Impact d’une sieste sur plasticité cérébrale induite par stimulation magnétique transcrânienne

Chez l’humain, différents protocoles de stimulation magnétique transcrânienne répétée (SMTr) peuvent être utilisés afin de manipuler expérimentalement la plasticité cérébrale au niveau du cortex moteur primaire (M1). Ces techniques ont permis de mieux comprendre le rôle du sommeil dans la régulation de la plasticité cérébrale. Récemment, une étude a montré que lorsqu’une première session de stimulation SMTr au niveau de M1 est suivie d’une nuit de sommeil, l’induction subséquente de la plasticité par une deuxième session SMTr est augmentée. La présente étude a investigué si ce type de métaplasticité pouvait également bénéficier d’une sieste diurne. Quatorze sujets en santé ont reçu deux sessions de intermittent theta burst stimulation (iTBS) connue pour son effet facilitateur sur l’excitabilité corticale. Les sessions de stimulation étaient séparées par une sieste de 90 minutes ou par une période équivalente d’éveil. L’excitabilité corticale était quantifiée en terme d’amplitude des potentiels évoqués moteurs (PEM) mesurés avant et après chaque session de iTBS. Les résultats montrent que la iTBS n’est pas parvenue à augmenter de manière robuste l’amplitude des PEMs lors de la première session de stimulation. Lors de la deuxième session de stimulation, la iTBS a produit des changements plastiques variables et ce peu importe si les sujets ont dormi ou pas. Les effets de la iTBS sur l’excitabilité corticale étaient marqués par une importante variabilité inter et intra-individuelle dont les possibles causes sont discutées.

Ethanol consumption and pineal melatonin daily profile in rats

It is well known that melatonin participates in the regulation of many important physiological functions such as sleep-wakefulness cycle, motor coordination and neural plasticity, and cognition. However, as there are contradictory results regarding the melatonin production diurnal profile under alcohol consumption, the aim of this paper was to study the phenomenology and mechanisms of the putative modifications on the daily profile of melatonin production in rats submitted to chronic alcohol intake. The present results show that rats receiving 10% ethanol in drinking water for 35 days display an altered daily profile of melatonin production, with a phase delay and a reduction in the nocturnal peak. This can be partially explained by a loss of the daily rhythm and the 25% reduction in tryptophan hydroxylase activity and, mainly, by a phase delay in arylalkylamine N-acetyltransferase gene expression and a 70% reduction in its peak activity. Upstream in the melatonin synthesis pathway, the results showed that noradrenergic signaling is impaired as well, with a decrease in beta 1 and alpha 1 adrenergic receptors` mRNA contents and in vitro sustained loss of noradrenergic-stimulated melatonin production by glands from alcohol-treated rats. Together, these results confirm the alterations in the daily melatonin profile of alcoholic rats and suggest the possible mechanisms for the observed melatonin synthesis modification.

Prevention of social stress-escalated cocaine self-administration by CRF-R1 antagonist in the rat VTA

Intermittent exposure to social defeat stress can induce long-term neural plasticity that may influence escalated cocaine-taking behavior. Stressful encounters can lead to activation of dopamine neurons in the ventral tegmental area (VTA), which are modulated by corticotropin releasing factor (CRF) neurons.The study aims to prevent the effects of intermittently scheduled, brief social defeat stress on subsequent intravenous (IV) cocaine self-administration by pretreatment with a CRF receptor subtype 1 (CRF-R1) antagonist.Long-Evans rats were submitted to four intermittent social defeat experiences separated by 72 h over 10 days. Two experiments examined systemic or intra-VTA antagonism of CRF-R1 subtype during stress on the later expression of locomotor sensitization and cocaine self-administration during fixed (0.75 mg/kg/infusion) and progressive ratio schedules of reinforcement (0.3 mg/kg/infusion), including a continuous 24-h "binge" (0.3 mg/kg/infusion).Pretreatment with a CRF-R1 antagonist, CP 154,526, (20 mg/kg i.p.) prior to each social defeat episode prevented the development of stress-induced locomotor sensitization to a cocaine challenge and prevented escalated cocaine self-administration during a 24-h "binge". In addition, pretreatment with a CRF-R1 antagonist (0.3 mu g/0.5 mu l/side) into the VTA prior to each social defeat episode prevented stress-induced locomotor sensitization to a cocaine challenge and prevented escalated cocaine self-administration during a 24-h "binge".The current results suggest that CRF-R1 subtype in the VTA is critically involved in the development of stress-induced locomotor sensitization which may contribute to escalated cocaine self-administration during continuous access in a 24-h "binge".

