Theta Oscillations Support Prefrontal-hippocampal Interactions in Sequential Working Memory / 神经科学通报·英文版

The prefrontal cortex and hippocampus may support sequential working memory beyond episodic memory and spatial navigation. This stereoelectroencephalography (SEEG) study investigated how the dorsolateral prefrontal cortex (DLPFC) interacts with the hippocampus in the online processing of sequential information. Twenty patients with epilepsy (eight women, age 27.6 ± 8.2 years) completed a line ordering task with SEEG recordings over the DLPFC and the hippocampus. Participants showed longer thinking times and more recall errors when asked to arrange random lines clockwise (random trials) than to maintain ordered lines (ordered trials) before recalling the orientation of a particular line. First, the ordering-related increase in thinking time and recall error was associated with a transient theta power increase in the hippocampus and a sustained theta power increase in the DLPFC (3-10 Hz). In particular, the hippocampal theta power increase correlated with the memory precision of line orientation. Second, theta phase coherences between the DLPFC and hippocampus were enhanced for ordering, especially for more precisely memorized lines. Third, the theta band DLPFC → hippocampus influence was selectively enhanced for ordering, especially for more precisely memorized lines. This study suggests that theta oscillations may support DLPFC-hippocampal interactions in the online processing of sequential information.

Neuroestimulación del nervio vago, hipocampal y de núcleos anteriores y centromedianos del tálamo en epilepsia temporal: revisión de la literatura / Neurostimulation of the vagus nerve, hippocampal and anterior and centromedian nuclei of the thalamus in temporal epilepsy: literature review

Introducción: En pacientes con epilepsia del lóbulo temporal refractarios que no son candidatos a cirugía, se debe considerar la estimulación eléctrica cerebral como una opción. Contenido: La estimulación eléctrica cerebral es la administración directa de pulsos eléctricos al tejido nervioso que permite modular un sustrato patológico, interrumpir la manifestación clínica de las crisis y reducir la gravedad de estas. Así, dada la importancia de estos tratamientos para los pacientes con epilepsia del lóbulo temporal refractaria, se hace una revisión de cuatro tipos de estimulación eléctrica. La primera, la del nervio vago, es una buena opción en crisis focales y crisis generalizadas o multifocales. La segunda, la del hipocampo, es más útil en pacientes no candidatos a lobectomía por riesgo de pérdida de memoria, con resonancia magnética normal o sin esclerosis mesial temporal. La tercera, la del núcleo anterior, es pertinente principalmente en pacientes con crisis focales, pero debe realizarse con precaución en pacientes con alto riesgo de cambios cognitivos, como los ancianos, o en los que presentan alteración del estado de ánimo basal, y, por último, la del núcleo centromediano se recomienda para el tratamiento crisis focales en el síndrome de Rasmussen y crisis tónico-clónicas en el síndrome de Lennox-Gastaut. Conclusiones: El interés por la estimulación eléctrica cerebral ha venido aumentando, al igual que las estructuras diana en las cuales se puede aplicar, debido a que es un tratamiento seguro y eficaz en pacientes con epilepsia del lóbulo temporal para controlar las crisis, pues disminuye la morbimortalidad y aumenta la calidad de vida.

Introduction: In patients with refractory temporal lobe epilepsy who are not candidates for surgery, electrical brain stimulation should be considered as another option. Contents: Electrical brain stimulation is the direct administration of electrical pulses to nerve tissue that modulates a pathological substrate, interrupts the clinical manifestation of seizures, and reduces their severity. Thus, given the importance of these treatments for patients with refractory temporal lobe epilepsy, four types of electrical stimulation are reviewed. The first, vagus nerve stimulation, is a good option in focal seizures and generalized or multifocal seizures. The second, hippocampal stimulation, is more useful in patients who are not candidates for lobectomy due to the risk of memory loss, with normal MRI or without mesial temporal sclerosis. The third, the anterior nucleus, is mainly in patients with focal seizures, but with caution in patients at high risk of cognitive changes such as the elderly, or in those with baseline mood disturbance and, finally, the centromedian nucleus is recommended for the treatment of focal seizures in Rasmussen's syndrome and tonic-clonic seizures in Lennox-Gastaut syndrome. Conclusions: the interest in brain electrical stimulation has been increasing as well as the target structures in which it can be applied because it is a safe and effective treatment in patients with temporal lobe epilepsy to control seizures, decreasing morbidity and mortality and increasing quality of life

Epileptogénesis y corteza piriforme: entendiendo a la epilepsia del lóbulo temporal más allá del hipocampo / Epileptogenesis and the piriform cortex: understanding temporal lobe epilepsy beyond the hippocampus

Introducción: Con la experiencia de los registros electroencefalográficos invasivos y el fracaso quirúrgico después de la cirugía, se ha hecho evidente que la epilepsia del lóbulo temporal es mucho más compleja de lo que se creía, y en la actualidad es considerada una enfermedad de redes anatomofuncionales y no de lesiones estructurales. Contenido: La información neurofisiológica e imagenológica actual permite concluir que en esta epilepsia están involucradas varias redes neuronales temporales y extratemporales que contribuyen a la extensión de la zona epileptógena. Una forma de entender el concepto de red epiléptica en la epilepsia del lóbulo temporal es a partir del conocimiento de la corteza piriforme. Varios estudios clínicos han mostrado que en pacientes con epilepsia del lóbulo temporal asociada a esclerosis hipocampal existe una disfunción interictal del procesamiento olfatorio que es más significativa, en comparación con pacientes con epilepsia focal extrahipocampal y controles sanos. Esta alteración es, probablemente, la consecuencia de una red neuronal disfuncional que se extiende más allá del hipocampo y que afecta a otras estructuras cercanas, incluida la corteza piriforme. Conclusión: En este artículo llevamos a cabo una revisión narrativa de la literatura con el objetivo de establecer un vínculo entre la corteza piriforme y la epileptogénesis del lóbulo temporal, y demostramos que esta enfermedad es la consecuencia de una disfunción de redes neuronales que no depende exclusivamente de una anormalidad estructural en el hipocampo o en estructuras cercanas.

