ERP effects and perceived exclusion in the Cyberball paradigm: Correlates of expectancy violation?

Sarah Weschke, Michael Niedeggen

Abstract

A virtual ball-tossing game called Cyberball has allowed the identification of neural structures involved in the processing of social exclusion by using neurocognitive methods. However, there is still an ongoing debate if structures involved are either pain- or exclusion-specific or part of a broader network. In electrophysiological Cyberball studies we have shown that the P3b component is sensitive to exclusion manipulations, possibly modulated by the probability of ball possession of the participant (event “self”) or the presumed co-players (event “other”). Since it is known from oddball studies that the P3b is not only modulated by the objective probability of an event, but also by subjective expectancy, we independently manipulated the probability of the events “self” and “other” and the expectancy for these events. Questionnaire data indicate that social need threat is only induced when the expectancy for involvement in the ball-tossing game is violated. Similarly, the P3b amplitude of both “self” and “other” events was a correlate of expectancy violation. We conclude that both the subjective report of exclusion and the P3b effect induced in the Cyberball paradigm are primarily based on a cognitive process sensitive to expectancy violations, and that the P3b is not related to the activation of an exclusion-specific neural alarm system.

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Keywords:

Social exclusion, Cyberball, P3b, Probability, Expectancy

Differential parietal and temporal contributions to music perception in improvising and score-dependent musicians, an fMRI study

Robert Harris, Bauke M. de Jong

Abstract

Using fMRI, cerebral activations were studied in 24 classically-trained keyboard performers and 12 musically unskilled control subjects. Two groups of musicians were recruited: improvising (n=12) and score-dependent (non-improvising) musicians (n=12). While listening to both familiar and unfamiliar music, subjects either (covertly) appraised the presented music performance or imagined they were playing the music themselves. We hypothesized that improvising musicians would exhibit enhanced efficiency of audiomotor transformation reflected by stronger ventral premotor activation. Statistical Parametric Mapping revealed that, while virtually ‘playing along׳ with the music, improvising musicians exhibited activation of a right-hemisphere distribution of cerebral areas including posterior-superior parietal and dorsal premotor cortex. Involvement of these right-hemisphere dorsal stream areas suggests that improvising musicians recruited an amodal spatial processing system subserving pitch-to-space transformations to facilitate their virtual motor performance. Score-dependent musicians recruited a primarily left-hemisphere pattern of motor areas together with the posterior part of the right superior temporal sulcus, suggesting a relationship between aural discrimination and symbolic representation. Activations in bilateral auditory cortex were significantly larger for improvising musicians than for score-dependent musicians, suggesting enhanced top-down effects on aural perception. Our results suggest that learning to play a music instrument primarily from notation predisposes musicians toward aural identification and discrimination, while learning by improvisation involves audio-spatial-motor transformations, not only during performance, but also perception.

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Keywords:

Music improvisation, Score-dependency, Aural perception, Audiomotor transformation, Parietal cortex, Premotor cortex

Effects of production training and perception training on lexical tone perception – A behavioral and ERP study

Shuang Lu, Ratree Wayland, Edith Kaan

Abstract

The present study recorded both behavioral data and event-related brain potentials to examine the effectiveness of a perception-only training and a perception-plus-production training procedure on the intentional and unintentional perception of lexical tone by native English listeners. In the behavioral task, both the perception-only and the perception-plus-production groups improved on the tone discrimination abilities after the training session. Moreover, the participants in both groups generalized the improvements gained through the trained stimuli to the untrained stimuli. In the ERP task, the Mismatch Negativity was smaller in the post-training task than in the pre-training task. However, the two training groups did not differ in tone processing at the intentional or unintentional level after training. These results suggest that the employment of the motor system does not specifically benefit the tone perceptual skills. Furthermore, the present study investigated whether some tone pairs are more easily confused than others by native English listeners, and whether the order of tone presentation influences non-native tone discrimination. In the behavioral task, Tone2-Tone1 (rising-level) and Tone2-Tone4 (rising-falling) were the most difficult tone pairs, while Tone1-Tone2 and Tone4-Tone2 were the easiest tone pairs, even though they involved the same tone contrasts respectively. In the ERP task, the native English listeners had good discrimination when Tone2 and Tone4 were embedded in strings of Tone1, while poor discrimination when Tone1 was inserted in the context of Tone2 or Tone4. These asymmetries in tone perception might be attributed to the interference of native intonation system and can be altered by training.

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Keywords:

Speech perception, Speech production, Lexical tone, Training, Discrimination, ERP

Incomplete inhibition of central postural commands during manual motor imagery

Hayley Boulton, Suvobrata Mitra

Abstract

Imagined movements exhibit many of the behavioral and neurophysiological characteristics of executed actions. As a result, they are considered simulations of physical actions with an inhibition mechanism that suppresses overt movement. This inhibition is incomplete, as it does not block autonomic preparation, and it also does not effectively suppress postural adjustments planned in support of imagined movements. It has been suggested that a central inhibition command may fail to suppress postural adjustments because it may not have access to afference-based elaborations of the postural response that occur downstream of central motor planning. Here, we measured changes in the postural response associated with imagining manual reaching movements under varying levels of imagined loading of the arm. We also manipulated stance stability, and found that postural sway reduced with increased (imagined) arm loading when imagining reaching movements from the less stable stance. As there were no afferent signals associated with the loading constraint, these results suggest that postural adjustments can leak during motor imagery because the postural component of the central motor plan is itself not inhibited effectively.

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Keywords:

Motor imagery, Motor planning, Posture control

Perceptual and cognitive neural correlates of the useful field of view test in older adults

Jennifer L. O׳Brien, Jennifer J. Lister, Carol L. Peronto, Jerri D. Edwards

Abstract

The Useful Field of View Test (UFOV) is often used as a behavioral assessment of age-related decline in visual perception and cognition. Poor performance may reflect slowed processing speed, difficulty dividing attention, and difficulty ignoring irrelevant information. However, the underlying neural correlates of UFOV performance have not been identified. The relationship between older adults׳ UFOV performance and event-related potential (ERP) components reflecting visual processing was examined. P1 amplitude increased with better UFOV performance involving object identification (subtest 1), suggesting that this task is associated with stimulus processing at an early perceptual level. Better performance in all UFOV subtests was associated with faster speed of processing, as reflected by decreases in P3b latency. Current evidence supports the hypothesis that the UFOV recruits both early perceptual and later cognitive processing involved in attentional control. The implications of these results are discussed.

