Abstract: Traumatic spinal cord injury (SCI) causes severe and permanent functional deficits due to the primary mechanical insult followed by secondary tissue degeneration. The cascade of secondary degenerative events constitutes a range of therapeutic targets which, if successfully treated, could significantly ameliorate functional loss after traumatic SCI. During the early hours after injury, potent pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) are synthesized and released, playing key roles in secondary tissue degeneration. In the present investigation, the ability of rolipram and thalidomide (FDA approved drugs) to reduce secondary tissue degeneration and improve motor function was assessed in an experimental model of spinal cord contusion injury. The combined acute single intraperitoneal administration of both drugs attenuated TNF-alpha and IL-1beta production and improved white matter sparing at the lesion epicenter. This was accompanied by a significant (2.6 point) improvement in the BBB locomotor score by 6 weeks. There is, at present, no widely accepted intervention strategy that is appropriate for the early treatment of human SCI. The present data suggest that clinical trials for the acute combined application of rolipram and thalidomide may be warranted. The use of such "established drugs" could facilitate the early initiation of trials.
Abstract: The improvement of regeneration and functional recovery after peripheral nerve injury is a major challenge in neurosurgery. Although microsurgical techniques for nerve reconstruction have seen great advancements over the last years, the clinical outcome with patients is often unsatisfactory. The aim of the present study was to investigate if administration of the iron chelator Deferroxamine (DFO), can improve postoperative outcome in the rat median nerve reconstruction model.
Abstract: Collagens are extracellular proteins characterized by a triple helical structure and predominantly involved in the formation of fibrillar and microfibrillar networks of the extracellular matrix and basement membranes. There are 29 collagen types which differ in size, structure, and function. In the peripheral nervous system, two classes of collagen molecules are expressed: fibril forming collagens (type-I, III, and V) and basement membrane collagens (type-IV). Collagens are required for normal extracellular matrix assembly and play an important role in the regulation of Schwann cell function. After injury collagen production in the severed nerve often exceeds the ideal response which is suggested to hinder the growth of sprouting axons into the appropriate distal fascicles and therefore delays and limits nerve regeneration. Both surgical techniques and pharmacological agents are developed to reduce injury induced scarring but despite this nerve regeneration is frequently incomplete. The aim of the present review is to provide the reader a clear overview of the current knowledge with respect to collagens in the peripheral nervous system and to emphasize its role after nerve injury.
Abstract: The transcriptional activator retinoic acid (RA) supports axonal regeneration of several neuronal cell populations in vitro, and it has been suggested that its receptor RARbeta2 may be used to support axonal regeneration in the adult mammalian spinal cord. We have previously shown that spinal cord injury induces activity of the RA synthesizing enzyme retinaldehyde dehydrogenase (RALDH)2 in NG2-positive cells. This report quantifies the increase of RALDH2 protein in the injured spinal cord and characterizes the RALDH2/NG2 expressing cells probably as a unique RA synthesizing subpopulation of activated oligodendrocyte precursors or "polydendrocytes". In the uninjured spinal cord low levels of RALDH2 are present in oligodendrocytes as well as in the meninges and in blood vessels. Following injury there is a significant increase in RALDH2 in these latter two tissues and, given that the RALDH2/NG2 positive cells are clustered in the same area, this implies that these are specific foci of RA synthesis. It is presumed that these cells release RA in a paracrine fashion in the region of the wound; however, the RALDH2/NG2-immunoreactive cells expressed the retinoid receptors RARalpha, RARbeta, RXRalpha and RXRbeta, suggesting that RA also serves an autocrine function.
Abstract: The subthalamic nucleus (STN) plays an important role in motor and non-motor behavior in Parkinson's disease, but its involvement in gait functions is largely unknown. In this study, we investigated the role of the STN on gait in a rat model of PD using the CatWalk method. Parkinsonian rats received bilateral high frequency stimulation (HFS) with different stimulation amplitudes of the STN. Rats were rendered parkinsonian by bilateral injections of 6-hydroxydopamine (6-OHDA) into the striatum. One group of 6-OHDA animals was implanted bilaterally with stimulation electrodes at the level of the STN. Stimulations were performed at 130 Hz (frequency), 60 micros (pulse width) and varying amplitudes of 0, 3, 30 and 150 microA. Rats were evaluated in an automated quantitative gait analysis method (CatWalk method). After behavioral evaluations, rats were killed and the brains processed for histological stainings to determine the impact of the dopaminergic lesion (tyrosine hydroxylase immunohistochemistry) and the localization of the electrode tip (hematoxylin-eosin histochemistry). Results show that bilateral 6-OHDA infusion significantly decreased (70%) the number of dopaminergic cells in the substantia nigra pars compacta (SNc). Due to 6-OHDA treatment, the gait parameters changed considerably. There was a general slowness. The most pronounced effects were seen at the level of the hind paws. Due to implantation of STN electrodes the step pattern changed. STN electrical stimulation improved the general slowness but induced slowing of the forelimb movement. Furthermore, we found that HFS with a medium amplitude significantly changed speed, the so-called dynamic aspect of gait. The static features of gait were only significantly influenced with low amplitude. Remarkably, STN stimulation affected predominantly the forepaws/limbs.
