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  • Publication
    The Evolution of Physical Performance throughout an Entire Season in Female Football Players
    (MDPI, 2024) Reyes Laredo, Francisco; Pareja Blanco, Fernando; López-Lluch, Guillermo; Rodríguez-Bies, Elisabeth
    Research on the evolution of performance throughout a season in team sports is scarce and mainly focused on men’s teams. Our aim in this study was to examine the seasonal variations in relevant indices of physical performance in female football players. Twenty-seven female football players were assessed at week 2 of the season (preseason, PS), week 7 (end of preseason, EP), week 24 (half-season, HS), and week 38 (end of season, ES). Similar to the most common used conditioning tests in football, testing sessions consisted of (1) vertical countermovement jump (CMJ); (2) 20 m running sprint (T20); (3) 25 m side-step cutting maneuver test (V-CUT); and (4) progressive loading test in the full-squat exercise (V1-LOAD). Participants followed their normal football training procedure, which consisted of three weekly training sessions and an official match, without any type of intervention. No significant time effects were observed for CMJ height (p = 0.29) and T20 (p = 0.11) throughout the season. However, significant time effects were found for V-CUT (p = 0.004) and V1-LOAD (p = 0.001). V-CUT performance significantly improved from HS to ES (p = 0.001). Significant increases were observed for V1-LOAD throughout the season: PS-HS (p = 0.009); PS-ES (p < 0.001); EP-ES (p < 0.001); and HS-ES (p = 0.009). These findings suggest that, over the course of the season, female football players experience an enhancement in muscle strength and change of direction ability. However, no discernible improvements were noted in sprinting and jumping capabilities during the same period.
  • Publication
    Calorie Restriction Rescues Mitochondrial Dysfunction in Adck2-Deficient Skeletal Muscle
    (Frontiers Media, 2022) Hernández Camacho, Juan Diego; Moreno Fernández-Ayala, Daniel José; Vicente-García, Cristina; Navas-Enamorado, Ignacio; López-Lluch, Guillermo; Oliva, Clara; Artuch, Rafael; Garcia-Villoria, Judith; Ribes, Antonia; de Cabo, Rafael; Carvajal, Jaime; Navas, Plácido
    ADCK2 haploinsufficiency-mediated mitochondrial coenzyme Q deficiency in skeletal muscle causes mitochondrial myopathy associated with defects in beta-oxidation of fatty acids, aged-matched metabolic reprogramming, and defective physical performance. Calorie restriction has proven to increase lifespan and delay the onset of chronic diseases associated to aging. To study the possible treatment by food deprivation, heterozygous Adck2 knockout mice were fed under 40% calorie restriction (CR) and the phenotype was followed for 7 months. The overall glucose and fatty acids metabolism in muscle was restored in mutant mice to WT levels after CR. CR modulated the skeletal muscle metabolic profile of mutant mice, partially rescuing the profile of WT animals. The analysis of mitochondria isolated from skeletal muscle demonstrated that CR increased both CoQ levels and oxygen consumption rate (OCR) based on both glucose and fatty acids substrates, along with mitochondrial mass. The elevated aerobic metabolism fits with an increase of type IIa fibers, and a reduction of type IIx in mutant muscles, reaching WT levels. To further explore the effect of CR over muscle stem cells, satellite cells were isolated and induced to differentiate in culture media containing serum from animals in either ad libitum or CR diets for 72 h. Mutant cells showed slower differentiation alongside with decreased oxygen consumption. In vitro differentiation of mutant cells was increased under CR serum reaching levels of WT isolated cells, recovering respiration measured by OCR and partially beta-oxidation of fatty acids. The overall increase of skeletal muscle bioenergetics following CR intervention is paralleled with a physical activity improvement, with some increases in two and four limbs strength tests, and weights strength test. Running wheel activity was also partially improved in mutant mice under CR. These results demonstrate that CR intervention, which has been shown to improve age-associated physical and metabolic decline in WT mice, also recovers the defective aerobic metabolism and differentiation of skeletal muscle in mice caused by ADCK2 haploinsufficiency.