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Keywords:

Aging, Cognitive decline, Visual perception, Processing speed, Attention, Useful Field of View Test, Event-related potential

Microinjection of orexin-A into the rat locus coeruleus nucleus induces analgesia via cannabinoid type-1 receptors

Hossein Mohammad-Pour Kargar, Hossein Azizi, Javad Mirnajafi-Zadeh, Ali Reza Mani, Saeed Semnanian

Abstract

Locus coeruleus (LC) nucleus is involved in noradrenergic descending pain modulation. LC receives dense orexinergic projections from the lateral hypothalamus. Orexin-A and -B are hypothalamic peptides which modulate a variety of brain functions via orexin type-1 (OX1) and orexin type-2 (OX2) receptors. Previous studies have shown that activation of OX1 receptors induces endocannabinoid synthesis and alters synaptic neurotransmission by retrograde signaling via affecting cannabinoid type-1 (CB1) receptors. In the present study the interaction of orexin-A and endocannabinoids was examined at the LC level in a rat model of inflammatory pain. Pain was induced by formalin (2%) injection into the hind paw. Intra-LC microinjection of orexin-A decreased the nociception score during both phases of formalin test. Furthermore, intra-LC microinjection of either SB-334867 (OX1 receptor antagonist) or AM251 (CB1 receptor antagonist) increased flinches and also the nociception score during phase 1, 2 and the inter-phase of formalin test. The analgesic effect of orexin-A was diminished by prior intra-LC microinjection of either SB-334867 or AM251. This data show that, activation of OX1 receptors in the LC can induce analgesia and also the blockade of OX1 or CB1 receptors is associated with hyperalgesia during formalin test. Our findings also suggest that CB1 receptors may modulate the analgesic effect of orexin-A. These results outline a new mechanism by which orexin-A modulates the nociceptive processing in the LC nucleus.

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Keywords:

Locus coeruleus nucleus, Orexin, Endocannabinoid, SB-334867, AM251, Formalin test, Rat

The H2S-producing enzyme CSE is dispensable for the processing of inflammatory and neuropathic pain

Katharina M.J. Syhr, Meike Boosen, Stephan W. Hohmann, Sebastian Longen, Yvette Köhler, Josef Pfeilschifter, Karl-Friedrich Beck, Gerd Geisslinger, Achim Schmidtko, Wiebke Kallenborn-Gerhardt

Abstract

Accumulating lines of evidence indicate that hydrogen sulfide (H2S) contributes to the processing of chronic pain. However, the sources of H2S production in the nociceptive system are poorly understood. Here we investigated the expression of the H2S releasing enzyme cystathionine γ-lyase (CSE) in the nociceptive system and characterized its role in chronic pain signaling using CSE deficient mice. We show that paw inflammation and peripheral nerve injury led to upregulation of CSE expression in dorsal root ganglia. However, conditional knockout mice lacking CSE in sensory neurons as well as global CSE knockout mice demonstrated normal pain behaviors in inflammatory and neuropathic pain models as compared to WT littermates. Thus, our results suggest that CSE is not critically involved in chronic pain signaling in mice and that sources different from CSE mediate the pain relevant effects of H2S.

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Keywords:

CTH, CSE, Hydrogen sulfide, Chronic pain, Knockout mice, Dorsal root ganglia

Exposure to prenatal stress has deleterious effects on hippocampal function in a febrile seizure rat model

Lihle Qulu, W.M.U. Daniels, Musa V. Mabandla

Abstract
Prenatal stress has been shown to result in the development of a number of neurological disorders in the offspring. Most of these disorders are a result of an altered HPA axis resulting in higher than normal glucocorticoid levels in the affected neonate. This leaves the offspring prone to immune challenges. Therefore the aim of the present study was to investigate the effects of prenatal stress and febrile seizures on behavior and hippocampal function. Pregnant dams were exposed to restraint stress during the third trimester. Following birth, febrile seizures were induced in two week old pups using lipopolysaccharide and kainic acid. A week later, anxiety-like behavior and navigational ability was assessed. Trunk blood was used to measure basal corticosterone concentration and hippocampal tissue was collected and analyzed. Our results show that exposure to prenatal stress increased basal corticosterone concentration. Exposure to prenatal stress exacerbated anxiety-like behavior and impaired the rat׳s navigational ability. Exposure to prenatal stress resulted in reduced hippocampal mass that was exacerbated by febrile seizures. However, exposure to febrile seizures did not affect hippocampal mass in the absence of prenatal stress. This suggests that febrile seizures are exacerbated by exposure to early life stressors and this may lead to the development of neurological symptoms associated with a malfunctioning hippocampus.

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Keywords:

Prenatal stress, Febrile seizures, Corticosterone, Anxiety, Apoptosis, Hippocampus

Environmental enrichment does not reverse the effects of maternal deprivation on NMDAR and Balb/c mice behaviors

Kubra Akillioglu, M. Bertan Yilmaz, Ayper Boga, Secil Binokay, Sabriye Kocaturk-Sel

Abstract

Early adverse life experiences have been associated with anxiety-like behavior and memory impairment. N-methyl-d-aspartate receptors (NMDARs) play an important role in brain development. Enriched environments are known to positively influence emotional and cognitive functions in the brain. We examined the effects of maternal deprivation (MD) on NMDAR subunits in the hippocampus, locomotor activity, anxiety behaviors, and learning-memory performance of Balb/c mice. We also examined whether these effects could be reversed by raising the offspring in an enriched environment. The mice were separated from their mothers for a single 24 h episode on postnatal day (PND) 9. The mice were weaned on day 21 and were housed under either standard (SE) or enriched (EE) environmental conditions. Emotional behaviors and cognitive processes of mice were evaluated using an open field (OF) test, an elevated plus maze (EPM) test, and a Morris water-maze (MWM). NMDAR subunits (GluN1, GluN2A, and GluN2B) mRNA expression levels in the hippocampus were examined by real-time PCR. In OF, MD had no effect on horizontal locomotor activity. MD increased anxiety-like behaviors in the EPM and decreased spatial learning performance in MWM; however, these effects were not reversed by EE. MD (in SE and EE conditions) increased GluN1, GluN2A, and GluN2B mRNA expressions in the hippocampus. In conclusion, MD led to the deterioration of the emotional and cognitive processes during adulthood. Moreover, environmental enrichment did not reverse the deleterious effects of the MD on emotional and cognitive functions and increased the NMDAR levels.

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Keywords:

Maternal deprivation, Environmental enrichment, NMDA receptor, Hippocampus

Stability of resting state networks in the female brain during hormonal changes and their relation to premenstrual symptoms

Timo De Bondt, Dirk Smeets, Pim Pullens, Wim Van Hecke,  Yves Jacquemyn, Paul M. Parizel

Abstract
Resting-state fMRI is a promising imaging technique to evaluate functions in the human brain in health and disease. Different hormonal stages of the female menstrual cycle and hormonal contraceptives use affect results in task-based fMRI; it is however not yet clarified whether resting state networks are also altered. A population of 18 women with a natural cycle, and 19 women using hormonal contraceptives was examined in a longitudinal study-design. The natural cycle group was scanned at 3 time-points (follicular phase, ovulation, luteal phase), and the contraceptives group was scanned twice (inactive pill-phase, active pill-phase). Blood samples were acquired to evaluate hormonal concentrations, and premenstrual symptoms were assessed through daily record of severity of problems questionnaires. Results show no major alterations in the default mode network and the executive control network between different hormonal phases, across or within groups. A positive correlation of functional connectivity in the posterior part of the default mode network (DMN) was found with premenstrual-like symptoms in the hormonal contraceptives group. Using the current methodology, the studied resting state networks seem to show a decent stability throughout menstrual cycle phases. Also, no effect of hormonal contraceptive use is found. Interestingly, we show for the first time an association of DMN alterations with premenstrual-like symptoms, experienced during the inactive pill-phase by a sub-population of women.

