The effect of CA1 α2 adrenergic receptors on memory retention deficit induced by total sleep deprivation and the reversal of circadian rhythm in a rat model.

The α2 adrenergic receptors which abundantly express in the CA1 region of the hippocampus play an important role in the regulation of sleep and memory retention processes. Based on the available evidence, the aim of our study was to investigate consequences of the activation and deactivation of CA1 α2 adrenergic receptors (by clonidine and yohimbine, respectively) on the impairment of memory retention induced by total sleep deprivation (TSD) and the reversal of circadian rhythm (RCR) in a rat model. To this end, the water box apparatus and passive avoidance task were in turn used to induce sleep deprivation and assess memory retention. Our findings suggested that TSD (for 24 and 36, but not 12h) and RCR (12h/day for 3 consecutive days) impair memory function. The post-training intra-CA1 administration of yohimbine (α2 adrenergic receptor antagonist) on its own, at the dose of 0.1µg/rat, decreased the step-through latency and locomotor activity in the TSD- sham treated but not undisturbed sleep rats. Unlike yohimbine, clonidine (α2 adrenergic receptor agonist), in all applied doses (0.001, 0.01 and 0.1µg/rat), failed to induce such an effect. While the subthreshold dose of yohimbine (0.001µg/rat) abrogated the impairment of memory retention induced by the 24-h TSD, it could potentiate the impairment of memory retention induced by 36-h TSD, suggesting the modulatory effect of yohimbine. Moreover, the subthreshold dose of clonidine (0.1µg/rat) restored the memory retention deficit in TSD rats (24 and 36h). On the other hand, the subthreshold dose of clonidine (0.1µg/rat), but not yohimbine (0.001µg/rat) restored the memory retention deficit in RCR rats. Such interventions however did not alter the locomotor activity. The above observations proposed that CA1 α2 adrenergic receptors play a potential role in memory retention deficits induced by TSD and RCR.

Withstanding the obstructive sleep apnea syndrome at the expense of arousal instability, altered cerebral autoregulation and neurocognitive decline.

The present review attempts to put together the available evidence and potential research paradigms at the interface of obstructive sleep apnea syndrome (OSAS), sleep micro- and macrostructure, cerebral vasoreactivity and cognitive neuroscience. Besides the significant health-related consequences of OSAS including hypertension, increased risk of cardio- and cerebrovascular events, notable neurocognitive lapses and excessive daytime somnolence are considered as potential burdens. The intermittent nocturnal hypoxia and hypercapnia which occur in OSAS are known to affect cerebral circulation and result in brain hypoperfusion. Arousal instability is then resulted from altered cyclic alternating patterns (CAPs) reflected in sleep EEG. In chronic state, some pathological loss of gray matter may be resulted from obstructive sleep apnea. This is proposed to be related to an upregulated proinflammatory state which may potentially result in apoptotic cell loss in the brain. On this basis, a pragmatic framework of the possible neural mechanisms which underpin obstructive sleep apnea-related neurocognitive decline has been discussed in this review. In addition, the impact of OSAS on cerebral autoregulation and sleep microstructure has been articulated.

A computer-based selective visual attention test for first-grade school children: design, development and psychometric properties.

BACKGROUND: Visual attention is known as a critical base for learning. The purpose of the present study was to design, develop and evaluate the test-retest and internal consistency reliability as well as face, content and convergent validity of the computer- based selective visual attention test (SeVAT) for healthy first-grade school children. METHODS: In the first phase of this study, the computer-based SeVAT was developed in two versions of original and parallel. Ten experts in occupational therapy helped to measure the content validity using the CVR and CVI methods. Face validity was measured through opinions collected from 10 first-grade children. The convergent validity of the test was examined using the Spearman correlation between the SeVAT and Stroop test. In addition, test-retest reliability was determined by measuring the intra-class correlation (ICC) between the original and parallel versions of the SeVAT in a single session. The internal consistency was calculated by Cronbach's alpha coefficients. Sixty first grade children (30 girls/30boys) participated in this study. RESULTS: The developed test was found to have good content and face validity. The SeVAT showed an excellent test-retest reliability (ICC= 0.778, p<0.001) and internal consistency (Cronbach's Alpha of original and parallel tests were 0.857 and 0.831, respectively). SeVAT and Stroop test demonstrated a positive correlation upon the convergent validity testing. CONCLUSION: Our results suggested an acceptable reliability and validity for the computer-based SeVAT in the assessment of selective attention in children. Further research may warrant the differential validity of such a test in other age groups and neuro-cognitively disordered populations.

