Regulatory effect and mechanism of novel sedative hypnotic compound YZG-331 on glutamate and its receptor / 药学学报

This study investigated the effect of a novel adenosine derivative YZG-331 on the glutamate (Glu) content and its receptor N-methyl-D-aspartate receptor (NMDAR) in mouse frontal cortex. All procedures in this research were approved by the Institutional Animal Care and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. High performance liquid chromatography (HPLC) was used to detect the Glu contents in the mouse frontal cortex tissue homogenate and extracellular fluid which were collected by brain microdialysis method. Western blot and co-immunoprecipitation methods were used to detect the expressions of NMDAR in cell membranes and endosomes, as well as the expression levels of endocytosis-related proteins and their interaction. The results showed that there was no significant change in Glu content in the dialysates from mouse frontal cortex within 0-0.5 h period and 0.5-1 h period after intragastric administration of YZG-331 (40 mg·kg-1). Compare to the control group, the Glu content in mouse frontal cortex homogenates has no significant statistical differences after 15 minutes of administration of compound YZG-331. YZG-331 significantly decreased the expressions of NMDAR subunits NR1 and NR2B in the mouse frontal cortex cell membrane, meanwhile significantly increased the expressions of NR1 and NR2B proteins in the frontal cortex endosomes. It also increased the phosphorylation levels of NMDAR subunit NR2B in the frontal cortex. In addition, the result of co-immunoprecipitation which used NR2B as bait protein showed that the expression of postsynaptic density-95 (PSD95) in NR2B and PSD95 immunoprecipitation complexes in mouse frontal cortex tissues was significantly reduced. These results indicate that YZG-331 does not affect the Glu content in mouse frontal cortex, but it weakens the interaction between NR2B and PSD95 by increasing the phosphorylation level of NR2B in the mouse frontal cortex. Therefore, it reduces the membrane stability of NMDAR and promotes NMDAR's endocytosis, which leading to the decrease of excitotary transmission. It may be one of the mechanisms of YZG-331 to exert sedative and hypnotic effects.

Effect of moxibustion on body weight and peripheral and cerebral cortical IL-6 and IL-10 levels in fatigue rats / 针刺研究

OBJECTIVE: To observe the effect of moxibustion at "Zusanli"(ST36) on peripheral and central IL-6, IL-10 and IL-10/IL-6 changes in fatigue rats, so as to explore its mechanisms underlying relief of fatigue. METHODS: Twenty-one male SD rats were randomly divided into normal control, model and moxibustion groups with 7 rats in each group. The fatigue model was induced by exhausted weight-loaded swimming, once daily for 21 days. Moxibustion was applied to bilateral ST36 once every other day, for successive 11 times. The overall state and the body weight were observed. The levels of IL-6 and IL-10 in the serum, gastrocnemius and frontal cortex tissues were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with the normal group, the body weight was significantly reduced on the 7th, 14th, and 21st day in the model group (P<0.05), and considerably increased on the 14th and 21st day in the moxibustion group relevant to the model group (P<0.05). After modeling, the levels of IL-6 in the serum, gastrocnemius and frontal cortex were significantly increased (P<0.05, P<0.01), while those of IL-10 was obviously decreased (P<0.05, P<0.01) in the model group relevant to the normal group, and ratio of IL-10/IL-6 was obviously decreased in the serum and frontal cortex of the model group relevant to the normal group (P<0.01). After the moxibustion intervention, the levels of IL-10 in the serum and frontal cortex were significantly increased (P<0.05), and ratio of IL-10/IL-6 in the serum and frontal cortex was significantly increased (P<0.01), while the IL-6 contents in the gastrocnemius and frontal cortex were notably decreased in the moxibustion group relevant to the model group (P<0.05). CONCLUSION: Moxibustion can inhibit weight-loaded swimming induced decrease of body weight in fatigue rats, which may be associated with its effects in balancing the levels of peripheral and central pro-inflammatory cytokine IL-6 and anti-inflammatory cytokine IL-10.