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Keywords:
Resting state fMRI, Menstrual cycle, Hormonal contraception, Premenstrual symptoms

NMDA receptor binding is reduced within mesocorticolimbic regions following chronic inhalation of toluene in adolescent rats

Alec Lindsay Ward Dick, Tine Pooters, Sarah Gibbs, Emma Giles, Ashleigh Qama, Andrew John Lawrence, Jhodie Rubina Duncan

Abstract

The purposeful inhalation of volatile solvents, such as toluene, to induce self-intoxication is prevalent, particularly within adolescent populations. Chronic misuse results in cognitive and neurobiological impairments, as well as an increased risk for addictive behaviours in adulthood. Toluene-induced neuroadaptations within mesocorticolimbic circuitry are thought, in part, to mediate some of the adverse outcomes of toluene misuse, however our understanding of the neuroadaptive processes remains equivocal. An understanding of these processes is particularly important relative to exposure that occurs during adolescence and at concentrations that reflect various patterns of use. Therefore, we exposed male adolescent Wistar rats (postnatal day [PN] 27) to either air or low or high concentrations of inhaled toluene in a chronic and intermittent fashion (CIT, 3,000 or 10,000 ppm) for 1 h/day, 3–5 times per week for 4 weeks to model different patterns of human inhalant abuse. Brains were subsequently analysed using autoradiography, qPCR and immunohistochemistry 3 days following the exposure period to investigate toluene-induced neuroadaptations within mesocorticolimbic circuitry. In CIT-exposed rats binding to N-methyl-D-aspartate (NMDA) receptors containing the GluN2B subunit, as determined using [3H]-ifenprodil, was decreased in a concentration-related manner in the caudal cingulate cortex, dorsal striatum and accumbens; however, this was not associated with changes in GluN2B protein expression. There were no differences in [3H]-epibatidine binding to heteromeric neuronal nicotinic acetylcholine (nACh) receptors. Relative expression of mRNA transcripts encoding NMDA, nACh, γ-aminobutyric acid type-A (GABAA) and dopamine receptor subunits was unchanged in all regions assessed following CIT. Our data suggest that adolescent CIT exposure impacts NMDA receptors within regions of corticostriatal circuitry, possibly via post-translational mechanisms. Dysfunctional glutamatergic signalling within corticostriatal regions may contribute to the adverse outcomes observed following adolescent toluene abuse.

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Keywords:

Inhalant abuse, Animal model, Autoradiography, qPCR, NMDA, GluN2B

Dysrhythmia of timed movements in Parkinson׳s disease and freezing of gait

Christopher M. Tolleson, David G. Dobolyi, Olivia C. Roman, Kristen Kanoff, Scott Barton, Scott A. Wylie, Michael Kubovy, Daniel O. Claassen

Abstract

A well-established motor timing paradigm, the Synchronization-Continuation Task (SCT), quantifies how accurately participants can time finger tapping to a rhythmic auditory beat (synchronization phase) then maintain this rhythm after the external auditory cue is extinguished, where performance depends on an internal representation of the beat (continuation phase). In this study, we investigated the hypothesis that Parkinson׳ disease (PD) patients with clinical symptoms of freezing of gait (FOG) exhibit exaggerated motor timing deficits. We predicted that dysrhythmia is exacerbated when finger tapping is stopped temporarily and then reinitiated under the guidance of an internal representation of the beat. Healthy controls and PD patients with and without FOG performed the SCT with and without the insertion of a 7-s cessation of motor tapping between synchronization and continuation phases. With no interruption between synchronization and continuation phases, PD patients, especially those with FOG, showed pronounced motor timing hastening at the slowest inter-stimulus intervals during the continuation phase. The introduction of a gap prior to the continuation phase had a beneficial effect for healthy controls and PD patients without FOG, although patients with FOG continued to show pronounced and persistent motor timing hastening. Ratings of freezing of gait severity across the entire sample of PD tracked closely with the magnitude of hastening during the continuation phase. These results suggest that PD is accompanied by a unique dysrhythmia of measured movements, with FOG reflecting a particularly pronounced disruption to internal rhythmic timing.

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Keywords:

Parkinson׳s disease, Motor timing, Paced finger tapping test, Freezing of gait

Electrolytic lesions of the bilateral ventrolateral orbital cortex inhibit methamphetamine-associated contextual memory formation in rats

Yan Zhao, Peng Liu, Zheng Chu, Fei Liu, Wei Han, Xi Xun, Yong-hui Dang

Abstract

The memories that are formed between rewarding and drug-associated contextual cues have been suggested to contribute to drug addiction relapse. Recent evidence has indicated that the ventrolateral orbital cortex (VLO) plays important roles in reward-based learning and reversal learning. However, whether the VLO is required for methamphetamine-induced contextual memory formation is not well understood. In the present study, a three-phase methamphetamine-induced conditioned place preference (CPP) model was used to investigate the effects of VLO lesions on the formation of drug-associated contextual memories in rats. We found that the VLO lesions themselves elicited no observable effects on place preferences. However, the VLO lesions delayed the acquisition and extinction phases of CPP without affecting the expression level. Furthermore, the VLO lesions did not have an obvious influence on CPP reinstatement. These results indicate that electrolytic lesions of the bilateral ventrolateral orbital cortex can inhibit the formation of methamphetamine-induced contextual memories in rats. Moreover, VLO may not be critically involved in memory storage and retrieval.

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Keywords:

Ventrolateral orbital cortex, Methamphetamine, Conditioned place preference, Memory

Audio–visual integration through the parallel visual pathways

Peter Kaposvari, Gergo Csete, Anna Bognara, Peter Csibri, Eszter Toth, Nikoletta Szabo, c, Laszlo Vecsei, Gyula Sary, Zsigmond Tamas Kincses

Abstract

Audio–visual integration has been shown to be present in a wide range of different conditions, some of which are processed through the dorsal, and others through the ventral visual pathway. Whereas neuroimaging studies have revealed integration-related activity in the brain, there has been no imaging study of the possible role of segregated visual streams in audio–visual integration. We set out to determine how the different visual pathways participate in this communication. We investigated how audio–visual integration can be supported through the dorsal and ventral visual pathways during the double flash illusion. Low-contrast and chromatic isoluminant stimuli were used to drive preferably the dorsal and ventral pathways, respectively. In order to identify the anatomical substrates of the audio–visual interaction in the two conditions, the psychophysical results were correlated with the white matter integrity as measured by diffusion tensor imaging.The psychophysiological data revealed a robust double flash illusion in both conditions. A correlation between the psychophysical results and local fractional anisotropy was found in the occipito-parietal white matter in the low-contrast condition, while a similar correlation was found in the infero-temporal white matter in the chromatic isoluminant condition. Our results indicate that both of the parallel visual pathways may play a role in the audio–visual interaction.