  • Publication
    FUNCTIONAL STATES OF RATS CORTICAL CIRCUITS DURING UNPREDICTABLE AVAILABILITY OF A REWARD-RELATED CUE
    (Nature Publishing Group, 2016-11-21) I. Fernández-Lamo, R. Sánchez-Campusano, A. Gruart, and J.M. Delgado-García; Sánchez-Campusano, Raudel; Gruart, Agnès
    Proper performance of acquired abilities can be disturbed by the unexpected occurrence of external changes. Rats trained with an operant conditioning task (to press a lever in order to obtain a food pellet) using a fixed-ratio (1:1) schedule were subsequently placed in a Skinner box in which the lever could be removed randomly. Field postsynaptic potentials (fPSPs) were chronically evoked in perforant pathway-hippocampal CA1 (PP-CA1), CA1-subiculum (CA1-SUB), CA1- medial prefrontal cortex (CA1-mPFC), mPFC-nucleus accumbens (mPFC-NAc), and mPFC-basolateral amygdala (mPFC-BLA) synapses during lever IN and lever OUT situations. While lever presses were accompanied by a significant increase in fPSP slopes at the five synapses, the unpredictable absence of the lever were accompanied by decreased fPSP slopes in all, except PP-CA1 synapses. Spectral analysis of local field potentials (LFPs) recorded when the animal approached the corresponding area in the lever OUT situation presented lower spectral powers than during lever IN occasions for all recording sites, apart from CA1. Thus, the unpredictable availability of a reward-related cue modified the activity of cortical and subcortical areas related with the acquisition of operant learning tasks, suggesting an immediate functional reorganization of these neural circuits to address the changed situation and to modify ongoing behaviors accordingly.
  • Publication
    A VARIABLE OSCILLATOR UNDERLIES THE MEASUREMENT OF TIME INTERVALS IN THE ROSTRAL MEDIAL PREFRONTAL CORTEX DURING CLASSICAL EYEBLINK CONDITIONING IN RABBITS
    (Society for Neuroscience, 2015-11-04) C.R. Caro-Martín, R. Leal-Campanario, R. Sánchez-Campusano, J.M. Delgado-García, A. Gruart; Leal Campanario, Rocío; Sánchez-Campusano, Raudel; Gruart, Agnès
    We were interested in determining whether rostral medial prefrontal cortex (rmPFC) neurons participate in the measurement of conditioned stimulus– unconditioned stimulus (CS-US) time intervals during classical eyeblink conditioning. Rabbits were conditioned with a delay paradigm consisting of a tone as CS. The CS started 50, 250, 500, 1000, or 2000msbefore and coterminated with an air puff (100 ms) directed at the cornea as the US. Eyelid movements were recorded with the magnetic search coil technique and the EMG activity of the orbicularis oculi muscle. Firing activities of rmPFC neurons were recorded across conditioning sessions. Reflex and conditioned eyelid responses presented a dominant oscillatory frequency of 12 Hz. The firing rate of each recorded neuron presented a single peak of activity with a frequency dependent on the CS-US interval (i.e., 12 Hz for 250 ms, 6 Hz for 500 ms, and 3 Hz for 1000 ms). Interestingly, rmPFC neurons presented their dominant firing peaks at three precise times evenly distributed with respect to CS start and also depending on the duration of the CS-US interval (only for intervals of 250, 500, and 1000 ms). No significant neural responses were recorded at very short (50 ms) or long (2000 ms) CS-US intervals. rmPFC neurons seem not to encode the oscillatory properties characterizing conditioned eyelid responses in rabbits, but are probably involved in the determination of CS-US intervals of an intermediate range (250 –1000 ms). We propose that a variable oscillator underlies the generation of working memories in rabbits.
