The Responses of Neurons of the Somatosensory Cortex to Stimulation of the Posterior Thalamus (PO) in WAG/Rij Rats Genetically Predisposed to Absence Epilepsy

In genetically predisposed WAG/Rij rats and healthy Wistar rats, we studied functioning of the paralemniscal region of the thalamo-cortical system. The responses of neurons of the somatosensory cortex to single electrical stimulation of the posterior nucleus of the thalamus were recorded in two- to three-monthold rats within the period when the epileptic activity was not developed. We revealed lower number of shortterm inhibitory responses in WAG/Rij rats as compared to Wistar rats. This may create preconditions for the spreading of spike-wave activity in the somatosensory cortex, which is an electrophysiological sign of absence epilepsy.     

Anxiety and behavior in WAG/Rij strain rats with genetically induced absence attacks

Behavior of nonlinear rats and animals from Wistar and WAG/Rij (with inborn generalized absence epilepsy) strains was examined in the elevated plus-maze and the hole board. WAG/Rij rats demonstrated low exploratory behavior in both tests. In the elevated plus-maze, WAG/Rij rats were more balanced and more anxious than Wistar and nonlinear rats. Administration of ethosuximide completely eliminated spike-wave discharges but did not change behavioral interstrain differences. Since the spike-wave patterns develop in WAG/Rij at the age of 3 months, the behavior of young (2-moth-old) pups from different strains was compared and significant differences were revealed. Correlation between the genetically defined features (spike-wave discharges) and behavioral peculiarities in WAG/Rij rats is supposed.     

Dopamine-dependent character of depressive-like behavior in WAG/Rij rats with genetic absence epilepsy

Placebo-treated WAG/Rij rats (as compared to normal Wistar rats without seizure pathology) exhibited depressive-like behavior similar to that of intact rats of the same strain: decreased exploratory activity in the open field test, increased immobility in the forced swimming test, decreased sucrose consumption and preference (anhedonia). Chronic injection of tricyclic antidepressant imipramine (15 mg/kg. i.p., for 15 days) exerted a therapeutic (antidepressant) effect on depressive-like behavior in WAG/Rij rats. After cessation of antidepressant therapy, the behavior of WAG/Rij rats didn't significantly differ from that of Wistar rats. Acute (single) injection of selective D2/D3 dopamine receptor antagonist raclopride (100 microg/kg, i.p., 15 min prior to behavioral testing) aggravated the symptoms of depressive-like behavior and suppressed antidepressant effect of chronic injection of imipramine in WAG/Rij rats, whereas it didn't exert a substantial effect on behavior of Wistar rats. Injection of D2/D3 dopamine receptor agonist Parlodel (bromocriptine) counteracted the depressive-like behavior in WAG/Rij rats and didn't exert substantial influence on behavior of Wistar rats with the exception of a decrease in immobility time in the forced swimming test. Injections of imipramine and raclopride didn't exert significant influences on the level of general locomotor activity and anxiety both in WAG/Rij and Wistar rats. The results demonstrate the dopamine-dependent character of depressive-like behavior in WAG/Rij rats, and indicate possible involvement of dopamine D2-like receptors in mediation of the antidepressant effect of imipramine on genetically determined depressive-like behavior in WAG/Rij rats.     

Temporal sequence of SWD emergence and spontaneous jerks in WAG/Rij rats with absence epilepsy

In rat model of absence epilepsy, abnormal complex movements of cervicothorathic part (jerks) were observed in the state of passive wakefulness. When a desynchronized low-amplitude electrical activity was recorded in the parietal and visual cortex, either SWD or jerks were observed. The SWD appearance prevented a jerk. If the discharge appeared between jerks, the interval between jerks increased. Particularly important is the fact that after subtraction of the discharge duration, the distribution of intervals between jerks became the same as in the absence of the SWD. This finding shows that an SWD just interrupts the development of a jerk. That is, when the discharge is over, the jerk develops from the level at which it was stopped by the discharge rather than from the initial level of excitation.     

