Effects of the dimeric PSD-95 inhibitor UCCB01-144 on functional recovery after fimbria-fornix transection in rats.

Pharmacological inhibition of PSD-95 is a promising therapeutic strategy in the treatment of stroke, and positive effects of monomeric and dimeric PSD-95 inhibitors have been reported in numerous studies. However, whether therapeutic effects will generalize to other types of acute brain injury such as traumatic brain injury (TBI), which has pathophysiological mechanisms in common with stroke, is currently uncertain. We have previously found a lack of neuroprotective effects of dimeric PSD-95 inhibitors in the controlled cortical impact model of TBI in rats. However, as no single animal model is currently able to mimic the complex and heterogeneous pathophysiology of TBI, it is necessary to assess treatment effects across a range of models. In this preliminary study we investigated the neuroprotective abilities of the dimeric PSD-95 inhibitor UCCB01-144 after fimbria-fornix (FF) transection in rats. UCCB01-144 or saline was injected into the lateral tail vein of rats immediately after sham surgery or FF-transection, and effects on spatial delayed alternation in a T-maze were assessed over a 28-day period. Task acquisition was significantly impaired in FF-transected animals, but there were no significant effects of UCCB01-144 on spatial delayed alternation after FF-transection or sham surgery, although decelerated learning curves were seen after treatment with UCCB01-144 in FF-transected animals. The results of the present study are consistent with previous research showing a lack of neuroprotective effects of PSD-95 inhibition in experimental models of TBI.

Effects of Dimeric PSD-95 Inhibition on Excitotoxic Cell Death and Outcome After Controlled Cortical Impact in Rats.

Therapeutic effects of PSD-95 inhibition have been demonstrated in numerous studies of stroke; however only few studies have assessed the effects of PSD-95 inhibitors in traumatic brain injury (TBI). As the pathophysiology of TBI partially overlaps with that of stroke, PSD-95 inhibition may also be an effective therapeutic strategy in TBI. The objectives of the present study were to assess the effects of a dimeric inhibitor of PSD-95, UCCB01-144, on excitotoxic cell death in vitro and outcome after experimental TBI in rats in vivo. In addition, the pharmacokinetic parameters of UCCB01-144 were investigated in order to assess uptake of the drug into the central nervous system of rats. After a controlled cortical impact rats were randomized to receive a single injection of either saline or two different doses of UCCB01-144 (10 or 20 mg/kg IV) immediately after injury. Spatial learning and memory were assessed in a water maze at 2 weeks post-trauma, and at 4 weeks lesion volumes were estimated. Overall, UCCB01-144 did not protect against NMDA-toxicity in neuronal cultures or experimental TBI in rats. Important factors that should be investigated further in future studies assessing the effects of PSD-95 inhibitors in TBI are discussed.

Effects of different delayed exercise regimens on cognitive performance in fimbria­fornix transected rats.

Studies have shown that exercise can positively influence cognitive performance after brain injury. This study investigated the effects of different exercise regimens on allocentric place learning after fimbria­fornix (FF) transection. One hundred and sixteen pre­shaped rats were subjected either to a mechanical transection of the FF or control sham surgery and divided into following groups: i) no exercise (NE), ii) voluntary exercise in a running wheel (RW), iii) forced swimming exercise administered as interval training of short (3x5 min) duration (FS­SI), iv) forced swimming exercise administered as interval training of long (3x15 min) duration (FS­LI), v) forced swimming exercise administered as one session of short (5 min) duration (FS­SS), and vi) forced swimming exercise administered as one session of long (15 min) duration (FS­LS). The exercise was initiated 21 days post­surgery. Subsequently, all animals were administered 28 acquisition sessions in an 8­arm radial maze. Both sham operated and lesioned animals showed a significant learning response, however, the lesion induced a marked and lasting impairment, which was not alleviated neither by voluntary nor forced (spaced or one­session only) exercise regimens. Exercise regimens had no effect on the place learning of control sham animals. We conclude that the lesion location as well as factors related to the exercise­ and cognitive testing protocols can profoundly influence the potential of exercise as a general recovery­promoting method.