Effect of moxibustion on IL-6/STAT3 signaling in frontal cortex of fatigue rats / 针刺研究

OBJECTIVE: To observe the effect of moxibustion on interleukin-6(IL-6)/signal transduction and transcriptional activator 3(STAT3) signaling pathway in the frontal cortex of fatigue rats, so as to reveal its mechanisms underlying alleviation of fatigue. METHODS: Twenty-one male SD rats were randomly divided into normal control, model, and moxibustion groups (n＝7 rats in each group). The fatigue model was established by forcing the rats to have an exhausted swim under load condition, once daily for 21 days. Moxibustion was applied to bilateral "Zusanli"(ST36) for about 15 min, once every other day for 21 days. The level of IL-6 in the frontal cortex was detected by ELISA, and the expression of Janus kinase 2 (JAK2), phosphorylated JAK2 (p-JAK2), signal transduction and transcriptional activator 3(STAT3) and phosphorylated STAT3 (p-STAT3) proteins in the frontal cortex was detected by Western blot. RESULTS: After modeling, the levels of IL-6 content and p-STAT3 protein expression and ratio of p-STAT3/STAT3 were significantly increased in the model group relevant to the normal control group (P0.05). CONCLUSION: Moxibustion intervention can relieve fatigue in fatigue rats, which is associated with its function in inhibiting IL-6/STAT3 signaling pathway to reduce inflammatory injury.

Moringa Regimen Corrects Nicotine-induced Deficits in Behaviour, Altered Energy Metabolism and Neurotransmitter Processing in Rat Brain

Background: Nicotine is the addictive component oftobacco smoking. It has been reported to have anegative neuromodulatory role in the CNS. Moringaoleifera is a medicinal plant with reported antioxidant,anticonvulsant, anti-inflammatory and neuroprotective properties. Aim and Objectives: This studywas purposed to investigate the neuronal adaptationpotentials of Moringa Oleifera (MO) on nicotineinduced behavioural decline and perturbed bioenergetics. Material and Methods: Twenty-four adultmale Wistar rats were used. The treatment regimen wasas follows; control group received distilled water, MOgroup received 200 mg/kg of MO, Nicotine Groupreceived 1.38 mg/kg body weight of nicotine, andNicotine + MO group received combined treatment of200 mg/kg body weight of MO after 1.38 mg/kg bodyweight of nicotine for 28 days. The animals weresubjected to Morris water maze for spatial memory, Ymaze for working memory and elevated-plus mazetests for anxiety levels after which they were sacrificedfor spectrophotometric analysis of global proteinexpression, neural bioenergetics (lactate dehydrogenase and glucose-6-phosphate dehydrogenase), andAcetylcholinesterase (AChE) levels. Results: Nicotineinfusion caused a reduction in the escape latencyperiod, increased the percentage incorrect alternation,and elevated the anxiety levels of rats. Theseobservations were indicative of decreased synapticactivity in the brain. Together with, nicotine inducedchromatolytic changes in cells of the frontal cortex andhippocampus. Co-administration with MO preventednicotine-associated memory decline, perturbedglucose bioenergetics, induced chromatolysis andhistomorphological distortion in the frontal cortex andhippocampus. Conclusion: Our data demonstrate thatMO administration enhances experience-dependentneuroplasticity and cognitive behaviour function inlaboratory animals, modulates energy metabolism andreduced oxidant stress possibly through enhancedproduction of key antioxidant enzymes against thedamaging effects of nicotine. It provided evidence thatMO can be further developed as a means to protect thebrain from oxidative stress-induced injury.

fNIRS Assessment during an Emotional Stroop Task among Patients with Depression: Replication and Extension

