Fimbria-fornix Lesions Research Articles

Behavioral deficits after intrahippocampal fetal septal grafts in rats with selective fimbria-fornix lesions.

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.

Hippocampal function is required for feedback control of an internal clock's criterion.

A discrete-trial peak-interval procedure was used to evaluate the effects of hippocampal damage on the control of an internal clock's criterion. Rats first received either lesions of the fimbria-fornix or sham operations. Following surgery rats were trained on a 20-s peak-interval procedure and later were transferred to a 10-s peak-interval procedure. Rats with sham operations were maximally responsive about the time that reinforcement was sometimes made available (10 or 20 s) and showed an oscillation of successive peak-time values similar to biological feedback control systems. In contrast, rats with fimbria-fornix lesions were maximally responsive at a time about 20% earlier than the time that reinforcement was made available (8 or 16 s) and showed no control of successive peak-time values. Taken together, these results demonstrate that a fimbria-fornix lesion reduces the remembered time of reinforcement stored in reference memory, interferes with the internal control of temporal criteria stored in working memory, and has no effect on the animal's sensitivity to stimulus duration or the acquisition of a new temporal criterion.

Hippocampal and amygdaloid involvement in working memory for nonspatial stimuli.

Hippocampal lesions in rats lead to an impairment of performance in spatial delayed conditional discriminations. The effect of such lesions on nonspatial tasks is controversial. In monkeys, both the hippocampus and the amygdala are involved in nonspatial delayed conditional discriminations. The effect of amygdaloid lesions in rats on this type of task has not been studied. To clarify the role of hippocampus and amygdala in a cue-relevant/space-irrelevant delayed conditional discrimination, rats were trained on a delayed match-to-sample task with visual and tactile cues as discriminative stimuli. Rats were then given one of five lesions: control, complete fimbria-fornix, partial fimbria-fornix, complete amygdala, or partial amygdala. Amygdaloid lesions, partial or complete, did not impair choice accuracy. Fimbria-fornix lesions did impair choice accuracy, and the magnitude and duration of the impairment was a function of the size of the lesion. Partial fimbria-fornix lesions produced a slight impairment that disappeared with continued testing. Complete fimbria-fornix lesions produced chance performance throughout postoperative testing. These results indicate that the fimbria-fornix, but not the amygdala, is involved in nonspatial delayed match-to-sample.

Differential effects of drugs on the behaviour of rats with selective fimbria-fornix lesions and intrahippocampal septal cell transplants

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.

Nucleus basalis magnocellularis and medial septal area lesions differentially impair temporal memory

Functional dissociations between the medial septal area (MSA) and the nucleus basalis magnocellularis (NBM) were examined using the concepts and experimental procedures developed by scalar timing theory. Rats were tested in variations of a signalled discrete-trial peak-interval schedule of reinforcement in which the response rate functions identified the time when the rats expected reinforcement. The variations assessed aspects of both reference and working memory for information obtained from prior trials and from the current trial. A double dissociation was found in reference memory. Rats with NBM lesions, like those with frontal cortex (FC) lesions, remembered the time of reinforcement as having occurred later than it actually did; rats with MSA lesions, like those with fimbria-fornix (FF) lesions, remembered the time of reinforcement as having occurred earlier than it did. A single dissociation was found in working memory. MSA lesions and FF lesions impaired working memory, while NBM and FC lesions had no effect on it. These data begin to identify the brain mechanisms underlying temporal memory; they indicate that the frontal and hippocampal systems are both involved, but in complementary ways; and they provide information that helps specify more clearly the functions of the frontal and hippocampal systems.

Susceptibility to pentylenetetrazol-induced and audiogenic seizures in rats with selective fimbria-fornix lesions and intrahippocampal septal grafts

At the age of 31 days, Long-Evans female rats received electrolytic lesions either of the medial fimbria ( N = 24), of the dorsal subcallosal fornix ( N = 24), or of both structures ( N = 24). Ten rats were used as sham-operated controls. Ten days later, half the rats of each lesion group received intrahippocampal grafts of acetylcholinerich fetal basal forebrain cell suspensions. Twelve months after grafting, all surviving rats, except six grafted rats which became very difficult to handle (because they developed convulsive behavior) were tested for reactivity to pentylenetetrazol (30 mg/kg, i.p.) and to sound (120 dB, 90 s). Grafted rats were found to be more reactive to the drug and less reactive to sound than their nongrafted counterparts with similar lesions. Reactivity to pentylenetetrazol of grafted rats was correlated with body weight and extent of graft-induced hippocampal damage, but not with graft size. Reactivity to sound, which was apparently not dependent on hippocampal damage or graft size, might be related to enhanced graft-derived cholinergic activity in the hippocampus. Our results show that intrahippocampal septal grafts interfere in opposite directions with the seizure-inducing treatments used, so that it can be assumed that the physiologic mechanisms by which grafts do so and by which these treatments induce seizures are likely to be different.