  • Publication
    SPIKE SORTING BASED ON SHAPE, PHASE, AND DISTRIBUTION FEATURES, AND K-TOPS CLUSTERING WITH VALIDITY AND ERROR INDICES
    (Nature Publishing Group, 2018-12-12) C.R. Caro-Martín, J.M. Delgado-García, A. Gruart, R. Sánchez-Campusano*
    Spike sorting is one of the most important data analysis problems in neurophysiology. The precision in all steps of the spike-sorting procedure critically affects the accuracy of all subsequent analyses. After data preprocessing and spike detection have been carried out properly, both feature extraction and spike clustering are the most critical subsequent steps of the spike-sorting procedure. The proposed spike sorting approach comprised a new feature extraction method based on shape, phase, and distribution features of each spike (hereinafter SS-SPDF method), which reveal significant information of the neural events under study. In addition, we applied an efficient clustering algorithm based on K-means and template optimization in phase space (hereinafter K-TOPS) that included two integrative clustering measures (validity and error indices) to verify the cohesion-dispersion among spike events during classification and the misclassification of clustering, respectively. The proposed method/algorithm was tested on both simulated data and real neural recordings. The results obtained for these datasets suggest that our spike sorting approach provides an efficient way for sorting both single-unit spikes and overlapping waveforms. By analyzing raw extracellular recordings collected from the rostralmedial prefrontal cortex (rmPFC) of behaving rabbits during classical eyeblink conditioning, we have demonstrated that the present method/algorithm performs better at classifying spikes and neurons and at assessing their modulating properties than other methods currently used in neurophysiology. *R. Sánchez-Campusano. Corresponding Author. Email: rsancam@upo.es.
  • Publication
    OPERANT CONDITIONING DEFICITS AND MODIFIED LOCAL FIELD POTENTIAL ACTIVITIES IN PARVALBUMIN-DEFICIENT MICE
    (Nature Publishing Group, 2021-02-03) A. Lintas*, R. Sánchez-Campusano*, A.E.P. Villa, A. Gruart, J.M. Delgado-García; Sánchez-Campusano, Raudel; Gruart, Agnès
    Altered functioning of GABAergic interneurons expressing parvalbumin (PV) in the basal gangliathalamo-cortical circuit are likely to be involved in several human psychiatric disorders characterized by deficits in attention and sensory gating with dysfunctional decision-making behavior. However, the contribution of these interneurons in the ability to acquire demanding learning tasks remains unclear. Here, we combine an operant conditioning task with local field potentials simultaneously recorded in several nuclei involved in reward circuits of wild-type (WT) and PV-deficient (PVKO) mice, which are characterized by changes in firing activity of PV-expressing interneurons. In comparison with WT mice, PVKO animals presented significant deficits in the acquisition of the selected learning task. Recordings from prefrontal cortex, nucleus accumbens (NAc) and hippocampus showed significant decreases of the spectral power in beta and gamma bands in PVKO compared with WT mice particularly during the performance of the operant conditioning task. From the first to the last session, at all frequency bands the spectral power in NAc tended to increase in WT and to decrease in PVKO. Results indicate that PV deficiency impairs signaling necessary for instrumental learning and the recognition of natural rewards. *These authors contributed equally: Alessandra Lintas and Raudel Sánchez-Campusano. Email: rsancam@upo.es. Email: alessandra.lintas@unil.ch.
  • Publication
    DYNAMIC ASSOCIATIONS IN THE CEREBELLAR-MOTONEURON NETWORK DURING MOTOR LEARNING
    (Society for Neuroscience, 2009-08-26) R. Sánchez-Campusano, A. Gruart, and J.M. Delgado-García; Sánchez-Campusano, Raudel; Gruart, Agnès
    We assessed here true causal directionalities in cerebellar–motoneuron (MN) network associations during the classical conditioning of eyelid responses. For this, the firing activities of identified facial MNs and cerebellar interpositus (IP) nucleus neurons were recorded during the acquisition of this type of associative learning in alert behaving cats. Simultaneously, the eyelid conditioned response (CR) and the EMG activity of the orbicularis oculi (OO) muscle were recorded. Nonlinear association analysis and time-dependent causality method allowed us to determine the asymmetry, time delays, direction in coupling, and functional interdependences between neuronal recordings and learned motor responses.Weconcluded that the functional nonlinear association between the IP neurons and OO muscle activities was bidirectional and asymmetric, and the time delays in the two directions of coupling always lagged the start of the CR. Additionally, the strength of coupling depended inversely on the level of expression of eyeblink CRs, whereas causal inferences were significantly dependent on the phase information status. In contrast, the functional association between OO MNs and OO muscle activities was unidirectional and quasisymmetric, and the time delays in coupling were always of opposed signs. Moreover, information transfer in cerebellar–MN network associations during the learning process required a “driving common source” that induced the mere “modulating coupling” of the IP nucleus with the final common pathway for the eyelid motor system. Thus, it can be proposed that the cerebellum is always looking back and reevaluating its own function, using the information acquired in the process, to play a modulating-reinforcing role in motor learning.
