Delayed voluntary physical exercise restores "when" and "where" object recognition memory after traumatic brain injury.

Physical exercise has been associated with improved cognition and may even reduce memory deficits after brain injuries. The aims of this work were to: 1) assess whether voluntary physical exercise can reduce the deficits associated with traumatic brain injury (TBI) in two different components of episodic-like memory based on object recognition, temporal order memory ("when"), and object location memory ("where"); and 2) determine whether changes in levels of brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex, as well as alterations in hippocampal cytokines, insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF), may influence the effects exercise has on either or both tasks. The rats were distributed into a sham group, a TBI group that remained sedentary (TBI-sed), and a TBI group that had access to a running wheel for a 25-day period from post-injury day 11 (TBI-exe). The rats were sacrificed after the "where" memory task, at post-injury day 37. Physical exercise restored the "when" and "where" memories, which had been impaired by the TBI, and increased the concentration of BDNF in the hippocampus, but not the prefrontal cortex. Neither TBI nor exercise were found to significantly affect hippocampal cytokines, IGF-1 or VEGF at this time post-injury. BDNF levels showed significant positive correlations with exercise, and with "when" (but not "where") memory. These results indicate that post-injury physical exercise restores "when" and "where" object recognition memory tasks after TBI, and that increased BDNF seems to be involved in this effect, particularly with regard to "when" memory.

The benefits of voluntary physical exercise after traumatic brain injury on rat's object recognition memory: A comparison of different temporal schedules.

Physical exercise can reduce the cognitive decline associated with traumatic brain injury, yet little is known about the optimal administration schedules. Here, different protocols of voluntary wheel running were evaluated for their effects on object recognition memory (ORM), neuroprotection (NeuN+ cells), microglial reactivity (Iba1 staining) and neurogenesis (DCX+ cells) after controlled cortical impact injury (CCI). CCI-lesioned rats were divided into a sedentary group and three exercise groups: early discontinued exercise (3 weeks of exercise initiated 4 days post-injury, followed by 4 weeks in a sedentary state); delayed exercise (3 weeks of exercise initiated 4 weeks post-injury), and early continuous exercise (7 weeks of exercise starting 4 days post-injury). The deficits induced by CCI in a 24 h ORM test were reversed in the delayed exercise group and reduced in the early discontinued and early continuous groups. The early discontinued protocol also reduced the loss of NeuN+ cells in the hilus, while attenuated microglial reactivity was found in the dorsal hippocampus of both the early exercising groups. Running at the end of the experiment increased the number of DCX+ cells in the early continuous and delayed groups, and an inverted U-shaped relationship was found between the mean daily exercise time and the amount of neurogenesis. Thus, exercise had benefits on memory both when it was commenced soon and later after injury, although the neural mechanisms implicated differed. Accordingly, the effects of exercise on memory and neurogenesis appear to not only depend on the specific temporal schedule but also, they may be influenced by the amount of daily exercise.

Posttraining Epinephrine Reverses Memory Deficits Produced by Traumatic Brain Injury in Rats.

The aim of this research is to evaluate whether posttraining systemic epinephrine is able to improve object recognition memory in rats with memory deficits produced by traumatic brain injury. Forty-nine two-month-old naïve male Wistar rats were submitted to surgical procedures to induce traumatic brain injury (TBI) or were sham-operated. Rats were trained in an object recognition task and, immediately after training, received an intraperitoneal injection of distilled water (Sham-Veh and TBI-Veh group) or 0.01 mg/kg epinephrine (TBI-Epi group) or no injection (TBI-0 and Sham-0 groups). Retention was tested 3 h and 24 h after acquisition. The results showed that brain injury produced severe memory deficits and that posttraining administration of epinephrine was able to reverse them. Systemic administration of distilled water also had an enhancing effect, but of a lower magnitude. These data indicate that posttraining epinephrine and, to a lesser extent, vehicle injection reduce memory deficits associated with TBI, probably through induction of a low-to-moderate emotional arousal.

Traumatic brain injury in late adolescent rats: effects on adulthood memory and anxiety.

The consequences of traumatic brain injury (TBI) sustained during late adolescence (7 weeks old) on spontaneous object recognition memory and on anxiety-like behaviors in the elevated plus maze were tested in rats during adulthood. Testing took place at 2 different postinjury times, in separate groups: 3 and 6 weeks, when animals were 10 and 13 weeks old, respectively. The rats were either submitted to controlled cortical impact injury, an experimental model of focal TBI with contusion, or were sham-operated. TBI animals failed to remember the familiar object and had a significantly lower performance than sham-operated animals, indicating memory disruption, when the retention delay was 24 hr, but not when it was 3 hr. TBI did not have any significant effect on the main anxiety-related behaviors, but it reduced time in the central platform of the elevated plus maze. The effects of TBI on memory and on anxiety-like behaviors were similar at the 2 postinjury times. In both TBI and sham-operated groups, animals tested 6 weeks after surgery had lower anxiety-related indices than those tested at 3 weeks, an effect that might be indicative of reduced anxiety levels with increasing age. In summary, focal TBI with contusion sustained during late adolescence led to object recognition memory deficits in a 24-hr test during adulthood but did not have a major impact on anxiety-like behaviors. Memory deficits persisted for at least 6 weeks after injury, indicating that spontaneous modifications of these functional disturbances did not take place along this time span.