The effect of combined therapies on recovery after acquired brain injury: Systematic review of preclinical studies combining enriched environment, exercise, or task-specific training with other therapies.

BACKGROUND: Acquired brain injuries (ABI) have devastating effects for the affected individual as well as society. Many studies have investigated the effect of different monotherapies. However, functional recovery is typically only partial. One possible strategy to promote a greater degree of recovery is to apply monotherapies in combination with one or more treatments. OBJECTIVE: The objective of this systematic review is to investigate if approaches combining enriched environment (EE), exercise, or task-specific training with other monotherapies, further enhance the degree of recovery after ABI. METHOD: Scopus, PsychINFO, and PubMed databases were searched in March 2016 with the following search strings: exercise (or) enriched environment (or) environmental enrichment (or) rehabilitation (and) traumatic brain injury (or) ischemia (or) stroke (and) rat (or) rodent. Studies were included if they (1) were in English, (2) used adult animals subjected to brain injury, (3) included EE, and/or exercise, and/or task-specific training as post-injury treatment strategies, (4) included at least one group receiving another monotherapy. Out of 2.168 hits, 29 studies fulfilled the inclusion criteria. RESULTS: Despite several trends for enhanced recovery after combined therapies, this systematic review of 29 studies does not indicate that combined therapies confer consistent combined effects on motor, cognitive, or cerebral recovery according to present criteria for combined effect. CONCLUSION: Combined treatments continue to provide hope for enhanced recovery after ABI, however, the research area is in its infancy. This systematic review does not provide conclusive evidence. This is likely due to sparse knowledge regarding optimal treatment parameters. Combined treatments, however, hold the best promise regarding treatment of the complex changes induced by ABI.

In vitro and in vivo effects of a novel dimeric inhibitor of PSD-95 on excitotoxicity and functional recovery after experimental traumatic brain injury.

PSD-95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury (TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a novel dimeric inhibitor of PSD-95, UCCB01-147, on histopathology and long-term cognitive outcome after controlled cortical impact (CCI) in rats. As excitotoxic cell death is thought to be a prominent part of the pathophysiology of TBI, we also investigated the neuroprotective effects of UCCB01-147 and related compounds on NMDA-induced cell death in cultured cortical neurons. Anesthetized rats were given a CCI or sham injury, and were randomized to receive an injection of either UCCB01-147 (10 mg/kg), the non-competitive NMDAR-receptor antagonist MK-801 (1 mg/kg) or saline immediately after injury. At 2 and 4 weeks post-trauma, spatial learning and memory were assessed in a water maze, and at 3 months, brains were removed for estimation of lesion volumes. Overall, neither treatment with UCCB01-147 nor MK-801 resulted in significant improvements of cognition and histopathology after CCI. Although MK-801 provided robust neuroprotection against NMDA-induced toxicity in cultured cortical neurons, UCCB01-147 failed to reduce cell death and became neurotoxic at high doses. The data suggest potential differential effects of PSD-95 inhibition in stroke and TBI that should be investigated further in future studies taking important experimental factors such as timing of treatment, dosage, and anesthesia into consideration.

Delayed voluntary exercise does not enhance cognitive performance after hippocampal injury: an investigation of differentially distributed exercise protocols.

Voluntary exercise has previously been shown to enhance cognitive recovery after acquired brain injury (ABI). The present study evaluated effects of two differentially distributed protocols of delayed, voluntary exercise on cognitive recovery using an allocentric place learning task in an 8-arm radial maze. Fifty-four Wistar rats were subjected to either bilateral transection of the fimbria-fornix (FF) or to sham surgery. Twenty-one days postinjury, the animals started exercising in running wheels either for 14 consecutive days (FF/exercise daily [ExD], sham/ExD) or every other day for 14 days (FF/exercise every second day [ExS], sham/ExS). Additional groups were given no exercise treatment (FF/not exercise [NE], sham/NE). Regardless of how exercise was distributed, we found no cognitively enhancing effects of exercise in the brain injured animals. Design and protocol factors possibly affecting the efficacy of post-ABI exercise are discussed.