  • Publication
    THE CEREBELLAR INTERPOSITUS NUCLEUS AND THE DYNAMIC CONTROL OF LEARNED MOTOR RESPONSES
    (Society for Neuroscience, 2007-06-20) R. Sánchez-Campusano, A. Gruart, and J.M. Delgado-García; Sánchez-Campusano, Raudel; Gruart, Agnès
    The role played by the cerebellum in movement control requires knowledge of interdependent relationships between kinetic neural commands and the performance (kinematics) of learned motor responses. The eyelid motor system is an excellent model for studying how simple motor responses are elaborated and performed. Kinetic variables (n 24) were determined here by recording the firing activities of orbicularis oculi motoneurons and cerebellar interpositus neurons in alert cats during classical conditioning, using a delay paradigm. Kinematic variables (n 36) were selected from eyelid position, velocity, and acceleration traces recorded during the conditioned stimulus– unconditioned stimulus interval. Optimized experimental and analytical tools allowed us to determine the evolution of kinetic and kinematic variables, the dynamic correlation functions relating motoneuron and interpositus neuron firing to eyelid conditioning responses, the falling correlation property of the interpositus nucleus across the successive training sessions, the time and significance of the linear relationships between these variables, and finally, the phase-inversion property of interpositus neurons with respect to acquired conditioned responses. Whereas motoneurons encoded eyelid kinematics at every instant of the dynamic correlation range and generated the natural oscillatory properties of the neuromuscular elements involved in eyeblinks, interpositus neurons did not directly encode eyelid performance: namely, their contribution was only slightly significant in the dynamic correlation range, and this regularity caused the integrated neuronal activity to oscillate by progressively inverting phase information. Therefore, interpositus neurons seem to play a modulating role in the dynamic control of learned motor responses, i.e., they could be considered a neuronal phase-modulating device.
  • Publication
    DIFFERENTIAL CONTRIBUTION OF HIPPOCAMPAL CIRCUITS TO APPETITIVE AND CONSUMMATORY BEHAVIORS DURING OPERANT CONDITIONING OF BEHAVING MICE
    (Society for Neuroscience, 2013-02-06) M.T. Jurado-Parras, R. Sánchez-Campusano, N.P. Castellanos, F. del-Pozo, A. Gruart, and J.M. Delgado-García; Sánchez-Campusano, Raudel; Gruart, Agnès
    Operant conditioning is a type of associative learning involving different and complex sensorimotor and cognitive processes. Because the hippocampus has been related to some motor and cognitive functions involved in this type of learning (such as object recognition, spatial orientation, and associative learning tasks), we decided to study in behaving mice the putative changes in strength taking place at the hippocampal CA3–CA1 synapses during the acquisition and performance of an operant conditioning task. Mice were chronically implanted with stimulating electrodes in the Schaffer collaterals and with recording electrodes in the hippocampal CA1 area and trained to an operant task using a fixed- ratio (1:1) schedule. We recorded the field EPSPs (fEPSPs) evoked at the CA3–CA1 synapse during the performance of appetitive (going to the lever, lever press) and consummatory (going to the feeder, eating) behaviors. In addition, we recorded the local field potential activity of the CA1 area during similar behavioral displays. fEPSPs evoked at the CA3–CA1 synapse presented larger amplitudes for appetitive than for consummatory behaviors. This differential change in synaptic strength took place in relation to the learning process, depending mainly on the moment in which mice reached the selected criterion. Thus, selective changes in CA3–CA1 synaptic strength were dependent on both the behavior display and the learning stage. In addition, significant changes in theta band power peaks and their corresponding discrete frequencies were noticed during these behaviors across the sequence of events characterizing this type of associative learning but not during the acquisition process.