Involvement of the CA1 GABAA receptors in MK-801-induced anxiolytic-like effects: an isobologram analysis.

There seems to be a close relationship between hippocampal N-methyl-D-aspartic acid (NMDA) and GABAA receptors with respect to the modulation of behavior that occurs in the CA1 region of the hippocampus. This study investigated the possible involvement of the CA1 GABAA receptors in anxiolytic-like effects induced by (+)-MK-801 (a noncompetitive antagonist of the NMDA subtype of the glutamate receptor). Male Wistar rats were subjected to the elevated plus-maze apparatus and open arm time (%OAT), and open arm entries (%OAE) for anxiety-related behaviors, and closed arm entries that correspond to the locomotor activity were assessed. An intra-CA1 injection of (+)-MK-801 (2 µg/rat) and muscimol (0.5 µg/rat; a GABAA receptor agonist) increased %OAT and %OAE by themselves while not altering the closed arm entries, indicating an anxiolytic-like effect of these drugs. Injection of bicuculline (0.1, 0.25, and 0.5 µg/rat; a GABAA receptor antagonist) did not alter any of the anxiety-related parameters. An intra-CA1 injection of a subthreshold dose of muscimol (0.1 µg/rat) or bicuculline (0.5 µg/rat), 5 min before injection of subthreshold and effective doses of (+)-MK-801 (0.5, 1 and 2 µg/rat), increased and decreased the anxiolytic-like effect of (+)-MK-801, respectively. The isobologram analysis of these findings suggested a synergistic anxiety-like effect of intra-CA1 (+)-MK-801 and muscimol. In conclusion, the CA1 GABAA receptors appear to be involved in anxiolytic-like behaviors induced by (+)-MK-801.

Neuroprotective and restorative effects of the brain-derived neurotrophic factor in retinal diseases.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin proposed to be implicated in ameliorating the course of some neurodegenerative disorders. Given the fact that retina is considered as an out-pouching of the central nervous system, its related diseases have long been suggested to receive protective influence from this signaling molecule. The role of BDNF in retinal neurorestoration, neuroprotection and oxidative stress has extensively been tested over the past two decades. Nonetheless, almost the entire related literature root in animal studies and clinical research on this topic is lacking. Although much of the evidence have validated the protective properties of BDNF against various retinal cell diseases, bringing such insights into clinical context would depend on further well-designed research. The present review is an attempt to categorize and discuss the available evidence with regard to the BDNF and retinal diseases.

Repetitive Arm Movements During Sleep: A Polysomnographic Assessment.

Sleep-related movement disorders should be differentiated from parasomnias, sleep-associated behavioral disorders, and epilepsy. Polysomnography (PSG) is the gold standard in evaluating such disorders. Periodic leg movement disorder during sleep (PLMS), hypnic jerks, bruxism, rhythmic movement disorder, restless legs syndrome, and nocturnal leg cramps have broadly been discussed in the literature. However, periodic arm movement disorder in sleep (PAMS) is a less-appreciated entity perhaps because arm surface electromyography is not an integral part of the standard polysomnography. Results from our PSG study in a case suspected for PAMS prompted us to herewith discuss this problem.

Possible involvement of the CA1 GABAA receptors upon acquisition and expression of the ACPA-induced place preference in mice.

