lesions of the infracallosal and supracallosal septohippocampal pathways on a battery of behavioral tasks over two postoperative periods (14-65 and 75-150 days, respectively). During the first period, rats with lesions of the infracallosal pathways, whether given alone or in combination with lesions of the supracallosal pathways, were more active in the open field and in their home cage, and showed increased reactivity to novel extracage stimuli. Behavioral results during the second postoperative period were similar to those of the first except that rats with lesions of the infracallosal pathways (either alone or in combination with lesions of the supracallosal pathways) were no longer hyperactive in their home cage and rats with the infracallosal lesion alone were no longer hyperactive in the open field. We also observed in rats with lesions of the infracallosal pathways impaired performance in the radial-arm maze task, whether conducted under an uninterrupted protocol (first and second postoperative periods) or with a 1-min intratrial interruption (second postoperative period). Thus, behavioral deficits were observed only in rats with a lesion to the infracallosal component of the septohippocampal pathways, the behavior of rats with the combined lesions being similar to that of rats with single lesions of the infracallosal pathways in most measures. The behavior of rats with lesions of the supracallosal pathways did not differ from that of sham-operated controls in any measure at either postoperative period. Acute, systemic injections of oxotremorine (0.03 or 0.1 mg/kg, ip) or pilocarpine (0.32 or 1.0 mg/kg, ip), two muscarinic agonists, did not affect radial-arm maze performance under either the uninterrupted or the interrupted protocol. The use of nonspecific muscarinic agonists does not appear to be sufficient to enhance radial-arm maze performance in rats with infracallosal septohippocampal lesions which, in contrast to supracallosal lesions, were shown to induce a deficit in this task. (C) 1994 Academic Press, Inc.

Long-Evans female rats sustained aspirative lesions of the septohippocampal pathways and, 2 weeks later, received intrahippocampal suspension grafts prepared from the regions including either the medial septum and the diagonal band of Broca (group S), or the mesencephalic raphe (group R), or from both these regions together (group S + R). Sham-operated (group SHAM) and lesion-only (group LES) rats were used as controls. Six months after grafting, high affinity synaptosomal uptake of choline (HACU) and serotonin (HASU), choline acetyltransferase (ChAT) activity and, using HPLC, the content of serotonin ([5-HT]), 5-hydroxyindolacetic acid ([5-HIAA]) and noradrenaline ([NA]) were determined in three rostro-caudal segments of the hippocampus (designated hereafter as the dorsal, the 'middle' and the ventral segments). In all three segments of the dorsal hippocampus, septohippocampal lesions decreased HACU, ChAT activity, HASU and [5-HT]; [5-HIAA] was decreased only in the middle and ventral hippocampal segments. The lesions also resulted in an above normal increase of [NA]. Septal grafts increased HACU and ChAT in the three hippocampal regions, had no effect on serotonergic markers and attenuated the lesion-induced increase of [NA] in only the dorsal and middle hippocampal segments. Raphe grafts increased HASU, [5-HT] and [5-HIAA] in the dorsal and middle hippocampal segments, had no effects on cholinergic markers and did not affect the lesion-induced increase of [NA]. Co-grafts increased HACU, ChAT activity, HASU, [5-HT] and [5-HIAA], and attenuated the lesion-induced increase in [NA]. These data demonstrate that grafts of fetal neurons placed into the denervated hippocampus may induce a neurochemical recovery which depends upon the anatomical origin of the grafted cells. They also show that co-grafting allows to combine the neurochemical properties of two fetal brain regions grafted separately. Furthermore, our findings suggest that graft-derived cholinergic reinnervation of the hippocampus prevents the lesion-induced increase of noradrenaline concentration which is likely to result from sympathetic sprouting. Thus, our data confirm the results of a previous experiment carried out at a post-grafting delay of 10-11 months, and show that the graft-induced effects reported previously are already massively present by 6 months after surgery.

