Contribution of chemical and electrical transmission to the low delta-like intrinsic retinal oscillation in mice: A role for daylight-activated neuromodulators.

Basal electroretinogram (ERG) oscillations have shown predictive value for modifiable risk factors for type 2 diabetes. However, their origin remains unknown. Here, we seek to establish the pharmacological profile of the low delta-like (δ1) wave in the mouse because it shows light sensitivity in the form of a decreased peak frequency upon photopic exposure. Applying neuropharmacological drugs by intravitreal injection, we eliminated the δ1 wave using lidocaine or by blocking all chemical and electrical synapses. The δ1 wave was insensitive to the blockade of photoreceptor input, but was accelerated when all inhibitory or ionotropic inhibitory receptors in the retina were antagonized. The sole blockade of GABAA, GABAB, GABAC, and glycine receptors also accelerated the δ1 wave. In contrast, the gap junction blockade slowed the δ1 wave. Both GABAA receptors and gap junctions contribute to the light sensitivity of the δ1 wave. We further found that the day light-activated neuromodulators dopamine and nitric oxide donors mimicked the effect of photopic exposure on the δ1 wave. All drug effects were validated through light flash-evoked ERG responses. Our data indicate that the low δ-like intrinsic wave detected by the non-photic ERG arises from an inner retinal circuit regulated by inhibitory neurotransmission and nitric oxide/dopamine-sensitive gap junction-mediated communication.

Potential contributions of the intrinsic retinal oscillations recording using non-invasive electroretinogram to bioelectronics.

Targeted electric signal use for disease diagnostics and treatment is emerging as a healthcare game-changer. Besides arrhythmias, treatment-resistant epilepsy and chronic pain, blindness, and perhaps soon vision loss, could be among the pathologies that benefit from bioelectronic medicine. The electroretinogram (ERG) technique has long demonstrated its role in diagnosing eye diseases and early stages of neurodegenerative diseases. Conspicuously, ERG applications are all based on light-induced responses. However, spontaneous, intrinsic activity also originates in retinal cells. It is a hallmark of degenerated retinas and its alterations accompany obesity and diabetes. To the extent that variables extracted from the resting activity of the retina measured by ERG allow the predictive diagnosis of risk factors for type 2 diabetes. Here, we provided a comparison of the baseline characteristics of intrinsic oscillatory activity recorded by ERGs in mice, rats, and humans, as well as in several rat strains, and explore whether zebrafish exhibit comparable activity. Their pattern was altered in neurodegenerative models including the cuprizone-induced demyelination model in mice as well as in the Royal College of Surgeons (RCS-/-) rats. We also discuss how the study of their properties may pave the way for future research directions and treatment approaches for retinopathies, among others.

Spontaneous Activity of Neuronal Ensembles in Mouse Motor Cortex: Changes after GABAergic Blockade.

The mouse motor cortex exhibits spontaneous activity in the form of temporal sequences of neuronal ensembles in vitro without the need of tissue stimulation. These neuronal ensembles are defined as groups of neurons with a strong correlation between its firing patterns, generating what appears to be a predetermined neural conduction mode that needs study. Each ensemble is commonly accompanied by one or more parvalbumin expressing neurons (PV+) or fast spiking interneurons. Many of these interneurons have functional connections between them, helping to form a circuit configuration similar to a small-world network. However, rich club metrics show that most connected neurons are neurons not expressing parvalbumin, mainly pyramidal neurons (PV-) suggesting feed-forward propagation through pyramidal cells. Ensembles with PV+ neurons are connected to these hubs. When ligand-gated fast GABAergic transmission is blocked, temporal sequences of ensembles collapse into a unique synchronous and recurrent ensemble, showing the need of inhibition for coding cortical spontaneous activity. This new ensemble has a duration and electrophysiological characteristics of brief recurrent interictal epileptiform discharges (IEDs) composed by the coactivity of both PV- and PV+ neurons, demonstrating that GABA transmission impedes its occurrence. Synchronous ensembles are clearly divided into two clusters one of them lasting longer and mainly composed by PV+ neurons. Because an ictal-like event was not recorded after several minutes of IEDs recording, it is inferred that an external stimulus and/or fast GABA transmission are necessary for its appearance, making this preparation ideal to study both the neuronal machinery to encode cortical spontaneous activity and its transformation into brief non-ictal epileptiform discharges.

Bilateral enucleation at birth modifies calcium spike amplitude, but not frequency, in neurons of the somatosensory thalamus and cortex: Implications for developmental cross-modal plasticity.