A plethora of investigations has substantiated a close relationship between cannabinoidergic and GABAergic systems in hippocampal CA1. The crucial role of these two systems in regulation of the addictive behaviors is well described. The aim of the current study was to investigate whether the CA1 GABAA receptors are involved in ACPA (a selective CB1 cannabinoid receptor agonist)-induced rewarding effects using the condition place preference (CPP) protocol. Moreover, the hole-board paradigm was used to measure the exploratory behaviors which may potentially influence this phenomenon. Results showed that ACPA (0.02mg/kg, i.p.) induced CPP. Applying a 3-day conditioning schedule, we found that the sole administration of the GABAA receptor agonist, muscimol (0.125, 0.25 and 0.5µg/mouse; intra-CA1), or the GABAA receptor antagonist, bicuculline (0.0635, 0.125 and 0.25µg/mouse; intra-CA1), fail to induce CPP or CPA (condition place aversion). Similarly, injection of the subthreshold dose of muscimol (0.125µg/mouse, intra-CA1) decreased the CPP acquisition induced by ACPA. Similar intervention with the subthreshold dose of bicuculline (0.125µg/mouse, intra-CA1) did not alter the CPP acquisition induced by ACPA. Furthermore, the sole intra-CA1 administration of muscimol (0.125, 0.25 and 0.5µg/mouse) and bicuculline (0.0635, 0.125 and 0.25µg/mouse; intra-CA1) prior to testing, did not induce CPP or CPA. Similar interventions revealed that muscimol and bicuculline increase and decrease CPP expression induced by ACPA, respectively. The ACPA- and muscimol-induced CPP could be blocked by bicuculline. Taken together, the CA1 GABAA receptors seem to be possibly involved in the modulation of acquisition or expression process upon ACPA-induced CPP.

Intracranial meningiomas: Prognostic factors and treatment outcome in patients undergoing postoperative radiation therapy.

BACKGROUND: Meningioma constitutes 20% of the intracranial neoplasms. Followed by surgery as the primary treatment for most patients, radiotherapy becomes indicated in high-grade tumors with incomplete surgical removal. We evaluated the prognostic factors and overall outcome in meningioma patients who underwent radiotherapy. MATERIALS AND METHODS: In this retrospective analysis, data from all patients with documented diagnosis of meningioma who referred to the Omid and Ghaem Oncology Centers (Mashhad, Iran) from 2002 to 2013 were included. We calculated the overall survival rates using the Kaplan-Meier method and compared the survival curves between groups by the log-rank test. RESULTS: Eighty-three patients with a median age of 50 years (ranging: 16-84) were included. Grade I, II, and III meningiomas were seen in 40 (48%), 31 (37%), and 12 (15%) patients, respectively. Radiation therapy was indicated due to tumor recurrence, incomplete excision, or tumor grade in 32, 8, and 43 patients, respectively. Tumor grade had a significant effect on the overall survival with a 3-year overall survival of 76.7%, 43.5%, and 13.3% in Grade I, II, and III, respectively (P < 0.001). Gender, age, and tumor location were not correlated with the overall survival. Moreover, patients with Grade II and III who underwent total resection had a significantly higher overall survival than those with subtotal resection or biopsy alone (5-year survival rates of 82% vs. 17.1%, respectively; P = 0.008). CONCLUSION: Tumor grade was the most important prognostic factor in meningioma patients undergoing radiation therapy. In patients with Grade II and III tumors, the extent of surgical resection is significantly correlated with the overall survival.

Flow Augmentation in Acute Ischemic Stroke.

There is an urgent need for additional therapeutic options for acute ischemic stroke considering the major pitfalls of the options available. Herein, we briefly review the role of cerebral blood flow, collaterals, vasoreactivity, and reperfusion injury in acute ischemic stroke. Then, we reviewed pharmacological and interventional measures such as volume expansion and induced hypertension, intra-aortic balloon counterpulsation, partial aortic occlusion, extracranial-intracranial carotid bypass surgery, sphenopalatine ganglion stimulation, and transcranial laser therapy with regard to their effects on flow augmentation and neuroprotection.

Brain-derived neurotrophic factor in patients with advanced age-related macular degeneration.

