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International audience; Because of its severity, chronicity, resistance to usual therapy and its consequences on quality of life, neuropathic pain represents a real clinical challenge. Fundamental research on this pathology uses metabolic, pharmacological or traumatic models in rodents that reproduce the characteristic human pain symptoms. In 1996, Mosconi and Kruger morphologically described a model of peripheral neuropathy in which a cuff of polyethylene tubing was placed around the sciatic nerve in rats. In the present study, we evaluated the behavioral consequences of this neuropathic pain model in C57Bl/6J mice which is the main genetic background used for studies in transgenic mice. A short cuff of polyethylene tubing was unilaterally placed around the main branch of the sciatic nerve. It induced an ipsilateral heat thermal hyperalgesia lasting around 3 weeks, and a sustained ipsilateral mechanical allodynia lasting at least 2 months. We showed that this neuropathic pain model is insensitive to ketoprofen, a non-steroidal anti-inflammatory drug. Morphine treatment acutely suppressed the mechanical allodynia, but tolerance to this effect rapidly developed. The analysis of video recordings revealed that most aspects of spontaneous behavior remained unaffected on the long term, excepted for a decrease in the time spent at social interaction for the neuropathic mice. Using the elevated plus-maze and the marble-burying test, we also showed that neuropathic mice develop an anxiety phenotype. Our data indicate that sciatic nerve cuffing in mice is a pertinent model for the study of nociceptive and emotional consequences of sustained neuropathic pain.

Previous studies have produced conflicting results about the effects of intracerebral injection of NGF after septal damage in rats: in one experiment, behavioral deficits in maze tasks were exacerbated by NGF administration whereas they were alleviated in another one. The present investigation aimed to clarify the effects of NGF and to identify factors liable to induce different behavioral outcomes. Behavioral effects were assessed following a postsurgical delay of five months using various parameters: food consumption in a novel environment, spontaneous activity, locomotion in an open-field, immobility in a tail suspension test, spontaneous alternation in a T-maze and performance in a radial eight-arm maze. Possible influence of intrahippocampal sympathetic fiber ingrowth occurring after septal lesions was ruled out, as the comparison of rats subjected to superior cervical ganglia removal with their lesion-control counterparts showed few behavioral differences, even after NGF administration. All lesioned rats showed reduced adaptability in most of these tests. Grafts partially reversed the lesion-induced deficit in spontaneous alternation. A single intracerebral NGF injection was found to ameliorate radial maze performance, whether rats were grafted or not. However, it appeared that the number of strategies available to NGF-rats in the radial maze task was as limited as for lesion-control rats. These findings suggest that NGF-rats do not recover spatial abilities lost after septal lesions, but are able to make more efficient use of remaining capacities to master the maze task.

This study examined how possible nerve growth factor (NGF)-induced behaviour changes after septal damage might be modulated by the lesion extent, the dose of NGF administered and the delay between surgery and the onset of testing. In a first experiment, young rats which received electrolytic septal lesions of high or low intensity (inducing respectively large and mild lesions) were treated with 10 or 30 micrograms NGF administered intrahippocampally in a single injection. They were tested 4 months postoperatively for open field ambulation, spontaneous alternation and radial maze performance. It was observed that irrespective of the severity of the lesions rats were impaired in the spontaneous alternation and radial maze tests; however, no obvious changes appeared in the open field test. While an NGF injection did not affect behavioural performances in rats with large lesions, it was capable of ameliorating behavioural deficits in the spontaneous alternation and radial maze tests of rats with mild lesions in both NGF dosage groups. It was also seen that lesions produced a general decrease in hippocampal choline acetyltransferase (ChAT) activity, which was not significantly affected by an NGF administration. There was no significant correlation between ChAT activity and behavioural performance of NGF-treated rats. In a second experiment, young rats received mild septal lesions and were treated with 10 micrograms NGF. These rats were tested 2 weeks postoperatively for radial maze performance. NGF rats exhibited similar behaviour to controls with regard to all of the variables measured. The present results suggest that a single NGF administration spares some abilities to use spatial information efficiently providing lesions are partial.