OBJECTIVE: Accumulated evidence collected via functional near-infrared spectroscopy (fNIRS) has been reported with regard to mental disorders. A previous finding revealed that emotional words evoke left frontal cortex activity in patients with depression. The primary aim of the current study was to replicate this finding using an independent dataset and evaluate the brain region associated with the severity of depression using an emotional Stroop task. METHODS: Oxygenized and deoxygenized hemoglobin recording in the brain by fNIRS on 14 MDD patients and 20 normal controls. RESULTS: Hyperactivated oxygenized hemoglobin was observed in the left frontal cortex on exposure to unfavorable stimuli, but no significant difference was found among patients with depression compared with healthy controls on exposure to favorable stimuli. This result is consistent with previous findings. Moreover, an evoked wave associated with the left upper frontal cortex on favorable stimuli was inversely correlated with the severity of depression. CONCLUSION: Our current work using fNIRS provides a potential clue regarding the location of depression symptom severity in the left upper frontal cortex. Future studies should verify our findings and expand them into a precise etiology of depression.

Application of repetitive transcranial magnetic stimulation in the treatment of obsessive-compulsive disorder / 上海交通大学学报（医学版）

At present, a considerable proportion of patients with obsessive-compulsive disorder (OCD) cannot be effectively relieved by standard drug and psychotherapy, so researchers have turned their attention to new directions of physiotherapy. Repetitive transcranial magnetic stimulation (rTMS), as an adjuvant therapy for refractory OCD, is a non-invasive nerve stimulation technique. Many studies have shown that rTMS is effective in the treatment of OCD. However, there were also disputes in the selection of stimulation targets, parameter settings and so on. This article systematically combs the setting and application of standard rTMS in the treatment of OCD, and comprehensive therapeutic effect of rTMS, and then discusses the deficiency of treatment so far, in order to put forward the future development direction and promote clinical treatment progress.

Progressive Grey Matter Volume Changes in Patients with Schizophrenia over 6 Weeks of Antipsychotic Treatment and Their Relationship to Clinical Improvement / 神经科学通报·英文版

Cross-sectional and longitudinal studies have identified widespread and progressive grey matter volume (GMV) reductions in schizophrenia, especially in the frontal lobe. In this study, we found a progressive GMV decrease in the rostral medial frontal cortex (rMFC, including the anterior cingulate cortex) in the patient group during a 6-week follow-up of 40 patients with schizophrenia and 31 healthy controls well-matched for age, gender, and education. The higher baseline GMV in the rMFC predicted better improvement in the positive score on the Positive and Negative Syndrome Scale (PANSS), and this might be related to the improved reality-monitoring. Besides, a higher baseline GMV in the posterior rMFC predicted better remission of general symptoms, and a lesser GMV reduction in this region was correlated with better remission of negative symptoms, probably associated with ameliorated self-referential processing and social cognition. Besides, a shorter disease course and higher educational level contributed to better improvement in the general psychopathological PANSS score, and a family history was negatively associated with improvement of the negative and total PANSS scores. These phenomena might be important for understanding the neuropathological mechanisms underlying the symptoms of schizophrenia and for making clinical decisions.

The Roles of Frontal Cortex in Primary Insomnia : Findings from Functional Magnetic Resonance Imaging Studies

Insomnia is a common sleep-related symptom which occurs in many populations, however, the neural mechanism underlying insomnia is not yet known. The hyperarousal model explains the neural mechanism of insomnia to some extent, and the frontal cortex dysfunction has been known to be related to primary insomnia. In this review, we discuss studies that applied resting state and/or task-related functional magnetic resonance imaging to demonstrate the deficits/dysfunctions of functional activation and network in primary insomnia. Empirical evidence of the hyperarousal model and proposed relation between the frontal cortex and other brain regions in primary insomnia are examined. Reviewing these studies could provide critical insights regarding the pathophysiology, brain network and cerebral activation in insomnia and the development of novel methodologies for the diagnosis and treatment of insomnia.

