Chronic infusion of Montanoa tomentosa reduces despair-like behavior and activates hypothalamic oxytocin neurons in male Wistar rats / La infusión crónica de Montanoa tomentosa reduce la conducta de desesperanza y activa las neuronas hipotalámicas de oxitocina en ratas Wistar macho

Montanoa tomentosa is used in traditional Mexican medicine to treat reproductive and mood disorders. Preclinical studies support the idea that acute administration of M. tomentosa induces an antidepressant-like response that may be related to oxytocin activation in hypothalamic cells, however, it is unknown whether this behavioral and neuroendocrine effect is maintained when chronically administered. Here, 39 adults male Wistar rats were subjected to two conditions: without and with the forced swimming test (FST). Each group received for 28 consecutive days p.o., vehicle (1 mL/kg); fluoxetine (1 mg/kg); or M. tomentosa (50 mg/kg). M. tomentosa and fluoxetine treatments significantly decreased the total immobility time compared with that using vehicle without producing any significant change in locomotor activity. No significant between-treatment differences were found in the number of oxytocinergic neurons, indicating that chronic infusion of M. tomentosa exerts antidepressant-like effects, similar to those of Fluoxetine, independently of oxytocinergic activation.

Montanoa tomentosa es utilizada en la medicina tradicional mexicana para tratar trastornos reproductivos y de estado de ánimo. Estudios preclínicos, reportan que la administración aguda de M. tomentosa produce efectos tipo antidepresivo asociados con la activación de células hipotalámicas oxitocinérgicas, pero se desconoce si estos efectos conductual y neuroendocrino se mantienen después de un tratamiento crónico. Se incluyeron 39 ratas macho adultas Wistar bajo dos condiciones: sin y con inducción de estrés por nado forzado. Cada grupo recibió durante 28 días consecutivos p.o., vehículo (1mL/kg); fluoxetina (1 mg/kg); o M. tomentosa(Mt; 50 mg/kg). Los tratamientos con M. tomentosa y fluoxetina disminuyeron significativamente el tiempo total de inmovilidad comparado con vehículo, sin cambio significativo en la locomoción. No hubo diferencias significativas en el número de neuronas oxitocinérgicas entre tratamientos, lo que indica que la infusión crónica de M. tomentosa ejerce efectos tipo antidepresivos similares a Fluoxetina, independientemente de la activación oxitocinérgica.

Investigating Morphological Changes of the Hippocampus After Prolonged Aerobic Exercise in Mice: Neural Function and Learning Capabilities / Investigación de los Cambios Morfológicos del Hipocampo Después De un Ejercicio Aeróbico Prolongado en Ratones: Función Neuronal y Capacidades de Aprendizaje

SUMMARY: Both the academic and popular worlds have paid close attention to the link between exercise and cognitive performance. It is increasingly important to understand the numerous mechanisms by which exercise might influence cognitive abilities in view of the continuous societal issues caused by aging populations and the prevalence of disorders associated to cognitive decline. A rising amount of evidence showing a favorable association between physical activity and cognitive well-being serves as the foundation for the justification for studying the effects of exercise on cognitive function and learning ability. The study employed an 8-week treadmill based on exercise on male adults C57BL/6 mice. The exercise group were engaged in 5 sessions a week gradually increasing the intensity of the protocol by 5 % each week. The Mice cognitive assessments were done using Morris Water Maze and Novel Object Recognition tests. The long term-impact on learning ability were further assessed through immmohistochemistry and molecular analysis of the hippocampal and prefrontal cortex tissues of the animals' brain tissues. The findings showed improved spatial learning abilities, recognition memory, and heighted synaptic plasticity indicated by elevated synaptic makers. The study underscores the role of long-term aerobic exercise in augmenting cognitive performance. It not only contributes to the understanding of the interplay between neuroplasticity and cognitive benefits but also the growing body of research on the impact of exercise on cognitive function.