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Keywords:

MRI, DTI, TBSS, Multisensory, Doubleflash

The role of visual deprivation and experience on the performance of sensory substitution devices

H. Christiaan Stronks, Amy C. Nau, Michael R. Ibbotson, Nick Barnes

Abstract

It is commonly accepted that the blind can partially compensate for their loss of vision by developing enhanced abilities with their remaining senses. This visual compensation may be related to the fact that blind people rely on their other senses in everyday life. Many studies have indeed shown that experience plays an important role in visual compensation. Numerous neuroimaging studies have shown that the visual cortices of the blind are recruited by other functional brain areas and can become responsive to tactile or auditory input instead. These cross-modal plastic changes are more pronounced in the early blind compared to late blind individuals. The functional consequences of cross-modal plasticity on visual compensation in the blind are debated, as are the influences of various etiologies of vision loss (i.e., blindness acquired early or late in life). Distinguishing between the influences of experience and visual deprivation on compensation is especially relevant for rehabilitation of the blind with sensory substitution devices. The BrainPort artificial vision device and The vOICe are assistive devices for the blind that redirect visual information to another intact sensory system. Establishing how experience and different etiologies of vision loss affect the performance of these devices may help to improve existing rehabilitation strategies, formulate effective selection criteria and develop prognostic measures. In this review we will discuss studies that investigated the influence of training and visual deprivation on the performance of various sensory substitution approaches.

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Keywords:

Sensory substitution, Rehabilitation, Cross-modal plasticity, Training, Learning, Visual deprivation

Environmental enrichment and working memory tasks decrease hippocampal cell proliferation after wheel running – A role for the prefrontal cortex in hippocampal plasticity?

Andrea T.U. Schaefers

Abstract

Despite an increasing amount of evidence about the regulation of adult hippocampal neurogenesis on the local level, less attention has been paid to its systemic embedding in wider brain circuits. The aim of the present study was to obtain evidence for a potential role of the prefrontal cortex in the regulation of adult hippocampal neurogenesis. We hypothesised that activation of the prefrontal cortex by environmental enrichment or a working-memory task would decrease previously enhanced cell proliferation rates. Wheel running was applied as a common stimulator of cell proliferation in CD1 mice reared under deprivation of natural environmental stimulation. Next, the animals were assigned to four groups for different treatments in the following three days: housing under continued deprivation, environmental enrichment, a spatial-delayed alternation task in an automated T-maze that activates the prefrontal cortex by working-memory requirements or a control task in the automated T-maze differing only in the single parameter working-memory-associated delay. Both the environmental enrichment and spatial-delayed alternation tasks decreased cell proliferation rates in the dentate gyrus compared to deprived housing and the control task in the T-maze. As the control animals underwent the same procedures and stressors and differed only in the single parameter working-memory-associated delay, the working-memory requirement seems to be the crucial factor for decreasing cell proliferation rates. Taken together, these results suggest that the prefrontal cortex may play a role in the regulation of hippocampal cell proliferation.

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Keywords:

Hippocampal cell proliferation, Prefrontal cortex, Working memory, Environmental enrichment, Automated T-maze

Protection of the brain following cerebral ischemia through the attenuation of PARP-1-induced neurovascular unit damage in rats

Ruixue Zhang, Shi Tang, Weiwei Huang, Xiaomin Liu, Guohua Li, Heng Chi, Meijia Zhu, Jiyou Tang

Abstract

Cerebral ischemia is a major health crisis throughout the world, and the currently available thrombolytic therapy is unsatisfactory. Cell death following cerebral ischemia is mediated by a complex pathophysiological interaction of various mechanisms. During an ischemic insult, not only neurons but all of the components of the neurovascular unit, such as glia, endothelia, pericytes and basal membranes, are destroyed. Previous studies have shown that excessive stimulation of poly (ADP-ribose) polymerase (PARP-1) is crucial for cerebral injury after ischemic insult, which is an important cause of cell death in all cell types within the neurovascular unit. To investigate whether PARP-1 plays an important role in protecting the neurovascular unit following cerebral ischemia, we evaluated neurobehavioral deficits, PARP-1 activity, blood brain barrier (BBB) disruption and neurovascular unit deficits using Western blot analysis, TTC staining and electron microscopy in an MCAO rat model. The results revealed that PARP-1 enzymatic activity was dramatically increased after ischemia. Inhibition of PARP-1 significantly reduced the extent of both cerebral infarction and edema, improved neurological scores, and attenuated the damage to the neurovascular unit in cerebral ischemia. Collectively, these findings demonstrate that the down-regulation of PARP-1 activity contributes to reducing post-ischemic brain damage via protection of the neurovascular unit.

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Keywords:

Neurovascular unit, Poly(ADP-ribose) polymerase Cerebral ischemia

Sustained delivery of chondroitinase ABC by poly(propylene carbonate)-chitosan micron fibers promotes axon regeneration and functional recovery after spinal cord hemisection

Shilei Ni, Tongliang Xia, Xingang Li, Xiaodong Zhu, Hongxu Qi, Shanying Huang, Jiangang Wang

Abstract

We describe the sustained delivery of chondroitinase ABC (ChABC) in the hemisected spinal cord using polypropylene carbonate (PPC) electrospun fibers with chitosan (CS) microspheres as a vehicle. PPC and ChABC-loaded CS microspheres were mixed with acetonitrile, and micron fibers were generated by electrospinning. ChABC release was assessed in vitro with high-performance liquid chromatography (HPLC) and revealed stabilized and prolonged release. Moreover, the released ChABC showed sustained activity. PPC-CS micron fibers with or without ChABC were then implanted into a hemisected thoracic spinal cord. In the following 4 weeks, we examined functional recovery and performed immunohistochemical analyses. We found that sustained delivery of ChABC promoted axon sprouting and functional recovery and reduced glial scarring; PPC-CS micron fibers without ChABC did not show these effects. The present findings suggest that PPC-CS micron fibers containing ChABC are a feasible option for spinal cord injury treatment. Furthermore, the system described here may be useful for local delivery of other therapeutic agents.

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Keywords:

ChABC, Spinal cord injury, PPC, Chitosan, Electrospinning

Lentiviral-mediated overexpression of nerve growth factor (NGF) prevents beta-amyloid [25–35]-induced long term potentiation (LTP) decline in the rat hippocampus

Shukhrat S. Uzakov, Andrey D. Ivanov, Sergey V. Salozhin, Vladimir A. Markevich, Natalia V. Gulyaeva

Abstract

We have explored the potential neuroprotective effect of local lentiviraly-mediated overexpression of nerve growth factor (NGF) on in vivo long-term potentiation (LTP) in the rat hippocampus under pathological conditions. The suspension of lentiviral particles was prepared using a genetic construct containing the human NGF gene under the control of a neuron-specific CaMKII promoter. Two weeks after the viral injection NGF concentration in the hippocampus doubled. In vivo recordings of total electrical activity in the dentate gyrus were performed. While the increased expression of NGF did not affect the amplitude of evoked postsynaptic potentials recorded after a high-frequency stimulation of the perforant path, it prevented the LTP decline induced by the i.c.v. administration of 50 nM beta-amyloid (25–35) 1 h prior to tetanization. Our results demonstrate that increased endogenous NGF concentration can rescue hippocampal neuronal function from beta-amyloid peptide induced impairment.