Bilateral eye enucleation at birth (BE) leads to an expansion of the primary somatosensory cortex (S1) in rat pups. Although increased growth of the somatosensory thalamo-cortical afferents (STCAs) in part explains S1 expansion, timing mechanisms governing S1 formation are also involved. In this work, we begin the search of a developmental clock by intending to document the existence of putative clock neurons in the somatosensory thalamus (VPM) and S1 based upon changes of spontaneous spike amplitude; a biophysical property sensitive to circadian regulation; the latter known to be shifted by enucleation. In addition, we also evaluated whether STCAs growth rate and segregation timing were modified, as parameters the clock might time. We found that spontaneous spike amplitude transiently, but significantly, increased or decreased in VPM and S1 neurons of BE rat pups, respectively, as compared to their control counterparts. The growth rate and segregation timing of STCAs was, however, unaffected by BE. These results support the existence of a developmental clock that ticks differently in the VPM and S1 after BE. This observation, together with the fact that STCAs growth rate and segregation timing is unchanged, suggests that S1 expansion in BE rats may in part be controlled at the cortical level.

On the Origin of the 1,000 Hz Peak in the Spectrum of the Human Tympanic Electrical Noise.

The spectral analysis of the spontaneous activity recorded with an electrode positioned near the round window of the guinea pig cochlea shows a broad energy peak between 800 and 1,000 Hz. This spontaneous electric activity is called round window noise or ensemble background activity. In guinea pigs, the proposed origin of this peak is the random sum of the extracellular field potentials generated by action potentials of auditory nerve neurons. In this study, we used a non-invasive method to record the tympanic electric noise (TEN) in humans by means of a tympanic wick electrode. We recorded a total of 24 volunteers, under silent conditions or in response to stimuli of different modalities, including auditory, vestibular, and motor activity. Our results show a reliable peak of spontaneous activity at ~1,000 Hz in all studied subjects. In addition, we found stimulus-driven responses with broad-band noise that in most subjects produced an increase in the magnitude of the energy band around 1,000 Hz (between 650 and 1,200 Hz). Our results with the vestibular stimulation were not conclusive, as we found responses with all caloric stimuli, including 37°C. No responses were observed with motor tasks, like eye movements or blinking. We demonstrate the feasibility of recording neural activity from the electric noise of the tympanic membrane with a non-invasive method. From our results, we suggest that the 1,000 Hz component of the TEN has a mixed origin including peripheral and central auditory pathways. This research opens up the possibility of future clinical non-invasive techniques for the functional study of auditory and vestibular nerves in humans.

Metabolic profile and spontaneous physical activity modulation under short-term food restriction in young rats

Abstract AIMS The aim of this study was to investigate the effects of short-term food restriction (6-weeks) on metabolic profile and spontaneous physical activity (SPA) of young male Wistar rats. METHODS Thirty rats had their baseline SPA measured at 21 days-old and were separated into two groups at 28 days-old: Control (CG) and 50% of food restriction (FR). The food restriction protocol lasted six weeks, being the SPA measured weekly by a gravimetric apparatus. At the end of the experiment, biochemical analyses were performed in serum and tissue samples with statistical significance set at 5%. RESULTS FR showed less SPA than CG, as occurred for body mass, water intake, adipose tissue and liver, heart and soleus glycogen, serum glucose, total protein, triglycerides and total cholesterol (P<0.05). CONCLUSION Data set demonstrates that low substrate stores signaled to decrease spontaneous physical activity to save energy.(AU)

Wnts in adult brain: from synaptic plasticity to cognitive deficiencies.

During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, however, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and post-synaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer's disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype is not yet established but when the cognitive decline starts.

Wnt signaling: role in LTP, neural networks and memory.

Wnt components are key regulators of a variety of developmental processes, including embryonic patterning, cell specification, and cell polarity. The Wnt signaling pathway participates in the development of the central nervous system and growing evidence indicates that Wnts also regulates the function of the adult nervous system. In fact, most of the key components including Wnts and Frizzled receptors are expressed in the adult brain. Wnt ligands have been implicated in the regulation of synaptic assembly as well as in neurotransmission and synaptic plasticity. Deregulation of Wnt signaling has been associated with several pathologies, and more recently has been related to neurodegenerative diseases and to mental and mood disorders. In this review, we focus our attention on the Wnt signaling cascade in postnatal life and we review in detail the presence of Wnt signaling components in pre- and postsynaptic regions. Due to the important role of Wnt proteins in wiring neural circuits, we discuss recent findings about the role of Wnt pathways both in basal spontaneous activities as well as in activity-dependent processes that underlie synaptic plasticity. Finally, we review the role of Wnt in vivo and we finish with the most recent data in literature that involves the effect of components of the Wnt signaling pathway in neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling, as well as the data that support a neuroprotective role of Wnt proteins in relation to the pathogenesis of Alzheimer's disease.