Long-Evans female rats sustained aspirative lesions of the septohippocampal pathways and, 2 weeks later, received into the dorsal hippocampus grafts prepared from the septal area (rich in cholinergic neurons; Group Sep) or from the mesencephalic raphe (poor in cholinergic neurons; Group Rap) of rat fetuses. Lesion-only (Group Les) and virtually intact (Group Sham) rats served as controls. Between 9.5 and 10.5 months after grafting surgery, we found the lesions to decrease choline acetyltransferase activity (ChAT), high affinity synaptosomal uptake of [3H]choline (HACU) and serotonin concentration ([5-HT]), as well as to increase the noradrenaline concentration ([NA]) in the dorsal hippocampus. Raphe grafts increased [5-HT] to 456% of normal, but had only weak or no effects on the other lesion-induced modifications in brain neurochemistry. Septal grafts dramatically increased ChAT activity and HACU, enhanced [5-HT], and reduced [NA] to near-normal levels. We also found a significant negative correlation between HACU and [NA] in rats with lesions, whether grafted or not. These data show that grafts providing the denervated hippocampus with a new cholinergic innervation might be able to exert inhibitory effects on the lesion-induced increase of [NA]. Since such an increase is indicative of sympathetic sprouting, the finding of reduced [NA] in rats with graft-derived cholinergic reinnervation of the hippocampus is in line with the hypothesis that hippocampal cholinergic denervation plays a crucial role in the induction of sympathetic sprouting. However, our data do not allow to distinguish whether grafts rich in cholinergic neurons inhibited the sympathetic sprouting itself, or rather reduced the NA content of sprouted fibers.

3t 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 activitu, 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 affects on hippocampal AChE positivity, increased both the ChAT activity and the choline uptake to 70% ad 38% of 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 irich 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. However, our behavioral data also suggest that separate or combined attenuation of the lesion-induced cholinergic and serotonergic deficits in the dorsal hippocampus does not seem to be a sufficient condition to induce attenuation of the lesion-induced behavioral deficits (hyperactivity, impaired memory).

After twenty years of intensive research, the possibility to induce recovery from various disorders in brain damaged mammals by means of intracerebral grafts of fetal CNS tissue is well documented and largely accepted by the scientific community. However, there are several reports on animal research suggesting that intracerebral grafts may fail to induce the expected recovery after brain injury or even that they may cause deficits which are actually more pronounced than those induced by the lesions alone. In addition, attempts to produce functional benefits with catecholamine-releasing tissue grafts in the brain of Parkinsonian patients have given limited and variable results; graft-induced deleterious effects have also been occasionally reported in a few clinical cases. One way to progress towards a better understanding of such disappointing, although informative, discrepancies between successful and less successful experimental studies and clinical trials would be to consider that there are several factors which may influence, in one direction or the other, the survival, development, integration and functional expression of intracerebral fetal CNS grafts. The present review considers the following factors: (i) some of the technical factors such as the constraints of transplantation surgery, the origin of donor tissue, the implantation site, the age of both the donor and the recipient, and tissue manipulations prior to grafting (i.e., cryopreservation, culture, genetic modification); (ii) exogenous and endogenous neurotrophic factors, the latter being distinguished by whether they may be host- or graft-derived; (iii) immunological factors (from the particular immunological status of the brain to some effects of immunosuppression in the case of xenografting)', (iv) pharmacological factors, with a particular focus on experimental data suggesting that administration of drugs may or might contribute to elicit, enhance or block some functional effects of grafts. It is concluded that all these factors may become simultaneously operative and interacting, thereby presiding over the functional outcome of intracerebral grafting in both experimental research and clinical trials.

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.