Neural Mechanism of Post-stroke Depression:A Functional Near-infrared Spectroscopy Study / 中国康复理论与实践

Objective To observe the change of the relative concentration of oxygenated hemoglobin in the frontal cortex during cognitive processing in patients with post-stroke depression (PSD), and to discuss the neural mechanism and changes of working memory function of PSD preliminarily. Methods From February to August,2017,20 patients with PSD(PSD group)and 20 patients with non-depressive(con-trol group)were recruited.NIRSport portable functional near-infrared spectroscopy system was used to observe the change of the relative concentration of hemoglobin in the frontal cortex during the emotional face gender judgment task and"1-back"working memory task. Results Compared with the control group,the change of the relative concentration of oxygenated hemoglobin in the pre-frontal cortex was significantly lower after the negative emotion faces were presented in PSD group(t=3.872,P<0.001).In the implementation of the"1-back",the change of the relative concentration of oxygenated hemoglo-bin in the left prefrontal cortex was significantly lower in PSD group than in the control group(t=2.475,P<0.05), however,there was no significant difference in the change in the right prefrontal cortex between two groups(t=1.773,P=0.084). Conclusion The prefrontal cortex activity decrease in patients with PSD after the negative emotion faces were present-ed.The left prefrontal working memory function is impaired.The patients with PSD have disorder of oxygen me-tabolism in the prefrontal lobe.

Early Postnatal Valproic Acid Exposure Increase the Protein Level of Astrocyte Markers in Frontal Cortex of Rat

OBJECTIVE: In our previous study, it has been reported that valproic acid (VPA) effects gliogenesis and increases the number of glial precursor cells during the early postnatal period. However there is no specific report that whether this process is going on up to the age of mature brain development and the consequence effect of this ongoing gliogenesis process. METHODS: As an ongoing study, using Immunoblotting analysis, we checked the level of glial protein and glial-derived factor markers in the frontal cortex of a rat brain at postnatal day (PND) 21. RESULTS: The finding of the study suggests that, in the VPA group (p < 0.05), early exposure elicited significantly to increase the expression level of glial protein cells at PND 21 in the frontal cortex of rat brain. CONCLUSION: Therefore we suggest that, alter gliogenesis and abnormal number of glial cells modulate the neurobiological dysfunction and induces the risk of neurodevelopmental disorders.

Dynamic changes of blood flow in frontal cortex of diabetic rats / 中国药理学通报

Aim To investigate the changes of cerebral blood flow in rats with diabetic cognitive impairment by two-channel laser Doppler flowmeter,and to explore the changes of cerebral blood flow in diabetic rats with cognitive impairment and to investigate the changes of cerebral blood flow lesions and the central nervous system function changes in the study to provide pre-foundation.Methods Thirty-four male Wistar rats were randomly divided into two groups:blank control group and diabetic model group.The rats in the model group were treated with streptozotocin (STZ) 60 mg · kg-1,and the glucose oxidase method was used to determine fasting blood glucose ≥ 16.7 mmol · L-1 as the standard of the model.The Water maze was used to observe the behavioral changes of diabetic rats.Dual-channel laser doppler flowmeter was used to measure cerebral blood flow in diabetic rats with cognitive impairment.Another 34 male Wistar rats were randomly divided into two groups:control group and diabetic model group.Dual-channel laser doppler flowmeter was used to dynamically monitor cerebral blood flow on 0 d,7 d,14 d,21 d,28 d,35 d,42 d,56 d and 75 d.ELISA was applied to detect the concentration of iNOS,eNOS and ET-1 in cerebrospinal fluid.Results Morris water maze test showed that the time of the platform (latency) was significantly longer than that of the blank control group(P ＜0.05).The cerebral blood flow/100 g of diabetic rats with cognitive impairment was significantly lower than that of the control group (P ＜ O.05),and the blood flow in the model group was significantly lower than that in the model group (P ＜ 0.05).Compared with control group,iNOS and eNOS concentrations were markedly elevated,while ET-1 concentration obviously decreased.Conclusions The decrease of blood flow in the frontal cortex of diabetic rats with cognitive impairment suggests that it may be one of the factors leading to cognitive impairment in diabetes mellitus.Cerebral blood flow reduction occurs in the early stages of diabetes,followed by no significant deterioration.Cerebral blood flow may not be related to the changes of NO and ET-1,but the trend of cerebral blood flow may be related to the change of the two.