  • Publication
    THE CLAUSTRUM IS INVOLVED IN COGNITIVE PROCESSES RELATED TO THE CLASSICAL CONDITIONING OF EYELID RESPONSES IN BEHAVING RABBITS
    (Oxford University Press, 2021-01) M. Mar Reus-García, R. Sánchez-Campusano, J. Ledderose, G.K. Dogbevia, M. Treviño, M.T. Hasan, A. Gruart, J.M. Delgado-García; Sánchez-Campusano, Raudel; Gruart, Agnès
    It is assumed that the claustrum (CL) is involved in sensorimotor integration and cognitive processes.We recorded the firing activity of identified CL neurons during classical eyeblink conditioning in rabbits, using a delay paradigm in which a tone was presented as conditioned stimulus (CS), followed by a corneal air puff as unconditioned stimulus (US). Neurons were identified by their activation from motor (MC), cingulate (CC), and medial prefrontal (mPFC) cortices. CL neurons were rarely activated by single stimuli of any modality. In contrast, their firing was significantly modulated during the first sessions of paired CS/US presentations, but not in well-trained animals. Neuron firing rates did not correlate with the kinematics of conditioned responses (CRs). CL local field potentials (LFPs) changed their spectral power across learning and presented well-differentiated CL–mPFC/CL–MC network dynamics, as shown by crossfrequency spectral measurements. CL electrical stimulation did not evoke eyelid responses, even in trained animals. Silencing of synaptic transmission of CL neurons by the vINSIST method delayed the acquisition of CRs but did not affect their presentation rate. The CL plays an important role in the acquisition of associative learning,mostly in relation to the novelty of CS/US association, but not in the expression of CRs.
  • Publication
    A DIFFERENTIAL AND TIMED CONTRIBUTION OF IDENTIFIED HIPPOCAMPAL SYNAPSES TO ASSOCIATIVE LEARNING IN MICE
    (Oxford University Press, 2015-09) A. Gruart, R. Sánchez-Campusano, A. Fernández-Guizán, and J.M. Delgado-García; Gruart, Agnès; Sánchez-Campusano, Raudel
    Although it is generally assumed that the hippocampus is involved in associative learning, the specific contribution of the different synapses present in its intrinsic circuit or comprising its afferents and efferents is poorly defined. We studied here activity-dependent changes in synaptic strength of 9 hippocampal synapses (corresponding to the intrinsic hippocampal circuitry and to its main inputs and outputs) during the acquisition of a trace eyeblink conditioning in behaving mice. The timing and intensity of synaptic changes across the acquisition process was determined. The evolution of these timed changes in synaptic strength indicated that their functional organization did not coincide with their sequential distribution according to anatomical criteria and connectivity. Furthermore, we explored the functional relevance of the extrinsic and intrinsic afferents to CA3 and CA1 pyramidal neurons, and evaluated the distinct input patterns to the intrinsic hippocampal circuit. Results confirm that the acquisition of a classical eyeblink conditioning is a multisynaptic process in which the contribution of each synaptic contact is different in strength, and takes place at different moments across learning. Thus, the precise and timed activation of multiple hippocampal synaptic contacts during classical eyeblink conditioning evokes a specific, dynamic map of functional synaptic states in that circuit.