Tanto el mundo académico como el popular han prestado mucha atención al vínculo entre el ejercicio y el rendimiento cognitivo. Es cada vez más importante comprender los numerosos mecanismos por los cuales el ejercicio podría influir en las capacidades cognitivas en vista de los continuos problemas sociales causados por el envejecimiento de la población y la prevalencia de trastornos asociados al deterioro cognitivo. Una cantidad cada vez mayor de evidencia que muestra una asociación favorable entre la actividad física y el bienestar cognitivo sirve como base para justificar el estudio de los efectos del ejercicio sobre la función cognitiva y la capacidad de aprendizaje. El estudio se realizó en ratones machos adultos C57BL/6 utilizándose en los ejercicios una cinta rodante durante 8 semanas. El grupo de ejercicio realizó 5 sesiones por semana aumentando gradualmente la intensidad del protocolo en un 5 % cada semana. Las evaluaciones cognitivas de los ratones se realizaron utilizando las pruebas Morris Water Maze y Novel Object Recognition. El impacto a largo plazo en la capacidad de aprendizaje se evaluó mediante inmunohistoquímica y análisis molecular de los tejidos del hipocampo y la corteza prefrontal de los tejidos cerebrales de los animales. Los hallazgos mostraron mejoras en las habilidades de aprendizaje espacial, la memoria de reconocimiento y una mayor plasticidad sináptica indicada por unos creadores sinápticos elevados. El estudio subraya el papel del ejercicio aeróbico a largo plazo para aumentar el rendimiento cognitivo. No sólo contribuye a la comprensión de la interacción entre la neuroplasticidad y los beneficios cognitivos, sino también al creciente conjunto de investigaciones sobre el impacto del ejercicio en la función cognitiva.

Acteoside Attenuates Recognition Memory Impairment in CUMS Rats via Regulating Synaptic Plasticity and mTOR Signaling Pathway / El Acteoside Atenúa el Deterioro de la Memoria de Reconocimiento en Ratas ELCI Mediante la Regulación de la Plasticidad Sináptica y la Vía de Señalización mTOR

SUMMARY: We evaluated the role and mechanism of acteoside in the regulation of memory impairment induced by chronic unpredictable mild stress (CUMS). CUMS was used to induce depression in rats and the successful establishment of CUMS model were verified by forced swimming test and sucrose preference test. The Y-maze test and novel object recognition test assessed memory functions. The structural changes in the cortex and hippocampus were observed by hematoxylin and eosin (HE) staining. Immunofluorescence staining and western blotting determined the protein levels. Y-maze test and novel object recognition test showed that there was memory performance impairment in rats of CUMS group, which was improved by the acteoside treatment. HE staining showed that CUMS exposure damaged the structure in the cortex and hippocampus, while the acteoside treatment alleviated the structural changes. Compared with the control group, the levels of BNDF and CREB in the cortex and hippocampus of the CUMS group were significantly decreased. Acteoside significantly reversed the expressions of these proteins in CUMS rats. Meanwhile, compared with the control group, the levels of p-mTOR and p- P70S6K in the cortex and hippocampus of the CUMS group were significantly increased, and these changes were significantly reversed by acteoside. Nevertheless, the effect of acteoside on mTOR signaling was markedly blocked by rapamycin, a specific inhibitor of mTOR signaling. Acteoside can attenuate memory impairment and ameliorate neuronal damage and synaptic plasticity in depression rats probably via inhibiting the mTOR signaling pathway. Acteoside may serve as a novel reagent for the prevention of depression.

Evaluamos el papel y el mecanismo del acteoside en la regulación del deterioro de la memoria inducido por estrés leve crónico impredecible (ELCI). Se utilizó ELCI para inducir depresión en ratas y el establecimiento exitoso del modelo ELCI se verificó mediante una prueba de natación forzada y una prueba de preferencia de sacarosa. La prueba del laberinto en Y y la prueba de reconocimiento de objetos novedosos evaluaron las funciones de la memoria. Los cambios estructurales en la corteza y el hipocampo se observaron mediante tinción con hematoxilina y eosina (HE). La tinción por inmunofluorescencia y la transferencia Western determinaron los niveles de proteína. La prueba del laberinto en Y y la prueba de reconocimiento de objetos novedosos mostraron que había un deterioro del rendimiento de la memoria en ratas del grupo ELCI, que mejoró con el tratamiento con acteósidos. La tinción con HE mostró que la exposición a ELCI dañó la estructura de la corteza y el hipocampo, mientras que el tratamiento con actósidos alivió los cambios estructurales. En comparación con el grupo de control, los niveles de BNDF y CREB en la corteza y el hipocampo del grupo ELCI disminuyeron significativamente. Acteoside revirtió significativamente las expresiones de estas proteínas en ratas ELCI. Mientras tanto, en comparación con el grupo control, los niveles de p-mTOR y p-P70S6K en la corteza y el hipocampo del grupo ELCI aumentaron significativamente, y estos cambios fueron revertidos significativamente ELCI por el acteoside. Sin embargo, el efecto del acteoside sobre la señalización de mTOR fue notablemente bloqueado por la rapamicina, un inhibidor específico de la señalización de mTOR. El acteoside puede atenuar el deterioro de la memoria y mejorar el daño neuronal y la plasticidad sináptica en ratas con depresión, probablemente mediante la inhibición de la vía de señalización mTOR. Acteoside puede servir como un reactivo novedoso para la prevención de la depresión.