Introduction: With the experience of invasive EEG recordings and surgical failure after surgery, it has become clear that temporal lobe epilepsy is much more complex than previously thought, and currently, is conceptualized as a disease of anatomical networks instead of structural lesions. Content: The current neurophysiological and imaging information allows us to conclude that several temporal and extratemporal anatomical networks are involved in this type of epilepsy. One way of understanding the concept of the epileptic network in temporal lobe epilepsy is from the knowledge of the piriform cortex. Several clinical studies have shown that in patients with temporal lobe epilepsy associated with hippocampal sclerosis exists an interictal dysfunction of olfactory processing that is more significant compared to patients with focal extra-hippocampal epilepsy and healthy controls. This alteration is probably the consequence of a dysfunctional neural network that extends beyond the hippocampus and affects other nearby structures, including the piriform cortex. Conclusion: In this article, we carry out a narrative review of the literature with the aim of establishing a link between the piriform cortex and temporal lobe epileptogenesis, demonstrating that this disease is the consequence of a dysfunctional network that does not depend exclusively of a hippocampal structural abnormality.

HDAC2 Inhibits Hippocampal Neurogenesis and Impairs the Cognitive Function in Prenatally Stressed Adult Offspring / HDAC2 Inhibe la Neurogénesis del Hipocampo y Afecta la Función Cognitiva en la Descendencia Adulta Estresada Prenatalmente

SUMMARY: The objective of this study was to investigate the mechanism of prenatal stress on the cognitive function of offspring, and clarify the change of histone deacetylase 2 (HDAC2) expression in hippocampal neurons of offspring. 16 pregnant SD rats were randomly divided into control group and stress group, with eight rats in each group. The stress group received restrained stress from 15 to 21 days of pregnancy, while the control group did not receive any treatment. Anxiety-like behavior and spatial memory, learning and memory ability were detected in open field, elevated plus maze, novel object recognition test, and Barnes maze. Nissl staining was used to detect the function of hippocampal neurons. Western blot was used to detect the expression of HDAC2 protein in hippocampal neurons of adult offspring. Immunofluorescence staining was used to detect the expression of HDAC2 protein and hippocampal neurogenesis. The learning and memory ability of adult offspring was decreased. The prenatal stress damaged the function of hippocampal neurons , the expression of HDAC2 was down-regulated, and the number of neurons was reduced. Maternal prenatal stress can down- regulate the expression of HDAC2 in the hippocampus of offspring, inhibits hippocampal neurogenesis and impairs the cognitive function.

El objetivo de este estudio fue investigar el mecanismo del estrés prenatal en la función cognitiva de la descendencia y aclarar el cambio de la expresión de la histona desacetilasa 2 (HDAC2) en las neuronas del hipocampo de la descendencia. 16 ratas SD preñadas se dividieron aleatoriamente en un grupo de control y un grupo de estrés, con ocho ratas en cada grupo. El grupo de estrés recibió estrés durante 15 a 21 días de pre, preñez, mientras que el grupo de control no recibió ningún tratamiento. El comportamiento similar a la ansiedad y la memoria espacial, el aprendizaje y la capacidad de memoria se detectaron en campo abierto, laberinto en cruz elevado, prueba de reconocimiento de objetos novedosos y laberinto de Barnes. La tinción de Nissl se utilizó para detectar la función de las neuronas del hipocampo. Se utilizó Western blot para detectar la expresión de la proteína HDAC2 en las neuronas del hipocampo de la descendencia adulta. La tinción de inmunofluorescencia se utilizó para detectar la expresión de la proteína HDAC2 y la neurogénesis del hipocampo. La capacidad de aprendizaje y memoria de la descendencia adulta se redujo. El estrés prenatal dañó la función de las neuronas del hipocampo, se reguló negativamente la expresión de HDAC2 y se redujo el número de neuronas. El estrés prenatal materno puede regular a la baja la expresión de HDAC2 en el hipocampo de la descendencia, inhibe la neurogénesis del hipocampo y deteriora la función cognitiva.

A psicopatia e o criminoso nato: a modernização do positivismo criminológico / Psychopathy and the born criminal: the modernization of criminological positivism / Psicopatía y el criminal nato: la modernización del positivismo criminológico

O conceito de psicopatia é habitualmente associado a uma psicopatologia caracterizada pela falta de empatia, manipulação, agressividade, impulsividade, egocentrismo, crueldade e criminalidade. Já amplamente aceito pela comunidade científica, o conceito costuma ser utilizado em contextos jurídico-penais na validação de seu funcionamento punitivo. Dentre as concepções que alicerçaram o surgimento histórico desse conceito, destaca-se o papel do criminoso nato de Lombroso. Nesse sentido, este estudo buscou evidenciar como o conceito contemporâneo de psicopatia se firma enquanto modernização das concepções lombrosianas acerca do criminoso nato. Para isso, nos apoiamos na psicopatolologia para realizar um estudo comparativo entre as produções de Lombroso e as pesquisas contemporâneas acerca da psicopatia. Dentre as principais similaridades, destacamos a ênfase atribuída à suposta natureza criminal, etiologicamente decorrente de sua configuração orgânica. No mais, tais concepções também se assemelham no destaque de um déficit afetivo e moral, assim como na descrição da tendência a ser canhoto, egoísta, mentiroso, resistente à dor, narcisista, impulsivo, promíscuo, cruel, maléfico e inapto ao trabalho. Assim como fez Lombroso, as pesquisas acerca da psicopatia costumam ser realizadas com sujeitos já previamente criminalizados; condicionando uma seletividade étnico-racial e de classe. Descritos como sujeitos perigosos, incuráveis e intratáveis, ambas as concepções promovem a defesa do acirramento da punição jurídico-penal. Concluímos que a criminalidade nata de Lombroso continua a ser expressa no conceito de psicopatia, visto que as funções jurídico-penais e socioeconômicas de sua definição exercem o mesmo papel na legitimação científica da violência de Estado, encarceramento em massa e racismo estrutural.(AU)

