The neuroprotective effects of fibronectin mats and fibronectin peptides following spinal cord injury in the rat.

We have shown previously that mats made from the glycoprotein fibronectin are permissive for axonal growth when implanted into the injured spinal cord. Recent evidence has indicated that fibronectin and its peptides also have neuroprotective effects in the CNS. We have therefore examined the neuroprotective effects of fibronectin applied to a spinal cord injury site. Adult rats with fibronectin mats implanted into a spinal cord lesion cavity had decreased apoptosis in the intact adjoining spinal cord tissue at 1 and 3 days post-injury compared to rats that had gelfoam implanted into the lesion cavity. Rats with fibronectin mat implants also showed enhanced hindlimb locomotor performance for the first 3 weeks post-surgery compared to control animals. To further examine the neuroprotective potential of fibronectin following spinal cord injury, we examined the effects of placing fibronectin mats over the site of a spinal cord hemisection or of delivering a solution derived from a dissolved fibronectin mat. The effects of these treatments were compared with control animals and animals that were treated with a fibronectin peptide (PRARIY) that has been shown to decrease secondary damage in a rodent model of cerebral ischemia. Results showed that both types of fibronectin mat treatment resulted in decreased lesion size, apoptosis, and axonal damage within the first week post-injury compared to control animals and were comparable in their neuroprotective efficacy to treatment with the fibronectin peptide. The results of the current study indicate that fibronectin based biomaterials have neuroprotective effects following spinal cord injury, in addition to their previously reported ability to promote axonal regeneration.

Reg-2 expression in dorsal root ganglion neurons after adjuvant-induced monoarthritis.

Reg-2 is a secreted protein that is expressed de novo in motoneurons, sympathetic neurons, and dorsal root ganglion (DRG) neurons after nerve injury and which can act as a Schwann cell mitogen. We now show that Reg-2 is also upregulated by DRG neurons in inflammation with a very unusual expression pattern. In a rat model of monoarthritis, Reg-2 immunoreactivity was detected in DRG neurons at 1 day, peaked at 3 days (in 11.6% of DRG neurons), and was still present at 10 days (in 5%). Expression was almost exclusively in the population of DRG neurons that expresses the purinoceptor P2X(3) and binding sites for the lectin Griffonia simplicifolia IB4, and which is known to respond to glial cell line-derived neurotrophic factor (GDNF). Immunoreactivity was present in DRG cell bodies and central terminals in the dorsal horn of the spinal cord. In contrast, very little expression was seen in the nerve growth factor (NGF) responsive and substance P expressing population. However intrathecal delivery of GDNF did not induce Reg-2 expression, but leukemia inhibitory factor (LIF) had a dramatic effect, inducing Reg-2 immunoreactivity in 39% of DRG neurons and 62% of P2X(3) cells. Changes in inflammation have previously been observed predominantly in the neuropeptide expressing, NGF responsive, DRG neurons. Our results show that changes also take place in the IB4 population, possibly driven by members of the LIF family of neuropoietic cytokines. In addition, the presence of Reg-2 in central axon terminals implicates Reg-2 as a possible modulator of second order dorsal horn cells.

Neurochemical characterization of neuronal populations expressing protein kinase C gamma isoform in the spinal cord and gracile nucleus of the rat.