Spatial learning and memory following fimbria-fornix transection and grafting of fetal septal neurons to the hippocampus.

The ability of intrahippocampal grafts of fetal septal-diagonal band tissue, rich in developing cholinergic neurons, to ameliorate cognitive impairments induced by bilateral fimbria-fornix transections in rats was examined in three experiments using the Morris water-maze to test different aspects of spatial memory. Experiment 1. Rats with fimbriafornix lesions received either septal cell suspension grafts or solid septal grafts; normal rats and rats with lesions alone were used as controls. Sixteen weeks after surgery, the rats' spatial learning and memory were tested in the water-maze using a place test, designed to investigate place navigation performance, in which rats learned to escape from the water by swimming to a platform hidden beneath the water's surface. After 5 days of training, the rats were given a spatial probe test in which the platform was removed from the tank to test spatial reference memory. Experiment 2. The same rats used in Exp. 1 were tested in a delayed-match-to-sample, working memory version of the water-maze task. The platform was located in one of two possible locations during each trial, which was composed of 2 swims. If the rat remembered the location of the platform on the 2nd swim of a trial, it should find the platform more quickly on that swim, and thereby demonstrate working memory. Experiment 3. Prior to receiving fimbria-fornix lesions, normal rats were trained in a modification of the water-maze task using alternating cue navigation and place navigation trials (i.e., with visible or non-visible escape platforms). The retention and reacquisition of the place task and the spatial probe test were examined in repeated tests up to 6 months after the lesion and intrahippocampal grafting of septal cell suspensions. The effects of central muscarinic cholinergic receptor blockade with atropine were also tested. Normal rats performed well in both the place and spatial probe tests. In contrast, rats with fimbria-fornix lesions only were unable to acquire or retain spatial information in any test. Instead, these rats adopted a random, non-spatial search strategy, whereby their latencies to find the platform decreased in the place navigation tasks. Sixty to 80% of the rats with septal suspension or solid grafts had recovered place navigation, i.e., the ability to locate the platform site in the tank, in Exp. 1 and 3, and they showed a significantly improved performance in the working memory test in Exp. 2. Atropine abolished the recovered place navigation in the grafted rats, whereas normal rats were impaired to a lesser extent.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of selective lesions of Fimbria-Fornix on learning set in the rat

The effects of selective partial lesions of the Fimbria-Fornix (FiFx) on reversal and place learning sets were investigated in rats by using a T-maze and a semi-circular multiple discrimination apparatus. Lesions restricted to the Fimbria (Fi) produced a significant deficit in reversal and place learning set, whereas lesions to the Fornix (Fx) only disturbed the learning set based on a reversal procedure. Combined Fi+Fx lesions resulted in impairment in the retention of spatial discrimination tested in the two mazes. Ventral Hippocampal Commissure (vhc) had no significant effect on reversal learning set. These results confirm previous data that the hippocampal formation is involved in learning transfer, and suggest that the Fi and the Fx may play a role in learning set. Our data also confirm previous demonstrations of the ability of rats to rapidly acquire place learning set.