Motor behavior was investigated in rats following acute and chronic gamma-aminobutyric acid (GABA) microinfusions into the nucleus basalis. For acute treatment, the rats received GABA (100 micrograms in 1 microliter), then saline, or these solutions in the reverse order, into the nucleus basalis contralateral to their preferred turning direction in a radial maze. For chronic treatment, half the rats received saline (1 microliter/h for 4 days), and than GABA (100 micrograms/microliters/h) for the same period of time ('saline-first' group). In the other half, this sequence was reversed ('GABA-first' group). Acute microinjections of GABA decreased turning towards the non-injected side; chronic treatment enhanced this effect by reversing the preferred turning direction. Return to initial turning direction was observed after acute GABA-injection in both experimental groups, but only in the 'saline-first' group after chronic treatment. The 'GABA-first' group showed gliosis in and around the nucleus basalis area and a reduction of cortical acetyl-cholinesterase-positivity which were significantly greater than in the 'saline-first' group. This, chronic saline pretreatment is associated with diminished neurotoxicity of chronic GABA infusion and with a reversibility of the drug-induced behavioral effects.

Fetal septal transplants have been shown to promote behavioral recovery in young adult rats with aspiration fimbria-fornix lesions, rats with septal lesions and in intact aged rats. The present study examined the behavioral impact of intrahippocampal septal cell suspension transplants (T) in young female rats that had received, 10 days earlier, either medial fimbria lesions (Group FI.T), dorsal (subcallosal) fornix lesions (Group FO.T) or these two lesions together (Group FIFO.T). Relative to rats with lesions only (groups FI, FO and FIFO), grafted rats, irrespective of lesion locus, displayed unexpected impairments in (i) a serial alternation learning task, 5 weeks and 6 months after transplantation, and (ii) in a radial maze, 7 months after transplantation. In the first alternation test, Group FIFO showed impaired performance relative to Groups FI, FO and the sham-operated controls (Group S). In the second alternation test, Groups FO.T and FO showed impaired performance relative to Groups FI.T and FI, and only the performance of Group FI did not differ from that of Group S. In the radial maze, Groups FI, FO and FIFO all showed impaired performance relative to Group S. By contrast, there were no deleterious effects of lesions or of grafts in the acquisition and retention of a step-through passive avoidance task, 10 weeks after transplantation. Our findings on the effects of selective fimbria-fornix lesions did not confirm the report that rats with FI lesions but not those with FO lesions are unable to learn a serial alternation task, nor the report that FO lesions impair passive avoidance retention. Acetylcholinesterase (AChE) histochemistry revealed that grafts were present but graft-derived innervation of the host hippocampus varied from extensive to almost non-existent in all transplant groups. AChE-positivity in the dorsal hippocampus (DH) was not related to behavioral performance. However, the grafts often grew to a considerable size within the host brain and in many rats, especially those in Group FI.T, produced moderate to extreme damage of the host DH. There was a significant positive correlation between errors in the radial maze and graft-induced DH damage but no relationship between errors and graft size. The results indicate that, after partial lesions of the fimbria-fornix, intrahippocampal septal grafts survive well but are likely to damage recipient structures and result in behavioral impairments.

