Bruno Will

Fimbria–Fornix vs Selective Hippocampal Lesions in Rats: Effects on Locomotor Activity and Spatial Learning and Memory ☆

The behavioral effects of interrupting the axons that pass in the fimbria and dorsal fornix were compared with the effects of selective removal of the cells that comprise the hippocampus with ibotenic acid. Starting 4.5 months after surgery, lesioned and control rats were (i) trained in both the Morris water maze and the eight-arm radial maze using protocols that placed an emphasis on either working memory (WM) or reference memory (RM) and (ii) tested for locomotor activity in the home cage. In comparison to sham-operated rats, the rats from both lesion groups were impaired in most learning/memory tasks, but there were some interesting differences between the two lesioned groups. When compared to rats with fimbria-fornix lesions (FIFX rats), hippocampal rats (HIPP rats) were slower in learning to swim to a visible platform and showed a greater impairment than FIFX rats in the radial-maze task when the testing procedure required the utilization of RM and WM in a more demanding WM task. In the test of locomotor activity, FIFX and control rats did not differ, but HIPP rats were more active than the rats in both other groups. The pattern of results obtained after a 4.5-month recovery period support the following general conclusions. (1) While there are some similarities in the effects on behavior of interrupting the axons in the fimbria-fornix compared to removing the hippocampus, there are some important differences. (2) From the findings that are available, a possible explanation to account for the difference between FIFX and HIPP rats is that the 4.5-month survival time permitted some recovery in the group of rats with FIFX lesions. (3) While it is well known that the Morris water maze and the radial-arm maze tasks provide useful measures of spatial learning and memory processes, our results suggest that the information provided by the two spatial learning tasks may differ in important respects.

Brain plasticity, learning, and memory

Ivan Divac and Jesper Mogensen Institute of Neurophysiology University of Copenhagen School of Medicine The present chapter offers in a capsular form a concept of organization of the non-limbic division of the mammalian forebrain. We first draw attention to certain structural and functional properties of the prosencephalon and conclude that interrelated parts of the thalamus, isocortex and neostriatum constitute functional systems. In the next step we attribute to these systems distinct properties which can be related to well established psychological phenomena. Finally, one of testable predictions is presented.

Long-term effects of nerve growth factor and neural transplants on behavior of rats with medial septal lesions

The present experiment investigated the interaction between exogenous nerve growth factor (NGF) and intrahippocampal septal grafts on the behavior of rats after a medial septum lesion. Young female rats received a bilateral injection of a fetal septal cell suspension into the dorsal hippocampus either immediately (immediate grafts) or 8 days after the lesion (delayed grafts). For delayed grafts, a higher concentration of endogenous neurotrophic factors can be assumed to be present in the deafferentated host tissue at the time of transplantation. One group of rats with lesions received NGF with the immediate grafts, another group received NGF alone. A sham-operated group and 3 groups with lesions (and given either immediate or delayed intrahippocampal saline injections, or no other treatment) constituted controls. The animals were tested for spontaneous alternation and for performance in a radial 8-arm maze, 1, 5 and 9 months postoperatively. Medial septal lesions reduced spontaneous alternation but, 9 months after surgery, recovery was observed in both lesion-control rats and in rats with delayed grafts (but not with immediate grafts). In the radial maze task, lesions produced a persistent impairment, although both immediate and delayed grafts reduced this deficit several months after surgery (more markedly and rapidly in the case of delayed grafts). NGF, however, increased the maze learning deficit especially 5 months postoperatively. These latter results are in contrast to findings of earlier studies showing transient beneficial effects of NGF administration. It is suggested that the effects of NGF in the present study might be due to an enhanced sprouting of sympathetic fibers into the hippocampal formation.

Effects of differential environments on recovery from neonatal brain lesions, measured by problem-solving scores and brain dimensions

Abstract To study effects of differential experience on recovery from brain lesions and on gross anatomy of the brain, we ran two experiments with rats of the Berkeley S1 strain. On the day of birth, some animals received lesions directed to the occipital cortex, but in many cases subcortical damage also resulted; other animals were sham-operated. In Experiment 1, half the rats lived in restricted environments and half in enriched environments from Day 5 or 6 until about Day 65; in Experiment 2 the differential environments were begun on Day 25 and lasted until Day 65. The rats were then pretrained and tested on the standard 12 Hebb-Williams problems. Both experiments yielded significant overall effects of brain status (lesion vs. control) and of environment (impoverished vs. enriched). The effects of environment were larger in Experiment 2 where the lesions were smaller than in Experiment 1. Considerable generality was demonstrated for the beneficial effects of environment on behavioral recovery since it was obtained with both sexes, with large lesions in Experiment 1 and with relatively small lesions in Experiment 2, with both immediate and delayed environmental therapy, and with shorter periods of enriched experience than had been employed previously. The enriched experience benefits brain injured rats even though their learning ability is impaired. The length and width of the cerebral hemispheres were also found to be affected by lesions and, to a lesser extent, by environmental treatment.