Abstract: An aberrant cholesterol metabolism in the brain may contribute to the pathogenesis of Alzheimer's disease (AD). The LDL receptor (LDLR) regulates plasma cholesterol levels and recently we and others obtained evidence that it is also involved in regulating brain cholesterol homeostasis. Moreover, we found that LDLR-deficient mice display impaired spatial memory. Because cholesterol, in part derived from cellular uptake via LDLR, is required for peripheral cell proliferation and growth, we examined the effect of absence of the LDLR on hippocampal proliferation and the density of synaptic connections. Mice deficient for the LDLR displayed a reduced number of proliferating (BrdU-labeled) cells in the hippocampus as compared to wild type control mice. In addition, the number of synaptophysin-immunoreactive presynaptic boutons in the hippocampal CA1 and the dentate gyrus (DG) areas, but not in cortical areas, was lower in the LDLR-knockout mice than in the control mice. In vitro experiments showed that LDLR activity is increased when cell growth is enhanced by the addition of N2 supplement. This further supports a role for the LDLR in the outgrowth of neurites. These findings support the notion that, similar to its role in the periphery, the LDLR is important for the cellular uptake of cholesterol in the brain and that disturbance of this process affects neuronal plasticity.
Abstract: A variety of animal models for neurological disease and injury exist and locomotor performance is an important outcome parameter in studies employing these models. The CatWalk, an automated quantitative gait analysis method is a method to study over-ground locomotor performance in large groups of animals. In the present study, we used the CatWalk which allowed us to investigate strain differences in over-ground locomotion in three commonly used strains of laboratory rat (i.e. Lewis, Wistar and Sprague-Dawley rats) based on objective data-analysis in a large number of animals. The present results revealed marked strain differences on the static paw parameters; base-of-support, and the relative paw position. Furthermore, strain differences were noted on the static parameter stride length and the dynamic parameters stance-, swing- and stepcycle duration, which are due logically to morphological differences between strains. The parameters related to coordination did not reveal any differences between the strains. Furthermore, the swing duration and the cruciate and alternate patterns i.e. regular step patterns Ca ("cruciate" pattern type a) and Ab ("alternate" pattern type b) were shown to be differentially affected by the locomotor speed. We conclude that differences in gait traits exist between the three laboratory rat strains investigated and several of the examined gait parameters showed strain dependent interdependency with locomotor speed.
Abstract: The physiological reactions after spinal cord injury are accompanied by local synthesis of the transcriptional activator retinoic acid (RA). RA exerts its effects by binding to retinoic acid receptors (RAR) which heterodimerize with retinoid X receptors (RXR) and then act as ligand-activated transcription factors. To identify possible cellular targets of RA we investigated protein levels and cellular distribution of retinoid receptors in the rat spinal cord at 4, 7, 14 and 21 days after a contusion injury. In the nonlesioned spinal cord, immunoreactivity for RARalpha, RXRalpha, RXRbeta and RXRgamma was localized in the cytosol of neurons, that of RXRalpha and RXRbeta in astrocytes and that of RARalpha, RXRalpha and RXRgamma in some oligodendrocytes. After contusion injury RARalpha and all RXRs appeared in the cell nuclei of reactive microglia and macrophages. This nuclear staining began at 4 days, was most prominent at 7 and 14 days and had decreased at 21 days after injury. A similar nuclear translocation was also observed for the RARalpha, RXRalpha and RXRbeta staining in neurons situated around the border of the contusion. These observations suggest that RA participates as a signal for the physiological responses of microglia and neurons after CNS injury.