Oxytocin neuron activation by acute infusion of Montanoa genus plants in the Wistar rats / Activación de neuronas de oxitocina por la infusión aguda de plantas del género de Montanoa en la rata Wistar

In tradition al Mexican medicine, plants from the Montanoa genus, family Asteraceae ( Montanoa tomentosa , Montanoa grandiflora , and Montanoa frutescens ) have been used to induce labor owing to their uterotonic properties like those produced by oxytocin (OXT). However, w hether infusions of these plants can activate hypothalamic OXT - producing neurons is unknown. To test this possibility, five independent groups of Wistar rats (n=4) were included: intact, vehicle, and three groups that received 50 mg/kg p.o. of M. tomentosa , M. grandiflora , and M. frutescens infusions, respectively. Ninety min after treatment, the brains were obtained and processed using double - labeled immunohistochemistry for Fos protein and oxytocin (Fos/OXT - ir). Rats that received Montanoa infusions had s ignificantly greater number of Fos/OXT - ir cells in the paraventricular (PVN) and supraoptic (SON) nuclei, with respect to intact and vehicle groups. These findings demonstrate that Montanoa infusions activated OXT neurons, an effect that may be related to the reported pharmacological properties.

En la medicina tradicional mexicana, plantas del género Montanoa , familia Asteraceae ( Montanoa tomentosa , Montanoa grandiflora y Montanoa frutescens ), se han utilizado para inducir el parto debido a sus propiedades uterotónicas, aparentemente similares a las producidas por la hormona oxitocina (OXT). Sin embargo, se desconoce si las infusiones de estas plantas pueden activar neuronas hipotalámicas productoras de OXT. Para probar esta posibilidad, se incluyeron cinco grupos independientes (n=4): intacto, vehículo y tres grupos que recibieron 50 mg/kg p.o. de infusiones de M. tomentosa , M. grandiflora , y M. frute scens , respectivamente. Noventa minutos después del tratamiento, los cerebros fueron obtenidos y procesados por doble marcaje de inmunohistoquímica para la proteína Fos y oxitocina (Fos/OXT - ir). Las ratas que recibieron infusiones de Montanoa aumentaron si gnificativamente el número de células Fos/OXT - ir en los núcleos paraventricular (PVN) y supraóptico (SON), respecto a los grupos intacto y vehículo. Estos hallazgos demuestran que las infusiones de Montanoa activan neuronas de OXT, lo que podría estar rela cionado con sus propiedades farmacológicas

Role of 5-hydroxytryptamine type 3 receptors in the regulation of anxiety reactions / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

5-Hydroxytryptamine (5-HT) type 3 receptor (5-HT3R) is the only type of ligand-gated ion channel in the 5-HT receptor family. Through the high permeability of Na+, K+, and Ca2+ and activation of subsequent voltage-gated calcium channels (VGCCs), 5-HT3R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system (CNS). 5-HT3Rs are widely expressed in the medial prefrontal cortex (mPFC), amygdala (AMYG), hippocampus (HIP), periaqueductal gray (PAG), and other brain regions closely associated with anxiety reactions. They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions. 5-HT3Rs mediate the activation of the cholecystokinin (CCK) system in the AMYG, and the γ‍-aminobutyric acid (GABA) "disinhibition" mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons (IINs). In contrast, a 5-HT3R-induced GABA "disinhibition" mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects. 5-HT2R-mediated regulation of anxiety reactions are also activated by 5-HT3R-activated 5-HT release in the HIP and PAG. This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT3Rs. However, given the circuit specific modulation of 5-HT3Rs on emotion, systemic use of 5-HT3R agonism or antagonism alone seems unlikely to remedy anxiety, which deeply hinders the current clinical application of 5-HT3R drugs. Therefore, the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.