Female Long-Evans rats were given electrolytic lesions of either the medial fimbria bilaterally (Fi, n = 24), the dorsal fornix (Fo, n = 24), or both structures (FF, n = 24) at 31 days of age. Ten rats were given sham-operations. Ten days later, half the rats with lesions received bilateral intrahippocampal grafts of embryonic septal cell suspensions (FiT, FoT, FFT, respectively). As already reported in a separate publication (J.C. Dalrymple-Alford, C.R. Kelche, J.C. Cassel, G. Toniolo, V. Pallage, & B.E. Will, 1987, Experimental Brain Research, 210, 115-128), 7 months after transplant surgery, grafted rats were found to be more impaired in an eight-arm radial maze than nongrafted rats. The present report concerns a pharmacological study carried out in the same rats 11 months after grafting. We examined the effects of ip injections of physostigmine (0.01, 0.05, 0.10 mg/kg) and then of d-amphetamine (1.6 mg/kg), as compared with baseline control injections of saline. Just prior to the drug treatments, performances of grafted and nongrafted rats did not differ significantly, but impairments in grafted rats reappeared during subsequent no-injection and saline control trials. Physostigmine failed to affect significantly the performances in rats of any group. d-Amphetamine improved performances in grafted rats with medial fimbria lesions, impaired performances in grafted rats with dorsal fornix lesions, and did not change performances in grafted rats with both lesions, as compared with their respective nongrafted counterparts. Histological analysis revealed variable reinnervation of the host structure and substantial graft-induced lesions of the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-Evans female rats sustained aspirative lesions of the fimbria-fornix pathways and part of the overlying structures (Lesion). Eight or 9 days later, one third of these lesioned rats received intrahippocampal septal cell suspension grafts (Sept-G) and another third received grafts of hippocampal origin (Hipp-G). Sham-operated rats (Sham) served as controls. For each surgical treatment, 3 subgroups were assigned to one of 3 experiments which differed by the delay separating grafting from testing. Three months (EXP1), seven months (EXP2) and twelve months (EXP3) after grafting, rats were tested for reactivity to pentylenetetrazol (PTZ, 30 mg/kg, i.p.) and to sound (10-20 kHz peaks, 120 dB, 90 s), two models of generalized convulsive seizures. Three months after grafting, lesion-only rats showed increased reactivity to PTZ as compared to Sham rats; both types of grafts (Sept-G, Hipp-G) attenuated this lesion-induced effect. Whether 7 or 12 months after grafting, no significant between-group differences were observed anymore. Three months after grafting, reactivity to sound tended to increase in lesion-only rats and was significantly increased in both groups with grafts (Sept-G, Hipp-G) as compared to the Sham group. Seven months after grafting, only Hipp-G rats showed increased reactivity to sound compared to Sham or lesion-only rats. No significant between-group difference was observed at 12 months post-grafting. At all 3 delays, histological analyses revealed well integrated grafts, but only septal grafts provided the denervated hippocampus with an AChE-positive fiber ingrowth. Reactivity to PTZ or to sound was correlated neither with the size of the graft, nor with the acetylcholinesterase (AChE)-positive graft-derived reinnervation of the dorsal hippocampus. The present results suggest that hippocampal denervation may result in a temporary increase in reactivity to PTZ and susceptibility to sound, the former being transitorily attenuated and the latter being transitorily increased by both kinds of grafts. Our data confirm earlier reports showing that grafts may influence sensitivity to convulsive seizure-inducing treatments. In addition, these data indicate that this influence is not necessarily lasting and that the kind and duration of this influence is dependent upon the model of convulsive seizures used.

After unilateral entorhinal cortex lesions, acute ethanol exposure (mean daily intake = 16.3 +/- 0.3 g/kg for 15 days) of juvenile rats failed to alter lesion-induced axonal sprouting in the dentate gyrus. The distribution of acetylcholinesterase in the dentate gyrus was identified histochemically as an indicator of axonal sprouting. Comparisons between operated and intact sides were based on qualitative observations and quantitative morphometry techniques using a computerized image analyser to evaluate the widths of the bands of the molecular layer. Whether ethanol-exposed or not, rats with unilateral entorhinal cortex lesions exhibited substantial qualitative and quantitative evidence of axonal sprouting. These results indicate that a 15-day post-operative ethanol exposure had no effect on axonal sprouting in juvenile rats and thus qualify previous findings about ethanol-mediated effects on axonal sprouting.

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.

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The effects of acute administration of the dihydropyridine calcium channel antagonist, nimodipine, were studied on the actions of ethanol in the radial arm maze and the object recognition test. In the former test, the effects of the drugs were examined on the performance in finding the four baited arms, after previous training in this task. Ethanol, at 1 g/kg, increased both the number of re-entries into baited arms (counted as errors of working memory) and the total number of arm choices required to complete the task. Administration of nimodipine, 10 mg/kg, with the ethanol, completely prevented the deleterious effects on memory in this task, but had no effects on the performance when given in the absence of ethanol. In the object recognition task, ethanol, 1 g/kg, significantly decreased the differences in the time spent exploring novel and familiar objects. Nimodipine, 10 mg/kg, given with the ethanol, completely prevented this effect, but nimodipine alone had no effects. The lack of changes in total exploration times indicated that the effects of ethanol in these tests were not due to loss of motor co-ordination or of alertness. The results are discussed in the light of the known actions of the drugs on brain function.