A high-fat diet decreases GABA concentration in the frontal cortex and hippocampus of rats

BACKGROUND: It has been proposed that the γ-aminobutyric acid (GABA) plays a key role in the regulation of food intake and body weight by controlling the excitability, plasticity and the synchronization of neuronal activity in the frontal cortex (FC). It has been also proposed that the high-fat diet (HFD) could disturb the metabolism of glutamate and consequently the GABA levels, but the mechanism is not yet clearly understood. Therefore, the aim of this study was to investigate the effect of a HFD on the GABA levels in the FC and hippocampus of rats. RESULTS: The HFD significantly increased weight gain and blood glucose levels, whereas decreased the GABA levels in the FC and hippocampus compared with standard diet-fed rats. CONCLUSIONS: HFD decreases GABA levels in the FC and hippocampus of rat, which likely disrupts the GABAergic inhibitory processes, underlying feeding behavior.

Effect of Heroin on DLG4 Expression in Hippocampus, Amygdala and Frontal Cortex of Rats / 法医学杂志

Objective To observe the expression of discs large hom olog 4 (DLG4) protein in hippocam-pus, am ygdala and frontal cortex of rats and evaluate postsynaptic density in heroin dependence. Meth-ods The rat heroin dependent m odel was established by increasing intraperitoneal injection of heroin. DLG4 proteins in hippocam pus, am ygdala and frontal cortex of heroin dependent 9, 18, 36 days rats w ere detected with im munohistochem ical staining and com pared with that in the control group. Results DLG4 proteins in hippocam pus, am ygdala and frontal cortex w ere gradually reduced with extension of heroin dependent tim e. Conclusion Heroin dependence can affect postsynaptic density of hippocam pus, am ygdala and frontal cortex. The changes becom e m ore apparent with extension of heroin dependence tim e.

Mente desorganizada y reacción catastrófica: regulación emocional intrínseca y extrínseca en sobrevivientes de lesión cerebral adquirida / Disorganized mind and catastrophic reaction: intrinsic and extrinsic emotion regulation in acquired brain injury survivors

La experiencia de tener una mente desorganiza es un fenómeno común luego de lesiones a la corteza frontal. Si bien en las últimas décadas existe un mayor conocimiento respecto a los mecanismos neuropsicológicos que colapsan en una mente desorganizada, las consecuencias emocionales de dicho problema han sido escasamente descritas. Este artículo sugiere que uno de los resultados más importantes de experimentar una mente desorganizada es la imposibilidad de utilizar dicha mente como fuente de autorregulación emocional. Además, propone que en situaciones de desorganización mental, los sobrevivientes de lesión cerebral tienden a utilizar las mentes-cerebros de otros como fuente de regulación afectiva, proceso conocido como regulación extrínseca. Por medio de la descripción de un caso clínico se intenta además demostrar como los procesos de regulación intrínseca y extrínseca se encuentran íntimamente relacionados...

The experience of a disorganized mind is a common phenomenon after pre-frontal cortex lesions. Even though during the last decades there has been a better understanding of the neuropsychological mechanisms that are often compromised in a disorganized mind, its emotional consequences have been scarcely described. This article suggests that a main problem of having a disorganized mind is the difficulty of using that same mind to self-regulate emotional states. In addition, this paper also proposes that in situations where the mind is in a state of disorganization, patients tend to use other’s people’s minds-brains as a source of affective regulation, a process commonly known as extrinsic regulation. Finally, the relationship between intrinsic and extrinsic regulatory processes is addressed through the description of a clinical case...