Role of the bed nucleus of the stria terminalis in cardiovascular changes following chronic treatment with cocaine and testosterone: A role beyond drug seeking in addiction?

Neural plasticity has been observed in the bed nucleus of the stria terminalis (BNST) following exposure to both cocaine and androgenic-anabolic steroids. Here we investigated the involvement of the BNST on changes in cardiovascular function and baroreflex activity following either single or combined administration of cocaine and testosterone for 10 consecutive days in rats. Single administration of testosterone increased values of arterial pressure, evoked rest bradycardia and reduced baroreflex-mediated bradycardia. These effects of testosterone were not affected by BNST inactivation caused by local bilateral microinjections of the nonselective synaptic blocker CoCl2. The single administration of cocaine as well as the combined treatment with testosterone and cocaine increased both bradycardiac and tachycardiac responses of the baroreflex. Cocaine-evoked baroreflex changes were totally reversed after BNST inactivation. However, BNST inhibition in animals subjected to combined treatment with cocaine and testosterone reversed only the increase in reflex tachycardia, whereas facilitation of reflex bradycardia was not affected by local BNST treatment with CoCl2. In conclusion, the present study provides the first direct evidence that the BNST play a role in cardiovascular changes associated with drug abuse. Our findings suggest that alterations in cardiovascular function following subchronic exposure to cocaine are mediated by neural plasticity in the BNST. The single treatment with cocaine and the combined administration of testosterone and cocaine had similar effects on baroreflex activity, however the association with testosterone inhibited cocaine-induced changes in the BNST control of reflex bradycardia. Testosterone-induced cardiovascular changes seem to be independent of the BNST. © 2013 IBRO.

Restoring tactile awareness through the rubber hand illusion in cervical spinal cord injury

BACKGROUND Bodily sensations are an important component of corporeal awareness. Spinal cord injury can leave affected body parts insentient and unmoving, leading to specific disturbances in the mental representation of one's own body and the sense of self. OBJECTIVE Here, we explored how illusions induced by multisensory stimulation influence immediate sensory signals and tactile awareness in patients with spinal cord injuries. METHODS The rubber hand illusion paradigm was applied to 2 patients with chronic and complete spinal cord injury of the sixth cervical spine, with severe somatosensory impairments in 2 of 5 fingers. RESULTS Both patients experienced a strong illusion of ownership of the rubber hand during synchronous, but not asynchronous, stroking. They also, spontaneously reported basic tactile sensations in their previously numb fingers. Tactile awareness from seeing the rubber hand was enhanced by progressively increasing the stimulation duration. CONCLUSIONS Multisensory illusions directly and specifically modulate the reemergence of sensory memories and enhance tactile sensation, despite (or as a result of) prior deafferentation. When sensory inputs are lost, and are later illusorily regained, the brain updates a coherent body image even several years after the body has become permanently unable to feel. This particular example of neural plasticity represents a significant opportunity to strengthen the sense of the self and the feelings of embodiment in patients with spinal cord injury.

Dynamics of a minimal model of interlocked positive and negative feedback loops of transcriptional regulation by cAMP-response element binding proteins.

cAMP-response element binding (CREB) proteins are involved in transcriptional regulation in a number of cellular processes (e.g., neural plasticity and circadian rhythms). The CREB family contains activators and repressors that may interact through positive and negative feedback loops. These loops can be generated by auto- and cross-regulation of expression of CREB proteins, via CRE elements in or near their genes. Experiments suggest that such feedback loops may operate in several systems (e.g., Aplysia and rat). To understand the functional implications of such feedback loops, which are interlocked via cross-regulation of transcription, a minimal model with a positive and negative loop was developed and investigated using bifurcation analysis. Bifurcation analysis revealed diverse nonlinear dynamics (e.g., bistability and oscillations). The stability of steady states or oscillations could be changed by time delays in the synthesis of the activator (CREB1) or the repressor (CREB2). Investigation of stochastic fluctuations due to small numbers of molecules of CREB1 and CREB2 revealed a bimodal distribution of CREB molecules in the bistability region. The robustness of the stable HIGH and LOW states of CREB expression to stochastic noise differs, and a critical number of molecules was required to sustain the HIGH state for days or longer. Increasing positive feedback or decreasing negative feedback also increased the lifetime of the HIGH state, and persistence of this state may correlate with long-term memory formation. A critical number of molecules was also required to sustain robust oscillations of CREB expression. If a steady state was near a deterministic Hopf bifurcation point, stochastic resonance could induce oscillations. This comparative analysis of deterministic and stochastic dynamics not only provides insights into the possible dynamics of CREB regulatory motifs, but also demonstrates a framework for understanding other regulatory processes with similar network architecture.