Abstract: Olfactory ensheathing cell (OEC) transplants stimulate axon regeneration and partial functional recovery after spinal cord injury. However, it remains unclear whether enriched OEC or mixed transplants of OEC and olfactory nerve fibroblasts (ONF) are optimal for stimulating axon regrowth. The neurite outgrowth stimulating effects of enriched OEC, ONF, and mixed OEC/ONF cultures on neonatal cerebral cortical neurons were compared using co-cultures. We show that (1) OEC are more neurite outgrowth promoting than ONF, and (2) ONF do not enhance the neurite outgrowth stimulating effects of OEC in mixed OEC/ONF cultures. Hence, our data indicate that there is no preference for the use of enriched OEC or mixed OEC/ONF cultures with respect to stimulation of neurite growth in vitro.
Abstract: Voluntary locomotor training as induced by enriched housing of rats stimulates recovery of locomotion after spinal cord injury (SCI). Generally it is thought that spinal neural networks of motor- and interneurons located in the ventral and intermediate laminae within the lumbar intumescence of the spinal cord, also referred to as central pattern generators (CPGs), are the 'producers of locomotion' and play a pivotal role in the amelioration of locomotor deficits after SCI. It has been suggested that locomotor training provides locomotor-specific sensory feedback into the CPGs, which stimulates remodeling of central nervous system pathways, including motor systems. Several molecules have been proposed to potentiate this process but the underlying mechanisms are not yet known. To understand these mechanisms, we studied the role of insulin-like growth factor (IGF) I in functional recovery from SCI under normal and enriched environment (EE) housing conditions. In a first experiment, we discovered that subcutaneous administration of IGF-I resulted in better locomotor recovery following SCI. In a second experiment, detailed analysis of the observed functional recovery induced by EE revealed full recovery of hindlimb coordination and stability of gait. This EE-dependent functional recovery was attenuated by alterations in the pre-synaptic bouton density within the ventral gray matter of the lumbar intumescence or CPG area. Neutralization of circulating IGF-I significantly blocked the effectiveness of EE housing on functional recovery and diminished the EE-induced alterations in pre-synaptic bouton density within the CPG area. These results support the use of IGF-I as a possible therapeutic aid in early rehabilitation after SCI.
Abstract: An area of increasing interest in spinal cord injury (SCI) research is the development of multi-factorial strategies to promote repair. In this respect, a prominent role is played by cell transplantation, the reparative effect of which can be enhanced by additional use of neurotrophic factors. Immature astrocytes have shown their merit in stimulating axon regeneration upon transplantation into the injured spinal cord. Brain-derived neurotrophic factor (BDNF) influences a wide range of descending axon tracts in the injured spinal cord. In the present study, we hypothesized that the neurite outgrowth of neonatal cortical neurons on immature astrocytes is enhanced in the presence of BDNF. To test this hypothesis, neonatal cortical neurons were cultured on neonatal astrocytes for 2 days in absence or presence of BDNF. The length of the longest neurite and the number of primary neurites per neuron were taken as measures to study neurite outgrowth. We show that BDNF dose-dependently enhanced neurite outgrowth of neonatal cerebral cortical neurons grown on immature astrocytes. Compared to conditions without BDNF, the length of the longest neurite increased by 25.5 and 28.8% in presence of 10 and 100 pg/ml BDNF, respectively. BDNF did not alter the density of the immature astrocytes. We conclude that the presence of BDNF enhances the neurite outgrowth on immature astrocytes. A multi-factorial strategy based on transplantation of neonatal astrocytes in the presence of additional BDNF is recommended and may stimulate axon regrowth after experimental injury to the central nervous system.
Abstract: Spinal cord stimulation (SCS) is an established treatment for chronic neuropathic pain. However, in recent studies conflicting results regarding the effect of SCS were noted in a selected group of patients suffering from complex regional pain syndrome and mechanical allodynia. In the present study we investigated the pain relieving effect of SCS in a rat experimental model of neuropathic pain as related to the severity of mechanical allodynia. Adult male rats (n=45) were submitted to a unilateral sciatic nerve ligation. The level of allodynia was tested using the withdrawal response to tactile stimuli with the von Frey test. A portion of these rats developed marked tactile hypersensitivity in the nerve-lesioned paw (von Frey test), similar to "tactile allodynia" observed after nerve injury in humans. Prior to SCS treatment the rats were subdivided into three groups based on the level of allodynia: mild, moderate and severe. All allodynic rats were treated with SCS (n=27) for 30 min (f=50 Hz; pulse width 0.2 ms and stimulation at 2/3 of motor threshold) at 16 days post-injury. Our data demonstrate a differential effect of SCS related to the severity of the mechanical allodynia. SCS leads to a faster and better pain relief in mildly allodynic rats as compared with the more severely allodynic rats. Thus, we suggest that the selection and subdivision of patient groups similar to those defined in our experimental setting (mild, moderate and severe allodynic) may provide better pre-treatment prediction of possible therapeutic benefits of SCS.