AIM: To investigate the serum level of the brain-derived neurotrophic factor (BDNF) in age-related macular degeneration (AMD) and healthy control subjects. The disruption in the tight balance of neuroinflammatory and neuroprotective processes in an immune-privileged site like retina is proposed to contribute to the pathogenesis of AMD. One of the main neuroprotective mediators in the central nervous system is BDNF with its serum level notably affected in several neurodegenerative disorders. METHODS: Thirty-six patients with AMD and 36 age-matched controls were enrolled in this study. The serum level of BDNF was measured using the enzyme-linked immunosorbent assay method. Results were analyzed to compare case and control values. Comparisons were also made between the BDNF level of wet- vs dry-AMD, and male vs female patients and controls. Analysis of variance (ANOVA) and Student's t-test were employed to analyze the data. RESULTS: The mean BDNF levels in AMD group were significantly higher than the control group. Furthermore, our analysis revealed greater BDNF values in all AMD subgroups compared to controls (P=0.004, 0.005, 0.001 and 0.02 for male wet-AMD, male dry-AMD, female wet-AMD and female dry-AMD vs controls, respectively). The BDNF level however did not vary between wet- and dry-AMD patients (P=0.74). While within-group comparisons in males and females of AMD and control groups did not show any difference in BDNF (P=0.16, 0.64 and 0.85 for wet-AMD, dry-AMD and control groups, respectively), between-group data showed a higher mean BDNF in both male and female AMD subjects than their peer controls. CONCLUSION: This study demonstrated that the serum BDNF level is different in patients with AMD as compared to subjects without AMD. Future attempts should be done to unravel beneficial or deleterious effect of this neurotrophin in the pathogenesis of AMD.

Homocysteine as a potential biomarker in bipolar disorders: a critical review and suggestions for improved studies.

INTRODUCTION: Homocysteine levels have been associated with major depression, but associations with bipolar disorder remain less clear. Some data suggest homocysteine levels have potential as a biomarker of treatment response; however the literature is mixed. AREAS COVERED: Oxidized forms of homocysteine can be potentially neurotoxic leading to glutamate toxicity, apoptotic transformation and neurodegenerative processes. High homocysteine may be a risk biomarker for bipolar disorders, but the empirical base remains too weak for firm conclusions. This review discusses the current literature for homocysteine levels as a biomarker. EXPERT OPINION: It is premature to foreclose the utility of homocysteine levels as a biomarker for bipolar disorder due the methodological inadequacies in the existing literature. These methodological design issues include lack of control for the confounding variables of concurrent medication, phase of bipolar disorder, gender, age, nutritional status, thyroid, liver and renal function, smoking or lean body mass. Well-powered association studies with confounder control could help shed more light on the important clinical question of homocysteine's utility as a biomarker in bipolar disorder. Future experiments are needed to examine the outcome of interventions modulating homocysteine for treating bipolar disorder. Only prospective randomized control trials will provide definitive evidence of the utility of homocysteine as a biomarker or therapeutic target.

The dual effect of CA1 NMDA receptor modulation on ACPA-induced amnesia in step-down passive avoidance learning task.

It is well documented that cannabinoids play an important role in certain hippocampal memory processes in rodents. On the other hand, N-Methyl-d-aspartate receptors (NMDARs) mediate the synaptic plasticity related to learning and memory processes which take place in the hippocampus. Such insights prompted us to investigate the influence of dorsal hippocampal (CA1) NMDA receptor agents on amnesia induced by cannabinoid CB1 receptor agonist, arachidonylcyclopropylamide (ACPA) in male mice. One-trial step-down passive avoidance and hole-board apparatuses were used to examine the memory retrieval and exploratory behaviors, respectively. Based on our findings, pre-training intraperitoneal (i.p.) administration of ACPA (0.01mg/kg) decreased memory acquisition. Moreover, pre-training intra-CA1 infusion of NMDA (0.001, 0.0125, 0.025 and 0.2µg/mouse), d-AP7 (0.5 and 1µg/mouse) or AM251 (50ng/mouse) impaired the memory acquisition. Meanwhile, NMDA-treated animals at the doses of 0.0005, 0.05 and 0.1µg/mouse acquired memory formation. In addition, intra-CA1 microinjection of NMDA (0.0005) plus different doses of ACPA potentiated the ACPA response, while NMDA (0.1) plus the lower or the higher dose of ACPA potentiated or restored the ACPA response, respectively. Further investigation revealed that a subthreshold dose of d-AP7 could potentiate the memory acquisition impairment induced by ACPA. Moreover, the subthreshold dose of AM251 did not alter the ACPA response, while the effective dose of the drug restored the memory acquisition impairment induced by ACPA. According to these results, we concluded that activation of the NMDA receptors in the CA1 mediates a dual effect on ACPA-induced amnesia in step-down passive avoidance learning task.