Psychopathy is usually associated with a psychopathology characterized by a lack of empathy, manipulation, aggressiveness, impulsivity, egocentrism, cruelty, and criminality. Widely accepted by the scientific community, this concept is often used in legal and criminal contexts to validate its punitive functioning. Among the conceptions that underpinned the historical emergence of psychopathy, Lombroso's born criminal stands out. Hence, this study analyzes how the contemporary concept of psychopathy updates Lombrosian conceptions about the born criminal. To do so, we rely on psychopathology to conduct a comparative study between Lombroso's work and contemporary research on psychopathy. Among the main similarities, we highlight the emphasis given to the supposed criminal nature, etiologically arising from its organic configuration. Moreover, such conceptions emphasize an affective and moral deficit, and describe a tendency toward left-handedness, selfishness, lying, pain-resistance, narcissism, impulsivity, promiscuousness, cruelty, maliciousness and unfitness for work. As did Lombroso, research on psychopathy is usually conducted with individuals who have already been criminalized, conditioning an ethnic-racial and class selectivity. By describing these subjects as dangerous, incurable and intractable, both conceptions advocate for increased legal and penal punishment. In conclusion, Lombroso's natural criminality continues to underpin the concept of psychopathy, since its legal-criminal and socioeconomic functions play the same role in scientifically legitimizing state violence, mass incarceration, and structural racism.(AU)

La psicopatía es un concepto generalmente asociado a una psicopatología que se caracteriza por la falta de empatía, la manipulación, agresividad, impulsividad, egocentrismo, crueldad y criminalidad. Ya ampliamente aceptado por la comunidad científica, este concepto se utiliza a menudo en contextos legales para validar su funcionamiento punitivo. Entre los conceptos que fundamentaron el surgimiento histórico de este concepto, destaca el papel del criminal nato de Lombroso. En este contexto, este estudio buscó mostrar cómo el concepto contemporáneo de psicopatía se establece como la modernización de las concepciones lombrosianas sobre el criminal nato. Para eso, se utiliza la psicopatología para realizar un estudio comparativo entre las producciones de Lombroso y la investigación contemporánea sobre psicopatía. Entre las principales similitudes, destaca el énfasis atribuido a su supuesta naturaleza criminal, resultado etiológico de su configuración orgánica. Además, estas concepciones también son similares al resaltar un déficit afectivo y moral, así como al describir la tendencia a ser zurdo, egoísta, mentiroso, resistente al dolor, narcisista, impulsivo, promiscuo, cruel, malévolo e inadecuado para el trabajo. Como hizo Lombroso, los estudios sobre psicopatía se suelen realizar con sujetos que ya han sido criminalizados; condicionando una selectividad étnica, racial y de clase. Calificados como sujetos peligrosos, incurables e intratables, ambas concepciones promueven la defensa del aumento de la pena legal. Se concluye que la criminalidad nata de Lombroso continúa expresándose en el concepto de psicopatía, ya que las funciones penales y socioeconómicas de su definición juegan el mismo papel en la legitimación científica de la violencia estatal, encarcelamiento masivo y racismo estructural.(AU)

Zuogui Jiangtang Jieyu Decoction promotes neural stem cell self-renewal and activates Shh signaling in the hippocampal dentate gyrus of diabetic rats with depression / 南方医科大学学报

OBJECTIVE@#To investigate the effect of Zuogui Jiangtang Jieyu Decoction (ZJJ) on Shh signaling and self-renewal of neural stem cells in the hippocampal dentate gyrus of diabetic rats with depression.@*METHODS@#Diabetic rat models with depression were randomly divided into model group, positive drug (metformin + fluoxetine) group, and low-, medium-, and high-dose ZJJ groups (n=16), with normal SD rats as the control group. The positive drugs and ZJJ were administered by gavage, and the rats in the control and model groups were given distilled water. After the treatment, blood glucose level was detected using test strips, and behavioral changes of the rats were assessed by forced swimming test and water maze test. ELISA was used to examine the serum level of leptin; The expressions of nestin and Brdu proteins in the dentate gyrus of the rats were detected using immunofluorescence assay, and the expressions of self-renewal marker proteins and Shh signaling proteins were detected using Western blotting.@*RESULTS@#The diabetic rats with depression showed significantly increased levels of blood glucose and leptin (P < 0.01) and prolonged immobility time in forced swimming test (P < 0.01) and increased stage climbing time with reduced stage seeking time and stage crossings in water maze test (P < 0.01). The expressions of nestin and Brdu in the dentate gyrus, the expressions of cyclin D1, SOX2, Shh, Ptch1, Smo in the hippocampus and the nuclear expression of Gli-1 were decreased (P < 0.01) while hippocampal Gli-3 expression was increased significantly (P < 0.01) in the rat models. Treatment of rat models with high-dose ZJJ significantly reduced the blood glucose (P < 0.01) and leptin level (P < 0.05) and improved their performance in behavioral tests (P < 0.01). The treatment also obviously increased the expressions of nestin, Brdu, cyclin D1, SOX2, Shh, Ptch1, and Smo and the nuclear expression of Gli-1 in the dentate gyrus (P < 0.01) and reduced hippocampal expression of Gli-3 (P < 0.05) in the rat models.@*CONCLUSION@#ZJJ can significantly improve the self-renewal ability of neural stem cells and activate Shh signaling in dentate gyrus of diabetic rats with depression.