Abstract: Transplantation of mixed cultures containing olfactory ensheathing cell (OEC) and olfactory nerve fibroblasts (ONF) has been shown to stimulate regrowth of both acutely and chronically injured corticospinal (CS) axons across small spinal cord lesion gaps. Here, we used a multifactorial transplantation strategy to stimulate regrowth of chronically injured CS axons across large spinal cord lesion gaps. This strategy combined the transplantation of aligned OEC/ONF-biomatrix complexes, as described previously (Deumens et al. [2004] Neuroscience 125:591-604), within the lesion gap with additional OEC/ONF injections rostral and caudal to the lesion site. We show an enhanced presence of injured CS axons directly rostral to the lesion gap, with no effects on injured CS axons at or caudal to the lesion gap. Furthermore, injured CS axons did not penetrate the OEC/ONF-biomatrix complex within the lesion gap. The enhanced presence of CS axons rostral to the lesion gap was not accompanied by any recovery of behavioral parameters assessed with the BBB locomotor rating scale or CatWalk gait analysis. We conclude that our multifactorial transplantation strategy should be optimized to create an OEC/ONF continuum in the injured spinal cord and thereby stimulate regrowth of injured CS axons across large spinal lesion gaps.
Abstract: Gait analysis plays an important role in the assessment of neurological function in many disease models. In this review, we focus on the newly developed CatWalk system for gait analysis. CatWalk was originally developed as a tool to enhance assessment of functional outcome in spinal cord injury (SCI) models. Although it is also of value in models of among others (neuropathic) pain and peripheral nerve damage, we will limit ourselves to its use in SCI models in this review. The system is positioned against well-established locomotor function tests, and it is indicated how CatWalk can enhance the usefulness of such tests. Development of the system started with the idea that it should enable objective assessment of coordination, and powerful measures of coordination are nowadays included in the analysis options provided by CatWalk. Therefore, a major part of this review is devoted to the history and meaning of these coordination measures.
Abstract: Regrowth of injured axons across rather small spinal cord lesion gaps and subsequent functional recovery has been obtained after many interventions. Long-distance regeneration of injured axons across clinically relevant large spinal lesion gaps is relatively unexplored. Here, we aimed at stimulating long-distance regrowth of the injured corticospinal (CS) tract. During development, an oriented framework of immature astrocytes is important for correct CS axon outgrowth. Furthermore, a continuous growth promoting substrate may be needed to maintain a CS axon regrowth response across relatively large spinal lesion gaps. Hence, we acutely transplanted poly(D,L)-lactide matrices, which after seeded with immature astrocytes render aligned astrocyte-biomatrix complexes (R. Deumens, et al. Alignment of glial cells stimulates directional neurite growth of CNS neurons in vitro. Neuroscience 125 (3) (2004) 591-604), into 2-mm long dorsal hemisection lesion gaps. In order to create a growth promoting continuum, astrocyte suspensions were also injected rostral and caudal to the lesion gap. During 2 months, locomotion was continuously monitored. Histological analysis showed that astrocytes injected into host spinal tissue survived, but did not migrate. None of the astrocytes on the biomatrices survived within the lesion gap. BDA-labeled CS axons did not penetrate the graft. However, directly rostral to the lesion gap, 120.9+/-38.5% of the BDA-labeled CS axons were present in contrast to 12.8+/-3.9% in untreated control animals. The observed anatomical changes were not accompanied by locomotor improvements as analyzed with the BBB and CatWalk. We conclude that although multifactorial strategies may be needed to stimulate long-distance CS axon regrowth, future studies should focus on enhancing the viability of cell/biomatrix complexes within large spinal lesion gaps.
