GM1 produces attenuation of short-term memory deficits in Hebb-Williams maze performance after unilateral entorhinal cortex lesions.

The Hebb-Williams maze was used to examine spatial abilities of adult male Sprague-Dawley rats with unilateral electrolytic entorhinal cortex lesions. The injured rats were treated for 14 days with either saline or ganglioside GM1. Testing was begun 7 weeks following injury, and involved 12 maze problems with independent configurations, with immediate starting replacement used for the six trials per problem. Compared to sham-operated counterparts, the rats with lesion plus saline treatment were impaired in total number of errors, initial entry errors, and repeat errors over 12 consecutive problems. GM1-treated rats showed improved performance, making significantly fewer total and repeat errors, indicating that this substance may be potentially useful as therapy after entorhinal cortex injury.

Ephrin-A binding and EphA receptor expression delineate the matrix compartment of the striatum.

The striatum integrates limbic and neocortical inputs to regulate sensorimotor and psychomotor behaviors. This function is dependent on the segregation of striatal projection neurons into anatomical and functional components, such as the striosome and matrix compartments. In the present study the association of ephrin-A cell surface ligands and EphA receptor tyrosine kinases (RTKs) with the organization of these compartments was determined in postnatal rats. Ephrin-A1 and ephrin-A4 selectively bind to EphA receptors on neurons restricted to the matrix compartment. Binding is absent from the striosomes, which were identified by mu-opioid receptor immunostaining. In contrast, ephrin-A2, ephrin-A3, and ephrin-A5 exhibit a different mosaic binding pattern that appears to define a subset of matrix neurons. In situ hybridization for EphA RTKs reveals that the two different ligand binding patterns strictly match the mRNA expression patterns of EphA4 and EphA7. Ligand-receptor binding assays indicate that ephrin-A1 and ephrin-A4 selectively bind EphA4 but not EphA7 in the lysates of striatal tissue. Conversely, ephrin-A2, ephrin-A3, and ephrin-A5 bind EphA7 but not EphA4. These observations implicate selective interactions between ephrin-A molecules and EphA RTKs as potential mechanisms for regulating the compartmental organization of the striatum.

Effects of unilateral entorhinal cortex lesion on retention of water maze performance.

In a previous study, adult male Sprague-Dawley rats with unilateral, electrolytic entorhinal cortex lesions showed significant deficits in acquisition of a water maze task that measured working memory. The 10 days of testing used two trials per day with an intertrial interval of 1 h, and the rats with entorhinal damage were impaired in total distance to the platform in both trials. In the present retention study, rats who learned the same task prior to injury and were then retested for 5 days after lesion showed only a first day deficit in total distance to platform in the second trial. Analysis of swim patterns indicated that rats with unilateral entorhinal lesions used an altered strategy in retention testing to find the platform in the second trial of each day and incorporated the use of headings appropriate for Trial 1 only. This altered or compensatory strategy was not the optimum choice for problem solution. Although the rats then were able to switch headings and find the platform without significant impairment in total distance to platform on days 2-5 of testing, the use of an initial incorrect strategy indicated subtle residual deficits in cue integration and use of working memory.

Acute ethanol administration reduces the cognitive deficits associated with traumatic brain injury in rats.

The present study was designed to determine whether a low dose of acute ethanol administration could attenuate cognitive deficits associated with traumatic brain injury. Adult male rats received oral administration of ethanol or drinking water 2 h prior to surgery to produce a blood ethanol concentration of 100 mg% and then received bilateral contusion injuries of the medial prefrontal cortex. Seven days after surgery, the rats began 10 days of testing for acquisition of spatial localization in the Morris water maze where they were required to find a hidden platform to escape from the water. The results indicate that the rats given ethanol at the time of injury later spent significantly less time searching for the hidden platform than their water-treated counterparts. On a memory probe test given on the final day of testing, in which the platform was removed from the pool, rats given the ethanol spent more time in the area where the platform had been located indicating that they learned its location better than the lesion/water controls. In addition, acute ethanol treatment reduced some of the histopathology that typically occurs following severe contusion of the medial frontal cortex but did not attenuate post-traumatic formation of edema. These results indicate that acute ethanol intoxication can reduce the severity of cognitive impairments caused by contusive traumatic brain injury and support the contention that there is a dose-response relationship of acute ethanol intoxication in the setting of traumatic brain injury.

Intraseptal injections of 192 IgG saporin produce deficits for strategy selection in spatial-memory tasks.

The involvement of the cholinergic septohippocampal system in strategies used to reach a spatial goal was examined by functionally inactivating this system with infusions of 192 IgG saporin, a potent cholinergic immunotoxin. Rats were initially trained on a win-shift radial arm maze (RAM) task and then given injections of either 192 IgG saporin (LES) or saline vehicle (CON) into the medial septum and vertical limb of the diagonal band. Rats were then retested postoperatively on the RAM to assess whether allocentric spatial strategies used to solve the task were impaired. The results indicated that injections of 192 IgG saporin into the septum of rats produced deficits in allocentric strategies used to locate the spatial goal when retested. In addition, place and response learning was also examined in a modified version of the Morris water maze task. In this task, rats with cholinergic lesions were mildly impaired in their ability to learn a place response. In order to clarify further whether rats may have been relying on allocentric or egocentric learning strategies to locate the platform, a probe trial was given on the final test day in which the visible platform was moved to a new location. Control rats swam either to the new platform location or the old platform location indicating the use of both an allocentric and egocentric response. However, rats with the cholinergic septal lesions swam to the new platform location indicating an egocentric response. Taken together, these results suggest that selective cholinergic lesions of the septum produce deficits in spatial strategies used to locate a spatial goal.