Neuronomodulation of Excitable Neurons / 神经科学通报·英文版

Neuronomodulation refers to the modulation of neural conduction and synaptic transmission (i.e., the conduction process involved in synaptic transmission) of excitable neurons via changes in the membrane potential in response to chemical substances, from spillover neurotransmitters to paracrine or endocrine hormones circulating in the blood. Neuronomodulation can be direct or indirect, depending on the transduction pathways from the ligand binding site to the ion pore, either on the same molecule, i.e. the ion channel, or through an intermediate step on different molecules. The major players in direct neuronomodulation are ligand-gated or voltage-gated ion channels. The key process of direct neuronomodulation is the binding and chemoactivation of ligand-gated or voltage-gated ion channels, either orthosterically or allosterically, by various ligands. Indirect neuronomodulation involves metabotropic receptor-mediated slow potentials, where steroid hormones, cytokines, and chemokines can implement these actions. Elucidating neuronomodulation is of great significance for understanding the physiological mechanisms of brain function, and the occurrence and treatment of diseases.

Temporal-spatial Generation of Astrocytes in the Developing Diencephalon / 神经科学通报·英文版

Astrocytes are the largest glial population in the mammalian brain. However, we have a minimal understanding of astrocyte development, especially fate specification in different regions of the brain. Through lineage tracing of the progenitors of the third ventricle (3V) wall via in-utero electroporation in the embryonic mouse brain, we show the fate specification and migration pattern of astrocytes derived from radial glia along the 3V wall. Unexpectedly, radial glia located in different regions along the 3V wall of the diencephalon produce distinct cell types: radial glia in the upper region produce astrocytes and those in the lower region produce neurons in the diencephalon. With genetic fate mapping analysis, we reveal that the first population of astrocytes appears along the zona incerta in the diencephalon. Astrogenesis occurs at an early time point in the dorsal region relative to that in the ventral region of the developing diencephalon. With transcriptomic analysis of the region-specific 3V wall and lateral ventricle (LV) wall, we identified cohorts of differentially-expressed genes in the dorsal 3V wall compared to the ventral 3V wall and LV wall that may regulate astrogenesis in the dorsal diencephalon. Together, these results demonstrate that the generation of astrocytes shows a spatiotemporal pattern in the developing mouse diencephalon.

El secuestro de la voluntad: bases moleculares de los cambios plásticos en la adicción / The hijacking of the will: molecular bases of plastic changes in addiction

Todas las drogas de abuso tienen en común la activación del sistema cerebral del placer. Los análisis imagenológicos han arrojado resultados de cambios estructurales en el cerebro de adictos a la cocaína e imágenes cerebrales en sujetos adictos muestran una disminución de la producción de dopamina que lleva a que la acción esté notoriamente amortiguada en relación con controles. Los estudios estructurales han mostrado reducciones de volumen de la sustancia gris y alteraciones circuitales de la sustancia blanca en el lóbulo frontal de adictos. La transición del uso recreativo a la adicción se asocia con cambios en la función de las neuronas que se acumulan con la administración repetida. La exposición crónica a la cocaína provoca aumentos de la arborización y de la densidad de las espinas dendríticas. El aumento de capacidad sináptica, ante el estímulo subcortical de una nueva presencia de la droga, toma el control de las funciones ejecutivas, «secuestrando¼ la capacidad de la voluntad consciente.

The activation of of the brain pleasure system is common to all abuse drugs. Imaging analyses have shown structural changes in the brain of cocaine addicts and a reduction of dopamine production which causes attenuation of its action when compared to control subjects. Structural studies in these patients show gray matter reduction and circuitry changes in frontal lobe white matter. Transition from recreational use to addiction is associated with changes in neuronal function which accumulate with repeated administration. Chronic exposure to cocaine leads to an increase in arborization and density of dendritic spines. When faced with new subcortical presence of the drug, the increase of synaptic capacity takes control of executive functions, "sequestering" the capacity for conscious will.