Increased Cortical Thickness in Professional On-Line Gamers

OBJECTIVE: The bulk of recent studies have tested whether video games change the brain in terms of activity and cortical volume. However, such studies are limited by several factors including cross-sectional comparisons, co-morbidity, and short-term follow-up periods. In the present study, we hypothesized that cognitive flexibility and the volume of brain cortex would be correlated with the career length of on-line pro-gamers. METHODS: High-resolution magnetic resonance scans were acquired in twenty-three pro-gamers recruited from StarCraft pro-game teams. We measured cortical thickness in each individual using FreeSurfer and the cortical thickness was correlated with the career length and the performance of the pro-gamers. RESULTS: Career length was positively correlated with cortical thickness in three brain regions: right superior frontal gyrus, right superior parietal gyrus, and right precentral gyrus. Additionally, increased cortical thickness in the prefrontal cortex was correlated with winning rates of the pro-game league. Increased cortical thickness in the prefrontal and parietal cortices was also associated with higher performance of Wisconsin Card Sorting Test. CONCLUSION: Our results suggest that in individuals without pathologic conditions, regular, long-term playing of on-line games is associated with volume changes in the prefrontal and parietal cortices, which are associated with cognitive flexibility.

Fear, anxiety and their disorders: past, present and future neural theories

This paper reviews the historical development of a two-dimensional (direction x distance (?)) neural model of defense. It begins with Miller's (1944) analysis, and model, of approach, avoidance and conflict; adds Hinde's (1966) ethological perspective and Flynn's (1967) neural model of fear; and then considers Gray's (1967, 1970) work linking barbiturate action to the hippocampus, McNaughton's (1977) extension of this to other classes of anxiolytics, and Gray & McNaughton's (1983) detailed behavioral comparison of anxiolytics and hippocampal lesions. This work led to Gray's (1982) detailed model of the neuropsychology of anxiety. Rapoport's (1989) model of the control of obsession by the cingulate cortex, and Ledoux's (1994) model of the control of both fear and anxiety to the amygdala, suggested a more complex organisation of defense systems. McNaughton (1989) argued that evolutionary function defines an emotion, and Blanchard and Blanchard (1990) argued for its assessment via ethoexperimental analysis. Graeff (1994) then produced a neural model that mapped defensive distance to neural level, treating all anxiety as being at a greater defensive distance than fear. Seeing this, and the treatment of anxiety as due to uncertainty (which is inconsistent with Miller's data), as being unsatisfactory, Gray and McNaughton (2000) and then McNaughton and Corr (2004) developed the two-dimensional model of defensive systems. This model is clearly incomplete at the present time and its links with neuroeconomics, personality, and stress and greater specification of frontal cortical contributions are suggested as directions for future development.

Virtual Reality Alcohol Treatment : Craving and EEG Responding to Multi-Sensory Stimulation in Patient with Alcohol Dependence / 신경정신의학

OBJECTIVES : In our previous report, alcohol dependent patients (ADP) with virtual reality treatment showed a greater decrease in cravings for alcohol and increase in alpha power of the frontal lobe, compared to ADP who underwent general treatment. For the showing different responsibility on alcohol consumption situation between ADP and healthy comparisons, we compared the change in cravings and alpha waves in frontal lobe during virtual reality treatment for alcohol dependence (VRT). METHODS : Thirty seven alcohol-dependent male inpatients diagnosed using DSM-IV, and 25 ageand education-matched healthy adult males were recruited. We measured the changes in cravings and Electroencephalogram (EEG) activity between alcoholic patients and healthy control subjects during VRT. RESULTS : During the VRT, ADP reported higher craving for alcohol during the high risk situation and lower craving for alcohol during aversive situation, compared to healthy controls. The alpha wave of frontal lobe activity in ADP was decreased while that in healthy subject was increased from relaxation to high risk situation (HRS). In ADP, the changes of EEG {Fp1-A1 (r=-0.48, p=0.04), F7-A1 (r=-0.49, p=0.03), Fp2-A2 (r=-0.46, p<0.05), and F8-A2 (r=-0.54, p=0.02)} in the frontal lobe were negatively correlated with the change of craving for alcohol. CONCLUSION : The present study demonstrated that the ready availability and the affinity of alcohol cues in ADP appear to be correlated with decreased function of the frontal lobe.