Dynamics of a minimal model of interlocked positive and negative feedback loops of transcriptional regulation by cAMP-response element binding proteins.

cAMP-response element binding (CREB) proteins are involved in transcriptional regulation in a number of cellular processes (e.g., neural plasticity and circadian rhythms). The CREB family contains activators and repressors that may interact through positive and negative feedback loops. These loops can be generated by auto- and cross-regulation of expression of CREB proteins, via CRE elements in or near their genes. Experiments suggest that such feedback loops may operate in several systems (e.g., Aplysia and rat). To understand the functional implications of such feedback loops, which are interlocked via cross-regulation of transcription, a minimal model with a positive and negative loop was developed and investigated using bifurcation analysis. Bifurcation analysis revealed diverse nonlinear dynamics (e.g., bistability and oscillations). The stability of steady states or oscillations could be changed by time delays in the synthesis of the activator (CREB1) or the repressor (CREB2). Investigation of stochastic fluctuations due to small numbers of molecules of CREB1 and CREB2 revealed a bimodal distribution of CREB molecules in the bistability region. The robustness of the stable HIGH and LOW states of CREB expression to stochastic noise differs, and a critical number of molecules was required to sustain the HIGH state for days or longer. Increasing positive feedback or decreasing negative feedback also increased the lifetime of the HIGH state, and persistence of this state may correlate with long-term memory formation. A critical number of molecules was also required to sustain robust oscillations of CREB expression. If a steady state was near a deterministic Hopf bifurcation point, stochastic resonance could induce oscillations. This comparative analysis of deterministic and stochastic dynamics not only provides insights into the possible dynamics of CREB regulatory motifs, but also demonstrates a framework for understanding other regulatory processes with similar network architecture.

Metodologías de modelado, monitorización y asistencia robótica en neurorrehabilitación funcional de extremidad superior

