Changes in the Expression of Genes of the Glutamate Transporter and Subunits of the NMDA and AMPA Receptors in the Rat Amygdala in the Lithium–Pilocarpine Model of Epilepsy

The molecular changes in the glutamatergic system of the rat amygdala were studied during the latent phase of the lithium–pilocarpine model of temporal lobe epilepsy in order to identify the potential involvement of these changes in epileptogenesis. The real-time PCR method was used to evaluate the mRNA expression of the NMDA and AMPA receptor subunits, as well as the excitatory amino acid transporter-2 (EAAT2) in the basolateral nucleus of the amygdala 7 days after the seizures caused by administration of pilocarpine. The results of the experiments were as follows: (1) an increase in the expression ratio of the GluN2a/GluN2b NMDA receptor subunits with an unchanged expression level of the GluN1 subunit; (2) increased expression of the GluA2 subunit of AMPA receptors with the invariance of GluA1, and (3) enhanced expression of the EAAT2. According to literature data, the expression of the same genes decreased in the hippocampus in the same model of epilepsy. Neurodegeneration was reported in both brain regions. The opposite changes in the expression of the glutamatergic system genes in the hippocampus and amygdala during the latent period of the lithium–pilocarpine model suggest the occurrence of factors that can both contribute to and hinder epileptogenesis.     

What is the role of the cerebellum in the pathophysiology of dystonia?

Journal of Neurology -     

Accumulation of α-synuclein in the bowel of patients in the pre-clinical phase of Parkinson’s disease

Parkinson’s disease primarily affects the central nervous system, but autopsy and small patient studies have revealed autonomic nervous system pathology in most cases. We looked for α-synuclein pathology in routinely acquired biopsies from patients and matched controls. Immunocytochemistry was performed and assessed blind to the clinical diagnoses. One hundred and seventeen gastrointestinal tissue samples from 62 patients, and 161 samples from 161 controls, were examined. Twelve biopsies from seven patients showed accumulation of α-synuclein within mucosal and submucosal nerve fibres, and ganglia, which was more extensive with an antibody to phosphorylated, than with an antibody to non-phosphorylated, α-synuclein. These included gastric, duodenal and colonic biopsies, and were taken up to 8 years prior to the onset of motor symptoms. All patients with positive biopsies had early autonomic symptoms and all controls were negative. This large scale study demonstrates that accumulation of α-synuclein in the gastrointestinal tract is a highly specific finding that could be used to confirm a clinical diagnosis of Parkinson’s disease. We have shown that α-synuclein accumulation occurs prior to the onset of motor symptoms in the upper, as well as the lower gastrointestinal tract, remains present in serial biopsies until the onset of motor symptoms and is predominantly composed of phosphorylated α-synuclein. Accumulation of α-synuclein in the bowel therefore offers an accessible biomarker which allows further study of the early stages of the disease and could be of value in the assessment of disease modifying treatments.     

The effects of the co-administration of the α₁-adrenoreceptor antagonist prazosin on the anxiolytic effect of citalopram in conditioned fear stress in the rat

Several studies have shown that the α₁-adrenoreceptor is involved in controlling extracellular serotonin levels. The administration of the α₁-adrenoreceptor antagonist prazosin was shown to decrease extracellular serotonin levels in the hippocampus, the prefrontal cortex and the raphe nucleus, while the administration of the α₁-adrenoreceptor agonist cirazoline was shown to increase serotonin levels. Furthermore, the elevation of serotonin levels induced by the selective serotonin reuptake inhibitor (SSRI) citalopram was attenuated by prazosin. Thus, α₁-adrenoreceptor antagonists may affect SSRI-induced increases in extracellular serotonin levels and their antidepressive and anxiolytic effects. However, little is known about the influence of α₁-adrenoreceptor antagonists on the behavioral pharmacological effects of SSRIs. The conditioned fear stress-induced freezing behavior is an animal model of anxiety and can detect the anxiolytic effect of SSRIs. To clarify whether an α₁-adrenoreceptor antagonist affects the anxiolytic action of SSRIs, we examined the effects of the co-administration of the α₁-adrenoreceptor antagonist prazosin and the SSRI citalopram using the contextual conditioned fear stress model. Low-dose prazosin (0.03 mg/kg) significantly attenuated the citalopram (3 mg/kg)-induced decrease in conditioned freezing. Moreover, high-dose (0.5 mg/kg), but not low-dose (0.03 mg/kg), prazosin significantly attenuated citalopram (10 mg/kg)-induced decreases in conditioned freezing. These drugs did not affect the spontaneous motor activity of the rats. Therefore, these results suggest that blocking the α₁-adrenoreceptor decreases the anxiolytic effect of citalopram.     