Virtual Reality Alcohol Treatment : Craving and EEG Responding to Multi-Sensory Stimulation in Patient with Alcohol Dependence / 신경정신의학

OBJECTIVES : In our previous report, alcohol dependent patients (ADP) with virtual reality treatment showed a greater decrease in cravings for alcohol and increase in alpha power of the frontal lobe, compared to ADP who underwent general treatment. For the showing different responsibility on alcohol consumption situation between ADP and healthy comparisons, we compared the change in cravings and alpha waves in frontal lobe during virtual reality treatment for alcohol dependence (VRT). METHODS : Thirty seven alcohol-dependent male inpatients diagnosed using DSM-IV, and 25 ageand education-matched healthy adult males were recruited. We measured the changes in cravings and Electroencephalogram (EEG) activity between alcoholic patients and healthy control subjects during VRT. RESULTS : During the VRT, ADP reported higher craving for alcohol during the high risk situation and lower craving for alcohol during aversive situation, compared to healthy controls. The alpha wave of frontal lobe activity in ADP was decreased while that in healthy subject was increased from relaxation to high risk situation (HRS). In ADP, the changes of EEG {Fp1-A1 (r=-0.48, p=0.04), F7-A1 (r=-0.49, p=0.03), Fp2-A2 (r=-0.46, p<0.05), and F8-A2 (r=-0.54, p=0.02)} in the frontal lobe were negatively correlated with the change of craving for alcohol. CONCLUSION : The present study demonstrated that the ready availability and the affinity of alcohol cues in ADP appear to be correlated with decreased function of the frontal lobe.

Neurobiology of apathy in Alzheimer's disease / Neurobiologia da apatia na doença de Alzheimer

Apathy is considered the most frequent neuropsychiatric disturbance in dementia and its outcome is generally deleterious. Apathy can be related to a dysfunction of the anatomical-system that supports the generation of voluntary actions, namely the prefrontal cortex and/or the prefrontal-subcortical circuits. In Alzheimer's disease, pathological and neuroimaging data indicate that apathy is likely due to a dysfunction of the medial prefrontal cortex. Accordingly, in this review article, we propose a pathophysiological model to explain apathetic behavior in Alzheimer's disease, combining data from neuroimaging, neuropathology and experimental research on the role of orbito-frontal cortex, anterior cingulate cortex, basal ganglia and dopamine in decision-making neurobiology.

Apatia é considerada a alteração neuropsiquiátrica mais freqüente nas demências e suas conseqüências são habitualmente deletérias. Apatia pode ser relacionada à disfunção do sistema anatômico responsável pela geração de ações voluntárias, conhecido com córtex pré-frontal e/ou circuitos pré-frontais-subcorticais. Na doença de Alzheimer, evidências neuropatológicas e de neuroimagem funcional indicam que a apatia é provavelmente decorrente da disfunção do córtex pré-frontal medial. Assim, neste artigo de revisão, apresentamos uma proposta de um modelo fisiopatológico para explicar o comportamento apático na doença de Alzheimer, combinando dados de neuropatologia, neuroimagem e experimentação animal sobre o papel do córtex órbito-frontal, cíngulo anterior, núcleos da base e dopamina na neurobiologia da tomada de decisão.

Dependencia de los sistemas de memoria al ciclo luz-oscuridad en la expresión de estrategias adaptativas. Primera parte