La Organización Mundial de la Salud (OMS) prevé que para el año 2020, el Daño Cerebral Adquirido (DCA) estará entre las 10 causas más comunes de discapacidad. Estas lesiones, dadas sus consecuencias físicas, sensoriales, cognitivas, emocionales y socioeconómicas, cambian dramáticamente la vida de los pacientes y sus familias. Las nuevas técnicas de intervención precoz y el desarrollo de la medicina intensiva en la atención al DCA han mejorado notablemente la probabilidad de supervivencia. Sin embargo, hoy por hoy, las lesiones cerebrales no tienen ningún tratamiento quirúrgico que tenga por objetivo restablecer la funcionalidad perdida, sino que las terapias rehabilitadoras se dirigen hacia la compensación de los déficits producidos. Uno de los objetivos principales de la neurorrehabilitación es, por tanto, dotar al paciente de la capacidad necesaria para ejecutar las Actividades de Vida Diaria (AVDs) necesarias para desarrollar una vida independiente, siendo fundamentales aquellas en las que la Extremidad Superior (ES) está directamente implicada, dada su gran importancia a la hora de la manipulación de objetos. Con la incorporación de nuevas soluciones tecnológicas al proceso de neurorrehabilitación se pretende alcanzar un nuevo paradigma centrado en ofrecer una práctica personalizada, monitorizada y ubicua con una valoración continua de la eficacia y de la eficiencia de los procedimientos y con capacidad de generar conocimientos que impulsen la ruptura del paradigma de actual. Los nuevos objetivos consistirán en minimizar el impacto de las enfermedades que afectan a la capacidad funcional de las personas, disminuir el tiempo de incapacidad y permitir una gestión más eficiente de los recursos. Estos objetivos clínicos, de gran impacto socio-económico, sólo pueden alcanzarse desde una apuesta decidida en nuevas tecnologías, metodologías y algoritmos capaces de ocasionar la ruptura tecnológica necesaria que permita superar las barreras que hasta el momento han impedido la penetración tecnológica en el campo de la rehabilitación de manera universal. De esta forma, los trabajos y resultados alcanzados en la Tesis son los siguientes: 1. Modelado de AVDs: como paso previo a la incorporación de ayudas tecnológicas al proceso rehabilitador, se hace necesaria una primera fase de modelado y formalización del conocimiento asociado a la ejecución de las actividades que se realizan como parte de la terapia. En particular, las tareas más complejas y a su vez con mayor repercusión terapéutica son las AVDs, cuya formalización permitirá disponer de modelos de movimiento sanos que actuarán de referencia para futuros desarrollos tecnológicos dirigidos a personas con DCA. Siguiendo una metodología basada en diagramas de estados UML se han modelado las AVDs 'servir agua de una jarra' y 'coger un botella' 2. Monitorización ubícua del movimiento de la ES: se ha diseñado, desarrollado y validado un sistema de adquisición de movimiento basado en tecnología inercial que mejora las limitaciones de los dispositivos comerciales actuales (coste muy elevado e incapacidad para trabajar en entornos no controlados); los altos coeficientes de correlación y los bajos niveles de error obtenidos en los corregistros llevados a cabo con el sistema comercial BTS SMART-D demuestran la alta precisión del sistema. También se ha realizado un trabajo de investigación exploratorio de un sistema de captura de movimiento de coste muy reducido basado en visión estereoscópica, habiéndose detectado los puntos clave donde se hace necesario incidir desde un punto de vista tecnológico para su incorporación en un entorno real 3. Resolución del Problema Cinemático Inverso (PCI): se ha diseñado, desarrollado y validado una solución al PCI cuando el manipulador se corresponde con una ES humana estudiándose 2 posibles alternativas, una basada en la utilización de un Perceptrón Multicapa (PMC) y otra basada en sistemas Artificial Neuro-Fuzzy Inference Systems (ANFIS). La validación, llevada a cabo utilizando información relativa a los modelos disponibles de AVDs, indica que una solución basada en un PMC con 3 neuronas en la capa de entrada, una capa oculta también de 3 neuronas y una capa de salida con tantas neuronas como Grados de Libertad (GdLs) tenga el modelo de la ES, proporciona resultados, tanto de precisión como de tiempo de cálculo, que la hacen idónea para trabajar en sistemas con requisitos de tiempo real 4. Control inteligente assisted-as-needed: se ha diseñado, desarrollado y validado un algoritmo de control assisted-as-needed para una ortesis robótica con capacidades de actuación anticipatoria de la que existe un prototipo implementado en la actualidad. Los resultados obtenidos demuestran cómo el sistema es capaz de adaptarse al perfil disfuncional del paciente activando la ayuda en instantes anteriores a la ocurrencia de movimientos incorrectos. Esta estrategia implica un aumento en la participación del paciente y, por tanto, en su actividad muscular, fomentándose los procesos la plasticidad cerebral responsables del reaprendizaje o readaptación motora 5. Simuladores robóticos para planificación: se propone la utilización de un simulador robótico assisted-as-needed como herramienta de planificación de sesiones de rehabilitación personalizadas y con un objetivo clínico marcado en las que interviene una ortesis robotizada. Los resultados obtenidos evidencian como, tras la ejecución de ciertos algoritmos sencillos, es posible seleccionar automáticamente una configuración para el algoritmo de control assisted-as-needed que consigue que la ortesis se adapte a los criterios establecidos desde un punto de vista clínico en función del paciente estudiado. Estos resultados invitan a profundizar en el desarrollo de algoritmos más avanzados de