Effects of voluntary physical exercise, citicoline, and combined treatment on object recognition memory, neurogenesis, and neuroprotection after traumatic brain injury in rats.

The biochemical and cellular events that lead to secondary neural damage after traumatic brain injury (TBI) contribute to long-term disabilities, including memory deficits. There is a need to search for single and/or combined treatments aimed at reducing these TBI-related disfunctions. The effects of citicoline and of voluntary physical exercise in a running wheel (3 weeks), alone or in combination, on TBI-related short-term (3 h) and long-term (24 h) object recognition memory (ORM) deficits and on neurogenesis and neuroprotection were examined using a rodent model of TBI (controlled cortical impact injury). Citicoline improved memory deficits at the two times tested, while physical exercise only in the long-term test. Physical exercise had a clear neuroprotective effect as indicated by reduced interhemispheric differences in hippocampal formation and lateral ventricle volumes and in density of mature neurons in the hilus of the dentate gyrus and the perirhinal cortex. Physical exercise also increased cell proliferation and neurogenesis in the granular cell layer of the dentate gyrus. Some degree of neuroprotection of citicoline was suggested by reduced interhemispheric differences in the volume of the hippocampal formation. Contrary to what was expected, the effects of citicoline and physical exercise did not sum up. Further, a negative interference between both treatments was found in several behavioral and histological variables. The promising profiles of both treatments as therapeutic tools in TBI when applied singly underscore the need to perform further works looking for other combined treatment regimens that increase the benefit of each treatment alone.

Effect of voluntary physical exercise and post-training epinephrine on acquisition of a spatial task in the barnes maze.

A number of experiments have shown that physical exercise improves acquisition and retention for a variety of learning tasks in rodents. Most of these works have been conducted with tasks associated with a considerable level of stress, physical effort and/or food deprivation that might interact with exercise, thus hindering the interpretation of the results. On the other hand, it is well established that post-training epinephrine is able to facilitate memory consolidation, but only a few works have studied its effect on the process of acquisition. The present work was aimed at studying whether 17 days of voluntary physical exercise (running wheels) and/or post-training epinephrine (0.01 or 0.05 mg/kg) could improve the acquisition of a spatial task in the Barnes maze, and whether the combination of the two treatments have additive effects. Our results showed that exercise improved acquisition, and 0.01 mg/kg of epinephrine tended to enhance it, by reducing the distance needed to find the escape hole. The combination of both treatments failed to further improve the acquisition level. We concluded that both treatments exerted their effect on acquisition by enhancing the process of learning itself, and that exercise is able to improve acquisition even using tasks with a low level of stress and physical effort.

Standard object recognition memory and "what" and "where" components: Improvement by post-training epinephrine in highly habituated rats.

The present work examined whether post-training systemic epinephrine (EPI) is able to modulate short-term (3h) and long-term (24 h and 48 h) memory of standard object recognition, as well as long-term (24 h) memory of separate "what" (object identity) and "where" (object location) components of object recognition. Although object recognition training is associated to low arousal levels, all the animals received habituation to the training box in order to further reduce emotional arousal. Post-training EPI improved long-term (24 h and 48 h), but not short-term (3 h), memory in the standard object recognition task, as well as 24 h memory for both object identity and object location. These data indicate that post-training epinephrine: (1) facilitates long-term memory for standard object recognition; (2) exerts separate facilitatory effects on "what" (object identity) and "where" (object location) components of object recognition; and (3) is capable of improving memory for a low arousing task even in highly habituated rats.

Effects of long-term voluntary exercise on learning and memory processes: dependency of the task and level of exercise.

The effect of long-term voluntary exercise (running wheel) on anxiety-like behaviour (plus maze and open field) and learning and memory processes (object recognition and two-way active avoidance) was examined on Wistar rats. Because major individual differences in running wheel behaviour were observed, the data were analysed considering the exercising animals both as a whole and grouped according to the time spent in the running wheel (low, high, and very-high running). Although some variables related to anxiety-like behaviour seem to reflect an anxiogenic compatible effect, the view of the complete set of variables could be interpreted as an enhancement of defensive and risk assessment behaviours in exercised animals, without major differences depending on the exercise level. Effects on learning and memory processes were dependent on task and level of exercise. Two-way avoidance was not affected either in the acquisition or in the retention session, while the retention of object recognition task was affected. In this latter task, an enhancement in low running subjects and impairment in high and very-high running animals were observed.