An overview of neuro-oncology research and practice in Iran, three years with the NOSC initiative.

Research and practice of neuro-oncology compiles clinical neuroscience expertise from neurosurgery, radiation oncology, neuroradiology, medical oncology, neuropathology and related disciplines to optimize planning and therapy in central nervous system malignancies. Such an interdisciplinary context prompted health-care providers from all related disciplines to establish the Neuro-Oncology Scientific Club (NOSC) in Iran and let it flourish since 3 years ago. With the advent of advanced technologies and through continued share of experience, NOSC members have tried to provide more integrated diagnoses and therapeutic care to brain tumor patients across the country. NOSC activities revolve around some key tenets including dissemination of education and updates, facilitation of institutional collaborations; data registry and patients' awareness. By virtue of recent insights on molecular characterization of brain tumors such as codeletion of chromosomes 1p and 19q in anaplastic gliomas and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastoma, a range of translational research is being followed within NOSC. The most recent NOSC meeting which was held in Tehran, recapitulated main advances and dealt with the current debates on functional neurosurgery, biological markers and neuroimaging, risk prediction models in high grade gliomas and clinical issues in pediatric neuro-oncology. This article gives an overview of current hotspots in neuro-oncology research and practice which are pursued within NOSC.

Approach to Patients with Severe Asthma: a Consensus Statement from the Respiratory Care Experts' Input Forum (RC-EIF), Iran.

Challenges in the assessment, diagnosis and management of severe, difficult-to-control asthma are increasingly regarded as clinical needs yet unmet. The assessments required to determine asthma severity, comorbidities and confounding factors, disease phenotypes and optimal treatment are among the controversial issues in the field. The respiratory care experts' input forum (RC-EIF), comprised of an Iranian panel of experts, reviewed the definition, appraised the available guidelines and provided a consensus for evaluation and treatment of severe asthma in adults. A systematic literature review followed by discussions during and after the forum, yielded the present consensus. The expert panel used the appraisal of guidelines for research and evaluation-II (AGREE-II) protocol to define an initial locally-adapted strategy for the management of severe asthma. Severe asthma is considered a heterogeneous condition with various phenotypes. Issues such as assessment of difficult-to-control asthma, phenotyping, the use of blood and sputum eosinophil count, exhaled nitric oxide to guide therapy, the position of anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty as well as the use of established, recently-developed and evolving treatment approaches were discussed and unanimously agreed upon in the panel. A systematic approach is required to ensure proper diagnosis, evaluate compliance, and to identify comorbidities and triggering factors in severe asthma. Phenotyping helps select optimized treatment. The treatment approach laid down by the Global Initiative for Asthma (GINA) needs to be followed, while the benefit of using biological therapies should be weighed against the cost and safety concerns.

Swimming improves the emotional memory deficit by scopolamine via mu opioid receptors.

AIMS: The aim of the present study was to investigate the effect of swimming exercise on elevated plus-maze (EPM)-associated memory deficit induced by intra-CA1 injection of scopolamine (a muscarinic acetylcholine receptor antagonist used to model Alzheimer's disease in rodents) in male mice. In addition, involvement of the mu opioid receptors in this phenomenon was investigated. MAIN METHODS: Bilateral guide cannulae were implanted to allow intra-CA1 microinjections. KEY FINDINGS: Data showed that mice with 10 and 20 days of swimming, only acquired the emotional memory, while 30 days of swimming exercise improved it. On the other hand, pretest intra-CA1 injection of scopolamine at the doses of 2 and 3 but not 1 µg/mouse reduced the emotional memory. Our results demonstrated that 20 days of swimming by itself and without any drug injection restored the emotional memory deficit induced by intra-CA1 injection of scopolamine, only at the dose of 2 but not 3 µg/mouse. Moreover, once daily injection of the subthreshold doses of morphine (2.5 and 5 mg/kg, i.p.) during the last 7 days of the 20 day-swimming intervention, improved the emotional memory deficit induced by scopolamine (3 µg/mouse) and this effect could be blocked by the subthreshold doses of naloxone (0.2 and 0.4 mg/kg). It was noted that all previous interventions did not alter the anxiety-like behaviors. SIGNIFICANCE: Swimming improved the emotional memory by itself and restored the emotional memory deficit induced by the intra-CA1 injection of scopolamine. Mu opioid receptor-dependent mechanism(s) is(are) suggested to play a role in this phenomenon.