  • Publication
    CONSENSUS PAPER: CURRENT VIEWS ON THE ROLE OF CEREBELLAR INTERPOSITUS NUCLEUS IN MOVEMENT CONTROL AND EMOTION
    (Springer Science+Business Media New York 2013, 2013-04-13) V. Perciavalle, R. Apps, V. Bracha, J.M. Delgado-García, A.R. Gibson, M. Leggio, A.J. Carrel, N. Cerminara, M. Coco, A. Gruart, and R. Sánchez-Campusano; Gruart, Agnès; Sánchez-Campusano, Raudel
    In the present paper, we examine the role of the cerebellar interpositus nucleus (IN) in motor and non-motor domains. Recent findings are considered, and we share the following conclusions: IN as part of the olivo-corticonuclear microcircuit is involved in providing powerful timing signals important in coordinating limb movements; IN could participate in the timing and performance of ongoing conditioned responses rather than the generation and/or initiation of such responses; IN is involved in the control of reflexive and voluntary movements in a task- and effector system-dependent fashion, including hand movements and associated upper limb adjustments, for quick effective actions; IN develops internal models for dynamic interactions of the motor system with the external environment for anticipatory control of movement; and IN plays a significant role in the modulation of autonomic and emotional functions.
  • Publication
    DYNAMIC CHANGES IN THE CEREBELLAR-INTERPOSITUS/RED-NUCLEUS-MOTONEURON PATHWAY DURING MOTOR LEARNING
    (Springer Science+Business Media, LLC 2010, 2011-12) R. Sánchez-Campusano, A. Gruart, and J.M. Delgado-García; Sánchez-Campusano, Raudel; Gruart, Agnès
    Understanding the role played by the cerebellum in the genesis and control of learned motor responses requires a precise knowledge of interdependent relationships between kinetic neural commands and the performance (kinematics) of the acquired movements. The eyelid motor system is a useful model for studying how simple motor responses are generated and performed. Here, we recorded the activity of interpositus, red nucleus, and/or facial motor neurons during classical eyeblink conditioning, using a delay paradigm. Experiments were carried out in behaving cats, and in conscious wild-type and (Purkinje cell devoid) Lurcher mice. Kinetic variables were determined by recording the firing activities of identified neurons at the mentioned nuclei, whilst kinematic variables were selected from the electromyographic activity of the orbicularis oculi muscle and/or from eyelid position recorded during the conditioned-stimulus/ unconditioned-stimulus interval. Whereas motoneurons encoded eyelid kinematics for acquired eyelid responses, interpositus, and red nucleus neurons did not directly encode eyelid performance, and the dynamic association between their neuronal activities was barely significant (from moderate to weak correlation, nonlinear coupling with high asymmetry, and neural firing activities that always lagged the beginning of the conditioned response). Nevertheless, interpositus and red nucleus neurons seem to play a modulating role in the dynamic control of this type of learned motor response, and present interesting adaptive properties in Lurcher mice. The analytical procedures proposed here could be very helpful in defining the functional state corresponding to each stage across the acquisition of new motor and cognitive abilities.
  • Publication
    THE ACTIVITY OF THE PRELIMBIC CORTEX IN RATS IS ENHANCED DURING THE COOPERATIVE ACQUISITION OF AN INSTRUMENTAL LEARNING TASK
    (Elsevier Ltd, 2019-09-12) A.R. Conde-Moro, F. Rocha-Almeida, R. Sánchez-Campusano, J.M. Delgado-García, A. Gruart; Sánchez-Campusano, Raudel; Gruart, Agnès
    The objective of this study was to identify the functional properties of the prefrontal cortex that allow animals to work together to obtain a mutual reward. We induced pairs of male rats to develop a cooperative behavior in two adjacent Skinner boxes divided by a metallic grille. The experimental boxes allowed the two rats to see and to smell each other and to have limited physical contact through the grille. Rats were progressively trained to climb onto two separate platforms (and stay there simultaneously for>0.5 s) to get food pellets for both. This set-up was compatible with the in vivo recording of local field potentials (LFPs) at the prelimbic (PrL) cortex throughout the task. A dominant delta/theta activity appeared mostly during the period in which rats were located on the platforms. Spectral powers were larger when rats had to stay together on the platforms than when they jumped individually onto them. When paired together, rats presented significant differences in the power of delta and low theta bands depending if they were leading or following the joint activity. PrL cortex encodes neural commands related to the individual and joint acquisition of an operant conditioning task by behaving rats.