Quantificação celular de encéfalos humanos em desenvolvimento / Cellular quantification of developing human brains

O desenvolvimento do encéfalo humano requer uma ação orquestrada de eventos, com variados tipos celulares que permanecem em uma coordenação precisa por um longo período, desde a vida intrauterina até vários anos após o nascimento. A desregulação desses processos, causados por agentes teratogênicos, ambientais ou processos intrínsecos maternos, pode afetar a estrutura e a função do sistema nervoso em desenvolvimento, ocasionando diferentes patologias, como distúrbios neurológicos ou em casos mais severos, até a morte. O Treponema pallidum é um desses agentes conhecidos por afetar o desenvolvimento na gestação. Técnicas quantitativas de caracterização do sistema nervoso (SN) nos permitem estudar de maneira eficiente a celularidade encefálica. Neste trabalho, o Fracionamento Isotrópico nos possibilitou registrar em números absolutos a celularidade de encéfalos humanos durante o desenvolvimento em períodos fetais até os primeiros meses de vida pós-natal. Em nosso estudo, foi possível analisar 10 encéfalos humanos em diferentes períodos do desenvolvimento. Conseguimos observar, em números absolutos, que o número total de células encefálicas varia de ~22 bilhões no início do terceiro trimestre da gestação até ~119 bilhões no quarto mês de vida pós-natal, as células neuronais variam de ~8 bilhões a ~27 bilhões e células não-neuronais variam de ~14 bilhões até 21 bilhões neste mesmo período. Observamos que o comportamento em números absolutos de células varia tanto por região quanto temporalmente. No telencéfalo, o maior crescimento do número de neurônios acontece no período fetal, enquanto no cerebelo acontece principalmente na vida pós-natal. Já a gliogênese acontece preferencialmente após o nascimento em ambas as regiões. Neste estudo foi possível comparar a composição celular do encéfalo de neonatos a termo com a do adulto, mostrando que no período a termo temos ~18% do número total de células. E complementarmente, verificamos que há uma diminuição do número de células do encéfalo de um caso de recém-nascido a termo com sífilis congênita em relação ao seu controle da mesma idade, com redução de 34% do número total de células do encéfalo e 32% do número de neurônios, caracterizando o efeito deletério dessa doença durante a gestação.(AU)

The development of the human brain requires an sequence of events, that envolve a several cell types, wich remain in precise coordination from intrauterine life to several years after birth. The disruption of these processes, caused by teratogenic, environmental agents or intrinsic maternal processes, can affect the structure and function of the developing nervous system, causing different pathologies, such as neurological disorders or, in severe cases, death. Treponema is known as one teratogenic factor that compromise the development during pregnancy. Quantitative techniques focus on the nervous system have enable us to efficiently study brain cellularity. In this work, Isotropic Fractionation has been used to register in absolute numbers the cellularity of human brains during development in fetal periods up to the first months of postnatal life. In our study, it was possible to analyze 10 cases in the development period. We observe, in absolute numbers, that the total number of brain cells varies from ~22 billion at the beginning of the third trimester of pregnancy to ~119 billion in the fourth month of postnatal life, neuronal cells vary from ~8 billion to ~27 billion and nonneuronal cells range from ~14 billion to 21 billion in this same period. We observed that the absolute cell numbers varies both by region and temporally. In the telencephalon, the number of neurons grows in the fetal period, while in the cerebellum it occurs in postnatal life. Gliogenesis occurs after birth in both regions. In this study, it was possible to compare the absolute values of brain cells in fullterm newborn with the values previously found in adults, demonstrating that we have only ~18% of the total number of cells. We verified that there is a deficit in all values of brain cells in a case of full-term newborn with congenital syphilis in relation to their control, with a reduction of 34% in the total number of brain cells and 32% in the number of neurons, characterizing the deleterious effect of this disease during pregnancy.(AU)