Two prominent features of Alzheimer’s disease are: 1. a marked decrease in forebrain cholinergic markers and 2. a strong impairment in cognitive functions. Since the late 1970s, evidence has accumulated indicating that nerve growth factor (NGF) acts as a neurotrophic factor for cholinergic neurons of the basal forebrain. There are conflicting data concerning the action of this protein on cognitive functions, particularly in animals with lesions affecting forebrain cholinergic systems. NGF has been reported to alleviate lesion-induced as well as aging-related behavioral impairments, but others have reported no NGF effect or even NGF-induced behavioral impairments (e.g., Will et al. 1988; Hefti et al. 1989). The present report attempts to clarify this issue. In a series of experiments conducted on female rats with medial septal lesions, we assessed the short- and long-term effects of a single intrahippocampal injection of NGF made at the time of lesion surgery. Behavior was measured in a test battery including spontaneous alternation and radial maze performance. The results were as follows: 1. a single injection of NGF was sufficient to alleviate some behavioral deficits in a long-lasting fashion; 2. the beneficial effect of NGF on behavioral recovery was dependent on the size of the septal lesion, since it was observed only in rats with small or medium-sized lesions; 3. even if exogenous NGF affected sympathetic sprouting induced by hippocampal cholinergic deafferentation (although this does not seem to be the case), such sprouting did not prevent the protein from facilitating behavioral recovery, and furthermore, superior cervical ganglionectomy did not affect behavioral expression following NGF treatment; and 4. when added to cholinergic-rich grafts (embryonic septal cell suspensions injected into the dorsal hippocampus), NGF increased the size of the grafts, especially when given in conjunction with ganglionectomy. These data support other findings showing beneficial effects of NGF treatment and suggest that repeated or chronic treatment may be no more efficient than acute treatment. These findings may also help us to understand some of discrepancies mentioned above.

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.

The effects of different postoperative physical environments on novelty seeking and maze learning were tested in rats that sustained dorsal hippocampal lesions at 30 days. After surgery, rats were isolated for one month, either with objects or without objects in their cages. All rats were moved daily to new cages and observed during the first 5 min; during these periods, sham-operated rats and rats with lesions interacted similarly with their environment. At the end of the differential housing period, rats were tested for their reactions towards a novel object introduced in their familiar environment (test 1) and towards a novel environment they were free to explore or to avoid (test 2). In test 1, rats with lesions made more contacts with the novel object than did intact rats, and rats previously housed with objects, whether they sustained lesions or not, climbed on the novel object more often than rats reared without objects. In test 2, rats with lesions made no clear distinction between the novel and familiar environments irrespective of their postoperative treatment; in contrast, intact rats housed with objects differed from intact rats housed without objects in their preference for the novel and familiar environments and in the locomotor activity they displayed in these environments. Following these two tests, learning performance was assessed in an 8-arm radial maze. Rats with lesions made more errors than the intact rats, and within the rats with lesions those reared with objects tended to make fewer errors than those reared without objects. The present study suggests that ‘enriching’ the physical environment by introducing various objects in the home cage is a sufficiently potent factor for altering in a rather general way the behaviour of isolated rats. The housing conditions affected (1) reactions towards a novel object in both rats with lesions and intact rats, (2) reactions towards a novel environment in intact rats only, and tended to affect (3) learning of a radial maze task in rats with lesions only.

Nerve growth factor (NGF) is a well-characterized protein that acts as a neurotrophic factor for catecholaminergic neurons of the peripheral sympathetic nervous system and for a subpopulation of peripheral sensory neurons. In the central nervous system, catecholaminergic neurons are not affected, but evidence obtained in recent years indicates that NGF acts as a neurotrophic factor for cholinergic neurons of the basal forebrain innervating cortex and hippocampus. Nerve growth factor affects survival, fiber growth, and expression of transmitter-specific enzymes by these cholinergic neurons. Intracerebral administration of NGF has been found in several studies to modify the behavioral recovery of animals from experimentally induced brain damage. Such effects were observed after lesions in target areas and areas of origin of forebrain cholinergic neurons (septum, fimbria-fornix, hippocampus, cortex) and also after lesions in hypothalamus, striatum, and nucleus accumbens, i.e., in areas not innervated by forebrain cholinergic neurons. The mechanisms mediating the behavioral effects of NGF and the possible involvement of central cholinergic and peripheral sympathetic neurons are discussed.

To compare the predictive value of "cognitive map" and "working memory" theories of hippocampal function, the performance of rats with dorsal hippocampal lesions was compared to that of control rats in a series of experiments. In Experiment I, experimental rats learned a spatial alternation task with normal ease, but in Experiment II, they were significantly impaired on an elevated 8-arm radial maze. In Experiment III, the performance of the same experimental and control rats was compared on two versions of a 16-arm enclosed radial maze. In the first version, carpet inserts served as cues to mark eight unbaited arms and each of the remaining arms contained one food pellet. While both experimental and control rats successfully avoided the set of cued arms, experimental rats reentered uncued baited arms more frequently than did control rats. In the second version no intramaze cues were provided, but the spatial distribution of baited and unbaited arms remained the same as that used in the first version. In this uncued version, experimental rats both entered unbaited arms and reentered baited arms more frequently than did control rats, i.e., they were impaired in both "reference" and "working" memory. These findings are compatible with the hypothesis that hippocampal lesions result in an impaired capacity to form cognitive maps but they are not compatible with the working memory hypothesis. Furthermore, twelve separate evaluators classed experimental rats as using fewer mapping and more orientation strategies than control rats in the 8-arm maze.

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.