Invasive candidiasis in critical care setting, updated recommendations from "Invasive Fungal Infections-Clinical Forum", Iran.

Invasive candidiasis (IC) bears a high risk of morbidity and mortality in the intensive care units (ICU). With the current advances in critical care and the use of wide-spectrum antibiotics, invasive fungal infections (IFIs) and IC in particular, have turned into a growing concern in the ICU. Further to blood cultures, some auxiliary laboratory tests and biomarkers are developed to enable an earlier detection of infection, however these test are neither consistently available nor validated in our setting. On the other hand, patients' clinical status and local epidemiology data may justify the empiric antifungal approach using the proper antifungal option. The clinical approach to the management of IC in febrile, non-neutropenic critically ill patients has been defined in available international guidelines; nevertheless such recommendations need to be customized when applied to our local practice. Over the past three years, Iranian experts from intensive care and infectious diseases disciplines have tried to draw a consensus on the management of IFI with a particular focus on IC in the ICU. The established IFI-clinical forum (IFI-CF), comprising the scientific leaders in the field, has recently come up with and updated recommendation on the same (June 2014). The purpose of this review is to put together literature insights and Iranian experts' opinion at the IFI-CF, to propose an updated practical overview on recommended approaches for the management of IC in the ICU.

Operationalizing Cognitive Science and Technologies' Research and Development; the "Brain and Cognition Study Group (BCSG)" Initiative from Shiraz, Iran.

Recent advances in brain and cognitive science studies have revolutionized concepts in neural dynamics, regulating mechanisms, coding systems and information processing networks which govern our function and behavior. Hidden aspects of neurological and psychiatric diseases are being understood and hopes for their treatment are emerging. Although the two comprehensive mega-projects on brain mapping are in place in the United States and Europe; the proportion of science contributed by the developing countries should not be downsized. With the granted supports from the Cognitive Sciences and Technologies Council (CSTC), Iran can take its role in research on brain and cognition further. The idea of research and development in Cognitive Sciences and Technologies (CST) is being disseminated across the country by CSTC. Towards this goal, the first Shiraz interdisciplinary meeting on CST was held on 9 January 2014 in Namazi hospital, Shiraz. CST research priorities, infrastructure development, education and promotion were among the main topics discussed during this interactive meeting. The steering committee of the first CST meeting in Shiraz decided to frame future research works within the "Brain and Cognition Study Group-Shiraz" (BCSG-Shiraz). The study group comprises scientific leaders from various allied disciplines including neuroscience, neurosurgery, neurology, psychiatry, psychology, radiology, physiology, bioengineering, biophysics, applied physics and telecommunication. As the headquarter for CST in the southern Iran, BCSG-Shiraz is determined to advocate "brain and cognition" awareness, education and research in close collaboration with CSTC. Together with CSTC, Shiraz Neuroscience Research center (SNRC) will take the initiative to cross boundaries in interdisciplinary works and multi-centric research projects within the study group.

Invasive candidiasis in intensive care unit; consensus statement from an Iranian panel of experts, July 2013.

Invasive candidiasis (IC) is associated with high mortality in intensive care unit (ICU) patients. Timely diagnosis of this potentially fatal condition remains a challenge; on the other hand, the criteria for initiating empirical antifungal therapy in critically ill patients are not well defined in different patient population and ICU settings. Alongside the international guidelines, reaching regional and local consensus on diagnosis and management of IC in ICU setting is essential. This report summarizes our present status of IC management in ICU, considered by a group of Iranian experts in the fields of intensive care and infectious diseases. A round table of 17 experts was held to review the available data and discuss the optimal treatment strategies for IC in critical care setting. Comparative published data on the management of IC were analytically reviewed and the commonly asked questions about the management of IC in ICU were isolated. These questions were interactively discussed by the panel and audience responses were taken to consolidate point-to-point agreement with the panel arriving at consensus in many instances. The responses indicated that patients' risk stratification, clinical discretion, fungal diagnostic techniques and the empirical therapy for IC are likely to save more patients. Treatment options were recommended to be based on the disease severity, prior azole exposure, and the presence of suspected azole-resistant Candida species. This report was reviewed, edited and discussed by all participants to include further evidence-based insights. The panel expects such endorsed recommendations to be soon formulated for implementation across the country.