Restoration of rhythmic slow activity (θ) in the subcortically denervated hippocampus by fetal CNS transplants

Solid pieces of the fetal septal region (SG) or hippocampus (HPC) were implanted in a cavity formed by aspiration of the fimbriafornix (FF) and the overlying cingulate cortex on one side in adult rats. In other lesioned animals cell suspensions obtained from the fetal septal area (SS) or the locus coeruleus region of the brainstem (LC) were injected stereotaxically into the deafferented host hippocampus. Six to 9 months after transplantation the animals had chronic recording electrodes implanted into both hippocampi. EEG and unit activity were monitored during running in a wheel, drinking and immobility. Unilateral fimbria-fornix lesions abolished rhythmic slow activity (RSA or theta, θ) in the ipsilateral hippocampus and no recovery was seen up to 9 months later in either the control FF-lesioned animals or in the rats with LC suspension grafts. Recovery of RSA, however,was observed in all animals with solid septal grafts and in some rats with solid HPC grafts. Similar to normal rats, RSA was present only during running and absent during drinking and sitting still. Coherence measurements of RSA between the transplanted and intact hemispheres resulted in high values (0.70–0.95). Concurrent with RSA, interneurons and granule cells in the host hippocampus fired rhythmically at RSA frequency (6–9 Hz). The depth profile and the antero-posterior distribution of the power of RSA correlated with the amount and distribution of the graft-induced acetylcholinesterase-positive reinnervation of the host hippocampus. In contrast to the animals with solid septal grafts, placed within the FF lesion cavity, the rats with intrahippocampal septal suspension grafts displayed only short duration bursts of RSA, and mainly during immobility. Based on these findings it is suggested that at least a proportion of the RSA ‘pacemaker’ cells of the host septum survives the transection of the fimbria-fornix fibers and that a graft of fetal septal or hippocampal tissue implanted into the lesion cavity may be capable of relaying this pacemaker activity to the host hippocampus. This effect may be due to the ability of the grafted tissue to promote the regeneration of new, direct or indirect, septo-hippocampal connections across the lesion cavity.

Chapter 16 Exogenous administration of neuronotrophic factors in vivo protects central nervous system neurons against axotomy induced degeneration

Publisher Summary The discovery and investigation of nerve growth factor (NGF) have opened the way to a search for other neuronotrophic factors capable of supporting survival and general growth of selected neurons in vitro and, potentially, in vivo. Recent studies by others have revealed that NGF can be selectively accumulated by the central nervous system (CNS) cholinergic neurons in vivo and can stimulate their choline acetyltransferase activity both in vivo and in vitro. The chapter describes an experimental septohippocampal model in the adult rat, which allows for (i) quantitative evaluation of cholinergic and other neuronal cell death in the septum, (ii) continuous infusion of the septum with exogenous agents, and (iii) the imposition of experimental lesions on the test system. By using such a model, scientists were able to obtain quantitative evidence that the survival of axotomized CNS neurons can be promoted in vivo by exogenously administered neuronotrophic factors. Specifically, continuous infusion of NGF either intraventricularly or intraparenchymally (i) drastically reduces the death of both cholinergic and noncholinergic neurons in the adult rat medial septum and vertical diagonal band regions, which would otherwise follow unilateral fimbria–fornix transection, and (ii) appears to promote massive intraseptal sprouting of cholinergic fibers unilaterally to the fimbria–fornix lesion.

Unilateral fimbria/fornix lesions attenuate behavioral symptoms induced by subsequent dorsal hippocampal lesions in rats

Adult rats were given a unilateral fimbria-fornix (5, 10, 15 μg colchicine or electrolytic) lesion 30 days before a restricted bilateral dorsal hippocampal lesion to assess the behavioral effects of temporally and structurally spaced lesions. The rats were tested 30 days after the second-stage surgery in the Hebb-Williams maze learning task. All rats with lesions were impaired in comparison with sham-operated control rats. However, those which sustained electrolytic or 5 μg colchicine fimbria-fornix lesions before hippocampal lesions were less impaired than rats which received hippocampal lesions alone or hippocampal lesions preceded by fimbria-fornix lesions with larger doses of colchicine.

Fimbria-fornix lesion increases nerve growth factor content in adult rat septum and hippocampus

Bilateral complete transection of the fimbria-fornix causes a significant increase in nerve growth factor (NGF) content both in the septum and hippocampus of the adult rat as measured by a sensitive immunoassay 7 days after lesioning. The finding, that elevation of NGF in septum (250%) was much more pronounced than that in the hippocampus (30–50%), cannot be explained by retrograde axonal transport. Degeneration of central cholinergic neurons might be a potential trigger for NGF production in the CNS.

Ultrastructural characterization of identified cholinergic neurons transplanted to the hippocampal formation of the rat.