Therapeutic effect and mechanism of Xiaoyao Kangai Jieyu Recipe on mice with breast cancer related depression through regulating COX pathway / 中国中药杂志

This study aimed to investigate the intervention effect and mechanism of Xiaoyao Kangai Jieyu Recipe(XKJR) on hip-pocampal microglia and neuronal damage in mice with breast cancer related depression. The mouse model of breast cancer related depression was established by inoculation of 4T1 breast cancer cells in axilla and subcutaneous injection of corticosterone(30 mg·kg~(-1)). The successfully modeled mice were randomly divided into a model group, a positive drug group(capecitabine 60 mg·kg~(-1)+fluoxetine 19.5 mg·kg~(-1)), and XKJR group(19.5 mg·kg~(-1) crude drug), with 6 in each group. Another 6 normal mice were taken as a normal group. The administration groups were given corresponding drugs by gavage, while the normal and model groups were given an equal volume of distilled water, once a day for 21 consecutive days. The depressive behavior of mice was assessed by glucose consumption test, open field test and novelty-suppressed feeding test. Hematoxylin and eosin(HE) staining and tumor suppression rate were used to evaluate the changes of axillary tumors. The mRNA expressions and the relative protein expressions of interleukin-1β(IL-1β), interleukin-18(IL-18), cyclooxyganese-2(COX-2) and glutamyl-prolyl-tRNA synthetase(EPRs) in the hippocampus of mice were determined by quantitative real-time polymerase chain reaction(qRT-PCR) and immunohistochemistry, respectively. Immunofluorescence was performed to detect the mean fluorescence intensity of CD11b, a marker of hippocampal microglia activation. Nissler staining and transmission electron microscopy were employed to observe the morphological changes and the ultramorphological changes of hippocampal neurons, respectively. The experimental results indicated that compared with the normal group, the model group had reduced glucose consumption and lowered number of total activities in open field test(P<0.05, P<0.01), prolonged first feeding latency in no-velty-suppressed feeding test(P<0.01), and significant depression-like behavior; the contents of IL-1β, IL-18, COX-2, and EPRs in hippocampus were increased(P<0.05, P<0.01), with hippocampal microglia activation and obvious neuronal damage. Compared with the model group, the positive drug group and the XKJR group presented an improvement in depressive behaviors, a decrease in the contents of IL-1β, IL-18, COX-2 and EPRs in hippocampus, and an alleviation in the activation of hippocampal microglia and neuronal damage; the tumor suppression rates of positive drug and XKJR were 40.32% and 48.83%, respectively, suggesting a lower tumor growth rate than that of the model group. In summary, XKJR may improve hippocampal microglia activation and neuronal damage in mice with breast cancer related depression through activating COX signaling pathway.

Antidepressant mechanism of Shenling Kaixin Granules based on BDNF/TrkB/CREB pathway / 中国中药杂志

To investigate the antidepressant mechanism of Shenling Kaixin Granules(SLKX) in treating chronic unpredictable mild stress(CUMS) model rats. Ninety male SD rats were randomly divided into control group, model group, Shugan Jieyu Capsules(110 mg·kg~(-1)) group and SLKX low-(90 mg·kg~(-1)), medium-(180 mg·kg~(-1)), and high-dose(360 mg·kg~(-1)) groups. Depression rat model was replicated by CUMS method. After treatment, the behavioral changes of rats were evaluated by sugar preference, open field, elevated cross maze and forced swimming experiments. The contents of interleukin 1 beta(IL-1β), tumor necrosis factor α(TNF-α), brain-derived neurotrophic factor(BDNF) and 5-hydroxytryptamine(5-HT) in serum were determined by enzyme linked immunosorbent assay(ELISA), and the activities of superoxide dismutase(SOD) and catalase(CAT) in hippocampal CA1 region were also detected. Pathological changes in hippocampal CA1 region were detected by hematoxylin-eosin(HE) staining, and Western blot was used to determine the expression of nerve growth factor(NGF), BDNF, phospho-tyrosine kinase receptor(p-TrkB)/TrkB, phospho-cAMP-response element binding protein(p-CREB)/CREB, nuclear factor E2 related factor 2(Nrf2), heme oxygenase 1(HO-1), B-cell lymphoma-2(Bcl-2)/Bcl-2 associated X protein(Bax) and caspase-3 in hippocampal CA1 region. RESULTS:: showed that compared with the control group, the model group had decreased sugar preference, reduced number of entries and time spent in the center of open field and shortened total distance of movement, reduced number of entries and proportion of time spent in open arm, and increased number and time of immobility in forced swimming experiment. Additionally, the serum contents of IL-1β and TNF-α and the expression of caspase-3 were higher, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1 and Bcl-2/Bax, and the Nrf2 nuclear translocation were lower in model group than in control group. Compared with the conditions in model group, the sugar preference, the number of entries and time spent in the center of open, total distance of movement, and the number of entries and proportion of time spent in open arm in treatment groups were increased while the number and time of immobility in forced swimming experiment were decreased; the serum contents of IL-1β and TNF-α and the expression of caspase-3 were down regulated, while the contents of BDNF and 5-HT, the activities of SOD and CAT in hippocampal CA1 region, the expressions of NGF, BDNF, p-TrkB/TrkB, p-CREB/CREB, HO-1, Bcl-2/Bax, and Nrf2 nuclear translocation were enhanced. In conclusion, SLKX might regulate the Nrf2 nucleus translocation by activating BDNF/TrkB/CREB pathway, lower oxidative stress damage in hippocampus, inhibit caspase-3 activity, and reduce apoptosis of hippocampal nerve cells, thereby playing an antidepressant role.