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Keywords:

Hippocampus, Plasticity, LTP, Beta-amyloid, NGF, Neurotrophins, Lentivirus

Down regulation of lncSCIR1 after spinal cord contusion injury in rat

Jing Wang, Bo Hu, Fei Cao, Shenggang Sun, Yunjian Qing Zhu

Abstract

Extensive changes occur at transcriptional level after traumatic spinal cord injury (SCI). In this study, we performed a large scale screening of expression changes of long (>200 nt) RNA transcripts including both coding and non-coding RNA species in a rat contusion SCI model. We validated significant down-regulation of one long non-coding RNA (lncSCIR1) at 1, 4, and 7 days postinjury. lncSCIR1 knockdown promoted astrocyte proliferation and migration in vitro. We further validated the strong association between lncSCIR1 knock down and the expression changes of four mRNAs after injury. Our data indicated that lncSCIR1 down-regulation might play a detrimental role in the pathophysiology of traumatic SCI and thereby provided new insights into the studies of potential therapeutic targets for traumatic central nervous system (CNS) injuries.

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Keywords:

Spinal cord injury, Contusion, RNA-Seq, Long non-coding RNA, lncSCIR1, Astrocyte 

Deleterious impacts of a 900-MHz electromagnetic field on hippocampal pyramidal neurons of 8-week-old Sprague Dawley male rats

Arzu Sahin, Ali Aslan, Orhan Bas, Ayse Ikinci, Cansu Ozyılmaz, Osman Fikret Sonmez, Serdar Colakoglu, Ersan Odacı

Abstract

Children are at potential risk due to their intense use of mobile phones. We examined 8-week-old rats because this age of the rats is comparable with the preadolescent period in humans. The number of pyramidal neurons in the cornu ammonis of the Sprague Dawley male rat (8-weeks old, weighing 180–250 g) hippocampus following exposure to a 900 MHz (MHz) electromagnetic field (EMF) were examined. The study consisted of control (CN-G), sham exposed (SHM-EG) and EMF exposed (EMF-EG) groups with 6 rats in each. The EMF-EG rats were exposed to 900 MHz EMF (1 h/day for 30 days) in an EMF jar. The SHM-EG rats were placed in the EMF jar but not exposed to the EMF (1 h/day for 30 days). The CN-G rats were not placed into the exposure jar and were not exposed to the EMF during the study period. All animals were sacrificed at the end of the experiment, and their brains were removed for histopathological and stereological analysis. The number of pyramidal neurons in the cornu ammonis of the hippocampus was estimated on Cresyl violet stained sections of the brain using the optical dissector counting technique. Histopathological evaluations were also performed on these sections. Histopathological observation showed abundant cells with abnormal, black or dark blue cytoplasm and shrunken morphology among the normal pyramidal neurons. The largest lateral ventricles were observed in the EMF-EG sections compared to those from the other groups. Stereological analyses showed that the total number of pyramidal neurons in the cornu ammonis of the EMF-EG rats was significantly lower than those in the CN-G (p<0.05) and the SHM-EG (p<0.05). In conclusion, our results suggest that pyramidal neuron loss and histopathological changes in the cornu ammonis of 8-week-old male rats may be due to the 900-MHz EMF exposure.

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Keywords

Electromagnetic field, Cell phone, Children; Hippocampus, Pyramidal neuron, Male rat

ACEA (a highly selective cannabinoid CB1 receptor agonist) stimulates hippocampal neurogenesis in mice treated with antiepileptic drugs

Marta Andres-Mach, Agnieszka Haratym-Maj, Miroslaw Zagaja, Radoslaw Rola,  Maciej Maj, Magdalena Chrościńska-Krawczyk, Jarogniew J. Luszczki

Abstract

Hippocampal neurogenesis plays a very important role in learning and memory functions. In a search for best neurological drugs that protect neuronal cells and stimulate neurogenesis with no side effects, cannabinoids proved to be a strong group of substances having many beneficial properties. The aim of this study was to evaluate the impact of ACEA (arachidonyl-2′-chloroethylamide—a highly selective cannabinoid CB1 receptor agonist) combined with a classical antiepileptic drug sodium valproate (VPA) on neural precursor cells׳ proliferation and differentiation in the mouse brain. All experiments were performed on adolescent CB57/BL male mice injected i.p. with VPA (10 mg/kg), ACEA (10 mg/kg) and PMSF (30 mg/kg) (phenylmethylsulfonyl fluoride—a substance protecting ACEA against degradation by the fatty-acid amidohydrolase) for 10 days. Next an acute response of proliferating neural precursor cells to ACEA and VPA administration was evaluated with Ki-67 staining (Time point 1). Next, in order to determine whether acute changes translated into long-term alterations in neurogenesis, proliferating cells were labeled with 5-bromo-2deoxyuridine (BrdU) followed by confocal microscopy used to determine the percentage of BrdU-labeled cells that showed mature cell phenotypes (Time point 2). Results indicate that ACEA with PMSF significantly increase the total number of Ki-67-positive cells when compared to the control group. Moreover, ACEA in combination with VPA increased the number of Ki-67-positive cells, whereas VPA administered alone had no impact on proliferating cells׳ population. Accordingly, neurogenesis study results indicate that the combination of ACEA+PMSF administered alone and in combination with VPA considerably increases the total number of BrdU-positive cells in comparison to the control group while ACEA+PMSF alone and in combination with VPA increased total numbers of BrdU-positive cells, newly born neurons and astrocytes as compared to VPA group but not to the control group. VPA administered alone decreased the number of newly born neurons with no significant impact on neurogenesis. These data provide substantial evidence that VPA administered chronically slightly decreases the proliferation and differentiation of newly born cells while combination of VPA+ACEA significantly increases the level of newborn neurons in the dentate subgranular zone.

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Keywords:

ACEA, Valproic acid, Hippocampal neurogenesis, Neural precursor cells

Alpha-fetoprotein (AFP) modulates the effect of serum albumin on brain development by restraining the neurotrophic effect of oleic acid

Alejandro G. Garcia-Garcia, Erica Polo-Hernandez, Arantxa Tabernero, Jose M. Medina

Abstract

We have previously shown that serum albumin controls perinatal rat brain development through the regulation of oleic acid synthesis by astrocytes. In fact, oleic acid synthesized and released by astrocytes promoted neurite growth, neuron migration and the arrangement of prospective synapses. In this work we show that alpha-fetoprotein (AFP) is also present in the brain during embryonic development, its concentrations peaking at E15.5 and at E19.5. However, after E19.5 AFP concentrations plummeted concurrently with a sharp increase in serum albumin concentrations. At E15.5, AFP is present in caudal regions of the brain, particularly in brain areas undergoing differentiation during this period, such as the thalamic reticular nucleus of the thalamus, the hypothalamus, the amygdala and the hippocampus. Albumin was not detected in the brain at E15.5 but stained brain cells substantially on day E19.5, showing a very similar distribution to that of AFP under the same circumstances. The concentrations of free oleic acid in the brain were inversely correlated with those of AFP, suggesting that the signals elicited by AFP and oleic acid can be inversely associated. GAP-43, a marker of axonal growth that is highly expressed by the presence of oleic acid, was not co-localized with AFP except in the marginal zone and areas delimiting the subplate. AFP prevented the increase in GAP-43 expression caused by the presence of oleic acid in neurons in primary culture in vitro and in organotypic cultures of embryonic rat brain ex vivo, suggesting that AFP may modulate the effect of serum albumin on brain development.