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Abstract: The ability to abstract, store and recover information from the environment in order to generate new strategies to solve problems is one of the most important qualities of the human brain. We mean by strategy, the sophisticated way to solve a problem. A strategy represents in essence the refinement of a given behavior to solve a problem. A strategy could be generalized to solve different problems. The generation of strategies is subjected to the correct functioning of the brain, meaning, alertness, attention, memory among others brain processes in good stand. In this work we focus on the role of memory in the generation of strategies. In this context, we focus on the literature concerning to memory systems, to show that different memory systems process and store different kinds of information. Therefore, the generation of a given strategy would require the participation of one system instead of other, or at least, one system would be commanding over the others. A memory system is defined as neural network consisting on a central structure communicated through afferences and efferences with others. The ones conveying information to this central structure would provide information from the internal or external environment to be interpreted and stored; while the ones that receive information from the central structure would execute its commands. Curiously, the role of central structure can be played by one structure "A" that in other conditions was under the control of a structure "B". In this condition, "B" is under the control of "A". In this review we sought to describe the anatomic and physiologic basis of the memory systems and their participation in the expression of strategies for the solution of specific problems. In this first part, we review the literature concerning to the hippocampus and striatum. Our endeavor was to make a synthesis of the main components of the functional neuroanatomy of memory and of its specific participation in the generation and expression of strategies, and also of the influence of the light-dark cycle on the strategies resulting from the interaction of these structures. In this review we focus mainly on the basic description of memory systems and on the data obtained from intact rats and of others with lesions and subject to electrophysiological experiments. Many studies reviewed on this first part confront subjects to situations where different solutions can be performed; basically this studies are conducted on mazes were the subject can use different kinds of information for spatial orientation. Depending on the nature of the information available or selected by the subject, investigators may infer the kind of strategy the subject is using to solve the problem. From this background, concepts such as stimulus-stimulus strategy and stimulus-response strategy have been generated. The first one consists of making associations between neutral stimuli, to make a conceptual map that guides the subject toward his/her objective. It has been related with the hippocampus function and it has been classically related to the processing, interpretation, and storage of contexts and events as well as to spatial navigation. We center our attention on studies carried out in mazes, showing that lesions or temporal inactivation of the hippocampus disturb the capacity of orientation by using spatial cues. We also review studies where the expression of spatial strategies is correlated with preferential activation of hippocampus detected with different techniques such as immuno-histochemistry and mycrodialisis in vivo. The stimulus-response strategy, on the other hand, consists on making associations between a particular stimulus and the immediate consequence of its presence. This kind of strategy has been related with the striatum, particularly with its dorsolateral region. For this section we discuss studies where lesions or inactivation of the dorsolateral striatum were performed, on rats submitted to tasks where the solution could be achieved by using stimu-lus-stimulus or stimulus-response strategy. In subjects with striatal dysfunction the ability to perform using a stimulus-response strategy was disrupted but not the ability to use a stimulus-stimu-lus strategy. In addition, we revise studies where the expression of the stimulus-response strategy is correlated with a preferential activation of the striatum over hippocampus. We additionally discuss the interaction hippocampus-striatum to solve a spatial task. We make special emphasis in describing the hippocampal and the striatal systems as independent systems that process and store different kinds of information; therefore, they seem to alternate their activity depending on the demand of the environment. This means that if a stimulus-stimulus strategy is required, the hippocampus will govern the response of the subject, increasing its activity that will be over the activity of the striatum. The opposite will occur if a stimulus-response strategy is required. Studies in humans and rats have been performed to understand the interaction between hippocampus and striatum with similar results. Apparently hippocampus appears more active during the first stages of learning, leading behavior and being expressed as stimulus-stimulus strategy. Later, in learning, the hippocampus decreases in activity and the striatum increases, thus becoming the leader structure. This later activation of stria-tum has been related with the phase of learning when the task is mastered and is starting to become a habit. Finally, we devoted special interest to describe the influence of the light dark cycle over these systems and over the goal-oriented behavior. And as we will see on the second part of this review, the functioning of these structures may be regulated by the light-dark cycle. We will review the influence of the presence or absence of light on neurotransmitters release. We will give evidence indicating that the neurochemical modulation depends greatly on the influence of the light-dark cycle and that it results obviously in a different activity of these structures and hence the behavior. In conclusion, when a subject is confronted with a specific problem, he/she can find the solution by using different strategies. At present, we can not say which are the mechanisms responsible for the selection of a particular strategy at a given mo-ment, but we can say that the expression of any strategy depends on the activity of structures such as the hippocampus and the striatum. In theory each structure represents a memory system or a fundamental part of a memory system. The interaction of the different memory systems, produce a scenario were each system provides, processes, and stores different information about the environment, and this information is useful to generate and exhibit a given strategy. On the second part of this review we will focus on the func-tioning and participation of the amygdala and prefrontal cortex, and the influence of the environment on the memory systems.