Evaluation of modified hemodilution combined therapy in the treatment of acute ischemic stroke in the elderly

IN T R O D U C T IO N Atpresent, throm bolysis therapy applied atthe early stage is devel- oped in patients w ith acute stroke, and itw orks w elland decreases disability rate.Butthrom bolysis therapy is notsuitable forsom e elder- ly patients w ho delaye…     

Does the definition of borders of the planum temporale influence the results in schizophrenia?

OBJECTIVE: The planum temporale, a highly asymmetric neocortical area of the temporal lobe, has a possible role in schizophrenia. The authors used three different anatomical definitions of the planum temporale to examine the anterior, posterior, and total planum temporale gray matter volumes simultaneously. METHOD: Magnetic resonance imaging was used to examine 30 male schizophrenic patients and 30 healthy male comparison subjects. The total planum temporale was identical in all three anatomical definitions applied to determine the border between the anterior and posterior planum temporale regions. RESULTS: No significant differences between men with and without schizophrenia were detected with regard to planum temporale volumes and asymmetry coefficients for any of the three definitions. CONCLUSIONS: The authors could not prove the hypothesis that the definition of planum temporale borders influences the results concerning possible disturbances of planum temporale asymmetry in patients with schizophrenia.     

An exploration of the relevance of the concept of “flow” in art therapy

Abstract

Mihaly Csikszentmihalyi, a psychologist, conducted research into the psychological state of happiness. A result of this work is the concept of “flow” (Csikszentmihalyi, 1992 Czikszentmihalyi, M. 1992. “Flow”: The psychology of happiness, USA: Harper & Row.  [Google Scholar]). Csikszentmihalyi's work has to date not been reviewed in art therapy literature for its relevance to our clinical practice or theoretical conceptualisation. Both art therapy and the concept of “flow” are concerned with the well-being of the individual. In this paper I will explore possible intersections between them. I present a summary of the salient features of Csikszentmihalyi's findings in regard to flow and explore how I have found that an understanding of this psychological state can be relevant in my art therapy practice. A consideration of the phenomenon of “flow” may be a way of re-addressing a balance between understanding an art therapy client's areas of “wellness” and “strength” as well as possible areas of “ illness” or “difficulty”.     

Kainate receptors in the CA2 region of the hippocampus

<正>The hippocampus is involved in important brain functions such as learning and memory,spatial navigation,fear processing,and social behavior(Dudek et al,2016).The most prominent areas of the hippocampus are typically denoted as the dentate gyrus and the three areas of the cornu ammonis(CA1,CA2,and CA3).Discovered by Lorente de Nó(1934),the CA2 region of the hippocampus is a relatively small area interposed between CA3 and CA1 that forms the nexus linking the input of the entorhinal corte...     

Feelings of Guilt in the Psychoanalyst†

Abstract

The current diathesis-stress model of schizophrenia proposes that a genetic deficit creates a predisposing vulnerability in the form of oversenstivity to stress. This model positions all psychosocial events on the stress side of the diathesis-stress equation. As an example of hypotheses that emerge when consideration is given to repositioning adverse life events as potential contributors to the diathesis, this article examines one possible explanation for the high prevalence of child abuse found in adults diagnosed schizophrenic. A traumagenic neurodevelopmental (TN) model of schizophrenia is presented, documenting the similarities between the effects of traumatic events on the developing brain and the biological abnormalities found in persons diagnosed with schizophrenia, including overreactivity of the hypothalamic-pituitary-adrenal (HPA) axis; dopamine, norepinephrine, and serotonin abnormalities; and structural changes to the brain such as hippocampal damage, cerebral atrophy, ventricular enlargement, and reversed cerebral asymmetry. The TN model offers potential explanations for other findings in schizophrenia research beyond oversensitivity to stress, including cognitive impairment, pathways to positive and negative symptoms, and the relationship between psychotic and dissociative symptomatology. It is recommended that clinicians and researchers explore the presence of early adverse life events in adults with psychotic symptoms in order to ensure comprehensive formulations and appropriate treatment plans, and to further investigate the hypotheses generated by the TN model.     