Adult human neural cells in culture following traumatic brain injury

Objective: The present study aims to evaluate the viability of adult human neural cells in culture obtained from traumatized brain tissues collected in emergency surgery procedures. Methods: Exploratory, descriptive, quantitative and cross-sectional study evaluating samples obtained from patients who underwent traumatic brain injury with extrusion of brain tissue submitted to cell culture in a standardized medium, being preserved during 168h. After observation under phase contrast microscopy and immunohistochemical processing for neuronal (MAP-2) and glial (GFAP) markers, morphometric parameters of neural cells (cell body area, dendritic field length and fractal dimension) were evaluated using ImageJ software, with data obtained after 24, 72 and 168h being compared using non-parametric Kruskal Wallis test, followed by Dunn's post hoc test. Results: The explant of the nervous tissue revealed a consolidated pattern of cell migration into the culture medium. Cell proliferation, upon reaching confluence, presented an aspect of cellular distribution juxtaposed along the culture medium at all time points analyzed. Both neurons and glial cells remained viable after 168h in culture, with their morphologies not varying significantly throughout the time points evaluated. Immunohistochemistry for MAP-2 showed a relatively well-preserved cytoskeletal organization. GFAP immunoreactivity revealed activated astrocytes especially at the later time point. Conclusions: Our results point out the viability of cell culture from traumatized human nervous tissue, opening up perspectives for the use of substances of natural origin that may contribute neuroprotectively to neuronal maintenance in culture, allowing future translational approach.

Capítulo 15: cerebelo / Chapter 15: Cerebellum

El cerebelo ocupa la fosa posterior (foto 15-1), por debajo del tentorio, y por delante del tronco cerebral al cual está unido sólo por tres estructuras , llamadas pedúnculos cerebelosos. El cerebelo, sólo representa un 10% del peso del encéfalo, pero contiene la mitad de las neuronas del mismo.

Directed differentiation of human induced pluripotent stem cells into midbrain / 南方医科大学学报

OBJECTIVE@#To establish an efficient protocol for directed differentiation of human induced pluripotent stem cells (hiPSCs) into functional midbrain dopaminergic progenitor cells (DAPs) in vitro.@*METHODS@#hiPSCs were induced to differentiate into DAPs in two developmental stages. In the first stage (the first 13 days), hiPSCs were induced into intermediate cells morphologically similar to primitive neuroepithelial cells (NECs) in neural induction medium containing a combination of small molecule compounds. In the second stage, the intermediate cells were further induced in neural differentiation medium until day 28 to obtain DAPs. After CM-DiI staining, the induced DAPs were stereotactically transplanted into the right medial forebrain bundle (MFB) of rat models of Parkinson's disease (PD). Eight weeks after transplantation, the motor behaviors of PD rats was evaluated. Immunofluorescence assay of brain sections of the rats was performed at 2 weeks after transplantation to observe the survival, migration and differentiation of the transplanted cells in the host brain microenvironment.@*RESULTS@#hiPSCs passaged stably on Matrigel showed a normal diploid karyotype, expressed the pluripotency markers OCT4, SOX2, and Nanog, and were positive for alkaline phosphatase. The primitive neuroepithelial cells obtained on day 13 formed dense cell colonies in the form of neural rosettes and expressed the neuroepithelial markers (SOX2, Nestin, and PAX6, 91.3%-92.8%). The DAPs on day 28 highly expressed the specific markers (TH, FOXA2, LMX1A and NURR1, 93.3-96.7%). In rat models of PD, the hiPSCs-DAPs survived and differentiated into TH+, FOXA2+ and Tuj1+ neurons at 2 weeks after transplantation. Eight weeks after transplantation, the motor function of PD rats was significantly improved as shown by water maze test (P < 0.0001) and apomorphine-induced rotation test (P < 0.0001) compared with rats receiving vehicle injection.@*CONCLUSION@#HiPSCs can be effectively induced to differentiate into DAPs capable of differentiating into functional neurons both in vivo and in vitro. In rat models of PD, the transplanted hiPSCs-DAPs can survive for more than 8 weeks in the MFB and differentiate into multiple functional neurocytes to ameliorate neurological deficits of the rats, suggesting the potential value of hiPSCs-DAPs transplantation for treatment of neurological diseases.