Effects of post-traumatic stress disorder on the excitability of glutamatergic and GABAergic neurons in dorsal and ventral hippocampus in mice / 生理学报

The purpose of this study was to investigate the effects of post-traumatic stress disorder (PTSD) on electrophysiological characteristics of glutamatergic and GABAergic neurons in dorsal hippocampus (dHPC) and ventral hippocampus (vHPC) in mice, and to elucidate the mechanisms underlying the plasticity of hippocampal neurons and memory regulation after PTSD. Male C57Thy1-YFP/GAD67-GFP mice were randomly divided into PTSD group and control group. Unavoidable foot shock (FS) was applied to establish PTSD model. The spatial learning ability was explored by water maze test, and the changes in electrophysiological characteristics of glutamatergic and GABAergic neurons in dHPC and vHPC were examined using whole-cell recording method. The results showed that FS significantly reduced the movement speed, and enhanced the number and percentage of freezing. PTSD significantly prolonged the escape latency in localization avoidance training, shortened the swimming time in the original quadrant, extended the swimming time in the contralateral quadrant, and increased absolute refractory period, energy barrier and inter-spike interval of glutamatergic neurons in dHPC and GABAergic neurons in vHPC, while decreased absolute refractory period, energy barrier and inter-spike interval of GABAergic neurons in dHPC and glutamatergic neurons in vHPC. These results suggest that PTSD can damage spatial perception of mice, down-regulate the excitability of dHPC and up-regulate the excitability of vHPC, and the underlying mechanism may involve the regulation of spatial memory by the plasticity of neurons in dHPC and vHPC.

Progress in application of adult endogenous neurogenesis in brain injury repair / 生理学报

Persistent neurogenesis exists in the subventricular zone (SVZ) of the ventricles and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus in the adult mammalian brain. Adult endogenous neurogenesis not only plays an important role in the normal brain function, but also has important significance in the repair and treatment of brain injury or brain diseases. This article reviews the process of adult endogenous neurogenesis and its application in the repair of traumatic brain injury (TBI) or ischemic stroke, and discusses the strategies of activating adult endogenous neurogenesis to repair brain injury and its practical significance in promoting functional recovery after brain injury.

Effects of Yizhi Tiaoshen acupuncture on learning and memory function and the expression of phosphorylated tau protein in the hippocampus of Alzheimer's disease model rats / 中国针灸

OBJECTIVE@#To observe the effects of Yizhi Tiaoshen (benefiting mental health and regulating the spirit) acupuncture on learning and memory function, and the expression of phosphorylated tubulin-associated unit (tau) protein in the hippocampus of Alzheimer's disease (AD) model rats, and explore the effect mechanism of this therapy on AD.@*METHODS@#A blank group and a sham-operation group were randomly selected from 60 male SD rats, 10 rats in each one. AD models were established in the rest 40 rats by the intraperitoneal injection of D-galactose and okadaic acid in the CA1 region of the bilateral hippocampus. Thirty successfully-replicated model rats were randomly divided into a model group, a western medication group and an acupuncture group, 10 rats in each one. In the acupuncture group, acupuncture was applied to "Baihui" (GV 20), "Sishencong" (EX-HN 1), "Neiguan" (PC 6), "Shenmen" (HT 7), "Xuanzhong" (GB 39) and "Sanyinjiao" (SP 6); and the needles were retained for 10 min. Acupuncture was given once daily. One course of treatment was composed of 6 days, with the interval of 1 day; the completion of treatment included 4 courses. In the western medication group, donepezil hydrochloride solution (0.45 mg/kg) was administrated intragastrically, once daily; it took 7 days to accomplish one course of treatment and a completion of intervention was composed of 4 courses. Morris water maze (MWM) and novel object recognition test (NORT) were used to assess the learning and memory function of the rats. Using HE staining and Nissl staining, the morphological structure of the hippocampus was observed. With Western blot adopted, the protein expression of the tau, phosphorylated tau protein at Ser198 (p-tau Ser198), protein phosphatase 2A (PP2A) and glycogen synthase kinase-3β (GSK-3β) in the hippocampus was detected.@*RESULTS@#There were no statistical differences in all of the indexes between the sham-operation group and the blank group. Compared with the sham-operation group, in the model group, the MWM escape latency was prolonged (P<0.05), the crossing frequency and the quadrant stay time in original platform were shortened (P<0.05), and the NORT discrimination index (DI) was reduced (P<0.05); the hippocampal cell numbers were declined and the cells arranged irregularly, the hippocampal neuronal structure was abnormal and the numbers of Nissl bodies decreased; the protein expression of p-tau Ser198 and GSK-3βwas increased (P<0.05) and that of PP2A decreased (P<0.05). When compared with the model group, in the western medication group and the acupuncture group, the MWM escape latency was shortened (P<0.05), the crossing frequency and the quadrant stay time in original platform were increased (P<0.05), and DI got higher (P<0.05); the hippocampal cell numbers were elevated and the cells arranged regularly, the damage of hippocampal neuronal structure was attenuated and the numbers of Nissl bodies were increased; the protein expression of p-tau Ser198 and GSK-3β was reduced (P<0.05) and that of PP2A was increased (P<0.05). There were no statistically significant differences in the above indexes between the acupuncture group and the western medication group (P>0.05).@*CONCLUSION@#Acupuncture therapy of "benefiting mental health and regulating the spirit" could improve the learning and memory function and alleviate neuronal injure of AD model rats. The effect mechanism of this therapy may be related to the down-regulation of GSK-3β and the up-regulation of PP2A in the hippocampus, and then to inducing the inhibition of tau protein phosphorylation.