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Keywords:

Alpha-fetoprotein, Serum albumin, Oleic acid, AP-43, Embryonic development

Neurite outgrowth promoting effect of 17-β estradiol is mediated through estrogen receptor alpha in an olfactory epithelium culture

Apryl E. Pooley, Minh Luong, Aseem Hussain, Britto P. Nathan

Abstract
Olfactory deficits are observed early in the course of chronic neurological disorders including Alzheimer׳s disease (AD). Estrogen treatment in post-menopausal women reduced the incidence of olfactory dysfunction, raising the possibility that estrogen treatment can cure olfactory deficits in preclinical stages of AD. In this study, we examined the estradiol׳s effects on neurite outgrowth in explant cultures of mouse olfactory epithelium (OE). We found that neurons in OE cultures treated with 100 pM 17-β estradiol (estradiol) had significantly longer neurite outgrowth than cultures treated with ethanol alone (vehicle). The OE neurons expressed estrogen receptors alpha (ERα) and ER beta (ERβ). Estrogen treatment upregulated both ERα and ERβ expression in OE culture. Treatment of OE cultures with propyl pyrazole triol (PPT), a selective agonist for ERα increased neurite outgrowth to comparable extent as estradiol treatment. In contrast, 2,3-bis-4-hydroxyphenyl (DPN), a specific agonist for ERβ, had no effect on neurite outgrowth. Furthermore, estradiol treatment increased neurite outgrowth in OE cultures derived from ERβ-deficient/knockout mice and wild-type littermates, but not in ERα-deficient/knockout mice. These data suggest that ERα mediates the neurite outgrowth promoting effects of estradiol in OE cultures. We propose that olfactory dysfunction in chronic neurological disorders, where estrogen deficiency is a risk factor, is an indicator of compromised axonal regeneration of olfactory sensory neurons.

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Keywords:
Olfactory, Estrogen, Estrogen receptors

Pre- and postnatal bisphenol A treatment does not alter the number of tyrosine hydroxylase-positive cells in the anteroventral periventricular nucleus (AVPV) of weanling male and female rats

Sherry A. Ferguson, Merle G. Paule, Zhen He 

Abstract

Exposure to Bisphenol A (BPA) may interfere with brain sexual differentiation. Altered numbers of tyrosine hydroxylase (TH) cells in the rodent anteroventral periventricular nucleus (AVPV) after developmental BPA treatment have been reported; however, definitive conclusions are lacking. The current study incorporated many of the guidelines suggested for endocrine disrupter research. Specifically, ethinyl estradiol (EE2) served as a reference estrogen, exogenous environmental estrogen exposure was controlled, BPA was administered orally, and subjects consumed a low phytoestrogen diet. Here, on gestational days 6–21, Sprague-Dawley rats (10–15/group) were gavaged with 2.5 or 25.0 µg BPA/kg/day or 5.0 or 10.0 µg EE2/kg/day or the vehicle (5 ml of 0.3% aqueous carboxymethylcellulose/kg/day). A naïve control group was weighed and restrained, but not gavaged. Beginning on postnatal day (PND) 1 and continuing until PND 21, the 4 pups/sex/litter were orally treated with the same dose their dam had received. On PND 21, 1/sex/litter was perfused and the brain removed. TH immunoreactivity (TH-ir) was counted in 8 images/pup by a technician blind to treatment status. ANOVA results indicated significantly higher TH-ir cells/mm2 in females (main effect of sex: p<0.01); however, there was no significant effect of treatment or a significant interaction of treatment with sex. In a separate untreated group of PND 21 Sprague-Dawley pups, AVPV volume was quantified and no significant sexual dimorphism was apparent. Similar to our reported results of behavioral assessments, the BPA treatment paradigm used here (2.5 or 25.0 µg BPA/kg/day administered orally) does not appear to cause significant alterations in AVPV TH-ir.

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Keywords:

Bisphenol A, Anteroventral paraventricular nucleus (AVPV), Tyrosine hydroxylase (TH), Prenatal, Postnatal, Rat

Metabotropic glutamate receptor 5 upregulates surface NMDA receptor expression in striatal neurons via CaMKII

Dao-Zhong Jin, Bing Xue, Li-Min Mao, John Q. Wang

Abstract

Metabotropic and ionotropic glutamate receptors are closely clustered in postsynaptic membranes and are believed to interact actively with each other to control excitatory synaptic transmission. Metabotropic glutamate receptor 5 (mGluR5), for example, has been well documented to potentiate ionotropic NMDA receptor activity, although underlying mechanisms are poorly understood. In this study, we investigated the role of mGluR5 in regulating trafficking and subcellular distribution of NMDA receptors in adult rat striatal neurons. We found that the mGluR1/5 agonist DHPG concentration-dependently increased NMDA receptor GluN1 and GluN2B subunit expression in the surface membrane. Meanwhile, DHPG reduced GluN1 and GluN2B levels in the intracellular compartment. The effect of DHPG was blocked by an mGluR5 selective antagonist MTEP but not by an mGluR1 selective antagonist 3-MATIDA. Pretreatment with an inhibitor or a specific inhibitory peptide for synapse-enriched Ca2+/calmodulin-dependent protein kinase II (CaMKII) also blocked the DHPG-stimulated redistribution of GluN1 and GluN2B. In addition, DHPG enhanced CaMKIIα activity and elevated GluN2B phosphorylation at a CaMKII-sensitive site (serine 1303). These results demonstrate that mGluR5 regulates trafficking of NMDA receptors in striatal neurons. Activation of mGluR5 appears to induce rapid trafficking of GluN1 and GluN2B to surface membranes through a signaling pathway involving CaMKII.

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Keywords:

mGluR, Striatum, GluN1, GluN2B, NR2B, G protein-coupled receptor, Phosphorylation, DHPG 

GluN2B-containing NMDA receptors are upregulated in plasma membranes by the sphingosine-1-phosphate analog FTY720P

Suzanne Attiori Essis, Marie-Elaine Laurier-Laurin, Elise Pepin, Michel Cyr, Guy Massicotte

Abstract

Sphingosine-1-phosphate (S1P) is a ceramide derivative serving not only as a regulator of immune properties but also as a modulator of brain functions. To better understand the mechanism underlying the effects of S1P on brain functions, we investigated the potential impact of S1P receptor (S1PR) activation on NMDA receptor subunits. We used acute rat hippocampal slices as a model system, and determined the effects of the active phosphorylated S1P analog, fingolimod (FTY720P) on various NMDA receptors. Treatment with FTY720P significantly increased phosphorylation of GluN2B-containing NMDA receptors at Tyr1472. This effect appears rather specific, as treatment with FTY720P did not modify GluN2B-Tyr1336, GluN2B-Ser1480, GluN2A-Tyr1325 or GluN1-Ser897 phosphorylation. Pre-treatment of hippocampal slices with the compounds W146 and PP1 indicated that FTY720P-induced GluN2B phosphorylation at Tyr1472 epitopes was dependent on activation of S1PR subunit 1 (S1PR1) and Src/Fyn kinase, respectively. Cell surface biotinylation experiments indicated that FTY720P-induced GluN2B phosphorylation at Tyr1472 was also associated with increased levels of GluN1 and GluN2B subunits on membrane surface, whereas no change was observed for GluN2A subunits. We finally demonstrate that FTY720P is inclined to favor Tau and Fyn accumulation on plasma membranes. These results suggest that activation of S1PR1 by FTY720P enhances GluN2B receptor phosphorylation in rat hippocampal slices, resulting in increased levels of GluN1 and GluN2B receptor subunits in neuronal membranes through a mechanism probably involving Fyn and Tau.