Bi-directional Control of Synaptic Input Summation and Spike Generation by GABAergic Inputs at the Axon Initial Segment / 神经科学通报·英文版

Differing from other subtypes of inhibitory interneuron, chandelier or axo-axonic cells form depolarizing GABAergic synapses exclusively onto the axon initial segment (AIS) of targeted pyramidal cells (PCs). However, the debate whether these AIS-GABAergic inputs produce excitation or inhibition in neuronal processing is not resolved. Using realistic NEURON modeling and electrophysiological recording of cortical layer-5 PCs, we quantitatively demonstrate that the onset-timing of AIS-GABAergic input, relative to dendritic excitatory glutamatergic inputs, determines its bi-directional regulation of the efficacy of synaptic integration and spike generation in a PC. More specifically, AIS-GABAergic inputs promote the boosting effect of voltage-activated Na+ channels on summed synaptic excitation when they precede glutamatergic inputs by >15 ms, while for nearly concurrent excitatory inputs, they primarily produce a shunting inhibition at the AIS. Thus, our findings offer an integrative mechanism by which AIS-targeting interneurons exert sophisticated regulation of the input-output function in targeted PCs.

miR-34b-3p Inhibition of eIF4E Causes Post-stroke Depression in Adult Mice / 神经科学通报·英文版

Post-stroke depression (PSD) is a serious and common complication of stroke, which seriously affects the rehabilitation of stroke patients. To date, the pathogenesis of PSD is unclear and effective treatments remain unavailable. Here, we established a mouse model of PSD through photothrombosis-induced focal ischemia. By using a combination of brain imaging, transcriptome sequencing, and bioinformatics analysis, we found that the hippocampus of PSD mice had a significantly lower metabolic level than other brain regions. RNA sequencing revealed a significant reduction of miR34b-3p, which was expressed in hippocampal neurons and inhibited the translation of eukaryotic translation initiation factor 4E (eIF4E). Furthermore, silencing eIF4E inactivated microglia, inhibited neuroinflammation, and abolished the depression-like behaviors in PSD mice. Together, our data demonstrated that insufficient miR34b-3p after stroke cannot inhibit eIF4E translation, which causes PSD by the activation of microglia in the hippocampus. Therefore, miR34b-3p and eIF4E may serve as potential therapeutic targets for the treatment of PSD.

Neural Mechanism Underlying Task-Specific Enhancement of Motor Learning by Concurrent Transcranial Direct Current Stimulation / 神经科学通报·英文版

The optimal protocol for neuromodulation by transcranial direct current stimulation (tDCS) remains unclear. Using the rotarod paradigm, we found that mouse motor learning was enhanced by anodal tDCS (3.2 mA/cm2) during but not before or after the performance of a task. Dual-task experiments showed that motor learning enhancement was specific to the task accompanied by anodal tDCS. Studies using a mouse model of stroke induced by middle cerebral artery occlusion showed that concurrent anodal tDCS restored motor learning capability in a task-specific manner. Transcranial in vivo Ca2+ imaging further showed that anodal tDCS elevated and cathodal tDCS suppressed neuronal activity in the primary motor cortex (M1). Anodal tDCS specifically promoted the activity of task-related M1 neurons during task performance, suggesting that elevated Hebbian synaptic potentiation in task-activated circuits accounts for the motor learning enhancement. Thus, application of tDCS concurrent with the targeted behavioral dysfunction could be an effective approach to treating brain disorders.

Chemogenetic and Optogenetic Manipulations of Microglia in Chronic Pain / 神经科学通报·英文版

Chronic pain relief remains an unmet medical need. Current research points to a substantial contribution of glia-neuron interaction in its pathogenesis. Particularly, microglia play a crucial role in the development of chronic pain. To better understand the microglial contribution to chronic pain, specific regional and temporal manipulations of microglia are necessary. Recently, two new approaches have emerged that meet these demands. Chemogenetic tools allow the expression of designer receptors exclusively activated by designer drugs (DREADDs) specifically in microglia. Similarly, optogenetic tools allow for microglial manipulation via the activation of artificially expressed, light-sensitive proteins. Chemo- and optogenetic manipulations of microglia in vivo are powerful in interrogating microglial function in chronic pain. This review summarizes these emerging tools in studying the role of microglia in chronic pain and highlights their potential applications in microglia-related neurological disorders.

