Chronic cognitive effects of bilateral subdural haematomas in the rat.

Humans suffering from subdural haematomas often show long-term cognitive dysfunctions. For identifying putative, recovery-enhancing therapeutics, animal models need to be developed in which recovery of function can be measured. For investigating whether and which type of recovery, i.e. spontaneous or training-induced recovery, or continuous partial retardation, is present in the rat model for bilateral subdural haematomas, spatial navigation abilities were assessed in the Morris water escape task in independent groups of rats at 1, 2, 4, 8, or 18 weeks after surgery. Complete spontaneous recovery seemed to occur at 8 weeks after injury. However, at 18 weeks after injury, the subdural haematoma caused a renewed deterioration of water maze performance, which was of a lesser degree than the impairments observed immediately after injury. This second phase performance deterioration was accompanied by an increase in generalised astrocyte reactivity. The rat subdural haematoma model provides an interesting tool for investigating spontaneous recovery processes of spatial navigation (8 weeks after injury), but also for progressive brain dysfunctions, considering the second phase of behavioural impairments seen at 18 weeks after injury.

Modelling cognitive dysfunctions with bilateral injections of ibotenic acid into the rat entorhinal cortex.

Neurodegenerative diseases, traumatic brain injury and stroke are likely to result in cognitive dysfunctioning. Animal models are needed in which these deficits and recovery of the affected functions can be investigated. In the present study, the entorhinal area was chosen as the target for lesioning and for assessing the lesion-induced deficits in the Morris water maze. The entorhinal cortex is regarded as an interface between the hippocampus and neocortex. Deafferentiating the hippocampus through entorhinal lesions impairs spatial learning. The effects of lesions, induced by either electrocoagulation (experiment 1) or ibotenate excitotoxicity (experiment 2), on spatial orientation behaviour were investigated. Water maze performance after unilateral or bilateral ibotenate injections into the entorhinal cortex was studied in the third experiment. In an additional study, the replicability of the spatial learning deficit after lesions induced by bilateral injections of ibotenic acid into the entorhinal cortex was assessed by comparing the results of nine experiments. We found that spatial learning was impaired after bilateral lesions aimed at the entorhinal cortex. The electrolytic lesion technique produced a relatively large sham effect, whereas the excitotoxic lesioning method did not. Unilateral injections of ibotenic acid into the entorhinal cortex did not affect spatial navigation. The ibotenate-induced lesions replicably produced deficits in the Morris tasks. The degree of the induced spatial learning impairments and the effects on the rate of acquisition during training, however, differed between experiments. This result suggests that the fundamental biological diversity between shipments of rats can account for variation in the effects of parahippocampal damage on spatial learning even in highly standardized experimental set-ups. Rats lesioned by bilateral injections of ibotenic acid into the entorhinal cortex provide an interesting and reliable model for investigating cognitive dysfunctions in neurodegenerative diseases, stroke or traumatic brain injury.

Effects of subdural haematoma on sensorimotor functioning and spatial learning in rats.

Twenty per cent of all strokes are haemorrhagic in character and are associated with severe disturbances in sensorimotor behaviour and cognition. Although spontaneous recovery of pre-stroke functioning occurs in some cases, the process is demanding, slow, and often incomplete. A first step in the preclinical testing of new putative, neuroprotective and recovery-supporting therapeutics is to validate animal models of brain injury. In a series of four experiments we evaluated the behavioural impairments and the time course of recovery of functional deficits in rats with an experimentally induced subdural haematoma. We found that unilateral subdural haematoma resulted in dysfunction in both simple reflexive (experiment 1) and skilled sensorimotor behaviour (experiment 2). Reflexive behaviour did not recover, or recovered only marginally, and neither did the deficits in skilled forepaw use. Bilateral subdural haematoma impaired the learning and memory performance of adult (experiment 3) and old rats (experiment 4) in the Morris water escape task. Considering the diversity of the deficits found in our experiments, we conclude that different models are needed to cover the broad range of deficits seen in stroke patients.

The effects of subdural haematoma on spatial learning in the rat.

Although memory deficits are one of the most persistent consequences of human subdural haematoma, cognitive functioning has hardly been investigated in the rat subdural haematoma model. In the present study, the effects on spatial learning of right- and left-sided unilateral subdural haematoma and of bilateral subdural haematoma induced above the sensorimotor cortical areas were evaluated. Spatial learning was assessed by standard acquisition in the Morris water escape task (five sessions). Additional issues addressed were sensorimotor functioning (footprint analysis), recovery of cognitive functioning (tested by an overtraining and a reversal training) and replicability of induced cognitive deficits. Following unilateral subdural haematoma surgery, hardly any impairments in the Morris water escape task were observed: rats with a unilateral right-sided subdural haematoma showed very mild, transient deficits, whereas rats with left-sided subdural haematoma were indistinguishable from controls. Bilateral subdural haematoma surgery led to a clear, although transient, performance deficit. We conclude that animals with bilateral subdural haematoma may provide a promising cognitive deficit model for investigating recovery of function.

Spatial learning deficits in rats after injection of vincristine into the dorsal hippocampus.

In the present study, performance in the Morris water escape task after bilateral lesioning of the dorsal hippocampus induced by the microtubule poison vincristine is discussed as a cognitive deficit model in rats. As we are especially interested in spontaneous or pharmacologically induced recovery processes after experimentally induced cognitive dysfunctions, the model should fulfil a number of criteria. Firstly, a clear dose-effect relationship between the dose of vincristine and the amount of spatial learning impairments should be present. Secondly, lesions must remain within the target area. Thirdly, there should be an observable behavioural recovery or compensation of the induced deficit. Two experiments evaluated the influence of the application volume (experiment 1) and the concentration of vincristine (experiment 2) on lesion location and size, and on spatial learning. The results of both experiments demonstrated that the effect of vincristine on the performance in the Morris water escape task seems to be characterized by an "all-or-none" relationship. Concentrations above a "threshold" value induced severe damage in the hippocampus and adjacent brain structures, whereas concentrations below the "threshold" value had marginal or no effects. The non-selective and highly toxic properties of vincristine make this neurotoxin an unsuitable tool for the establishment of a learning and memory deficit model.