Abstract: Cellular transplantation, including olfactory ensheathing cells (OEC) and olfactory nerve fibroblasts (ONF), after experimental spinal cord injury in the rat has previously resulted in regrowth of severed corticospinal (CS) axons across small lesion gaps and partial functional recovery. In order to stimulate CS axon regrowth across large lesion gaps, we used a multifactorial transplantation strategy to create an OEC/ONF continuum in spinal cords with a 2-mm-long dorsal hemisection lesion gap. This strategy involved the use of aligned OEC/ONF-poly(D,L)-lactide biomatrix bridges within the lesion gap and OEC/ONF injections at 1 mm rostral and caudal to the lesion gap. In order to test the effects of this complete strategy, control animals only received injections with culture medium rostral and caudal to the lesion gap. Anatomically, our multifactorial intervention resulted in an enhanced presence of injured CS axons directly rostral to the lesion gap (65.0 +/- 12.8% in transplanted animals versus 13.1 +/- 3.9% in control animals). No regrowth of these axons was observed through the lesion site, which may be related to a lack of OEC/ONF survival on the biomatrices. Furthermore, a 10-fold increase of neurofilament-positive axon ingrowth into the lesion site as compared to untreated control animals was observed. With the use of quantitative gait analysis, a modest recovery in stride length and swing speed of the hind limbs was observed. Although multifactorial strategies may be needed to stimulate repair of large spinal lesion gaps, we conclude that the combined use of OEC/ONF and poly(D,L)-lactide biomatrices is rather limited.
Abstract: Retinoic acid (RA) promotes growth and differentiation in many developing tissues but less is known about its influence on CNS regeneration. We investigated the possible involvement of RA in rat spinal cord injury (SCI) using the New York University (NYU) impactor to induce mild or moderate spinal cord contusion injury. Changes in RA at the lesion site were determined by measuring the activity of the enzymes for its synthesis, the retinaldehyde dehydrogenases (RALDHs). A marked increase in enzyme activity occurred by day 4 and peaked at days 8-14 following the injuries. RALDH2 was the only detectable RALDH present in the control or injured spinal cord. The cellular localization of RALDH2 was identified by immunostaining. In the noninjured spinal cord, RALDH2 was detected in oligodendroglia positive for the markers RIP and CNPase. Expression was also intense in the arachnoid membrane surrounding the spinal cord. After SCI the increase in RALDH2 was independent of the RIP- and CNPase-positive cells, which were severely depleted. Instead, RALDH2 was present in a cell type not previously identified as capable of synthesizing RA, that expressed NG2 and that was negative for markers of astrocytes, oligodendroglia, microglia, neurons, Schwann cells and immature lymphocytes. We postulate that the RALDH2- and NG2-positive cells migrate into the injured sites from the adjacent arachnoid membrane, where the RALDH2-positive cells proliferate substantially following SCI. These findings indicate that close correlations exist between RA synthesis and SCI and that RA may play a role in the secondary events that follow acute SCI.
Abstract: Axons within the adult mammalian central nervous system do not regenerate spontaneously after injury. Upon injury, the balance between growth promoting and growth inhibitory factors in the central nervous system dramatically changes resulting in the absence of regeneration. Axonal responses to injury vary considerably. In central nervous system regeneration studies, the spinal cord has received a lot of attention because of its relatively easy accessibility and its clinical relevance. The present review discusses the axon-tract-specific requirements for regeneration in the rat. This knowledge is very important for the development and optimalization of therapies to repair the injured spinal cord.
Abstract: The Basso, Beattie and Bresnahan (BBB) locomotor rating scale is the most widely used open field test and has been accepted as a valid way to assess locomotor function after spinal cord contusion injury in the rat. A limitation within the BBB locomotor rating scale is the correct assessment of forelimb (FL)-hindlimb (HL) coordination. This limitation can have major implications for the final assessment of locomotor function. In the present study, we show an objective method to assess coordination based on the regularity index (RI), achieved through the use of the CatWalk method. The RI grades the degree of coordination as the result of the number of normal step sequence patterns multiplied by four and divided by the total amount of paw placements. Using the RI, single walkway crossings can be objectively analyzed on coordination. Integration of the CatWalk based coordination into the BBB scale indicates that objective analysis of coordination results in reliable and more sensitive assessment of locomotor function. This new method has been tested successfully in determination of positive effects of enriched housing on functional recovery after spinal cord injury (SCI).