selección de parámetros a partir de baterías de simulaciones Estos trabajos han servido para corroborar las hipótesis de investigación planteadas al inicio de la misma, permitiendo, asimismo, la apertura de nuevas líneas de investigación. Summary The World Health Organization (WHO) predicts that by the year 2020, Acquired Brain Injury (ABI) will be among the ten most common ailments. These injuries dramatically change the life of the patients and their families due to their physical, sensory, cognitive, emotional and socio-economic consequences. New techniques of early intervention and the development of intensive ABI care have noticeably improved the survival rate. However, in spite of these advances, brain injuries still have no surgical or pharmacological treatment to re-establish the lost functions. Neurorehabilitation therapies address this problem by restoring, minimizing or compensating the functional alterations in a person disabled because of a nervous system injury. One of the main objectives of Neurorehabilitation is to provide patients with the capacity to perform specific Activities of the Daily Life (ADL) required for an independent life, especially those in which the Upper Limb (UL) is directly involved due to its great importance in manipulating objects within the patients' environment. The incorporation of new technological aids to the neurorehabilitation process tries to reach a new paradigm focused on offering a personalized, monitored and ubiquitous practise with continuous assessment of both the efficacy and the efficiency of the procedures and with the capacity of generating new knowledge. New targets will be to minimize the impact of the sicknesses affecting the functional capabilitiies of the subjects, to decrease the time of the physical handicap and to allow a more efficient resources handling. These targets, of a great socio-economic impact, can only be achieved by means of new technologies and algorithms able to provoke the technological break needed to beat the barriers that are stopping the universal penetration of the technology in the field of rehabilitation. In this way, this PhD Thesis has achieved the following results: 1. ADL Modeling: as a previous step to the incorporation of technological aids to the neurorehabilitation process, it is necessary a first modelling and formalization phase of the knowledge associated to the execution of the activities that are performed as a part of the therapy. In particular, the most complex and therapeutically relevant tasks are the ADLs, whose formalization will produce healthy motion models to be used as a reference for future technological developments. Following a methodology based on UML state-chart diagrams, the ADLs 'serving water from a jar' and 'picking up a bottle' have been modelled 2. Ubiquitous monitoring of the UL movement: it has been designed, developed and validated a motion acquisition system based on inertial technology that improves the limitations of the current devices (high monetary cost and inability of working within uncontrolled environments); the high correlation coefficients and the low error levels obtained throughout several co-registration sessions with the commercial sys- tem BTS SMART-D show the high precision of the system. Besides an exploration of a very low cost stereoscopic vision-based motion capture system has been carried out and the key points where it is necessary to insist from a technological point of view have been detected 3. Inverse Kinematics (IK) problem solving: a solution to the IK problem has been proposed for a manipulator that corresponds to a human UL. This solution has been faced by means of two different alternatives, one based on a Mulilayer Perceptron (MLP) and another based on Artificial Neuro-Fuzzy Inference Systems (ANFIS). The validation of these solutions, carried out using the information regarding the previously generated motion models, indicate that a MLP-based solution, with an architecture consisting in 3 neurons in the input layer, one hidden layer of 3 neurons and an output layer with as many neurons as the number of Degrees of Freedom (DoFs) that the UL model has, is the one that provides the best results both in terms of precission and in terms of processing time, making in idoneous to be integrated within a system with real time restrictions 4. Assisted-as-needed intelligent control: an assisted-as-needed control algorithm with anticipatory actuation capabilities has been designed, developed and validated for a robotic orthosis of which there is an already implemented prototype. Obtained results demonstrate that the control system is able to adapt to the dysfunctional profile of the patient by triggering the assistance right before an incorrect movement is going to take place. This strategy implies an increase in the participation of the patients and in his or her muscle activity, encouraging the neural plasticity processes in charge of the motor learning 5. Planification with a robotic simulator: in this work a robotic simulator is proposed as a planification tool for personalized rehabilitation sessions under a certain clinical criterium. Obtained results indicate that, after the execution of simple parameter selection algorithms, it is possible to automatically choose a specific configuration that makes the assisted-as-needed control algorithm to adapt both to the clinical criteria and to the patient. These results invite researchers to work in the development of more complex parameter selection algorithms departing from simulation batteries Obtained results have been useful to corroborate the hypotheses set out at the beginning of this PhD Thesis. Besides, they have allowed the creation of new research lines in all the studied application fields.