The ultrastructural features of cholinergic neurons transplanted to the rat hippocampal formation were studied by using a monoclonal antibody to choline acetyltransferase (ChAT). Septal cell suspensions were prepared from E-18 rat embryos and injected into the hippocampus of host rats that had been previously subjected to a bilateral transection of the fimbria-fornix. Rats with fimbria-fornix lesions alone and unoperated rats served as controls and were examined to characterize the native hippocampal cholinergic system. Both unoperated controls and rats with fimbria-fornix lesions showed a sparse population of intrinsic ChAT-immunoreactive neurons that were most numerous in the subgranular zone, the hilus fascia dentata, and near the hippocampal fissure. ChAT-positive terminals from controls formed synapses on dendritic structures that were primarily symmetrical. ChAT-positive dendrites in controls received synaptic input from nonimmunoreactive axon terminals. In rats with septal transplants, ChAT-immunoreactive transplant neurons were found that were either bipolar or multipolar. Axons of transplanted neurons were unmyelinated and arose either from the cell body or a primary dendritic process where they gave off numerous collaterals. Terminals from transplant neurons formed synapses with many nonimmunoreactive neurons. In transplant animals, two main targets of ChAT-immunoreactive terminals were identified: The great majority of synapses were symmetrical junctions with dendritic spines and shafts. A number of terminals were found that appeared to be juxtaposed to nonimmunoreactive axon terminals, possibly forming symmetrical axo-axonic connections. In contrast, such axo-axonic contacts were not observed in the controls. It is concluded that transplanted cholinergic neurons may reinnervate the host hippocampus; however, this reinnervation is different from what is seen in the intact hippocampal formation.

Acetylcholine-rich neuronal grafts in the forebrain of rats: Effects of environmental enrichment, neonatal noradrenaline depletion, host transplantation site and regional source of embryonic donor cells on graft size and acetylcholinesterase-positive fibre outgrowth

The importance of several factors influencing the survival of cholinergic-rich embryonic tissue transplanted to the adult rat forebrain and the extent of acetylcholinesterase-positive fibre innervation of the host brain was investigated in 3 experiments. In the first two experiments, embryonic ventral forebrain tissue was grafted to the neocortex of rats in which the intrinsic cortical cholinergic innervation had been removed by nucleus basalis lesions. Housing the host rats in an enriched environment produced a temporary enhancement of fibre outgrowth 4 weeks after transplantation, but this was not maintained after 10 weeks. Fibre outgrowth was greater when the grafts were transplanted to the noradrenaline-depleted neocortex than to the intact neocortex. Neither environmental enrichment nor noradrenaline depletion influenced graft survival or size. In the third experiment, the embryonic donor tissue was dissected to separate regions containing precursors of the nucleus basalis cholinergic cells from regions containing precursors of the septal cholinergic cells, and transplanted to either the neocortex following nucleus basalis lesions or to the hippocampus following fimbria-fornix lesions. Nucleus basalis grafts showed greater growth in size than septal grafts, and grafts placed into the hippocampus showed greater growth in size than grafts placed into the neocortex. More interestingly, the extent of fibre outgrowth depended on the appropriateness of the donor tissue to the host transplantation site: nucleus basalis tissue showed greater acetylcholinesterase-positive outgrowth than septal tissue in the neocortex, whereas septal tissue showed greater outgrowth than nucleus basalis tissue in the hippocampus.

Influence of endogenous and exogenous growth factors on choline-acetyltransferase (ChAT) activity in rats with fimbria-fornix lesions and acetylcholine-rich transplants in the hippocampus