Tu-Xian Decoction ameliorates diabetic cognitive impairment by inhibiting DAPK-1 / 中国天然药物

Tu-Xian decoction (TXD), a traditional Chinese medicine (TCM) formula, has been frequently administered to manage diabetic cognitive impairment (DCI). Despite its widespread use, the mechanisms underlying TXD's protective effects on DCI have yet to be fully elucidated. As a significant regulator in neurodegenerative conditions, death-associated protein kinase-1 (DAPK-1) serves as a focus for understanding the action of TXD. This study was designed to whether TXD mediates its beneficial outcomes by inhibiting DAPK-1. To this end, a diabetic model was established using Sprague-Dawley (SD) rats through a high-fat, high-sugar (HFHS) diet regimen, followed by streptozotocin (STZ) injection. The experimental cohort was stratified into six groups: Control, Diabetic, TC-DAPK6, high-dose TXD, medium-dose TXD, and low-dose TXD groups. Following a 12-week treatment period, various assessments-including blood glucose levels, body weight measurements, Morris water maze (MWM) testing for cognitive function, brain magnetic resonance imaging (MRI), and histological analyses using hematoxylin-eosin (H&E), and Nissl staining-were conducted. Protein expression in the hippocampus was quantified through Western blotting analysis. The results revealed that TXD significantly improved spatial learning and memory abilities, and preserved hippocampal structure in diabetic rats. Importantly, TXD administration led to a down-regulation of proteins indicative of neurological damage and suppressed DAPK-1 activity within the hippocampal region. These results underscore TXD's potential in mitigating DCIvia DAPK-1 inhibition, positioning it as a viable therapeutic candidate for addressing this condition. Further investigation into TXD's molecular mechanisms may elucidate new pathways for the treatment of DCI.

Physiological Roles of β-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology / 神经科学通报·英文版

The physiological functions of endogenous amyloid-β (Aβ), which plays important role in the pathology of Alzheimer's disease (AD), have not been paid enough attention. Here, we review the multiple physiological effects of Aβ, particularly in regulating synaptic transmission, and the possible mechanisms, in order to decipher the real characters of Aβ under both physiological and pathological conditions. Some worthy studies have shown that the deprivation of endogenous Aβ gives rise to synaptic dysfunction and cognitive deficiency, while the moderate elevation of this peptide enhances long term potentiation and leads to neuronal hyperexcitability. In this review, we provide a new view for understanding the role of Aβ in AD pathophysiology from the perspective of physiological meaning.

DJ1 Ameliorates AD-like Pathology in the Hippocampus of APP/PS1 Mice / 生物医学与环境科学（英文）

OBJECTIVE@#To explore whether the protein Deglycase protein 1 (DJ1) can ameliorate Alzheimer's disease (AD)-like pathology in Amyloid Precursor Protein/Presenilin 1 (APP/PS1) double transgenic mice and its possible mechanism to provide a theoretical basis for exploring the pathogenesis of AD.@*METHODS@#Adeno-associated viral vectors (AAV) of DJ1-overexpression or DJ1-knockdown were injected into the hippocampus of 7-month-old APP/PS1 mice to construct models of overexpression or knockdown. Mice were divided into the AD model control group (MC), AAV vector control group (NC), DJ1-overexpression group (DJ1 +), and DJ1-knockdown group (DJ1 -). After 21 days, the Morris water maze test, immunohistochemistry, immunofluorescence, and western blotting were used to evaluate the effects of DJ1 on mice.@*RESULTS@#DJ1 + overexpression decreased the latency and increased the number of platform traversals in the water maze test. DJ1 - cells were cured and atrophied, and the intercellular structure was relaxed; the number of age spots and the expression of AD-related proteins were significantly increased. DJ1 + increased the protein expression of Nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), light chain 3 (LC3), phosphorylated AMPK (p-AMPK), and B cell lymphoma-2 (BCL-2), as well as the antioxidant levels of total superoxide dismutase (T-SOD), total antioxidant capacity (T-AOC), and Glutathione peroxidase (GSH-PX), while decreasing the levels of Kelch-like hydrates-associated protein 1 (Keap1), mammalian target of rapamycin (mTOR), p62/sequestosome1 (p62/SQSTM1), Caspase3, and malondialdehyde (MDA).@*CONCLUSION@#DJ1-overexpression can ameliorate learning, memory, and AD-like pathology in APP/PS1 mice, which may be related to the activation of the NRF2/HO-1 and AMPK/mTOR pathways by DJ1.

Impaired cognitive map in transgenic animals relevant to Alzheimer's disease: from neurons to network / 生理学报

Alzheimer's disease (AD) is a typical cognitive disorder with an increasing incidence in recent years. AD is also one of the main causes of disability and death of the elderly in current aging society. One of the most common symptoms of AD is spatial memory impairment, which occurs in more than 60% of patients. This memory loss is closely related to the impairment of cognitive maps in the brain. The entorhinal grid cells and the hippocampal place cells are important cellular basis for spatial memory and navigation functions in the brain. Understanding the abnormal firing pattern of these neurons and their impaired coordination to neural oscillations in transgenic rodents is crucial for identifying the therapeutic targets for AD. In this article, we review recent studies on neural activity based on transgenic rodent models of AD, with a focus on the changes in the firing characteristics of neurons and the abnormal electroencephalogram (EEG) rhythm in the entorhinal cortex and hippocampus. We also discuss potential cell-network mechanism of spatial memory disorders caused by AD, so as to provide a scientific basis for the diagnosis and treatment of AD in the future.