Exercise-induced improvement in cognitive performance after fimbria-fornix transection depends on the timing of exercise administration.

BACKGROUND: Exercise after brain injury holds major therapeutic potentials, but it is still uncertain whether such an intervention should take place during the critical time window of intrinsic repair mechanisms. OBJECTIVE: To assess the effects of acute or delayed voluntary exercise in running wheels on post-injury allocentric place learning in an 8-arm radial maze. METHODS: Forty-eight pre-shaped male rats underwent fimbria-fornix transection (FF) or control surgery (Sham). The animals were divided into six groups: FF group with no access to exercise (FF/NE); FF group starting exercise 1day post-surgery (FF/E+1); FF group starting exercise 8days post-surgery (FF/E+8); FF group starting exercise 21days post-surgery (FF/E+21); Sham group with no access to exercise (Sham/NE), and Sham group starting exercise 1day post-surgery (Sham/E+1). After 7days of exercise 6h/day, all animals underwent 28 place learning acquisition sessions. RESULTS: The FF/E+21 group showed an enhanced acquisition of the task compared to FF/NE. The FF/E+1 and FF/E+8 groups also showed an enhanced task acquisition relative to FF/NE, however with a slower acquisition than the FF/E+21 group. CONCLUSION: The data underscores the link between exercise and functional recovery after brain injury and emphasizes the importance of optimal timing of this intervention.

Delayed restraint procedure enhances cognitive recovery of spatial function after fimbria-fornix transection.

PURPOSE: To i) evaluate the effect of a restraint procedure (7 days, 2 h/day) on place learning after fimbria-fornix transection (FF), ii) investigate effects of early vs. late administration of restraint, and iii) establish effects of the restraint procedure on expression of brain derived neurotrophic factor (BDNF) in prefrontal cortex and hippocampus. METHODS: Fifty rats subjected to FF or sham surgery and divided into groups exposed to restraint immediately (early restraint) or 21 days (late restraint) after surgery were trained to acquire an allocentric place learning task. In parallel, 29 animals were subjected to FF or sham surgery and an identical restraint procedure in order to measure concentrations of BDNF and corticosterone. RESULTS: The performance of the sham operated rats was positively affected by the late restraint. In FF-lesioned animals, the late restraint significantly improved task performance compared to the lesioned group with no restraint, while the early restraint was associated with a negative impact on task acquisition. Biochemical analysis after restraint procedure revealed a lesion-induced upregulation of BDNF in FF animals. CONCLUSIONS: The improved task performance of lesioned animals suggests a therapeutic effect of this manipulation, independent of BDNF. This effect is sensitive to the temporal administration of treatment.

The Effects of Exercise on Cognitive Recovery after Acquired Brain Injury in Animal Models: A Systematic Review.

The objective of the present paper is to review the current status of exercise as a tool to promote cognitive rehabilitation after acquired brain injury (ABI) in animal model-based research. Searches were conducted on the PubMed, Scopus, and psycINFO databases in February 2014. Search strings used were: exercise (and) animal model (or) rodent (or) rat (and) traumatic brain injury (or) cerebral ischemia (or) brain irradiation. Studies were selected if they were (1) in English, (2) used adult animals subjected to acquired brain injury, (3) used exercise as an intervention tool after inflicted injury, (4) used exercise paradigms demanding movement of all extremities, (5) had exercise intervention effects that could be distinguished from other potential intervention effects, and (6) contained at least one measure of cognitive and/or emotional function. Out of 2308 hits, 22 publications fulfilled the criteria. The studies were examined relative to cognitive effects associated with three themes: exercise type (forced or voluntary), timing of exercise (early or late), and dose-related factors (intensity, duration, etc.). The studies indicate that exercise in many cases can promote cognitive recovery after brain injury. However, the optimal parameters to ensure cognitive rehabilitation efficacy still elude us, due to considerable methodological variations between studies.