[Not Available].

Experimentally-induced total sleep deprivation (TSD) and chronic partial sleep restriction (CPSR) leads to the emergence of cognitive impairments. This is hypothesized to result from a consequent neuroinflammation which may also hasten the neurodegenerative processes. Neuroinflammatory markers such as tumor necrosis factor-alpha (TNFα) are thought to be potential culprits in SD-induced neurodegeneration. The effect of TSD and CPSR on memory and anxiety-related behaviors (using the Elevated Plus-Maze test-retest protocol) and serum level of brain derived neurotrophic factor (BDNF) and corticosterone were assessed in male Wistar rats subjected to the modified disk-over-water (DOW) apparatus. In addition, an immunohistochemical (IHC) study was done to possibly detect the amyloid-beta (Aß) and hyper-phosphorylated tau protein (HPτ) deposition in the dentate gyrus (DG) of the examined rats' hippocampi. Histomorphology and neuronal numerical density assessments were done at the same level across control and experimental animals. We also studied the above parameters in rats after intraperitoneal injection of the TNFα neutralizing antibody, infliximab (IFX). Rats subjected to TSD and CPSR which did not receive IFX, showed a more pronounced impairment of memory, elevated serum corticosterone and decreased BDNF levels. CPSR rats which underwent delayed brain excision following behavioral testing, showed deposition of the HPτ and revealed the least numerical density in the hippocampal DG neurons. Meanwhile, IHC study revealed no Aß deposition in the hippocampal DG of all examined rats. Interestingly, treatment with IFX, abrogated sleep restriction-induced cognitive decline, biochemical changes and the immunohistopathology in the hippocampal DG. Taken together, our findings indicated that CPSR (the SD model mimicking shift work) induces not only cognitive and biochemical changes, but also pathology in the hippocampal DG. This is possibly via activation of the inflammatory mechanisms in part through TNFα-dependent pathways.

Involvement of the dorsal hippocampal GABA-A receptors in histamine-induced facilitation of memory in the Morris water maze.

Several types of learning and memory processes are regulated by the hippocampus which is an important subcortical structure in the mammalians' brain. Previous investigations have shown that different receptor systems in the CA1 region of hippocampus are involved in learning and memory functions. Investigating the possible influence of dorsal hippocampal GABA-A receptors on histamine-induced spatial facilitation in adult male Wistar rats was the focus of the current study. Rats were bilaterally implanted with dorsal hippocampal (CA1) cannulae, recovered from surgery and then trained in Morris water maze (MWM) for 4 consecutive days. A block of four trials was given each day. All drugs were injected into CA1 regions, 5min before training. Pre-training intra-CA1 microinjection of muscimol, a GABA-A receptor agonist, at the dose of 0.01 or 0.02µg/rat, increased the traveled distance or the escape latency and traveled distance to the hidden platform, respectively, indicating a water maze spatial acquisition impairment. Intra-CA1 administration of bicuculline, a GABA-A receptor antagonist however, significantly decreased the escape latency and traveled distance to the hidden platform, suggesting a spatial learning facilitation. On the other hand, pre-training intra-CA1 microinjection of the subthreshold dose of muscimol plus different doses of histamine (0.025, 0.05 and 0.1µg/rat) did not alter the histamine response. Meanwhile, the co-administration of the ineffective dose of bicuculline together with histamine potentiated the spatial learning. Moreover, bilateral infusion of histamine (0.025, 0.05 and 0.1µg/rat) by itself, facilitated the spatial learning. Notably, the drug injections had no effect on swimming speed during the MWM training sessions. Our results suggest that the dorsal hippocampal (CA1) GABA-A mechanism(s) may influence the histamine-induced facilitation of spatial acquisition.