Research progress on the effects of childhood obstructive sleep apnea syndrome on cognition and brain functions / 生理学报

Obstructive sleep apnea syndrome (OSAS), a prevalent sleep disorder in children, is characterized by recurring upper airway obstruction during sleep. OSAS in children can cause intermittent hypoxia and sleep fragmentation, ultimately affect brain development and further lead to cognitive impairment if lack of timely effective intervention. In recent years, magnetic resonance imaging (MRI) and electroencephalogram (EEG) have been employed to investigate brain structure and function abnormalities in children with OSAS. Previous studies have indicated that children with OSAS showed extensive gray and white matter damage, abnormal brain function in regions such as the frontal lobe and hippocampus, as well as a significant decline in general cognitive function and executive function. However, the existing studies mainly focused on the regional activity, and the mechanism of pediatric OSAS affecting brain networks remains unknown. Moreover, it's unclear whether the alterations in brain structure and function are associated with their cognitive impairment. In this review article, we proposed two future research directions: 1) future studies should utilize the multimodal neuroimaging techniques to reveal the alterations of brain networks organization underlying pediatric OSAS; 2) further investigation is necessary to explore the relationship between brain network alteration and cognitive dysfunction in children with OSAS. With these efforts, it will be promising to identify the neuroimaging biomarkers for monitoring the brain development of children with OSAS as well as aiding its clinical diagnosis, and ultimately develop more effective strategies for intervention, diagnosis, and treatment.

Psilocybin facilitates fear extinction in mice by promoting hippocampal neuroplasticity / 中华医学杂志(英文版)

BACKGROUND@#Posttraumatic stress disorder (PTSD) and depression are highly comorbid. Psilocybin exerts substantial therapeutic effects on depression by promoting neuroplasticity. Fear extinction is a key process in the mechanism of first-line exposure-based therapies for PTSD. We hypothesized that psilocybin would facilitate fear extinction by promoting hippocampal neuroplasticity.@*METHODS@#First, we assessed the effects of psilocybin on percentage of freezing time in an auditory cued fear conditioning (FC) and fear extinction paradigm in mice. Psilocybin was administered 30 min before extinction training. Fear extinction testing was performed on the first day; fear extinction retrieval and fear renewal were tested on the sixth and seventh days, respectively. Furthermore, we verified the effect of psilocybin on hippocampal neuroplasticity using Golgi staining for the dendritic complexity and spine density, Western blotting for the protein levels of brain derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR), and immunofluorescence staining for the numbers of doublecortin (DCX)- and bromodeoxyuridine (BrdU)-positive cells.@*RESULTS@#A single dose of psilocybin (2.5 mg/kg, i.p.) reduced the increase in the percentage of freezing time induced by FC at 24 h, 6th day and 7th day after administration. In terms of structural neuroplasticity, psilocybin rescued the decrease in hippocampal dendritic complexity and spine density induced by FC; in terms of neuroplasticity related proteins, psilocybin rescued the decrease in the protein levels of hippocampal BDNF and mTOR induced by FC; in terms of neurogenesis, psilocybin rescued the decrease in the numbers of DCX- and BrdU-positive cells in the hippocampal dentate gyrus induced by FC.@*CONCLUSIONS@#A single dose of psilocybin facilitated rapid and sustained fear extinction; this effect might be partially mediated by the promotion of hippocampal neuroplasticity. This study indicates that psilocybin may be a useful adjunct to exposure-based therapies for PTSD and other mental disorders characterized by failure of fear extinction.

Effect of acupuncture at the acupoints for Yizhi Tiaoshen on the functional connectivity between the hippocampus and the brain in the patients with Alzheimer's disease / 中国针灸

OBJECTIVES@#To analyze the effect of acupuncture at the acupoints for Yizhi Tiaoshen (benefiting the intelligence and regulating the spirit) on the functional connectivity between the hippocampus and the whole brain in the patients with Alzheimer's disease (AD), and reveal the brain function mechanism of acupuncture in treatment of AD using resting state functional magnetic resonance imaging (rs-fMRI).@*METHODS@#Sixty patients with mild to moderate AD were randomly divided into an acupuncture + medication group (30 cases, 3 cases dropped out) and a western medication group (30 cases, 2 cases dropped out). In the western medication group, the donepezil hydrochloride tablets were administered orally, 2.5 mg to 5 mg each time, once daily; and adjusted to be 10 mg each time after 4 weeks of medication. Besides the therapy as the western medication group, in the acupuncture + medication group, acupuncture was supplemented at the acupoints for Yizhi Tiaoshen, i.e. Baihui (GV 20), Sishencong (EX-HN 1), and bilateral Shenmen (HT 7), Neiguan (PC 6), Zusanli (ST 36), Sanyinjiao (SP 6) and Xuanzhong (GB 39). The needles were retained for 30 min in one treatment, once daily; and 6 treatments were required weekly. The duration of treatment was 6 weeks in each group. The general cognitive function was assessed by the mini-mental state examination (MMSE) and Alzheimer's disease assessment scale-cognitive part (ADAS-Cog) before and after treatment in the two groups. Using the rs-fMRI, the changes in the functional connectivity (FC) of the left hippocampus and the whole brain before and after treatment were analyzed in the patients of the two groups (11 cases in the acupuncture + medication group and 12 cases in the western medication group).@*RESULTS@#After treatment, compared with those before treatment, MMSE scores increased and ADAS-Cog scores decreased in the two groups (P<0.05); MMSE score was higher, while the ADAS-Cog score was lower in the acupuncture + medication group when compared with those in the western medication group (P≤0.05). After treatment, in the western medication group, FC of the left hippocampus was enhanced with the left fusiform gyrus, the inferior frontal gyrus of the left triangular region, the bilateral superior temporal gyrus and the right superior parietal gyrus (P<0.05), while FC was weakened with the left inferior temporal gyrus, the left middle frontal gyrus and the right dorsolateral superior frontal gyrus when compared with that before treatment (P<0.05). After treatment, in the acupuncture + medication group, FC of the left hippocampus was increased with the right gyrus rectus, the left inferior occipital gyrus, the right superior temporal gyrus and the left middle occipital gyrus (P<0.05), and it was declined with the left thalamus (P<0.05) when compared with those before treatment. After treatment, in the acupuncture + medication group, FC of the left hippocampus was strengthened with the bilateral inferior temporal gyrus, the bilateral middle temporal gyrus, the right gyrus rectus, the bilateral superior occipital gyrus, the left lenticular nucleus putamen, the left calcarine fissure and surrounding cortex, the inferior frontal gyrus of the left insulae operculum, the left medial superior frontal gyrus and the right posterior central gyrus (P<0.05) compared with that of the western medication group.@*CONCLUSIONS@#Acupuncture at the acupoints for Yizhi Tiaoshen improves the cognitive function of AD patients, and its main brain functional mechanism is related to intensifying the functional connectivity of the left hippocampus with the default network (inferior temporal gyrus, middle temporal gyrus and superior frontal gyrus, gyrus rectus), as well as with the sensory (posterior central gyrus) and visual (calcarine fissure and surrounding cortex and superior occipital gyrus) brain regions.