Protein kinase C gamma (PKCgamma) is widely distributed throughout the CNS and is thought to play a role in long term hyper-excitability in nociceptive neurones. Here, we provide the first report of PKCgamma cells in the dorsal column nuclei of the adult rat. Retrograde labeling of PKCgamma cells from the thalamus with choleragenoid revealed that 25% of the PKCgamma positive gracile cells projected to the thalamus. Further, we have characterized the distribution of PKCgamma within gracile nucleus in terms of colocalization with various neurotransmitter receptors or enzymes and calcium binding proteins, and compared this with PKCgamma colocalization in cells of laminae I-III of the spinal cord. We show that approximately 90% of the PKCgamma cells in the gracile nucleus and 60% in the dorsal horn were immuno-positive for the AMPA receptor subunit glutamate 2/3 (GluR2/3). Little coexpression was seen with neurokinin 1 receptor, nitric oxide synthase (NOS) and the AMPA receptor subunit GluR1, markers of distinct neuronal subpopulations. In the spinal cord, a quarter of PKCgamma cells expressed calbindin, but very few cells did so in the gracile nucleus. Electrical stimulation at c-fiber strength of the normal or injured sciatic nerve was used to induce c-fos as a marker of postsynaptic activation in the spinal cord and gracile nucleus. Quantitative analysis of the number of PKCgamma positive gracile cells that expressed also c-fos increased from none to 24% after injury, indicating an alteration in the sensory activation pattern in these neurones after injury. C-fos was not induced in inner lamina II following c-fiber electrical stimulation of the intact or axotomized sciatic nerve, indicating no such plasticity at the spinal cord level. As dorsal column nuclei cells may contribute to allodynia after peripheral nerve injury, pharmacological modulation of PKCgamma activity may therefore be a possible way to ameliorate neuropathic pain after peripheral nerve injury.

A combination of intravenous and dietary docosahexaenoic acid significantly improves outcome after spinal cord injury.

Previous studies have shown that omega-3 polyunsaturated fatty acids such as alpha-linolenic acid and docosahexaenoic acid (DHA) are neuroprotective in models of spinal cord injury (SCI) in rodents. However, the mechanism of action underlying these effects has not been elucidated, and the optimum treatment regime remains to be defined. We have therefore carried out a detailed analysis of the effects of DHA in adult rats subject to thoracic compression SCI. Saline or DHA (250 nmol/kg) was administered intravenously (i.v.) 30 min after compression. After injury, the saline group received a standard control diet for 1 or 6 weeks, whereas DHA-injected animals received either a control or a DHA-enriched diet (400 mg/kg/day) for 1 or 6 weeks. Other groups received a DHA-enriched diet only for 1 week following injury, or received acute DHA (250 nmol/kg; i.v.) treatment delayed up to 3 h after injury. We also assessed oxidative stress and the inflammatory reaction at the injury site, neuronal and oligodendrocyte survival and axonal damage and the locomotor recovery. At 24 h, lipid peroxidation, protein oxidation, RNA/DNA oxidation and the induction of cyclooxygenase-2 were all significantly reduced by i.v. DHA administration. At 1 week and 6 weeks, macrophage recruitment was reduced and neuronal and oligodendrocyte survival was substantially increased. Axonal injury was reduced at 6 weeks. Locomotor recovery was improved from day 4, and sustained up to 6 weeks. Rats treated with a DHA-enriched diet in addition to the acute DHA injection were not significantly different from the acute DHA-treated animals at 1 week, but at 6 weeks showed additional improvements in both functional and histological outcomes. DHA treatment was ineffective if the acute injection was delayed until 3 h post-injury, or if the DHA was administered for 1 week solely by diet. Our results in a clinically relevant model of SCI show that significant neuroprotection can be obtained by combining an initial acute i.v. injection of DHA with a sustained dietary supplementation. Given that the safety and tolerability of preparations enriched in omega-3 fatty acids is already well-documented, such a combined DHA treatment regime deserves consideration as a very promising approach to SCI management.

Erythropoietin and carbamylated erythropoietin are neuroprotective following spinal cord hemisection in the rat.

The cytokine erythropoietin (EPO) has been shown to be neuroprotective in a variety of models of central and peripheral nervous system injury. Derivatives of EPO that lack its erythropoietic effects have recently been developed, and the initial reports suggest that they have a neuroprotective potential comparable to that of EPO. One such derivative is carbamylated EPO (CEPO). In the current study we compared the effects of treatment with EPO and CEPO on some of the early neurodegenerative events that occur following spinal cord injury (SCI) induced by hemisection. Adult male Wistar rats received a unilateral hemisection of the spinal cord. Thirty minutes and 24 h following injury, animals received an intraperitoneal injection of saline, EPO (40 microg/kg) or CEPO (40 microg/kg). Results indicated that 3 days post-injury, both CEPO and EPO decreased to a similar extent the size of the lesion compared with control animals. Both compounds also decreased the number of terminal transferase-mediated dUTP nick-end labelling (TUNEL)-labelled apopotic nuclei around the lesion site, as well as the number of axons expressing the injury marker beta-amyloid precursor protein. EPO and CEPO also increased Schwann cell infiltration into the lesion site, although neither compound had any effect on macrophage infiltration either within the lesion site itself or in the surrounding intact tissue. In addition, immunohistochemistry showed an increased expression of both the EPO receptor and the beta common receptor subunit, the components of the receptor complex proposed to mediate the neuroprotective effects of EPO and CEPO in neurons near the site of the injury. The results show that not only does CEPO have an efficacy comparable to that of EPO in its neuroprotective potential following injury, but also that changes in the receptors for these compounds following SCI may underlie their neuroprotective efficacy.