Effects of posttraining damage to the pedunculopontine tegmental nucleus on conditioned stimulus transfer in two-way active avoidance in rats.

The effects of posttraining excitotoxic lesions of the pedunculopontine tegmental nucleus (PPTg) on two-way active avoidance after changing the conditioned stimulus (CS) used during prelesion training were examined. Prelesion training was carried out with either a tone or a light as the CS, and this CS was changed during postlesion training. Replacing the tone with a light reduced the performance of control and lesioned rats, but the degree of reduction was higher in the latter. Replacing the light with a tone had slight detrimental effects in lesioned rats but not in controls. Thus, posttraining PPTg lesions slowed down the reacquisition of shuttle-box avoidance under conditions of CS transfer, an effect that may be attributable to disruption of attention and/or gating of sensory stimuli.

Posttraining epinephrine treatment reduces the need for extensive training.

We studied whether posttraining epinephrine accelerates the process of acquisition, and whether this effect leads to an enduring high level of performance on a long-term memory test (20 days). Rats were submitted to daily massed (30 trials) two-way active avoidance conditioning sessions followed by systemic epinephrine (0.01 mg/kg) or vehicle, until achieving a learning criterion (80% avoidances in one single session, maximum 14 sessions). By the sixth session, 78% of the animals with posttraining epinephrine attained the learning criterion compared to only the 23% of the rats in the vehicle group. Considering the whole acquisition phase, all the epinephrine treated animals, but only 66.67% in the vehicle group, reached the criterion. On the retention test, both groups maintained the level of performance reached at the end of the acquisition phase. We conclude that epinephrine accelerates the process of acquisition by enhancing memory consolidation, and that this effect might be especially useful in high demanding learning tasks, or for animals with low learning capacities.

Decreased anxiety levels related to aging.

The present experiment investigated the effects of aging on emotional behavior, without concomitant influences from any previous behavioral manipulation apart from weighing the rats. Anxiety-related behaviors were measured in the elevated plus-maze (EPM). Performance in the open field (OF) was also assessed to control for any effect of aging on exploratory behavior that could account for changes in emotional behavior. Fifty-two naïve male Wistar rats of 3 (3MO), 17 (17MO), or 24 (24MO) months, were submitted to two sessions (5 min each) of EPM, followed by two sessions (2 min each) of OF, on 4 consecutive days. The main emotional indices (open arm entries, ratio of open arm entries to total entries, time spent in open arms, ratio of time in open arms to time in four arms, open arm ends, and head dips) measured in the EPM indicated a lower level of anxiety in aged (24MO) than in young (3MO) rats, whereas middle-aged (17MO) rats showed intermediate values between those of 3MO and 24MO rats; 3MO rats showed higher general motor activity (number of rearings in closed arms of EPM and in OF, and higher number of areas crossed in OF) than 17MO and 24MO rats. We conclude that aging is associated with a decrease in anxiety and in general motor activity.

Automated sleep staging in rat with a standard spreadsheet.

A new method of automated sleep-wake staging in the rat is described. Hippocampal electroencephalographic (HPC) and nuchal electromyographic signals were recorded by a digital polygraph. The HPC channel was filtered off-line to obtain the original plus theta and delta waves. Statistics of each of these four channels were obtained every 5 s and exported to a standard spreadsheet. The automated staging consisted of five steps: (1) automatic detection of waking, nonrapid eye movement sleep and rapid eye movement sleep patterns (5-s periods); (2) calculation of statistics for each vigilance state; (3) final classification of 5-s periods; (4) construction of a primary 20-s epoch hypnogram; and (5) automatic refinement of the previous hypnogram. The system includes indices about the accuracy of the staging and was validated with five recordings of 23 h each. The global agreement between human and automatic scoring in the validation recordings was 94.32%.

Improvement of shuttle-box performance by anterodorsal medial septal lesions in rats.

Septal lesions impair a variety of tasks, including inhibitory avoidance and one way active avoidance. In contrast, these lesions improve two-way active avoidance, probably by reducing anxiety. The present work aimed to study whether anterodorsal medial septal lesion (a) improves performance of two-way active avoidance task (Experiment I), as it has been observed with wider septal lesion, and (b) affect anxiety and/or locomotor activity (Experiment II). This precise region was chosen because some evidences suggest that its lesion do not lead to a reduction of anxiety. Lesioned rats tended to make a higher, but statistically non-significant (P=0.074), number of avoidances regardless of the session, being this difference statistically significant on the retention session (RT). The same lesion did not appear to have an anxiolytic effect, and did not affected basal locomotor activity. Different possible explanations of our results are discussed.