Neuronal Response to Reward and Luminance in Macaque LIP During Saccadic Choice / 神经科学通报·英文版

Recent work in decision neuroscience suggests that visual saliency can interact with reward-based choice, and the lateral intraparietal cortex (LIP) is implicated in this process. In this study, we recorded from LIP neurons while monkeys performed a two alternative choice task in which the reward and luminance associated with each offer were varied independently. We discovered that the animal's choice was dictated by the reward amount while the luminance had a marginal effect. In the LIP, neuronal activity corresponded well with the animal's choice pattern, in that a majority of reward-modulated neurons encoded the reward amount in the neuron's preferred hemifield with a positive slope. In contrast, compared to their responses to low luminance, an approximately equal proportion of luminance-sensitive neurons responded to high luminance with increased or decreased activity, leading to a much weaker population-level response. Meanwhile, in the non-preferred hemifield, the strength of encoding for reward amount and luminance was positively correlated, suggesting the integration of these two factors in the LIP. Moreover, neurons encoding reward and luminance were homogeneously distributed along the anterior-posterior axis of the LIP. Overall, our study provides further evidence supporting the neural instantiation of a priority map in the LIP in reward-based decisions.

Somatostatin-Positive Neurons in the Rostral Zona Incerta Modulate Innate Fear-Induced Defensive Response in Mice / 神经科学通报·英文版

Defensive behaviors induced by innate fear or Pavlovian fear conditioning are crucial for animals to avoid threats and ensure survival. The zona incerta (ZI) has been demonstrated to play important roles in fear learning and fear memory, as well as modulating auditory-induced innate defensive behavior. However, whether the neuronal subtypes in the ZI and specific circuits can mediate the innate fear response is largely unknown. Here, we found that somatostatin (SST)-positive neurons in the rostral ZI of mice were activated by a visual innate fear stimulus. Optogenetic inhibition of SST-positive neurons in the rostral ZI resulted in reduced flight responses to an overhead looming stimulus. Optogenetic activation of SST-positive neurons in the rostral ZI induced fear-like defensive behavior including increased immobility and bradycardia. In addition, we demonstrated that manipulation of the GABAergic projections from SST-positive neurons in the rostral ZI to the downstream nucleus reuniens (Re) mediated fear-like defensive behavior. Retrograde trans-synaptic tracing also revealed looming stimulus-activated neurons in the superior colliculus (SC) that projected to the Re-projecting SST-positive neurons in the rostral ZI (SC-ZIrSST-Re pathway). Together, our study elucidates the function of SST-positive neurons in the rostral ZI and the SC-ZIrSST-Re tri-synaptic circuit in mediating the innate fear response.

Neural Correlates of Spatial Navigation in Primate Hippocampus / 神经科学通报·英文版

The hippocampus has been extensively implicated in spatial navigation in rodents and more recently in bats. Numerous studies have revealed that various kinds of spatial information are encoded across hippocampal regions. In contrast, investigations of spatial behavioral correlates in the primate hippocampus are scarce and have been mostly limited to head-restrained subjects during virtual navigation. However, recent advances made in freely-moving primates suggest marked differences in spatial representations from rodents, albeit some similarities. Here, we review empirical studies examining the neural correlates of spatial navigation in the primate (including human) hippocampus at the levels of local field potentials and single units. The lower frequency theta oscillations are often intermittent. Single neuron responses are highly mixed and task-dependent. We also discuss neuronal selectivity in the eye and head coordinates. Finally, we propose that future studies should focus on investigating both intrinsic and extrinsic population activity and examining spatial coding properties in large-scale hippocampal-neocortical networks across tasks.

Astrocytes in Chronic Pain: Cellular and Molecular Mechanisms / 神经科学通报·英文版

Chronic pain is challenging to treat due to the limited therapeutic options and adverse side-effects of therapies. Astrocytes are the most abundant glial cells in the central nervous system and play important roles in different pathological conditions, including chronic pain. Astrocytes regulate nociceptive synaptic transmission and network function via neuron-glia and glia-glia interactions to exaggerate pain signals under chronic pain conditions. It is also becoming clear that astrocytes play active roles in brain regions important for the emotional and memory-related aspects of chronic pain. Therefore, this review presents our current understanding of the roles of astrocytes in chronic pain, how they regulate nociceptive responses, and their cellular and molecular mechanisms of action.