Abstract: Olfactory ensheathing cells (OECs) together with olfactory nerve fibroblasts (ONFs) and neonatal astrocytes are potent stimulators of neurite growth in adulthood and during development, respectively. Since it is known that alignment of glial cells is important for the correct outgrowth of axon tracts, it was hypothesized that the alignment of glial cells stimulates directional and enhanced neurite outgrowth. Adult OEC/ONF and neonatal astrocytes were cultured either on biodegradable poly(d,l)-lactide matrices or in Petri dishes for 4 days. Thereafter neonatal cerebral cortical neurons were added. After a 2-days coculture period the cultures were fixed and processed for a combined MAP-2 and phosphorylated neurofilament (RT97) staining. The neurite growth (neurite elongation and neurite formation) and the neurite direction were assessed. We show that (1). OEC/ONF cultures are more potent in stimulating the length of the longest neurite of cocultured neurons, (2). alignment of glial is achieved in vitro on our biomatrices, (3). aligned glial/biomatrix complexes do not enhance neurite growth, and (4). aligned glial/biomatrix complexes direct neurite outgrowth. These data have significant implications for in vivo experiments focusing on glial transplantation. Transplanting glial/biomatrix complexes may stimulate the directional regrowth of severed axons across a lesion site.
Abstract: The nitric oxide (NO)-cyclic GMP (cGMP) signaling pathway is assumed to play an important role in processes underlying learning and memory. We used phosphodiesterase type 5 (PDE5) inhibitors to study the role of cGMP in object- and spatial memory. Our results and those reported in other studies indicate that elevated hippocampal cGMP levels are required to improve the memory performance of rodents in object recognition and passive avoidance learning, but not in spatial learning. The timing of treatment modulates the effects on memory and strongly supports a role for cGMP in early stages of memory formation. Alternative explanations for the improved memory performance of PDE5 inhibitors are also discussed. Immunocytochemical studies showed that in vitro slice incubations with PDE5 inhibitors increase NO-stimulated cGMP levels mainly in hippocampal varicose fibers. Reviewing the available data on the localization of the different components of the NO-cGMP signaling pathway, indicates a complex interaction between NO and cGMP, which may be independent of each other. It is discussed that further studies are needed, immunocytochemical and behavioral, to better understand the cGMP-mediated molecular mechanisms underlying memory formation.
Abstract: Recent high quality papers have renewed interest in the phenomenon of neurogenesis within the adult mammalian brain. Many studies now show that neurogenesis can be modulated by environmental factors including physical activity, stress, and learning. These findings have considerable implications for neuroscience in general, including the study of learning and memory, neural network plasticity, aging, neurodegeneration, and the recovery from brain injury. Although new light has been shed on this field, many contradictory findings have been reported. Here we propose two principle issues which underlie these inconsistencies, with particular focus on the interaction between learning and neurogenesis. The first issue relates to the basic methodology of measuring the generation of new brain cells, i.e., proliferation, as compared to survival of the newly made cells. Mostly, measures of neurogenesis reported are a combination of proliferation and survival, making it impossible to distinguish between these separate processes. The second aspect is in regards to the role of environmental factors which can affect both proliferation and survival independently. Especially the interaction between stress and learning is of importance since these might counteract each other in some circumstances. Reviewing the literature while taking these issues into account indicates that, in contrast to some findings, cell proliferation in the dentate gyrus of the hippocampus as a result of learning cannot be ruled out yet. On the other hand, increased survival of granule cells in the dentate gyrus as a result of hippocampal-dependent learning has been clearly demonstrated. Moreover, this learning-induced survival of granule cells, which were born before the actual learning experience, might provide a molecular mechanism for the 'use it or lose it' principle.
Abstract: In the present study, we tested the spatial learning behavior of four different mouse strains (129/Sv, BALB/c, C57BL and Swiss) in a newly developed circular maze. The maze was based on the circular Barnes maze, which was initially developed for rats. Since mice do not readily enter holes in floor, additional reinforcers (positive and negative) or pretraining procedures have been used to train the animals. Because these methods are not always desirable, we examined whether mice are more willing to enter escape holes (12), which were located in the rim of the apparatus. C57BL mice appeared to improve their performance on three different measures of spatial learning: latency to find escape hole, distance to escape hole and errors (visit to other holes). The other strains also improved their performance although this was only seen for one parameter (i.e. 129/Sv and BALB/c on latency, and Swiss on distance). When the animals were trained to find another location, it was found that only the performance of the C57BL mice was transiently impaired. The C57BL mice were also very efficient in improving their performance in a repeated acquisition paradigm (six trials per day on four successive days). Applying a probe trial procedure, a clear preference for the goal location was found. These findings indicate that these mice used a spatial search strategy. Although this circular maze can be used as an additional tool to assess spatial learning in (genetically modified) mice, it is noted that strain differences in spatial learning seem to be independent of task. Further, our data with different strains indicate that different measures of behavior should be evaluated to assess the spatial learning performance of mice.