Equal effects of typical environmental and specific social enrichment on posttraumatic cognitive functioning after fimbria-fornix transection in rats.

Enriched environment (EE) has been shown to have beneficial effects on cognitive recovery after brain injury. Typical EE comprises three components: (i) enlarged living area providing physical activation, (ii) sensory stimulation, and (iii) social stimulation. The present study assessed the specific contribution of the social stimulation. Animals were randomly divided into groups of (1) a typical EE, (2) pure social enrichment (SE), or (3) standard housing (SH) and subjected to either a sham operation or transection of the fimbria-fornix (FF). The effect of these conditions on acquisition of a delayed alternation task in a T-maze was assessed. The sham control groups were not affected by housing conditions. In the lesioned groups, both typical EE and SE improved the task acquisition, compared to SH. A baseline one-hour activity measurement confirmed an equal level of physical activity in the EE and SE groups. After delayed alternation testing, pharmacological challenges (muscarinergic antagonist scopolamine and dopaminergic antagonist SKF-83566) were used to assess cholinergic and dopaminergic contributions to task solution. Scopolamine led to a marked impairment in all groups. SKF-83566 significantly enhanced the performance of the lesioned group subjected to SE. The results demonstrate that housing in a typical as well as atypical EE can enhance cognitive recovery after mechanical injury to the hippocampus. The scopolamine challenge revealed a cholinergic dependency during task performance in all groups, regardless of lesion and housing conditions. The dopaminergic challenge revealed a difference in the neural substrates mediating recovery in the lesioned groups exposed to different types of housing.

Prefrontal cortex and hippocampus in behavioural flexibility and posttraumatic functional recovery: reversal learning and set-shifting in rats.

Within one experiment and one T-maze, we examined the consequences of (i) bilateral lesions of the anteromedial prefrontal cortex (PFC), (ii) bilateral transections of the fimbria-fornix (FF), or (iii) combined lesions of both PFC and FF (COMB) on rats' ability to perform reversal or set-shifting. Postoperatively, the animals were trained to perform a spatial discrimination go-right task. This was followed by (1) a spatial reversal go-left task (reversal learning), or (2) a visual pattern discrimination task (set-shift). Neither single (PFC or FF) lesion nor combined (COMB) lesions affected the animals' ability to acquire the original spatial discrimination task. Regarding the reversal learning, the performance of the PFC and the FF groups was not significantly different from that of the sham operated control animals (Sham). In contrast, animals with combined lesion of both structures were impaired on both error rate and acquisition speed relative to all other groups. Regarding the set-shifting, all lesioned groups were impaired relative to the Sham group both regarding the error rate and the acquisition speed. There was, however, no difference in the degree of impairment between the lesioned groups. We conclude that both the PFC and the hippocampus contributed to the mediation of the reversal learning and set-shifting. During functional recovery of reversal learning, these two structures exhibited a mutual dependency, whilst the functional recovery of set-shifting was mediated by a substrate outside these two structures.

Only repeated administration of the serotonergic agonist 8-OH-DPAT improves place learning of rats subjected to fimbria-fornix transection.