Monitoring visual attention on a neurorehabilitation environment based on interactive video

The use of new technologies in neurorehabilitation has led to higher intensity rehabilitation processes, extending therapies in an economically sustainable way. Interactive Video (IV) technology allows therapists to work with virtual environments that reproduce real situations. In this way, patients deal with Activities of the Daily Living (ADL) immersed within enhanced environments [1]. These rehabilitation exercises, which focus in re-learning lost functions, will try to modulate the neural plasticity processes [2]. This research presents a system where a neurorehabilitation IV-based environment has been integrated with an eye-tracker device in order to monitor and to interact using visual attention. While patients are interacting with the neurorehabilitation environment, their visual behavior is closely related with their cognitive state, which in turn mirrors the brain damage condition suffered by them [3] [4]. Patients’ gaze data can provide knowledge on their attention focus and their cognitive state, as well as on the validity of the rehabilitation tasks proposed [5].

Region-dependent dynamics of cAMP response element-binding protein phosphorylation in the basal ganglia

The cAMP response element-binding protein (CREB) is an activity-dependent transcription factor that is involved in neural plasticity. The kinetics of CREB phosphorylation have been suggested to be important for gene activation, with sustained phosphorylation being associated with downstream gene expression. If so, the duration of CREB phosphorylation might serve as an indicator for time-sensitive plastic changes in neurons. To screen for regions potentially involved in dopamine-mediated plasticity in the basal ganglia, we used organotypic slice cultures to study the patterns of dopamine- and calcium-mediated CREB phosphorylation in the major subdivisions of the striatum. Different durations of CREB phosphorylation were evoked in the dorsal and ventral striatum by activation of dopamine D1-class receptors. The same D1 stimulus elicited (i) transient phosphorylation (≤15 min) in the matrix of the dorsal striatum; (ii) sustained phosphorylation (≤2 hr) in limbic-related structures including striosomes, the nucleus accumbens, the fundus striati, and the bed nucleus of the stria terminalis; and (iii) prolonged phosphorylation (up to 4 hr or more) in cellular islands in the olfactory tubercle. Elevation of Ca2+ influx by stimulation of L-type Ca2+ channels, NMDA, or KCl induced strong CREB phosphorylation in the dorsal striatum but not in the olfactory tubercle. These findings differentiate the response of CREB to dopamine and calcium signals in different striatal regions and suggest that dopamine-mediated CREB phosphorylation is persistent in limbic-related regions of the neonatal basal ganglia. The downstream effects activated by persistent CREB phosphorylation may include time-sensitive neuroplasticity modulated by dopamine.

Nerve growth factor rapidly suppresses basal, NMDA-evoked, and AMPA-evoked nitric oxide synthase activity in rat hippocampus in vivo

In adult forebrain, nerve growth factor (NGF) influences neuronal maintenance and axon sprouting and is neuroprotective in several injury models through mechanisms that are incompletely understood. Most NGF signaling is thought to occur after internalization and retrograde transport of trkA receptor and be mediated through the nucleus. However, NGF expression in hippocampus is rapidly and sensitively regulated by synaptic activity, suggesting that NGF exerts local effects more dynamically than possible through signaling requiring retrograde transport to distant afferent neurons. Interactions have been reported between NGF and nitric oxide (NO). Because NO affects both neural plasticity and degeneration, and trk receptors can mediate signaling within minutes, we hypothesized that NGF might rapidly modulate NO production. Using in vivo microdialysis we measured conversion of l-[14C]arginine to l-[14C]citrulline as an accurate reflection of NO synthase (NOS) activity in adult rat hippocampus. NGF significantly reduced NOS activity to 61% of basal levels within 20 min of onset of delivery and maintained NOS activity at less than 50% of baseline throughout 3 hr of delivery. This effect did not occur with control protein (cytochrome c) and was not mediated by an effect of NGF on glutamate levels. In addition, simultaneous delivery of NGF prevented significant increases in NOS activity triggered by the glutamate receptor agonists N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Rapid suppression by NGF of basal and glutamate-stimulated NOS activity may regulate neuromodulatory functions of NO or protect neurons from NO toxicity and suggests a novel mechanism for rapidly mediating functions of NGF and other neurotrophins.

Adaptação e criação de exercícios técnicos para violino direcionados a alunos em iniciação ao instrumento

Relatório de estágio apresentado à Escola Superior de Artes Aplicadas do Instituto Politécnico de Castelo Branco para obtenção do Grau de Mestre em Ensino de Música - Instrumento e Música de Conjunto.