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Keywords:

NMDA receptor, sphingosine-1-phosphate analog FTY720P, GluN2B receptor phosphorylation, Fyn, Tau 

Different protocols of treadmill exercise induce distinct neuroplastic effects in rat brain motor areas

Caroline C. Real, Priscila C. Garciaa, Luiz R.G. Britto, Raquel S. Pires

Abstract

A variety of exercise protocols have been used to promote experimental neuroplasticity. However, the plastic brain responses generated by several aspects of training (types, frequency, regimens, duration) remain undetermined. The aim of this study was to compare the plastic changes in the glutamatergic system and synaptic proteins in motor cortex, striatum and cerebellum promoted by two different treadmill exercise regimens. The present study analyzed by immunohistochemistry and Western blotting the expression of the subunits of AMPA receptors (GluA1 and GluA2/3) and synaptic proteins (synapsin I and synaptophysin) in adult male Wistar rat brains. The animals were divided into animals subjected to two different frequencies of aerobic exercise groups and sedentary animals. The exercise groups were: intermittent treadmill exercise (ITE) – animals that exercised 3 times a week (every other day) during four weeks, and continuous treadmill exercise (CTE) – animals that exercised every day during four weeks. Our results reveal that different protocols of treadmill exercise were able to promote distinct synaptic reorganization processes among the exercised groups. In general, the intermittent exercise regimen induced a higher expression of presynaptic proteins, whereas the continuous exercise regimen increased postsynaptic GluA1 and GluA2/3 receptors.

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Keywords:

AMPA receptor, Synaptic protein, Synaptic plasticity, Physical exercise, Motor system

A novel mechanism for the anticonvulsant effect of furosemide in rat hippocampus in vitro CIH-induced neurocognitive impairments are associated with hippocampal Ca2+ overload, apoptosis, and dephosphorylation of ERK1/2 and CREB that are mediated by overactivation of NMDARs

Jing Wang, Hong Ming, Rui Chen, Jing-mei Ju, Wan-da Peng, Guo-Xing Zhang, Chun-feng Liu

Abstract

Chronic intermittent hypoxia (CIH) is commonly seen in patients with obstructive sleep apnea, and has been hypothesized to underlie the neurocognitive dysfunction in these patients. However, its cellular and molecular mechanisms remain to be defined. The present study aimed to investigate, in a mouse CIH model, the role of NMDA receptor (NMDAR) activation in mediating the CIH-induced neurocognitive impairments, caspase expression and dysregulated Ca2+ signaling pathways in hippocampus. Male ICR mice (n=45) were exposed to CIH (8 h/day) or room air (control) for 4 weeks. After 4-week treatment, neurobehavioral assessments were performed by Morris water maze test, hippocampal [Ca2+]i was evaluated by flow cytometry; and protein expressions of caspase-3, caspase-9, PARP, p-ERK1/2 and p-CREB in hippocampus were measured by Western blotting. Our results showed that, compared to control animals, 4-week exposure to CIH produced significant spatial learning and memory impairments in CIH mice. Increased caspase expression in hippocampus was observed in CIH mice associated with significant elevation of [Ca2+]i and dephosphorylation of ERK and CREB expression. When the NMDAR antagonist memantine was administered by intraperitoneal injection prior to daily exposure to CIH, at a sub-therapeutic dose of 5 mg/kg/day not shown to impact the neurobehavioral performance in control animals, the neurocognitive impairments as well as the neurobiochemical changes were abolished or normalized in the CIH mice. Our study suggests that overactivation of NMDARs and the Ca2+ overload-dependent ERK/CREB dysregulation is one of the important mechanisms in mediating the CIH-induced neurocognitive impairments.

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Keywords:

Chronic intermittent hypoxia, Neurocognitive impairments, Calcium overload, NMDA, Receptors, Memantin

A novel mechanism for the anticonvulsant effect of furosemide in rat hippocampus in vitro

Josiane Uwera, Steen Nedergaard, Mogens Andreasen

Abstract

Though both in vivo and in vitro studies have demonstrated an anticonvulsant effect of the loop diuretic furosemide, the precise mechanism behind this effect is still debated. The current study investigates the effect of furosemide on Cs-induced epileptiform activity (Cs-FP) evoked in area CA1 of rat hippocampal slices in the presence of Cs+ (5 mM) and ionotropic glutamatergic and GABAergic receptor antagonists. As this model diverges in several respects from other epilepsy models it can offer new insight into the mechanism behind the anticonvulsive effect of furosemide. The present study shows that furosemide suppresses the Cs-FP in a dose-dependent manner with a near complete block at concentrations≥1.25 mM. Because furosemide targets several types of ion transporters we examined the effect of more selective antagonists. Bumetanide (20 μM), which selectively inhibits the Na–K–2Cl co-transporter (NKCC1), had no significant effect on the Cs-FP. VU0240551 (10 μM), a selective antagonist of the K–Cl co-transporter (KCC2), reduced the ictal-like phase by 51.73±8.5% without affecting the interictal-like phase of the Cs-FP. DIDS (50 μM), a nonselective antagonist of Cl−/HCO3−-exchangers, Na+–HCO3−-cotransporters, chloride channels and KCC2, suppressed the ictal-like phase by 60.8±8.1% without affecting the interictal-like phase. At 500 μM, DIDS completely suppressed the Cs-FP. Based on these results we propose that the anticonvulsant action of furosemide in the Cs+-model is exerted through blockade of the neuronal KCC2 and Na+-independent Cl−/HCO3−-exchanger (AE3) leading to stabilization of the activity-induced intracellular acidification in CA1 pyramidal neurons.