Long-Evans female rats sustained electrolytic lesions of the fimbria and the dorsal fornix and, two weeks later, received intrahippocampal suspension grafts of fetal tissue. The grafts were prepared from regions including either the medial septum and the diagonal band of Broca (septal grafts), or the mesencephalic raphe (raphe grafts), or from both these regions together (co-grafts). All rats were submitted to a series of behavioural tests (home cage and open-field locomotion, spontaneous alternation, radial-arm maze and Morris water maze performance) run over two periods after grafting (one to nine weeks and 20–35 weeks). Two weeks after completion of behavioural testing, histological (acetylcholinesterase and Cresyl Violet staining) and/or neurochemical (choline acetyltransferase activity, high-affinity synaptosomal uptake of choline and serotonin, noradrenaline, serotonin and 5-hydroxyindolacetic acid concentrations) verifications were performed on the hippocampus.Compared to sham-operated rats, lesion-only rats exhibited hyperactivity which was transient in a familiar environment (home cage) and lasting in an unfamiliar one (open field), decreased rates of spontaneous T-maze alternation, and impaired memory performance in both the radial-arm maze and the Morris water maze. These rats also snowed decreased cholinergic and serotonergic markers with a maximal depletion in the septal two-thirds of the hippocampus. Noradrenaline concentration tended to be increased in the dorsal third of the hippocampus, but was not modified in the other two-thirds.While septal grafts specifically increased the cholinergic markers and raphe grafts the serotonergic ones, neither of these grafts produced a lasting effect on any behavioural variable. Conversely, the co-grafts, which increased both the cholinergic and serotonergic markers in the septal two-thirds of the hippocampus, completely normalized the Morris water maze probe trial performance, but failed to affect any of the other behavioural variables.Our present results confirm that grafts of fetal neurons injected into the denervated hippocampus may induce a neurochemical recovery that depends on the anatomical origin of the grafted cells, and that co-grafting two fetal brain regions allows the combination of their individual neurochemical properties. Furthermore, our results show that these neurochemical effects of the co-grafts may be involved in the recovery of behavioural function observed in the water maze. However, somewhat paradoxically, those effects appear inefficient for inducing any recovery in other behavioural tasks, even in the radial-arm maze, which is assumed to measure similar spatial functions. Finally, it is suggested that the co-grafts might be more efficient in attenuating the spatial reference memory (Morris water maze) rather than the spatial working memory (radial maze) deficits subsequent to fimbria-fornix lesions.

Enhanced graft survival in the hippocampus following selective denervation

The trophic effects of denervation on the survival of fetal cholinergic neuronal cell suspensions grafted to the hippocampal formation of the rat were assessed in the present study. Young adult female rats were injected with cell suspensions of neurons obtained from the fetal basal forebrain region into the hippocampal formation simultaneously with (or without) a fimbria-fornix transection, which removes the hippocampal cholinergic afferents. Four to six months later, one group of grafted animals was evaluated histochemically for: (1) transplant volume; (2) number of acetylcholinesterase-positive cells, and (3) size of acetylcholinesterase-positive cells in the graft. A parallel study was conducted to determine the total number and size of the acetylcholinesterase-positive cells in the septal-diagonal band-substantia innominata complex of the adult rat, to match with the cell survival and growth in the grafts. A second group of grafted rats was taken in parallel for biochemical analysis of choline acetyltransferase activity in the grafted hippocampus. The transplant volume in the rats with fimbria-fornix transection was greater than twice the volume seen in animals without flmbria-fornix lesion. In addition, the number of acetylcholinesterase-positive cells in the transplant was twice as great in the denervated animals as in the non-denervated ones. However, the number of acetylcholinesterase-positive cells per mm 3 of graft volume did not differ between the two groups, suggesting that the trophic effect of the denervation was not specific for the cholinergic neurons, but affected the entire grafted tissue. The hippocampal choline acetyltransferase activity of the animals that received the fimbria-fornix lesion simultaneously with transplantation was about three times higher than that of the rats that received grafts but no simultaneous fimbria-fornix transection. A control experiment with animals that received an aspirative lesion of the retrosplenial cortex, transecting the perforant path input, revealed no enhancing effect of hippocampal choline acetyltransferase activity over non-lesioned grafted animals. Thus, the denervation-enhancing effects of the fimbria-fornix lesion appear to be selective and not the result of a general wound-induced mechanism. These results strongly support the contention that neurotrophic factors are released as a result of denervation in the adult hippocampal formation, and that these neurotrophic factors can support survival and growth of central cholinergic neurons. However, the factors involved do not appear to be specific for the cholinergic neurons, but rather have their trophic effects on many types of cells.