Spinal cord compression and dorsal root injury cause up-regulation of activating transcription factor-3 in large-diameter dorsal root ganglion neurons.

Spinal cord injury causes damage to ascending and descending tracts, as well as to local circuits, but relatively little is known about the effect of such injury on sensory neurons located within adjoining ganglia. We have therefore used immunocytochemistry for activating transcription factor-3 (ATF3), a sensitive marker of axonal damage, in order to examine the effects of spinal cord injury in rats on dorsal root ganglion (DRG) neurons. A 50-g static compression injury applied to the dorsal surface of the T12 thoracic spinal cord led to an up-regulation of ATF3 that was maximal at 1 day and affected 12-14% of DRG neurons in ganglia caudal to the injury (T13-L3). A similar response was seen after a T12 hemisection that transected the dorsal columns except that compression injury, but not hemisection, also evoked ATF3 expression in ganglia just rostral to the injury (T10, T11). ATF3 was up-regulated exclusively in DRG neurons that were of large diameter and immunoreactive for heavy neurofilament. Small-diameter cells, including the population that binds the lectin Grifffonia simplicifolia IB4, did not express ATF3 immunoreactivity. A similar pattern of ATF3 expression was induced by dorsal rhizotomy. The data show for the first time that ATF3 is up-regulated after spinal cord and dorsal root injury, but that this up-regulation is confined to the large-diameter cell population.

Characterization of non-neuronal elements within fibronectin mats implanted into the damaged adult rat spinal cord.

Previous studies have shown that mats made from fibronectin (FN) integrate well into spinal cord lesion sites and support extensive axonal growth. Using immunohistochemistry, we have investigated the non-neuronal factors that contribute to these properties. Extensive vascularization was observed in FN mats by 1 week along with heavy macrophage infiltration by 3 days post-implantation. By 1 week post-implantation, laminin tubules had formed and were associated with axons and p75 immunoreactive Schwann cells. By 4 weeks post-implantation, most axons were associated with Schwann cell derived myelin. Few oligodendrocytes were present within the mat, even with an increase in the number of oligodendrocyte precursors around the implant site by 7 days post-implantation. Astrocyte proliferation also occurred in the intact tissue, with a prominent glial scar forming around the implant within 4 weeks. However, by 2 months post-implantation astrocytes were present in the FN implant site and were intermingled with the axons. Axonal ingrowth and integration of the FN mats is probably due to the ability of FN mats to support and organize infiltration of Schwann cells and deposition of laminin. At later time points, myelinated axons remain in the implant site, even after other elements (e.g. macrophages and laminin) have disappeared. Both of these properties are likely to be important in the design of biomaterial bridges for CNS regeneration.

The effects of treatment with antibodies to transforming growth factor beta1 and beta2 following spinal cord damage in the adult rat.