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

SummaryFetal 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.

Environmental Approaches to Recovery of Function from Brain Damage: A Review of Animal Studies (1981 to 1991)

During the sixties and seventies there has been a major shift in our beliefs about brain plasticity and, more specifically, about the effects of environment on both brain and behavior. This shift in beliefs concerns not only intact subjects in the course of development and adaptation but also, more recently, subjects having sustained brain or spinal cord injury. During the late seventies it became clear that the environment may play an important role in brain-damaged subjects, and this has led to an effort to “treat” disturbances induced by central nervous system (CNS) injury by means of environmental “therapy” (e.g. references 25,33,44,87). In 1981, at the first E.B.B.S. workshop on “recovery of function from brain damage”, we came to the conclusion that “there exists .... strong evidence that a postoperative or post-traumatic enriched experience significantly aids functional recovery after various kinds of brain injuries”, but we also acknowledged and even stressed “that a few studies have also obtained negative findings”88. In this latter case, we were referring to studies which failed to demonstrate any beneficial effects of postoperative enrichment or sensory stimulation.

Effects of postoperative housing conditions on functional recovery in rats with lesions of the hippocampus, subiculum, or entorhinal cortex

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.

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)

5,7‐DHT‐induced hippocampal 5‐HT depletion attenuates behavioural deficits produced by 192 IgG‐saporin lesions of septal cholinergic neurons in the rat

Adult Long–Evans male rats sustained injections of 5,7‐dihydroxytryptamine into the fimbria–fornix (2.5 µg/side) and the cingular bundle (1.5 µg/side) and/or to intraseptal injections of 192 IgG‐saporin (0.4 µg/side) in order to deprive the hippocampus of its serotonergic and cholinergic innervations, respectively. Sham‐operated rats were used as controls. The rats were tested for locomotor activity (postoperative days 18, 42 and 65), spontaneous T‐maze alternation (days 20–29), beam‐walking sensorimotor (days 34–38), water maze (days 53–64) and radial maze (days 80–133) performances. The cholinergic lesions, which decreased the hippocampal concentration of ACh by about 65%, induced nocturnal hyperlocomotion, reduced T‐maze alternation, impaired reference‐memory in the water maze and working‐memory in the radial maze, but had no effect on beam‐walking scores and working‐memory in the water maze. The serotonergic lesions, which decreased the serotonergic innervation of the hippocampus by about 55%, failed to induce any behavioural deficit. In the group of rats given combined lesions, all deficits produced by the cholinergic lesions were observed, but the nocturnal hyperlocomotion and the working‐memory deficits in the radial maze were attenuated significantly. These results suggest that attenuation of the serotonergic tone in the hippocampus may compensate for some dysfunctions subsequent to the loss of cholinergic hippocampal inputs. This observation is in close concordance with data showing that a reduction of the serotonergic tone, by pharmacological activation of somatodendritic 5‐HT1A receptors on raphe neurons, attenuates the cognitive disturbances produced by the intrahippocampal infusion of the antimuscarinic drug, scopolamine. This work has been presented previously [Serotonin Club/Brain Research Bulletin conference, Serotonin: From Molecule to the Clinic (satellite to the Society for Neuroscience Meeting, New Orleans, USA, November 2–3, 2000)].

Does post-operative environment attenuate or exacerbate symptoms which follow hippocampal lesions in rats?

Rats with dorsal hippocampal lesions (L) and control rats were tested pre- and post-operatively, on a spontaneous alternation task. Four days after surgery, the L group alternated significantly less than the control group. Starting on the fifth post-operative day, all rats were placed for either 7, 15 or 23 days in one of three different environments: enriched, social or impoverished. Environmental enrichment increased significantly spontaneous alternation in L rats, even for the shortest enrichment period. Although this result might be task and lesion specific, it clearly indicates that post-operative environmental enrichment can help to reduce post-operative symptoms in brain-damaged animals.