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Keywords:

Furosemide, NKCC1, KCC2, Cl−/HCO−3-exchanger, Seizure, pHi

Hippocampal signaling pathways are involved in stress-induced impairment of memory formation in rats

Maryam Sardari, Ameneh Rezayof, Fariba Khodagholi

Abstract

Stress is a potent modulator of hippocampal-dependent memory formation. The aim of the present study was to assess the role of hippocampal signaling pathways in stress-induced memory impairment in male Wistar rats. The animals were exposed to acute elevated platform (EP) stress and memory formation was measured by a step-through type passive avoidance task. The results indicated that post-training or pre-test exposure to EP stress impaired memory consolidation or retrieval respectively. Using western blot analysis, it was found that memory retrieval was associated with the increase in the levels of phosphorylated cAMP-responsive element binding protein (P-CREB), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and its downstream targets in the hippocampus. In contrast, the stress exposure decreased the hippocampal levels of these proteins. In addition, stress-induced impairment of memory consolidation or retrieval was associated with the decrease in the P-CREB/CREB ratio and the PGC-1α level in the hippocampus. On the other hand, the hippocampal level of nuclear factor E2-related factor 2 (Nrf2) and gamma-glutamylcysteine synthetase (γ-GCS) which are the master regulators of defense system were decreased by the stress exposure. The increased hippocampal levels of Nrf2 and it׳s downstream was observed during memory retrieval, while stress-induced impairment of memory consolidation or retrieval inhibited this hippocampal signaling pathway. Overall, these findings suggest that down-regulation of CREB/PGC-1α signaling cascade and Nrf2 antioxidant pathways in the hippocampus may be associated with memory impairment induced by stress.

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Keywords:

Acute stress, Memory formation, Hippocampal signaling pathway, Rat(s)

Effect of endurance training on seizure susceptibility, behavioral changes and neuronal damage after kainate-induced status epilepticus in spontaneously hypertensive rats

J. Tchekalarova, M. Shishmanova, D. Atanasova, M. Stefanova, L. Alova, N. Lazarov, K. Georgieva

Abstract

The therapeutic efficacy of regular physical exercises in an animal model of epilepsy and depression comorbidity has been confirmed previously. In the present study, we examined the effects of endurance training on susceptibility to kainate (KA)-induced status epilepticus (SE), behavioral changes and neuronal damage in spontaneously hypertensive rats (SHRs). Male SHRs were randomly divided into two groups. One group was exercised on a treadmill with submaximal loading for four weeks and the other group was sedentary. Immediately after the training period, SE was evoked in half of the sedentary and trained rats by KA, while the other half of the two groups received saline. Basal systolic (SP), diastolic (DP) and mean arterial pressure (MAP) of all rats were measured at the beginning and at the end of the training period. Anxiety, memory and depression-like behaviour were evaluated a month after SE. The release of 5-HT in the hippocampus was measured using a liquid scintillation method and neuronal damage was analyzed by hematoxylin and eosin staining. SP and MAP of exercised SHRs decreased in comparison with the initial values. The increased resistance of SHRs to KA-induced SE was accompanied by an elongated latent seizure-free period, improved object recognition memory and antidepressant effect after the training program. While the anticonvulsant and positive behavioral effects of endurance training were accompanied by an increase of 5-HT release in the hippocampus, it did not exert neuroprotective activity. Our results indicate that prior exercise is an effective means to attenuate KA-induced seizures and comorbid behavioral changes in a model of hypertension and epilepsy suggesting a potential influence of hippocampal 5-HT on a comorbid depression. However, this beneficial impact does not prevent the development of epilepsy and concomitant brain damage.

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Keywords:

Treadmill, Kainate, Behavior, 5-HT, Neuronal damage, Spontaneously hypertensive rats

Effects of prostaglandin E2 on synaptic transmission in the rat spinal trigeminal subnucleus caudalis

Yuka Mizutani, Yoshiaki Ohi, Satoko Kimur, Ken Miyazaw, Shigemi Goto, Akira Haji

Abstract

The spinal trigeminal subnucleus caudalis (Vc) receives preferentially nociceptive afferent signals from the orofacial area. Nociceptive stimuli to the orofacial area induce cyclooxygenase both peripherally and centrally, which can synthesize a major prostanoid prostaglandin E2 (PGE2) that implicates in diverse physiological functions. To clarify the roles of centrally-synthesized PGE2 in nociception, effects of exogenous PGE2 on synaptic transmission in the Vc neurons were investigated in the rat brainstem slice. Spontaneously occurring excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) were recorded, respectively, under pharmacological blockade of inhibitory and excitatory transmission by whole-cell patch-clamp mode. Perfusion of PGE2 (1–5 μM) increased the frequency of sIPSCs in a concentration-dependent manner but had no significant effect on the amplitude. Similarly to the effects on sIPSCs, PGE2 increased the sEPSC frequency without any effect on the amplitude. These facilitatory effects of PGE2 on spontaneous synaptic transmissions were blocked by an EP1 antagonist SC19220 but not by an EP4 antagonist AH23848. Electrical stimulation of the trigeminal tract evoked short latency EPSCs (eEPSCs) in the Vc neurons. PGE2 (5 μM) was ineffective on the eEPSCs. The present study demonstrated that PGE2 facilitated spontaneous synaptic transmissions in the Vc neurons through activating the presynaptic EP1 receptors but had no effect on the trigeminal tract-mediated excitatory transmission. These results suggest that centrally-synthesized PGE2 modifies the synaptic transmission in the Vc region, thereby contributing to the processing of nociceptive signals originated from the orofacial area.

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Keywords

Prostaglandin E2, Synaptic transmission, Spinal trigeminal nucleus, Whole-cell voltage-clamp recordings

Finding the place without the whole: Timeline involvement of brain regions

Natalia Arias, Marta Mendez, Guillermo Vallejo, Jorge L. Arias

Abstract

Mastering the Morris water maze (MWM) requires the animal to consolidate, retain and retrieve spatial localizations of relevant visual cues. However, it is necessary to investigate whether a reorganization of the neural networks takes place when part of the spatial information is removed. We conducted four experiments using the MWM. A classical reference memory procedure was performed over five training days, RM5 (n=7), and eight days, RM8 (n=7), with the whole room and all the spatial cues presented. Another group of animals were trained in the same protocol, but they received an additional day of training with only partial cues, PC (n=8). Finally, a third group of animals performed the classical task, followed by an overtraining with partial cues for four more days, OPC (n=8). After completing these tasks, cytochrome c-oxidase activity (CO) in several brain limbic system structures was compared between groups. In addition, c-Fos positive cells were measured in the RM5, RM8, PC and OPC groups. No significant differences were found among the four groups in escape latencies or time spent in the target quadrant. CO revealed involvement of the prefrontal and parietal cortices, dorsal and ventral striatum, CA1 and CA3 subfields of the dorsal hippocampus, basolateral and lateral amygdala, and mammillary nuclei in the PC group, compared to the RM group. In the OPC group, involvement of the ventral striatum and anteroventral thalamus and the absence of amygdala involvement were revealed, compared to the PC group. C-Fos results highlighted the role of the prefrontal cortex, dorsal striatum, anterodorsal thalamus and CA3 in the PC group, compared to the OPC, RM5 and RM8 groups. The animals were able to find the escape platform even when only a portion of the space where the cues were placed was available. Although the groups did not differ behaviorally, energetic brain metabolism and immediate early gene expression revealed the engagement of different neural structures in the groups that received more training without the entire surrounding space.

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Keywords:

Morris water maze, Spatial reference memory, Overtraining, Partial spatial cues, Cytochrome c-oxidase c-Fos