Acetylcholine-rich transplants in the hippocampus: influence of intrinsic growth factors and application of nerve growth factor on choline acetyltransferase activity

Three groups of rats received either unilateral fimbria-fornix lesions by aspiration through the overlying cingulate cortex (group I), a fimbria-fornix lesion followed by an intrahippocampal transplant of acetylcholine (ACh)-rich embryonic septal tissue (group II), or a similar septal transplant placed into the intact hippocampus, in the absence of the denervating lesion (group III). The 3 groups were subdivided into equal subgroups receiving 6 intrahippocampal injections of nerve growth factor (NGF) at 4-day intervals, control injections of cytochrome c, or no injections. On the 28th day all animals were sacrificed and the majority taken for biochemical analysis of hippocampal choline acetyltransferase (ChAT). The animals with intact hippocampi (group III) were given a denervating fimbria-fornix lesion 3 days prior to sacrifice in order to reveal graft-derived ChAT activity from intrinsic ChAT activity. The fimbria-fornix lesions (group I) depleted hippocampal ChAT activity to 15–20% of normal, which was not influenced by NGF injections. The ACh-rich grafts placed in the denervated hippocampus (group II) restored hippocampal ChAT activity to approximately 60% of the normal level, and this was promoted to approximately 84% by NGF, but not cytochrome c, injections into the hippocampus. Grafts placed into the intact hippocampus (group III) did not raise ChAT activity above the lesion-alone level, and this was not influenced by NGF injections. Acetylcholinesterase (AChE) histochemistry showed no difference in outgrowth from the grafts in the denervated hippocampus with or without NGF injections. The results are interpreted, in agreement with observations in tissue culture, as indicating that NGF enhances ChAT activity in grafted neurones, rather than promoting survival and growth per se.

Fornix-fimbria section and the partial reinforcement extinction effect.

Rats were trained to run in an alley for food reward given on every trial (continuous reinforcement, CR) or on a random 50% of trials (partial reinforcement, PR) and were then extinguished. Sham-operated controls showed the normal partial reinforcement extinction effect (PREE), in that PR-trained animals were significantly more resistant to extinction than CR-trained animals. The PREE was significantly reduced by lesions of the fornix-fimbria. The reduction was largely a consequence of a reduction in resistance to extinction in PR-trained rats with fimbria-fornix lesions. These results are discussed in the light of other experiments that have studied disconnections in the septo-hippocampal system.

Behavioral and neurochemical effects of intraventricular AF64A administration in rats

Ethylcholine aziridinium ion solution (AF64A), a putative specific cholinergic neurotoxin, was injected bilaterally into the lateral ventricles of rats. Following administration of 3 or 6 nmoles of AF64A, drinking and eating were depressed but returned to normal levels after several days; increased activity in the 6 nmole group persisted throughout the 21 days of observations. Performance on complex place and cue tasks indicated that injected animals were impaired in reference memory only on the place task, but working memory was impaired on both tasks. Neurochemical measurements in a separate group of animals one week after AF64A injections found large depletions of acetylcholine in hippocampus and corpus striatum, but not depletions of norepinephrine (hippocampus) or dopamine (striatum). Histological examination of the injection site revealed extensive damage to the fimbria-fornix similar to that seen after electrolytic lesions. Since the behavioral and neurochemical changes are similar to those previously found following fimbria-fornix lesions, it is concluded that the present results are possibly due to non-specific lesion effects of the neurotoxin rather than a specific effect on cholinergic systems.

Fimbria-Fornix lesions impair spatial working memory but not cognitive mapping.

Three experiments were designed to evaluate the relative merits of two theories of hippocampal function, the cognitive mapping theory and the working memory theory. Rats were tested in a series of maze tasks that varied in memory requirements. In the experiments that required cognitive mapping but not working memory (Experiments 1 and 3), rats with fimbria-fornix lesions reached stable levels of performance that were as accurate as those of control rats, and they also performed accurately during transfer tests, results demonstrating that they used a cognitive mapping strategy to solve the discrimination. In the experiment that required working memory (Experiment 2), rats with fimbria-fornix lesions performed at chance levels during all of postoperative testing, and they distributed their choices randomly between the correct and the incorrect goals. These results are seen as generally refuting the predictions made by the cognitive mapping theory and supporting the predictions made by the working memory theory. Additional analyses (Experiment 3) examined the nature of a transitory impairment exhibited by rats with fimbria-fornix lesions in two tasks that did not require working memory. Postoperatively, the performance of the rats with lesions was initially impaired but recovered to normal levels with a time course similar to that seen during preoperative acquisition. These results are seen as requiring an extension of the working memory theory of hippocampal function, and discussion is focused on the possibility of a temporary retrograde amnesia following fimbria-fornix lesions and the distinctions between different types of memory abilities.