Role of exosomes in the pathogenesis of inflammation in Parkinson’s disease

Inflammatory responses,including glial cell activation and peripheral immune cell infiltration,are involved in the pathogenesis of Parkinson’s disease(PD).These inflammatory responses appear to be closely related to the release of extracellular vesicles,such as exosomes.However,the relationships among different forms of glial cell activation,synuclein dysregulation,mitochondrial dysfunction,and exosomes are complicated.This review discusses the multiple roles played by exosomes in PD-associated inflammation and concludes that exosomes can transport toxicα-synuclein oligomers to immature neurons and into the extracellular environment,inducing the oligomerization ofα-synuclein in normal neurons.Misfoldedα-synuclein causes microglia and astrocytes to activate and secrete exosomes.Glial cell-derived exosomes participate in communications between glial cells and neurons,triggering anti-stress and anti-inflammatory responses,in addition to axon growth.The production and release of mitochondrial vesicles and exosomes establish a new mechanism for linking mitochondrial dysfunction to systemic inflammation associated with PD.Given the relevance of exosomes as mediators of neuron-glia communication in neuroinflammation and neuropathogenesis,new targeted treatment strategies are currently being developed that use these types of extracellular vesicles as drug carriers.Exosome-mediated inflammation may be a promising target for intervention in PD patients.     

BDNF–ERK–CREB signalling mediates the role of miR-132 in the regulation of the effects of oleanolic acid in male mice

Background

Although previous study has demonstrated that brain-derived neurotrophic factor (BDNF) is involved in the antidepressant-like effect of oleanolic acid, there is little information regarding the details of the molecular mechanism involved in this effect.

Methods

We used a chronic unpredictable mild stress (CUMS) model to test the antidepressant-like effect of oleanolic acid on depressant-like behaviour, miR-132 expression and synaptic protein expression in the male mouse hippocampus. Furthermore, we explored the possible signalling pathways associated with miR-132 expression that mediate the effect of oleanolic acid on neuronal proliferation.

Results

The results demonstrated that a 3-week treatment with oleanolic acid ameliorated CUMS-induced anhedonic and anxiogenic behaviours. Furthermore, we found that oleanolic acid led to the BDNF-related phosphorylation and activation of extracellular signal-regulated kinases (ERK) and cyclic adenosine monophosphate response element binding protein (CREB), which was associated with the upregulation of miR-132 and hippocampal neuronal proliferation. Moreover, experiments with an miR-132 antagomir revealed that targeting miR-132 led to inhibition of neuronal proliferation and the postsynaptic density protein 95, but did not affect presynaptic protein synapsin I.

Limitations

Several other stimuli can also induce CREB phosphorylation in the hippocampus. Thus, regulation of miR-132 may not be restricted to neurotrophic signalling.

Conclusion

Our results show that oleanolic acid induces the upregulation of miR-132, which serves as an important regulator of neurotrophic actions, mainly through the activation of the hippocampal BDNF–ERK–CREB signalling pathways.     

Prevalence and costs of headaches for the public health system in a town in the interior of the state of São Paulo

Despite the high prevalence, impact and economic importance of headaches, studies on this subject are rare in Brazil. The aim of the present study was to estimate the prevalence of headaches in the public health system of a town in the interior of the State of S?o Paulo, as well as to estimate the costs resulting from its management. Data refer to the year of 1998 and were obtained according to the following steps: 1) territorial and demographic characterization of the municipality; 2) characterization of the financial indices and social well-being; 3) budget characteristics of the municipality; 4) evaluation of the structuring of the medical service; 5) determination of the prevalence of headaches at different patient care levels; and 6) calculation of the costs of headaches. Headaches represented 7.9% of all visits at basic health units, 9.7% in the emergency room and 1.1% of hospital admissions. The total costs were R$ 85,131.31 (US$ 70,942.76) corresponding to R$ 7.59 (US$ 6,32) per inhabitant/year. The present study shows the need for epidemiological and economic impact studies, which would provide the basis for the rational use of health funds.     