The characteristics of motor asymmetry in rats with genetic epilepsy (the WAG/Rij strain)]

Motor asymmetry was studied in two groups of WAG/Rij rats with genetic absence epilepsy. A rat had to get food from the horizontal tube with preferable forelimb. The asymmetry coefficient Cas was calculated for the first 10, 50, and 100 trials. In the first group ("pure" absence epilepsy, n = 34) the percent of "left-handers", "right-handers", and ambidextrous calculated for the first 10 trials, was 56, 26, and 18, respectively. In the second group (mixed form of epilepsy, n = 27) this ratio was 19, 40, and 41%, respectively. The percent of ambidextrous, calculated for 50 and 100 trials, substantially decreased in both groups, and the above mentioned ratio became 62, 32, and 6% in the first group and 30, 63, and 7% in the second one. A possible association of pathogenesis of different forms of epilepsy with forelimb preference is discussed.     

Depression-like changes in behavior and c-fos gene expression in dopaminergic brain structures in WAG/Rij rats

In WAG/Rij rats with genetic absence epilepsy, inborn changes in behavior were observed such as decreased level of locomotion, exploratory activity, and grooming reactions in the open-field test, increased immobility in the forced-swimming test, and decreased sucrose consumption (anhedonia) as compared to Wistar rats completely lacking in seizure pathology. These behavioral alterations in WAG/Rij rats resemble the symptoms of human depression (psychomotor retardation, depressed mood, and anhedonia). No significant behavioral changes were found in the light-dark choice, social interaction, and elevated plus-maze tests. This suggests the absence of increased anxiety in WAG/Rij rats. In contrast to Wistar, WAG/Rij rats were sensitive only to chronic treatment with antidepressant imipramine like depressive patients. Behavioral "despair" induced by forced swimming led to C-fos gene expression in three brain structures (frontal cortex, nucleus accumbens, and striatum), which are, respectively, terminal regions of three dopaminergic brain systems (mesocortical, mesolimbc, and nigrostriatal). c-fos gene expression in the brain of WAG/Rij rats was substantially different from that in the brain of Wistar rats in both intensity (in WAG/Rij the c-fos gene expression was higher than in Wistar rats in all involved brain structures) and its distribution between the structures. The results suggest that WAG/Rij strain is a new experimental (genetic) model of absence epilepsy-related depression unassociated with increased anxiety.     

Pregnancy in WAG/Rij rats--changes in the levels of progesterone,estradiol and generalized absence epilepsy

Progesterone and oestradiol serum level was investigated in WAG/Rij rats with genetically determined absences. Blood samples were drawn before and after the pregnancy following the parturition. The serum concentration of progesterone increased after the 3rd day of pregnancy. There is no increasing of oestradiol during pregnancy as large as this. The progesterone is kept high to the 18th day of pregnancy and drastically decreased before the parturition. Common duration of absences--spontaneous spikewave discharges (SWD), frequency and the duration of every SWD decreased from 3rd to 19th days of pregnancy before the parturition. On the basis of these data and modern investigations, regulation of GABAA receptor expression during pregnancy by progesterone (Brusaartd A. B. et al., 1999) it can be assumed that the changes in the parameters of SWD are possibly correlated with the progesterone changes in serum during pregnancy in WAG/Rij rats.     

No Trade-Off between Learning Speed and Associative Flexibility in Bumblebees: A Reversal Learning Test with Multiple Colonies

Potential trade-offs between learning speed and memory-related performance could be important factors in the evolution of learning. Here, we test whether rapid learning interferes with the acquisition of new information using a reversal learning paradigm. Bumblebees (Bombus terrestris) were trained to associate yellow with a floral reward. Subsequently the association between colour and reward was reversed, meaning bees then had to learn to visit blue flowers. We demonstrate that individuals that were fast to learn yellow as a predictor of reward were also quick to reverse this association. Furthermore, overnight memory retention tests suggest that faster learning individuals are also better at retaining previously learned information. There is also an effect of relatedness: colonies whose workers were fast to learn the association between yellow and reward also reversed this association rapidly. These results are inconsistent with a trade-off between learning speed and the reversal of a previously made association. On the contrary, they suggest that differences in learning performance and cognitive (behavioural) flexibility could reflect more general differences in colony learning ability. Hence, this study provides additional evidence to support the idea that rapid learning and behavioural flexibility have adaptive value.     