We recently showed axonal ingrowth into fibronectin (FN) mats implanted into the spinal cord. However, little axonal growth was found from FN mats into intact spinal cord. Previous research has shown that this is due in part to astrocytosis around an area of CNS damage. Antibodies to transforming growth factor beta (TGFbeta) can diminish this astrocytosis. TGFbeta also has effects on macrophages and Schwann cells, both of which infiltrate the spinal cord following damage. We examined the axonal, Schwann cell, and macrophage infiltration into FN mats as well as the level of astrocytosis and chondroitin sulfate proteoglycan NG2 around FN implants incubated in TGFbeta antibodies and implanted into a lesion cavity in the spinal cord. We also examined the effects of applying TGFbeta antibodies to a spinal cord hemisection site. Anti-TGFbeta1 within FN mats resulted in extensive cavitation, with the area of damage being larger than the original lesion. Cavitation was also seen following application of anti-TGFbeta1 to a spinal cord hemisection site. No cavitation was seen following saline, non-immune IgG or anti-TGFbeta2 treatment. However, anti-TGFbeta2 treatment did result in diminished axonal growth and Schwann cell and macrophage infiltration. Around the implant site, anti-TGFbeta2 treatment resulted in a reduction in the level of astrocytosis but had not effect on levels of NG2. Similar effects were seen following anti-TGFbeta2 application to spinal cord hemisection sites. The results suggest that anti-TGFbeta1 exacerbates secondary damage by preventing the anti-inflammatory effect of endogenous TGFbeta1. Anti-TGFbeta2 did not enhance axonal regeneration in this model but did slightly reduce astrocytosis.

Stimulating regeneration in the damaged spinal cord.

Great progress has been made in recent years in experimental strategies for spinal cord repair. In this review we describe two of these strategies, namely the use of neurotrophic factors to promote functional regeneration across the dorsal root entry zone (DREZ), and the use of synthetic fibronectin conduits to support directed axonal growth. The junction between the peripheral nervous system (PNS) and central nervous system (CNS) is marked by a specialized region, the DREZ, where sensory axons enter the spinal cord from the dorsal roots. After injury to dorsal roots, axons will regenerate as far as the DREZ but no further. However, recent studies have shown that this barrier can be overcome and function restored. In animals treated with neurotrophic factors, regenerating axons cross the DREZ and establish functional connections with dorsal horn cells. For example, intrathecal delivery of neurotrophin 3 (NT3) supports ingrowth of A fibres into the dorsal horn. This ingrowth is revealed using a transganglionic anatomical tracer (cholera toxin subunit B) and analysis at light and electron microscopic level. In addition to promoting axonal growth, spinal cord repair is likely to require strategies for supporting long-distance regeneration. Synthetic fibronectin conduits may be useful for this purpose. Experimental studies indicate that fibronectin mats implanted into the spinal cord will integrate with the host tissue and support extensive and directional axonal growth. Growth of both PNS and CNS axons is supported by the fibronectin, and axons become myelinated by Schwann cells. Ongoing studies are aimed at developing composite conduits and promoting axonal growth from the fibronectin back into the spinal cord.

Immunohistochemical expression of the alpha5 integrin subunit in the normal adult rat central nervous system.

We investigated the distribution of the alpha5 integrin subunit in the normal adult rat CNS using immunohistochemical methods. Results indicated that the alpha5 integrin subunit was expressed on the vast majority of neurons throughout the brain and spinal cord. In general, neurons showed diffuse cytoplasmic labelling, although many cortical neurons in layers 4 and 5 did show punctate labelling on the cell surface. In addition, axons within the white matter of the brainstem and caudal CNS areas were labelled, with the most intense labelling seen within the white matter of the spinal cord. In addition, labelling of astrocytes was seen throughout white matter, with particularly heavy astrocyte labelling in the spinal cord. The widespread distribution of the alpha5 subunit suggests a general function for the alpha5beta1 integrin receptor (the only integrin receptor that includes the alpha5 subunit) in the adult CNS. The increased expression of fibronectin, the only known ligand for the alpha5beta1 integrin receptor, known to occur around the site of a CNS lesion suggests a possible role for the alpha5beta1 receptor in the response of neurons in the vicinity of a CNS injury.

Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity.

The neuropeptide galanin is expressed developmentally in the dorsal root ganglion (DRG) and is rapidly up-regulated 120-fold after peripheral nerve section in the adult. Here we report that adult mice carrying a loss-of-function mutation in the galanin gene have a 13% reduction in the number of cells in the DRG associated with a 24% decrease in the percentage of neurons that express substance P. These deficits are associated with a 2.8- and 2.6-fold increase in the number of apoptotic cells in the DRG at postnatal days 3 and 4, respectively. After crush injury to the sciatic nerve, the rate of peripheral nerve regeneration is reduced by 35% with associated long-term functional deficits. Cultured DRG neurons from adult mutant mice demonstrate similar deficits in neurite number and length. These results identify a critical role for galanin in the development and regeneration of sensory neurons.