Fluctuation of latent inhibition along the estrous cycle in the rat: Modeling the cyclicity of symptoms in schizophrenic women?

Latent inhibition (LI) is a cross-species selective attention phenomenon manifested as poorer conditioning of stimuli that had been experienced as irrelevant prior to conditioning. Disruption of LI by pro-psychotic agents such as amphetamine and its restoration by antipsychotic drugs (APDs) is a well-established model of psychotic symptoms of schizophrenia. There is evidence that in schizophrenic women symptom severity and treatment response fluctuate along the menstrual cycle. Here we tested whether hormonal fluctuation along the estrous cycle in female rats (as determined indirectly via the cellular composition of the vaginal smears) would modulate the expression of LI and its response to APDs. The results showed that LI was seen if rats were in estrus during pre-exposure stage and in metestrus during the conditioning stage of the LI procedure (estrus-metestrus) but not along the remaining sequential phases of the cycle (metestrus-diestrus, diestrus-proestrus and proestrus-estrus). Additionally, the efficacy of typical and atypical APDs, haloperidol and clozapine, respectively, in restoring LI depended on estrous condition. Only LI disruption in proestrus-estrus exhibited sensitivity to both APDs, whereas LI disruption in the other two phases was alleviated by clozapine but not haloperidol. Our results show for the first time that both the expression of LI and its sensitivity to APDs are modulated along the estrous cycle, consistent with fluctuations in psychotic symptoms and response to APDs seen along women's menstrual cycle. Importantly, the results indicate that although both low and high levels of hormones may give rise to psychotic-like behavior as manifested in LI loss, the pro-psychotic state associated with low hormonal level is more severe due to reduced sensitivity to typical APDs. The latter constellation may mimic states of increased vulnerability to psychosis coupled with reduced treatment response documented in schizophrenic women during periods associated with low levels of hormones.     

Modeling the Protonation States of the Catalytic Aspartates in β-Secretase and the Process of the Enzymatic Hydrolysis

背景：阿尔茨海默病(AD）主要表现为脑内β-淀粉样蛋白（Aβ）沉积，Aβ由β-淀粉酶（β- Secretase，BACE）催化水解淀粉样前体蛋白（amyloid precursor protein, APP）产生，但是BACE的催化机制至今仍不清楚。 目的：确定质子在BACE催化性氨基酸(Asp 32 和 Asp 228)中的精确定位，同时在计算机上模拟BACE催化底物APP蛋白的全部过程，揭示BACE催化水解底物的机制。 设计，时间和 SETTING: 全部的量子化学计算在中山大学中山医学院人体解剖教研室进行，2008年8月至2009年3月。 材料: 一台linux计算机工作站，商业性的大型药物设计软件包Schrodinger, 针对学术机构免费的量子化学软件 MOPAC 2007。 方法: 在计算机上构建了一个BACE催化模型，应用量子化学/分子力学(QM/MM)相结合的方法在密度泛函理论水平的基础上计算质子在BACE催化性氨基酸(Asp 32 和 Asp 228)中的精确定位； 在量子化学的半经验理论水平基础上模拟BACE催化水解底物肽EVNL/AAEF的全部过程。 主要结果指标: 计算BACE和底物在不同的单质子化状态下两个催化性氨基酸中的4个羧基氧原子的共面性；在模拟催化水解底物过程中检测BACE催化活性区域内空间和能量的变化。 结果： BACE的同分异构体228o,其4个催化氨基酸羧基氧原子形成的二面角为8.7°；而且利用这种同分异构体（228o）作为初始状态，催化水解底物的活化能最低（1.6959 kcal/mol），焓最高（-7.4055 kcal/mol）。 结论：在催化前，质子最有可能位于BACE的催化氨基酸Asp 228的外位羧基氧原子上,催化水解时，Asp 228作为催化酸，Asp 32 作为催化碱驱动催化水分子攻击底物，形成四面体中间物后，质子的换位到Asp 32的内位羧基氧原子上。