Low dose of disulfiram and l-dopa evoked synergistic modification in behavior of Wistar and WAG/Rij rats

Comparative analysis of behaviors of two rat strains, Wistar and WAG/Rij, was performed. No behavioral differences between Wistar and WAG/Rij were found in the emotional resonance test. Disulfiram injection produced similar effects in both rat strains. Animals of the first group (with slow acquisition of emotional resonance reaction) transformed into the animals of the second group (with fast acquisition). Passive avoidance conditioning was successfully reproduced in Wistar and was significantly impaired in WAG/Rij. A low dose of disulfiram injected before or immediately after conditioning substantially improved the reproduction to a greater extent in WAG/Rij than Wistar strains thus eliminating in interstrain differences. Active avoidance conditioning was more successful in WAG/Rij than in Wistar rats However, on the next day conditioning in WAG/Rij was substantially impaired. Administration of the low dose of disulfiram or L-DOPA prior to conditioning impaired the acquisition but improved the reproduction on the following day in both strains, but disulfiram injection after conditioning improved conditioning in WAG/Rij to a greater extent than in Wistar. Thus, the pharmacologic enhancement of the reward system substantially changed animal behavior and improved memory consolidation.     

Coccomyxa Gloeobotrydiformis Improves Learning and Memory in Intrinsic Aging Rats

Declining in learning and memory is one of the most common and prominent problems during the aging process. Neurotransmitter changes, oxidative stress, mitochondrial dysfunction and abnormal signal transduction were considered to participate in this process. In the present study, we examined the effects of Coccomyxa gloeobotrydiformis (CGD) on learning and memory ability of intrinsic aging rats. As a result, CGD treated (50 mg/kg·d or 100 mg/kg ·d for a duration of 8 weeks) 22-month-old male rats, which have shown significant improvement on learning and spatial memory ability compared with control, which was evidently revealed in both the hidden platform tasks and probe trials. The following immunohistochemistry and Western blot experiments suggested that CGD could increase the content of Ach and thereby improve the function of the cholinergic neurons in the hippocampus, and therefore also improving learning and memory ability of the aged rats by acting as an anti-inflammatory agent. The effects of CGD on learning and memory might also have an association with the ERK/CREB signalling. The results above suggest that the naturally made drug CGD may have several great benefit as a multi-target drug in the process of prevention and/or treatment of age-dependent cognitive decline and aging process.     

Effect of EEG Biofeedback on Cognitive Flexibility in Children with Attention Deficit Hyperactivity Disorder With and Without Epilepsy

Attention deficit hyperactivity disorder (ADHD) is one of the most common developmental disorders in school-aged children. Symptoms consistent with ADHD have been observed in 8–77 % of children with epilepsy. Researchers have been motivated to search for alternative forms of treatment because 30 % of patients with ADHD cannot be treated by psychostimulants. Several studies support the use of a multimodal treatment approach that includes neurofeedback (NF) for the long-term management of ADHD. These studies have shown that NF provides a sustained effect, even without concurrent treatment with stimulants. We aimed to assess cognitive flexibility in ADHD children with and without temporal lobe epilepsy (TLE), and to evaluate the effects of NF on cognitive flexibility in these groups of children. We prospectively evaluated 69 patients with ADHD aged 9–12 years. The control group was 26 ADHD children without TLE who received no treatment. The first experimental group comprised 18 children with ADHD. The second experimental group comprised 25 age-matched ADHD children with TLE. This group was further divided in two subgroups. One subgroup comprised those with mesial temporal lobe epilepsy (16 patients, 9 with hippocampal sclerosis and 7 with hippocampal atrophy), and the other with lateral temporal lobe epilepsy (9 patients, 5 with temporal lobe dysplasia, 3 with temporal lobe cysts, and 1 with a temporal lobe cavernoma). We treated their ADHD by conducting 30 sessions of EEG NF. Reaction time and error rates on the Trail Making Test Part B were compared before and after treatment, and significant differences were found for all groups of patients except those who had mesial temporal lobe epilepsy with hippocampal atrophy. Our results demonstrate that in most cases, NF can be considered an alternative treatment option for ADHD children even if they have TLE. Additional studies are needed to confirm our results.     