Modulation of network oscillatory activity and GABAergic synaptic transmission by CB1 cannabinoid receptors in the rat medial entorhinal cortex

Cannabinoids modulate inhibitory GABAergic neurotransmission in many brain regions. Within the temporal lobe, cannabinoid receptors are highly expressed, and are located presynaptically at inhibitory terminals. Here, we have explored the role of type-1 cannabinoid receptors (CB1Rs) at the level of inhibitory synaptic currents and field-recorded network oscillations. We report that arachidonylcyclopropylamide, an agonist at CB1R, inhibits GABAergic synaptic transmission onto both superficial and deep medial entorhinal (mEC) neurones, but this has little effect on network oscillations in beta/gamma frequency bands. By contrast, the CB1R antagonist/inverse agonist LY320135 (500?nM), increased GABAergic synaptic activity and beta/gamma oscillatory activity in superficial mEC, was suppressed, whilst that in deep mEC was enhanced. These data indicate that cannabinoid-mediated effects on inhibitory synaptic activity may be constitutively active in vitro, and that modulation of CB1R activation using inverse agonists unmasks complex effects of CBR function on network activity.

The Val66Met polymorphism of the BDNF gene influences trigeminal Pain-Related evoked responses

Cortical pain processing is associated with large-scale changes in neuronal connectivity, resulting from neural plasticity phenomena of which brain-derived neurotrophic factor (BDNF) is a central driver. The common single nucleotide polymorphism Val66Met is associated with reduced BDNF activity. Using the trigeminal pain-related evoked potential (tPREP) to repeated electrical painful stimuli, we investigated whether the methionine substitution at codon 66 of the BDNF gene was associated with changes in cortical processing of noxious stimuli. Fifty healthy volunteers were genotyped: 30 were Val/Val and 20 were Met-carriers. tPREPs to 30 stimuli of the right supraorbital nerve using a concentric electrode were recorded. The N2 and P2 component latencies and the N2-P2 amplitude were measured over the 30 stimuli and separately, by dividing the measurements in 3 consecutive blocks of 10 stimuli. The average response to the 30 stimuli did not differ in latency or amplitude between the 2 genotypes. There was a decrease in the N2-P2 amplitude between first and third block in the Val/Val group but not in Met-carriers. BDNF Val66Met is associated with reduced decremental response to repeated electrical stimuli, possibly as a result of ineffective mechanisms of synaptic memory and brain plasticity associated with the polymorphism. PERSPECTIVE: BDNF Val66Met polymorphism affects the tPREP N2-P2 amplitude decrement and influences cortical pain processing through neurotrophin-induced neural plasticity, or through a direct BDNF neurotransmitter-like effect. Our findings suggest that upcoming BDNF central agonists might in the future play a role in pain management.

The upstream Variable Number Tandem Repeat polymorphism of the monoamine oxidase type A gene influences trigeminal pain-related evoked responses

Monoamines have an important role in neural plasticity, a key factor in cortical pain processing that promotes changes in neuronal network connectivity. Monoamine oxidase type A (MAOA) is an enzyme that, due to its modulating role in monoaminergic activity, could play a role in cortical pain processing. The X-linked MAOA gene is characterized by an allelic variant of length, the MAOA upstream Variable Number Tandem Repeat (MAOA-uVNTR) region polymorphism. Two allelic variants of this gene are known, the high-activity MAOA (HAM) and low-activity MAOA (LAM). We investigated the role of MAOA-uVNTR in cortical pain processing in a group of healthy individuals measured by the trigeminal electric pain-related evoked potential (tPREP) elicited by repeated painful stimulation. A group of healthy volunteers was genotyped to detect MAOA-uVNTR polymorphism. Electrical tPREPs were recorded by stimulating the right supraorbital nerve with a concentric electrode. The N2 and P2 component amplitude and latency as well as the N2-P2 inter-peak amplitude were measured. The recording was divided into three blocks, each containing 10 consecutive stimuli and the N2-P2 amplitude was compared between blocks. Of the 67 volunteers, 37 were HAM and 30 were LAM. HAM subjects differed from LAM subjects in terms of amplitude of the grand-averaged and first-block N2-P2 responses (HAM>LAM). The N2-P2 amplitude decreased between the first and third block in HAM subjects but not LAM subjects. The MAOA-uVNTR polymorphism seemed to influence the brain response in a repeated tPREP paradigm and suggested a role of the MAOA as a modulator of neural plasticity related to cortical pain processing. Monoamines have an important role in neural plasticity, a key factor in cortical pain processing that promotes changes in neuronal network connectivity. Monoamine oxidase type A (MAOA) is an enzyme that, due to its modulating role in monoaminergic activity, could play a role in cortical pain processing. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.