Changes in truncated trkB and p75 receptor expression in the rat spinal cord following spinal cord hemisection and spinal cord hemisection plus neurotrophin treatment.

Although numerous studies have examined the effects of neurotrophin treatment following spinal cord injury, few have examined the changes that occur in the neurotrophin receptors following either such damage or neurotrophin treatment. To determine what changes occur in neurotrophin receptor expression following spinal cord damage, adult rats received a midthoracic spinal cord hemisection alone or in combination with intrathecal application of brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3). Using immunohistochemical and in situ hybridization techniques, p75, trkA, trkB, and trkC receptor expression was examined throughout the spinal cord. Results showed that trkA, full-length trkB, and trkC receptors were not present in the lesion site but had a normal expression pattern in uninjured parts of the spinal cord. In contrast, p75 receptor expression occurred on Schwann cells throughout the lesion site. BDNF and NT-3 (but not saline) applied to the lesion site increased this expression. In addition, the truncated trkB receptor was expressed in the border between the lesion and intact spinal cord. Truncated trkB receptor expression was also increased throughout the white matter ipsilateral to the lesion and BDNF (but not NT-3 or saline) prevented this increase. The study is the first to show changes in truncated trkB receptor expression that extend beyond the site of a spinal cord lesion and is one of the first to show that BDNF and NT-3 affect Schwann cells and/or p75 expression following spinal cord damage. These results indicate that changes in neurotrophin receptor expression following spinal cord injury could influence the availability of neurotrophins at the lesion site. In addition, neurotrophins may affect their own availability to damaged neurons by altering the expression of the p75 and truncated trkB receptor.

trkA, trkB, and trkC messenger RNA expression by bulbospinal cells of the rat.

Previous research has shown that corticospinal as well as rubrospinal neurons express the high-affinity trkB and trkC receptors but not the high-affinity trkA receptor. To determine if bulbospinal neurons in other brainstem areas show the same pattern of trk receptor expression, bulbospinal cells were labelled via the injection of the retrograde tracer FluoroGold into the spinal cord. Brainstem sections were then processed for in situ hybridization using oligonucleotide probes to the trkA, trkB, and trkC receptors. The results indicated that, although trkA expression occurred in brainstem areas that contain bulbospinal neurons (e.g., the vestibular nuclei, and the pontine reticular formation), very few FluoroGold-labelled cells expressed the trkA receptor. In contrast, at least 90% of bulbospinal cells in each brainstem area examined expressed the trkB receptor. Quantitative analysis indicated differences in the level of trkB labelling between bulbospinal cells in different brainstem areas, with the highest levels seen in the locus coeruleus and magnocellular portion of the red nucleus, and the lowest levels seen in the medial and superior vestibular nuclei and the raphe obscurus. With the exception of the accessory trigeminal nucleus, over 84% of bulbospinal cells in each brainstem area also expressed the trkC receptor. TrkC receptor expression was greatest in the locus coeruleus and subcoeruleus and lowest in the accessory trigeminal nucleus, the raphe magnus, and the vestibular nuclei. Results indicate that, as with other descending pathways, virtually all bulbospinal pathways should be amenable to treatment with brain-derived neurotrophic factor, neurotrophin-4/5 or neurotrophin-3, but not nerve growth factor, following spinal cord damage.

Monocular enucleation prevents retinal ganglion-cell loss following neonatal visual cortex damage in cats.