Serotonergic agonists may act neuroprotectively against brain injury. This study addressed the therapeutic potential of 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT), a selective 5-HT1A/7 receptor agonist, after mechanical brain injury, and evaluated its effects in terms of acquisition of an allocentric place learning task in a water maze. Rats were divided into 6 experimental groups, three of which were subjected to bilateral transection of fimbria-fornix (FF), while three groups were given control surgery (Sham). After surgery, within both the lesioned, and sham-operated animals, respectively, one group was administered a single dose of saline, one group was given a single dose (0.5 mg/kg/b.w.) of 8-OH-DPAT, and one group was treated with daily administration of 8-OH-DPAT (0.5 mg/kg/b.w.) for eight days. The acquisition of the water maze based place learning task started on the 8th day post-surgery and continued for 20 days. The results show that the lesioned group subjected to repeated administration of 8-OH-DPAT demonstrated a significantly improved acquisition of the place learning task compared to the vehicle injected lesion group. In contrast, the lesioned group treated with a single administration displayed impaired performance compared to the baseline lesion group. There were no significant effects of the 8-OH-DPAT administration in the sham control groups. We conclude that only the repeated stimulation of the 5-HT1A/7 system was associated with beneficial, recovery enhancing effects.

Delayed intensive acquisition training alleviates the lesion-induced place learning deficits after fimbria-fornix transection in the rat.

This study evaluates the effects of two learning paradigms, intensive vs. baseline, on the posttraumatic acquisition of a water maze based place learning task. Rats were subjected either to a control operation (Sham) or to a fimbria-fornix (FF) transection, which renders the hippocampus dysfunctional and disrupts the acquisition of allocentric place learning. All animals were administered 30 post-lesion acquisition sessions, which spanned either 10 or 30days. The acquisition period was followed by a 7day pause after which a retention probe was administered. The lesioned animals were divided into 3 groups: i) Baseline Acquisition Paradigm (BAP) once daily for 30days starting 1week post-surgery; ii) Early Intensive Acquisition Paradigm (EIAP) 3 times daily for 10days starting 1week post-surgery; and iii) Late Intensive Acquisition Paradigm (LIAP) 3 times daily for 10days starting 3weeks post-surgery. Within the control animals, one group followed the schedule of BAP, and one group followed the schedule of Intensive Acquisition Paradigm (IAP). All lesioned animals showed an impaired task acquisition. LIAP was beneficial in FF animals, in that it led to a better acquisition of the place learning task than the two other acquisition paradigms. The FF/EIAP group did not show improved acquisition compared to the FF/BAP group. The control animals were not differentially affected by the two learning schedules. The findings have implications for cognitive rehabilitation after brain injury and support the assumption that intensive treatment can lead to an improved learning, even when the neural structures underlying such a process are compromised. However, the timing of intensive treatment needs to be considered further.

Cognitive enhancing effects of an AMPA receptor positive modulator on place learning in mice.

This study presents an in vivo investigation of the arylpropylsulfonamide α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor positive modulator (R,R)-N,N-(2,20-[biphenyl-4-40-diyl]bis[propane-2,1-diyl])dimethanesulfonamide (PIMSD). The pharmacokinetics of the drug were examined in male C57BL/6J mice and the drug concentration in blood plasma determined after subcutaneous injection of 1mg/kg b.w. This analysis revealed a rapid increase of the plasma concentration, peaking within 30min after administration with a T(1/2) of approximately 30min and a peak plasma concentration of about 2µM. Analysis of brain tissue homogenates also indicated blood-brain barrier permeability of the compound. Cognitive enhancing effects of the drug were then studied on place learning in male C57BL/6J mice in a water maze. In order to elucidate the potential positive effects of PIMSD on spatial learning the muscarinergic antagonist scopolamine was utilized, which is known to impair spatial learning ability. The mice were divided into four groups and subjected to two sequential subcutaneous injections administered 25min prior to behavioural testing: (1) vehicle/vehicle; (2) PIMSD/vehicle; (3) scopolamine/vehicle; (4) PIMSD/scopolamine. PIMSD at a dose of 3mg/kg b.w. was able to partially reverse the impairment given by 0.5mg/kg b.w. scopolamine. These results suggest that arylpropylsulfonamides such as PIMSD may have a therapeutic use in the enhancement of cognitive function and support the hypothesis that AMPA receptor potentiation is one mechanism that can be targeted for diseases of cognitive impairment.

Indirect versus direct feedback in computer-based Prism Adaptation Therapy.