Effects of umbilical moxibustion on phobic behavior and monoamine neurotransmitters in stress-model rats / 中国针灸

OBJECTIVE@#To investigate the effects of umbilical moxibustion therapy on phobic behavior and the contents of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) in different brain regions of the stress-model rats and explore the potential mechanism of umbilical moxibustion on phobic behavior.@*METHODS@#Among 50 Wistar male rats, 45 rates were selected and randomly divided into a control group, a model group and an umbilical moxibustion group, 15 rats in each one; and the rest 5 rats were used for preparing the model of electric shock. The bystander electroshock method was adopted to prepare phobic stress model in the model group and the umbilical moxibustion group. After modeling, the intervention with umbilical moxibustion started in the umbilical moxibustion group, in which, the ginger-isolated moxibustion was applied at "Shenque" (CV 8), once daily, 2 cones for 20 min each time, for consecutively 21 days. After modeling and intervention completed, the rats in each group were subjected to the open field test to evaluate the state of fear. After intervention, the Morris water maze test and fear conditioning test were performed to evaluate the changes in learning and memory ability and the state of fear. Using high performance liquid chromatography (HPLC), the contents of NE, DA and 5-HT in the hippocampus, prefrontal cortex and hypothalamus were determined.@*RESULTS@#Compared with the control group, the horizontal and vertical activity scores were lower (P<0.01), the number of stool particles was increased (P<0.01), the escape latency was prolonged (P<0.01), the times of target quadrant were reduced (P<0.01), and the freezing time was prolonged (P<0.05) in the rats of the model group. The horizontal and vertical activity scores were increased (P<0.05), the number of stool particles was reduced (P<0.05), the escape latency was shortened (P<0.05, P<0.01), the times of target quadrant were increased (P<0.05), and the freezing time was shortened (P<0.05) in the rats of the umbilical moxibustion group when compared with the model group. The trend search strategy was adopted in the control group and the umbilical moxibustion group, while the random search strategy was used in rats of the model group. Compared with the control group, the contents of NE, DA and 5-HT in the hippocampus, prefrontal cortex and hypothalamus were reduced (P<0.01) in the model group. In the umbilical moxibustion group, the contents of NE, DA and 5-HT in the hippocampus, prefrontal cortex and hypothalamus were increased (P<0.05, P<0.01) when compared with the model group.@*CONCLUSION@#Umbilical moxibustion can effectively relieve the state of fear and learning and memory impairment of phobic stress model rats, which may be related to the up-regulation of contents of brain neurotransmitters, i.e. NE, DA, and 5-HT.

Study on effects of 40 Hz light flicker stimulation on spatial working memory in rats and its neural mechanism / 生物医学工程学杂志

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment, with the predominant clinical diagnosis of spatial working memory (SWM) deficiency, which seriously affects the physical and mental health of patients. However, the current pharmacological therapies have unsatisfactory cure rates and other problems, so non-pharmacological physical therapies have gradually received widespread attention. Recently, a novel treatment using 40 Hz light flicker stimulation (40 Hz-LFS) to rescue the cognitive function of model animals with AD has made initial progress, but the neurophysiological mechanism remains unclear. Therefore, this paper will explore the potential neural mechanisms underlying the modulation of SWM by 40 Hz-LFS based on cross-frequency coupling (CFC). Ten adult Wistar rats were first subjected to acute LFS at frequencies of 20, 40, and 60 Hz. The entrainment effect of LFS with different frequency on neural oscillations in the hippocampus (HPC) and medial prefrontal cortex (mPFC) was analyzed. The results showed that acute 40 Hz-LFS was able to develop strong entrainment and significantly modulate the oscillation power of the low-frequency gamma (lγ) rhythms. The rats were then randomly divided into experimental and control groups of 5 rats each for a long-term 40 Hz-LFS (7 d). Their SWM function was assessed by a T-maze task, and the CFC changes in the HPC-mPFC circuit were analyzed by phase-amplitude coupling (PAC). The results showed that the behavioral performance of the experimental group was improved and the PAC of θ-lγ rhythm was enhanced, and the difference was statistically significant. The results of this paper suggested that the long-term 40 Hz-LFS effectively improved SWM function in rats, which may be attributed to its enhanced communication of different rhythmic oscillations in the relevant neural circuits. It is expected that the study in this paper will build a foundation for further research on the mechanism of 40 Hz-LFS to improve cognitive function and promote its clinical application in the future.