Damage to primary visual cortex (VC) in young cats leads to severe retrograde degeneration of the dorsal lateral geniculate nucleus (dLGN) and selective transneuronal retrograde degeneration of a class of retinal ganglion cells (RGCs) that have a medium-size soma. Previous studies have shown that "programmed" RGC death associated with normal development in one eye can be attenuated by removal of the other eye, suggesting that binocular interactions can influence developmental RGC death. The present study investigated whether removal of one eye also attenuates the ganglion cell loss that accompanies an early VC lesion. Five one-week-old cats received a unilateral VC lesion (areas 17, 18, and 19), and three of these cats also underwent monocular enucleation at the same time. Two normal control animals also were examined. RGC measurements were made from flat-mounted retinae when the animals were 5 weeks old. Sampling was restricted to a retinal area corresponding to the retinotopic representation included in the VC lesion. Results indicate that there is a marked loss of medium-size RGCs in the hemiretinae projecting to the damaged hemisphere in cats that received a VC lesion alone. However, there is no such loss in VC-lesion animals that also have a monocular enucleation. These results indicate that the transneuronal RGC loss that occurs after an early visual cortex lesion can be influenced by binocular interactions.

NT-3, but not BDNF, prevents atrophy and death of axotomized spinal cord projection neurons.

Following spinal cord injury, projection neurons are frequently axotomized and many of the cells subsequently die. One goal in spinal injury research is to preserve damaged neurons so that ultimately they are accessible to regeneration-promoting strategies. Here we ask if neurotrophin treatment can prevent atrophy and death of axotomized sensory projection neurons. In adult rats, a hemisection was made in the thoracic spinal cord and axotomized neurons were retrogradely labelled with Fluoro-Gold. Four distinct populations of cells were identified in the lumbar spinal cord, and both numbers and sizes of labelled cells were assessed at different time points postlesion. A progressive and significant degeneration was observed over time with severe atrophy apparent in all cell populations and significant cell loss evident by 4 weeks postlesion. This time point was used to assess neurotrophin effects. Hemisected rats were treated with either neurotrophin 3 (NT-3) or brain-derived neurotrophic factor (BDNF, 12 microg/day for each), or a vehicle solution, delivered continuously to the lesion site via an osmotic minipump. Treatment with NT-3, but not BDNF, completely reversed cell atrophy in three of the four cell populations and also induced a significant increase in the number of surviving cells. In situ hybridization experiments showed trkB and trkC mRNA to be expressed in the majority of ascending spinal projection neurons, suggesting that these cells should be responsive to both BDNF and NT-3. However, only NT-3 treatment was neuroprotective, indicating that BDNF may not have reached the cell bodies of injured neurons. These results demonstrate that NT-3 may be of benefit in preventing the secondary cell loss that occurs following spinal injury.

Are neurons in cat posteromedial lateral suprasylvian visual cortex orientation sensitive? Tests with bars and gratings.

There is controversy in the literature concerning whether or not neurons in the cat's posteromedial lateral suprasylvian (PMLS) visual cortex are orientation selective. Previous studies that have tested cells with simple bar stimuli have found that few, if any, PMLS cells are orientation selective. Conversely, studies that have used repetitive stimuli such as gratings have found that most or all PMLS cells are orientation selective. It is not known whether this difference in results is due to the stimuli used or the laboratories using them. The present experiments were designed to answer this question by testing individual PMLS neurons for orientation sensitivity with both bar and grating stimuli. Using quantitative response measures, we found that most PMLS neurons respond well enough to stationary flashed stimuli to use such stimuli to test for orientation sensitivity. On the basis of these tests, we found that about 85% of the cells with well-defined receptive fields are orientation sensitive to flashed gratings, and a similar percentage are orientation sensitive to flashed bars. About 80% of the cells were orientation sensitive to both types of stimuli. The preferred orientations typically were similar for the two tests, and they were orthogonal to the preferred direction of movement. The strength of the orientation sensitivity (measured as the ratio of discharge to the preferred and nonpreferred orientations) was similar to both types of stimuli. However, the width of the orientation tuning curves was systematically broader to bars than to gratings. Several hypotheses are considered as to why previous studies using bars failed to find evidence for orientation sensitivity. In addition, a mechanism for the difference in orientation tuning to bars and gratings is suggested.

Bilateral destruction of the ventrolateral orbital cortex produces allocentric but not egocentric spatial deficits in rats.