Effect of Liraglutide on Corneal Kindling Epilepsy Induced Depression and Cognitive Impairment in Mice

GLP-1 play important role in neuroprotection and GLP-1 receptor deficit mice showed decreased seizure threshold and increased cognitive impairment. Therefore, study was premeditated to investigate the effect of liraglutide (GLP-1 analogue) on cornel kindling epilepsy induced co-morbidities in mice. Corneal kindling was induced by electrical stimulation (6 mA, 50 Hz, 3 s); twice daily for 13 days. Liraglutide (75 and 150 µg/kg) and phenytoin (20 mg/kg) were administered in corneal kindled groups. On day 14, elevated plus maze, passive shock avoidance paradigms were performed, and on day 15, retention was taken. On day 16 tail suspension test were performed. On 20th day challenge test was performed with same electrical stimulation and retention was observed on elevated plus maze and passive avoidance paradigm. Animal were sacrificed on 21st day for biochemical (LPO, GSH, and nitrite) and neurochemical (GABA, glutamate, DA, NE, 5-HT and their metabolites) estimation. Electrical stimulation by corneal electrode for 13 days developed generalized clonic seizures, increased cognitive impairment, oxidative stress and neurochemical alteration in mice brain. Co-treatment with liraglutide (75 and 150 μg/kg) significantly prevented the seizure severity, restored behavioural activity, oxidative stress and restored the altered level of neurotransmitters observed in corneal kindled mouse.

     

Valproate Administered after Traumatic Brain Injury Provides Neuroprotection and Improves Cognitive Function in Rats

Background

Traumatic brain injury (TBI) initiates a complex series of neurochemical and signaling changes that lead to pathological events including neuronal hyperactivity, excessive glutamate release, inflammation, increased blood-brain barrier (BBB) permeability and cerebral edema, altered gene expression, and neuronal dysfunction. It is believed that a drug combination, or a single drug acting on multiple targets, may be an effective strategy to treat TBI. Valproate, a widely used antiepileptic drug, has a number of targets including GABA transaminase, voltage-gated sodium channels, glycogen synthase kinase (GSK)-3, and histone deacetylases (HDACs), and therefore may attenuate a number of TBI-associated pathologies.

Methodology/Principal Findings

Using a rodent model of TBI, we tested if post-injury administration of valproate can decrease BBB permeability, reduce neural damage and improve cognitive outcome. Dose-response studies revealed that systemic administration of 400 mg/kg (i.p.), but not 15, 30, 60 or 100 mg/kg, increases histone H3 and H4 acetylation, and reduces GSK-3 activity, in the hippocampus. Thirty min post-injury administration of 400 mg/kg valproate improved BBB integrity as indicated by a reduction in Evans Blue dye extravasation. Consistent with its dose response to inhibit GSK-3 and HDACs, valproate at 400 mg/kg, but not 100 mg/kg, reduced TBI-associated hippocampal dendritic damage, lessened cortical contusion volume, and improved motor function and spatial memory. These behavioral improvements were not observed when SAHA (suberoylanilide hydroxamic acid), a selective HDAC inhibitor, was administered.

Conclusion/Significance

Our findings indicate that valproate given soon after TBI can be neuroprotective. As clinically proven interventions that can be used to minimize the damage following TBI are not currently available, the findings from this report support the further testing of valproate as an acute therapeutic strategy.     