Análise toxicológica da fase I do exsudato extraído do fruto de Mangifera indica L. / Análisis toxicológico de la fase I del exudado del fruto de Mangifera indica L. / Toxilogical analysis phase I of the exudates from Mangifera indica L. fruit

Introdução: as plantas representam ainda uma importante fonte de materia prima para a confecção de medicamentos. Mas, apesar do grande número de espécies vegetais no Brasil, apenas uma pequena parcela tem sido estudada adequadamente. A Mangifera indica, hoje integrante da flora brasileira, tem em suas diferentes partes, substâncias ativas importantes, embora não haja na literatura informações sobre os efeitos dos componentes existentes no exsudato do pedúnculo do fruto, principalmente das suas fases de separação espontânea. Objetivo: avaliação das respostas espontâneas em Rattus novergicus albinus, adultos, sob o efeito da fração hidrofílica do exsudato do pedúnculo do fruto de Mangifera indica. Métodos: a obtenção do exsudato do pedúnculo dos frutos de Mangifera indica de espécimes obtidos do Campus da Universidade Federal Rural de Pernambuco foi providenciada. Após um período de decantação de seis dias, espontaneamente, foram visualizadas quatro fases distintas. Da fase um, após os devidos processos de separação e pesagens, alíquotas de 0,5 mL foram administradas, intraperitonealmente, em cada animal, sendo a atividade espontânea observada por 100 min. Resultados: em relação ao grupo controle, foram observadas respostas comportamentais sugestivas, tais como tremores mandibulares, variações importantes nos ritmos de ventilação pulmonar, micção, cauda apoiada à superfície, catatonia, locomoção retrógrada, movimentos mandibulares, contração do focinho, inércia a estímulos para marcha, dificuldade de locomoção, hipnose, contração abdominal, piloereção na cauda e analgesia. Estas respostas apresentaram intervalos temporais de ocorrência característicos. Não ocorreram óbitos. Conclusões: as respostas observadas sugerem que importantes mecanismos fisiológicos sejam oportunamente acionados quando os animais estão sob os efeitos dos constituintes químicos da fase 1, hidrofílica, do exsudato de Mangifera indica; podendo, a partir de estudos posteriores, proporcionar a obtenção de drogas importantes para a medicina.

Introducción: las plantas representan aún una importante fuente de materia prima para la confección de medicamentos. Pero, a pesar del gran número de especies vegetales de Brasil, apenas una pequeña parte ha sido estudiada adecuadamente. Mangifera indica, integrante en la actualidad de la flora brasileña, tiene en sus diferentes partes sustancias activas importantes, sin embargo, no se encuentra en la literatura información sobre los efectos de los componentes existentes en el exudado del pedúnculo del fruto, principalmente en sus fases de separación espontánea. Objetivo: evaluar las respuestas espontáneas en Rattus novergicus albinus adultos, bajo el efecto de la fracción hidrofílica del exudado del pedúnculo del fruto de Mangifera indica. Métodos: se logró la obtención del exudado del pedúnculo de los frutos de Mangifera indica a partir de especímenes obtenidos del Campus de la Universidad Federal Rural de Pernambuco. Tras un período de decantación de 6 d, espontáneamente, se pudieron visualizar 4 fases diferentes. De la fase uno, tras los debidos procesos de separación de pesaje, se administraron alícuotas de 0,5 mL, intraperitonealmente, en cada animal y se observó la actividad espontánea durante 100 min. Resultados: comparado con el grupo de control, se observaron respuestas conductuales sugestivas, como temblores mandibulares, variaciones importantes en los ritmos de ventilación pulmonar, micción, cola apoyada en la superficie, catatonia, locomoción retrógrada, movimientos mandibulares, contracción del hocico, inercia a estímulos para marchar, dificultades en la locomoción, hipnosis, contracción abdominal, piloerección de la cola y analgesia. Estas respuestas presentaron intervalos temporales de ocurrencia característicos. No se produjeron muertes. Conclusiones: las respuestas observadas sugieren que importantes mecanismos fisiológicos son oportunamente accionados cuando los animales están bajo los efectos de los constituyentes químicos de la fase 1 del exudado hidrofílico de Mangifera indica. Sobre la base de estudios posteriores pudiera lograrse la obtención de drogas importantes para la medicina.

Introduction: the plants still represent an important source of raw material for making medicines. Despite the large number of plant species in Brazil, only a small portion has been adequately studied. Mangifera indica L, a member of the Brazilian flora, has important active substances in its various parts, although there is information in the literature on the effects of existing components in the exudate of the fruit peduncle, especially the spontaneous separation of phases. Objective: evaluation of spontaneous responses in Rattus novergicus albinus, adults under the influence of the hydrophilic fraction of the exudates from the stalk of the Mangifera indica fruit. Methods: the exudate obtained from the stalk of Mangifera indica fruits specimens obtained from the Campus UFRPE was provided. After a settling period of six days, four distinct phases were spontaneously seen. In phase one, after the separation and weighing processes, 0.5 mL aliquots were administered intraperitoneally in each animal, and the spontaneous activity was observed for 100 min. Results: compared with the control group, suggestive behavioral responses were observed such as mandibular tremors, important variations in pulmonary ventilation rates, urination, tail supported at the surface, catatonia, retrograde movement, jaw movements, contraction of the muzzle, inertia to gait stimulation, difficult walking, hypnosis, abdominal contraction, piloerection on the tail, and analgesia. These responses presented characteristic time intervals for occurrence. There were no deaths. Conclusions: the responses suggested that important physiological mechanisms are appropriately triggered when the animals are under the effects of the chemical constituents included in the first phase. Based on further studies, Mangifera indica L. hydrophilic exudate could allow obtaining important medical drugs.