Previous studies have implicated the ventrolateral orbital cortex (VLO) in spatial attention and orientation. Unilateral destruction of the VLO has been found to produce severe multimodal neglect to unilateral stimulation which is qualitatively quite similar to that found following unilateral destruction of either the medial agranular or posterior parietal cortices. A series of anatomical studies have shown that the VLO is reciprocally interconnected with both the medial agranular cortex and the posterior parietal cortex, which are involved in egocentric and allocentric spatial processing respectively. However, the role of the VLO in either egocentric or allocentric spatial processing has never been directly examined. The present study directly examined the role of the VLO in spatial learning by examining the effects of bilateral VLO destruction on performance in both egocentric (adjacent-arm maze task) and allocentric (cheeseboard task) spatial tasks. Subjects in either the cheese board task or the adjacent arm maze were given presurgical maze training and then were assigned to one of three surgical groups: a bilateral VLO group, a lesion control group which received bilateral destruction of the laterally adjacent lateral orbital cortex which has a quite different pattern of connectivity than the VLO, or a sham operated control group. The results indicated that the VLO operates were significantly impaired in the cheeseboard task (allocentric task) relative to controls, but displayed no deficits in the adjacent-arm maze (egocentric task), a pattern of results similar to those found for the posterior parietal cortex. The results of the present study strongly support the contention that the VLO is a component of the cortical circuitry for spatial processing in rodents.

Comparisons of hemi-inattention produced by unilateral lesions of the posterior parietal cortex or medial agranular prefrontal cortex in rats: neglect, extinction, and the role of stimulus distance.

Neglect in human and non-human primates has been demonstrated following unilateral lesions of both posterior parietal and prefrontal areas. While it has now been well established that a unilateral lesion of the rodent analog of dorsolateral prefrontal cortex, medial agranular cortex (AGm), results in neglect, the effects of unilateral damage restricted to rodent posterior parietal cortex (PPC) have not been examined in detail. The current study assessed rats with unilateral lesions of PPC or AGm on their ability to orient to unilateral and bilateral stimulation. Since it has been proposed in both the primate and rodent literatures that frontal areas may be responsible for the perception of near space while parietal areas may be responsible for far space, stimuli were presented at two different distances. Lesions of PPC and AGm resulted in severe neglect relative to control operates, with both PPC and AGm operates manifesting severe hemi-inattention and allesthesia relative to control operates. After behavioral recovery from neglect there was no evidence of extinction to bilateral simultaneous stimulation. While neglect to visual stimuli predominated in unilateral PPC operates, unilateral AGm operates had severe neglect in all modalities. In addition, while both left and right PPC operates showed contralesional neglect, AGm operates demonstrated the lateralized differences in neglect reported in previous studies. All groups demonstrated an approximately equivalent level of neglect to stimuli presented at the two different distances, and thus failed to support the suggestion of a peripersonal-extrapersonal dichotomy between frontal and parietal areas in rodents.

Spatial deficits and hemispheric asymmetries in the rat following unilateral and bilateral lesions of posterior parietal or medial agranular cortex.

Studies of spatial behavior in both the human and non-human primate have generally focused on the role of the posterior parietal and prefrontal cortices and have indicated that destruction of these regions produce allocentric and egocentric deficits, respectively. The present study examined the role of the rodent analogs of these regions, the posterior parietal (PPC) and medial agranular (AGm) cortices, in egocentric and allocentric spatial processing, and whether spatial processing in rodents is organized in a hemispatial and/or lateralized manner as has been found in the primate. Eighty male rats receiving either a unilateral or bilateral lesion of AGm or PPC were examined on an egocentric (adjacent arm) or an allocentric (cheeseboard) maze task. The results indicated that PPC and AGm have dissociable spatial functions. Bilateral AGm destruction resulted in egocentric spatial deficits, and unilateral AGm operates demonstrated an intermediate deficit. In contrast, bilateral PPC operates demonstrated a severe deficit in allocentric processing. In addition, there were lateralized differences in the performance of unilateral PPC operates. While right PPC lesions resulted in a significant deficit on the allocentric task, no such deficit was seen in left PPC operates. In addition, neither unilateral AGm nor unilateral PPC operates demonstrated a hemispatial impairment on either the egocentric or allocentric tasks.