Neuroactive steroids and GABAA receptor plasticity in the brain of the WAG/Rij rat, a model of absence epilepsy

The role of neuroactive steroids and GABA(A) receptors in the generation of spontaneous spike-and-wave discharges (SWDs) was investigated in the WAG/Rij rat model of absence epilepsy. The plasma, cerebrocortical, and thalamic concentrations of the progesterone metabolite 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG) were increased in the WAG/Rij rat at 2 months of age compared with those in control (Wistar) rats. In contrast, the brain and peripheral levels of 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-TH DOC) did not differ between the two rat strains at this age. At 6 months of age, when absence epilepsy worsens in WAG/Rij rats, the plasma concentration of 3alpha,5alpha-TH PROG remained high whereas that of 3alpha,5alpha-TH DOC had increased, the cerebrocortical levels of both 3alpha,5alpha-TH PROG and 3alpha,5alpha-TH DOC had increased, and the thalamic concentrations of these metabolites had decreased. At 6 months of age the expression of the alpha(4) and delta subunits of the GABA(A) receptor in relay nuclei was increased. Finally, chronic stress induced by social isolation elicited a reduction in the amount of 3alpha,5alpha-TH PROG in the thalamus of 2-month-old WAG/Rij rats that was associated with a reduction in the number and overall duration of SWDs at 6 months of age. Absence epilepsy in the WAG/Rij rat is thus associated with changes in the abundance of neuroactive steroids and in the expression of specific GABA(A) receptor subunits in the thalamus, a brain area key to the pathophysiology of this condition.     

Effects of heptapeptide selank on genetically-based and situation-provoked symptoms of depression in behavior in WAG/Rij and Wistar rats, and in BALB/c mice

A synthetic derivative of the endogenous peptide tuftsin heptapeptide selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) possesses an anxiolytic and psychostimulant effect, and represents a working element of a new peptide drug having completed the third phase of the clinical testing as a selective anxiolytic. The neurobiochemical spectrum of selank action combines mechanisms which are characteristics of antidepressants and psychostimulants: activation of the brain monoaminergic systems, dopamine synthesis and turnover, and modulation of the tyrosine hydroxylase activity. The aim of this study was to investigate the effect of selank in a new model of inherited (genetically-based) symptoms of depression in behavior of inbred WAG/Rij rats in comparison with its effect on situation-provoked symptoms of depression in behavior of BALB/c mice. Outbred Wistar rats constituted control group. Selank in high doses (1000-2000 microg/kg), after repeated injection counteracted symptoms of depression in behavior of WAG/Rij rats (increased immobilization in the forced swimming test and decreased sucrose intake or preference (anhedonia)). Selank in low doses (100 and 300 microg/kg) after single injection reduced the duration of immobility of BALB/c mice in the forced swimming test, but did not exert significant effect after repeated injection or after injection in high doses (600 and 900 microg/kg). Selank did not affect the level of general locomotor activity and anxiety in WAG/Rij rats, and did not exert substantial effect on the behavior of control Wistar rats. The results demonstrate the presence of antidepressant component in the spectrum of neuropsychotrophyc activity of selank and indicate the higher reliability of a new experimental model of depression (the WAG/Rij rats) as compared to the standard forced swimming test for the determination of antidepressant activity of a pharmacological drug.     

Rearing by foster Wistar mother with high level of maternal care counteracts the development of genetic absence epilepsy and comorbid depression in WAG/Rij rats

It has been shown for the first time that rearing by a foster Wistar mother with high level of maternal care (MC) counteracts the expression of genetic absence epilepsy (AE) and comorbid depression – reduces the number, duration and index of spike-wave discharges (SWDs) and immobility time in the forced swimming test, as well as exerts substantial effects on morphology and time-frequency dynamics of SWDs in WAG/Rij rats. It is supposed that increases in MC early in development might be used to counteract epileptogenesis and comorbid depression in people genetically predisposed to AE.     

Physical Training Moderates Blood-Brain-Barrier Disruption and Improves Cognitive Dysfunction Related to Transient Brain Ischemia in Rats

Neurophysiology - Cerebral ischemia induces structural and functional damage in the brain, which leads to cell death and cognitive dysfunction. According to the evidences, physical exercise...     