Prism Adaptation Therapy (PAT) is an intervention method in the treatment of the attention disorder neglect (Frassinetti, Angeli, Meneghello, Avanzi, & Ladavas, 2002; Rossetti et al., 1998). The aim of this study was to investigate whether one session of PAT using a computer-attached touchscreen would produce similar after-effects to the conventional box normally used in PAT. In four experiments, 81 healthy subjects and 7 brain-injured patients diagnosed with neglect were subjected to a single session of PAT under two conditions: (1) using the original box, and (2) using a computer-based implementation of PAT. The session of PAT included a pre-exposure step involving pointing at 30 targets without feedback; an exposure step involving pointing at 90 targets with prism goggles and feedback; and a post-exposure step involving pointing at 60 targets, with no goggles and no feedback. The results indicate that the expected similarity in the after-effect produced by the two conditions seems to occur only if subjects receive feedback on pointing precision by seeing their fingertip during the exposure step. Attempts to provide feedback indirectly via icons on the computer screen failed to produce the expected size in the after-effect. The findings have direct implications for computer-based treatment of visuospatial disorders in the future and computer-assisted rehabilitation in general.

Post-traumatic functional recovery and reorganization in animal models: a theoretical and methodological challenge.

Studies addressing cerebral functional localization face methodological and theoretical problems. Lesion experiments expect that when a functionally specialized structure is missing, its function can be deduced from the resulting impairments. Mostly, however, initial impairments are partially or fully eliminated through functional recovery. Apparently, such a recovery contradicts the notion of functional localization. In order to understand the mechanisms of recovery, improved methodology and a new theoretical framework are required. Insights into the mechanisms of recovery can be achieved by using "challenge" techniques, where functionally recovered individuals are exposed to organic and behavioral challenges, e.g. pharmacological manipulations or additional lesions, as well as modified test situations. Using such methods, a number of principles of functional recovery have emerged. We evaluate some of the available theories of post-traumatic recovery against these principles and find that none of them can account for the principles. Finally, we present a new conceptual framework - the Reorganization of Elementary Functions (REF) model. This model reconceptualizes the term "function", suggests mechanisms of post-traumatic reorganizations, and resolves the contradiction between localization and functional recovery.

The effects of repeated rehabilitation "tune-ups" on functional recovery after focal ischemia in rats.

BACKGROUND: For most stroke survivors, rehabilitation therapy is the only treatment option available. The beneficial effects of early rehabilitation on neuroplasticity and functional recovery have been modeled in experimental stroke using a combination of enriched environment and rehabilitation. However, the impact of a secondary intervention, such as a periodic return to therapy, remains unclear. OBJECTIVE: This study examines whether a return to enriched rehabilitation (ie, "tune-up") can further promote functional recovery or produce beneficial changes in brain plasticity in the chronic phase of stroke recovery. METHODS: Rats were exposed to focal ischemia (endothelin-1 applied to forelimb sensorimotor cortex and dorsolateral striatum) and allowed to recover either in standard housing or in a combination of enriched environment and rehabilitative reaching for 9 weeks. Animals were then exposed to rotating periods of standard housing (5 weeks) and intensive "tune-up" therapy consisting of various sensorimotor/cognitive activities (2 weeks). Functional recovery was assessed using the Montoya staircase, beam-traversing, and cylinder tests, and Golgi-Cox analysis was used to examine dendritic complexity in the contralesional forelimb motor cortex. RESULTS: Although early enriched rehabilitation significantly improved sensorimotor function in both the beam and staircase tests, "tune-up" therapy had no effect on recovery. Golgi-Cox analysis revealed no effect of treatment on dendritic complexity. CONCLUSIONS: This study reaffirms the benefits of early rehabilitation for functional recovery after stroke. However, "tune-up" therapy provided no benefit in ischemic animals regardless of earlier rehabilitation experience. It is possible that alternative approaches in the chronic phase may prove more effective.

Erythropoietin improves spatial delayed alternation in a T-maze in rats subjected to ablation of the prefrontal cortex.