Effects of a single intraseptal injection of NGF on spatial learning in the water maze.

Male Sprague-Dawley rats given electrolytic lesions of the septum followed by a single intraseptal injection of 5 microg of NGF were trained on a water maze task that assessed their ability to learn the location of a visible platform and the location of platform when it was submerged. Rats with damage to the septum acquired the visible platform version of the task but were significantly impaired in locating the submerged platform. Administration of NGF, however, produced an intermediate ameliorative effect on the measure of latency to find the hidden platform during these trials. In order to determine the relative strength of the place and cue responses learned during the visible and hidden platform training trials, a probe trial was given on the final test day in which the visible platform was moved to a new location. Control rats swam either to the new platform location or the old platform location indicating the use of both a place and cue response. However, both rats with septal damage alone and rats with septal lesions treated with NGF swam directly to the new platform location indicating the relative strength of the cue response. These results support previous findings indicating that a single injection of NGF can produce improvements on a cognitive task, but it may not be doing so by restoring lost spatial functions following septohippocampal damage.

Persistent short term memory deficits in Hebb-Williams maze performance are shown by rats with unilateral entorhinal cortex lesions.

The spatial abilities of adult, male Sprague-Dawley rats in the Hebb-Williams maze were examined at 6 months after unilateral electrolytic entorhinal cortex lesions. Compared with sham-operated rats, their performance was impaired in both initial entry and repeat entry errors over 12 consecutive problems, using immediate starting replacement for the 6 trials per problem. The configurations of the 12 maze problems are independent, and deficits were seen over the entire course of the testing. This study indicates that Hebb-Williams maze performance deficits after unilateral entorhinal cortex lesion are persistent and can be seen up to 6 months after injury.

Intraseptal injections of NGF attenuates edema formation following septal lesions in the rat.

Rats with electrolytic lesions of the medial septum received a single intraseptal injection of either nerve growth factor (NGF) or saline immediately following surgery. The formation of edema was then assessed at five time points following the lesions to the septum: 6 h, 1 day, 2 days, 3 days, and 5 days. Edema formation was detected as early as 6 h in both groups. However, by 2 days following surgery, the NGF treated rats had significantly less edema formation than their lesion alone counterparts. These results can be taken to indicate that NGF may alter locally mediating events that limit the effects of reactions associated with the inflammation of damaged tissue.

A single intraseptal injection of nerve growth factor facilitates radial maze performance following damage to the medial septum in rats.

Rats were trained on a radial maze and then given electrolytic lesions of the MS followed by a single intraseptal injection of 5 micrograms of NGF. Three days later they were re-tested on the maze. They were also post-operatively tested for hyperemotionality. MS lesions severely impaired performance on the radial maze and produced increased emotionality. MS lesions also produced a general decrease in hippocampal high affinity choline transport and acetylcholinesterase staining, which was not affected by NGF administration. NGF treatment ameliorated the behavioral deficit in the radial maze but had no effect on the hyperemotionality. In order to determine whether the NGF was working to restore previously learned spatial abilities, the type of learning strategy used by the animals was also assessed. NGF treatment did not restore previously learned spatial strategies but facilitated recovery of alternative learning strategies. The reduction in cognitive deficit was also paralleled by reduced ventricular enlargement in the NGF treated rats. The present results suggest that a single injection of NGF can produce a long-lasting improvement on a cognitive task and reduce some of the injury-induced, secondary reactive changes that occur following electrolytic MS lesions.

Medial septal lesions in rats produce permanent deficits for strategy selection in a spatial memory task.

Rats with medial septal (MS) lesions have been shown to consistently use a stereotypic response strategy rather than a nonstereotypic spatial learning strategy when solving a radial maze task. The present study examined the long-term effects of MS lesions on spatial memory performance to determine whether MS lesions permanently impair rats from using a nonstereotypic strategy. Male rats, initially trained on a radial maze, were given either MS or sham surgeries and were subsequently retested on the maze. Consistent with previous studies, all rats with MS lesions used a stereotypic strategy during the postoperative retest. However, when placed through a series of retraining phases that required the rat to use a nonstereotypic strategy to solve the task, none of the MS rats could solve the task. These results indicate that lesions of the medial septum produce permanent spatial memory deficits that cannot be restored through extensive behavioral training.

Lipoprotein-cyclodextrin interaction.

Interaction of cyclodextrins with native and isolated lipoproteins was studied by electrophoretic and spectroscopic means. Reaction between these two biomolecules resulted in the formation of soluble and insoluble complexes. Cyclodextrin-mediated precipitation of lipoproteins was strongly affected by the concentration of the oligosaccharide and the presence of guest molecules capable of being entrapped within the cyclodextrin cavity. Lipoprotein precipitation by cyclodextrins was observed under acidic, neutral as well as alkaline conditions. The ionic strength of the medium did not significantly affect this interaction. Under appropriate experimental conditions, most types of cyclodextrins were able to form complexes with the various lipoprotein classes. The ability of cyclodextrins to precipitate lipoproteins was in the order of beta-cyclodextrin greater than alpha-cyclodextrin greater than gamma-cyclodextrin and hydroxyalkylated beta-cyclodextrin. Among the lipoproteins, the order of reactivity with a given cyclodextrin was: low density lipoproteins greater than high density lipoproteins greater than very low density lipoproteins. Competitive studies using L-phenylalanine and methanol, both of which form inclusion complexes with cyclodextrins, reveal that molecular encapsulation plays an important role in the stabilization of beta-cyclodextrin-lipoprotein complexes. The present data also suggests that the binding of cyclodextrins to lipoproteins may involve the formation of exclusion complexes.