Aberrant Function of Learning and Cognitive Control Networks Underlie Inefficient Cognitive Flexibility in Anorexia Nervosa: A Cross-Sectional fMRI Study

ObjectivesPeople with Anorexia Nervosa exhibit difficulties flexibly adjusting behaviour in response to environmental changes. This has previously been attributed to problematic behavioural shifting, characterised by a decrease in fronto-striatal activity. Additionally, alterations of instrumental learning, which relies on fronto-striatal networks, may contribute to the observation of inflexible behaviour. The authors sought to investigate the neural correlates of cognitive flexibility and learning in Anorexia Nervosa.MethodThirty-two adult females with Anorexia Nervosa and thirty-two age-matched female control participants completed the Wisconsin Card Sorting Task whilst undergoing functional magnetic resonance imaging. Event-related analysis permitted the comparison of cognitive shift trials against those requiring maintenance of rule-sets and allowed assessment of trials representing learning.ResultsAlthough both groups performed similarly, we found significant interactions in the left middle frontal gyrus, precuneus and superior parietal lobule whereby blood-oxygenated-level dependent response was higher in Anorexia Nervosa patients during shifting but lower when maintaining rule-sets, as compared to healthy controls. During learning, posterior cingulate cortex activity in healthy controls decreased whilst increasing in the Anorexia Nervosa group, whereas the right precuneus exhibited the opposite pattern. Furthermore, learning was associated with lower blood-oxygenated-level dependent response in the caudate body, as compared to healthy controls.ConclusionsPeople with Anorexia Nervosa display widespread changes in executive function. Whilst cognitive flexibility appears to be associated with aberrant functioning of the fronto-parietal control network that mediates between internally and externally directed cognition, fronto-striatal alterations, particularly within the caudate body, were associated with instrumental learning. Together, this shows how perseverative tendencies could be a substrate of multiple high-order processes that may contribute to the maintenance of Anorexia Nervosa.     

GABA release and uptake measured in crude synaptosomes from Genetic Absence Epilepsy Rats from Strasbourg (GAERS).

GABA release and uptake were examined in Genetic Absence Epilepsy Rats from Strasbourg and in non-epileptic control animals, using crude synaptosomes prepared from the cerebral cortex and thalamus. Uptake of [3H]GABA over time was reduced in thalamic synaptosomes from epileptic rats, compared to controls. The affinity of the uptake process in thalamic synaptosomes was lower in epileptic animals. NNC-711, a ligand for the GAT-1 uptake protein, reduced synaptosomal uptake by more than 95%; beta-alanine, an inhibitor selective for the uptake proteins GAT-2 and -3, did not significantly reduce synaptosomal uptake. Autoradiography studies using [3H]tiagabine, a ligand selective for GAT-1, revealed no differences between the strains in either affinity or levels of binding. Ethanolamine O-sulphate (100 microM), a selective inhibitor of GABA-transaminase, did not affect uptake levels. Aminooxyacetic acid (10-100 microM), an inhibitor of GABA-transaminase and, to a lesser extent, glutamate decarboxylase, caused an increase in measured uptake in both thalamic and cortical synaptosomes, in both strains. We found no difference in in vitro basal or KCl-stimulated endogenous GABA release between epileptic and control rats. These results indicate that GABA uptake in the thalamus of Genetic Absence Epilepsy Rats from Strasbourg was reduced, compared to control animals. The lower uptake affinity in the epileptic animals probably contributed to the reduction in uptake over time. Uptake appeared to be mediated primarily by the 'neuronal' transporter GAT-1. Autoradiography studies revealed no differences in the number or affinity of this uptake protein. It is therefore possible that altered functional modulation of GAT-1 caused the decrease in uptake shown in the epileptic animals. Inhibition of GABA-transaminase activity had no effect on measured GABA uptake, whereas a reduction in glutamate decarboxylase activity may have affected measured uptake levels.