Systemically administered human recombinant erythropoietin (EPO) may have the potential to reduce the cognitive and behavioural symptoms of mechanical brain injury. In a series of studies we address this possibility. Previously, we studied the effects of EPO given to fimbria-fornix transected rats at the moment of injury. We have found that such treatment improves substantially the posttraumatic acquisition of allocentric place learning tasks administered in a water maze and in an 8-arm radial maze as well as a spatial delayed alternation task administered in a T-maze. It is, however, essential also to evaluate this clinically important ability of EPO after other types of mechanical brain injury. Consequently, we presently studied the effects of similarly administered EPO in rats subjected to bilateral subpial aspiration of the anteromedial prefrontal cortex as well as control operated rats, respectively. We evaluated the posttraumatic behavioural/cognitive abilities of these animals in a spatial delayed alternation task performed in a T-maze. Administration of EPO to the prefrontally ablated rats was associated with a reduction of the lesion-associated behavioural impairment--while such an impairment was clearly seen in the saline injected prefrontally ablated group. In sham operated rats administration of EPO did not influence the task acquisition significantly. The results of the present study confirm our previous demonstrations that EPO is able to reduce the behavioural/cognitive consequences of mechanical brain injury. This ability is emphasized by its relative independence on the type of lesion as well as the neural structure affected.

Therapeutic effects of a restraint procedure on posttraumatic place learning in fimbria-fornix transected rats.

Restraint procedures have been shown to influence the neural processes in the brain (dendritic changes or changes in the expression of neurotrophines, etc.) as well as to alter the behavioural performance. While many report deleterious effects of this procedure in normal animals, there are also indications of positive effects in the context of brain injury. In order to address the issue from the perspective of functional posttraumatic recovery, we studied 6 experimental groups of rats--3 groups undergoing a fimbria-fornix transection, and 3 groups remaining neurally intact. Within the lesioned and intact groups, respectively, one group of animals was subjected to an 8-day long restraint procedure (2 h daily) that ended immediately prior to the infliction of trauma; another group was subjected to the same procedure starting immediately after the infliction of trauma; and one group was not subjected to the restraint procedure at all. After a brief period of postoperative pause, the animals were tested on their acquisition of an 8-arm radial maze based place learning task and the effects of the restraint procedure on the task acquisition were evaluated. The results show that within the neurally intact groups, the administration of this procedure had no effect at all. However, the lesioned groups that were subjected to the restraint procedure showed significantly improved acquisition of the studied task compared to the lesioned animals that did not undergo the restraint procedure. The improved task performance suggests a therapeutic effect of this manipulation on the functional recovery after a mechanical trauma.

Erythropoietin improves spatial delayed alternation in a T-maze in fimbria-fornix transected rats.

Systemically administered human recombinant erythropoietin (EPO) may have the potential to reduce the cognitive and behavioural symptoms of a mechanical brain injury. In a series of studies we address this possibility. We have previously found that EPO given to fimbria-fornix transected rats at the moment of injury is able substantially to improve the posttraumatic acquisition of allocentric place learning tasks administered in a water maze as well as in an 8-arm radial maze. It is, however, essential to evaluate this clinically important ability of EPO within other cognitive domains, as well. Consequently, we presently studied the effects of similarly administered EPO in fimbria-fornix transected and control operated rats, respectively--evaluating the posttraumatic behavioural/cognitive abilities in a spatial delayed alternation task performed in a T-maze. Administration of EPO to the hippocampally injured rats was associated with a substantial reduction of the lesion-associated behavioural impairment--while such an impairment was clearly seen in the saline injected fimbria-fornix transected group. In contrast, EPO had no detectable effect on the task acquisition of non-lesioned animals. The results of the present study confirm our previous demonstrations that EPO is able to reduce or eliminate the behavioural/cognitive consequences of mechanical injury to the hippocampus--and emphasize that this ability is present across a broader spectrum of cognitive domains.