  • Publication
    THE EPIGENETIC FACTOR CBP IS REQUIRED FOR THE DIFFERENTIATION AND FUNCTION OF MEDIAL GANGLIONIC EMINENCE-DERIVED INTERNEURONS
    (Springer Nature, 2019-06) A. Medrano-Fernández, J.M. Delgado-García, B. Del-Blanco, M. Llinares, R. Sánchez-Campusano, R. Olivares, A. Gruart, A. Barco; Sánchez-Campusano, Raudel; Gruart, Agnès
    The development of inhibitory circuits depends on the action of a network of transcription factors and epigenetic regulators that are critical for interneuron specification and differentiation. Although the identity of many of these transcription factors is well established, much less is known about the specific contribution of the chromatin-modifying enzymes that sculpt the interneuron epigenome. Here, we generated a mouse model in which the lysine acetyltransferase CBP is specifically removed from neural progenitors at the median ganglionic eminence (MGE), the structure where the most abundant types of cortical interneurons are born. Ablation of CBP interfered with the development of MGE-derived interneurons in both sexes, causing a reduction in the number of functionally mature interneurons in the adult forebrain. Genetic fate mapping experiments not only demonstrated that CBP ablation impacts on different interneuron classes, but also unveiled a compensatory increment of interneurons that escaped recombination and cushion the excitatory-inhibitory imbalance. Consistent with having a reduced number of interneurons, CBPdeficient mice exhibited a high incidence of spontaneous epileptic seizures, and alterations in brain rhythms and enhanced low gamma activity during status epilepticus. These perturbations led to abnormal behavior including hyperlocomotion, increased anxiety and cognitive impairments. Overall, our study demonstrates that CBP is essential for interneuron development and the proper functioning of inhibitory circuitry in vivo.
  • Publication
    TRANSCRANIAL DIRECT-CURRENT STIMULATION MODULATES SYNAPTIC MECHANISMS INVOLVED IN ASSOCIATIVE LEARNING IN BEHAVING RABBITS
    (Proceedings of the National Academy of Sciences of the United States of America, 2012-04-24) J. Márquez-Ruiz, R. Leal-Campanario, R. Sánchez-Campusano, B. Molaee-Ardekani, F. Wendling, P.C. Miranda, G. Ruffini, A. Gruart, and J.M. Delgado-García; Leal Campanario, Rocío; Sánchez-Campusano, Raudel; Gruart, Agnès
    Transcranial direct-current stimulation (tDCS) is a noninvasive brain stimulation technique that has been successfully applied for modulation of cortical excitability. tDCS is capable of inducing changes in neuronal membrane potentials in a polarity-dependent manner. When tDCS is of sufficient length, synaptically driven aftereffects are induced. The mechanisms underlying these after-effects are largely unknown, and there is a compelling need for animal models to test the immediate effects and after-effects induced by tDCS in different cortical areas and evaluate the implications in complex cerebral processes. Here we show in behaving rabbits that tDCS applied over the somatosensory cortex modulates cortical processes consequent to localized stimulation of the whisker pad or of the corresponding area of the ventroposterior medial (VPM) thalamic nucleus. With longer stimulation periods, poststimulation effects were observed in the somatosensory cortex only after cathodal tDCS. Consistent with the polarity-specific effects, the acquisition of classical eyeblink conditioning was potentiated or depressed by the simultaneous application of anodal or cathodal tDCS, respectively, when stimulation of the whisker pad was used as conditioned stimulus, suggesting that tDCS modulates the sensory perception process necessary for associative learning. We also studied the putative mechanisms underlying immediate effects and after-effects of tDCS observed in the somatosensory cortex. Results when pairs of pulses applied to the thalamic VPM nucleus (mediating sensory input) during anodal and cathodal tDCS suggest that tDCS modifies thalamocortical synapses at presynaptic sites. Finally, we show that blocking the activation of adenosine A1 receptors prevents the long-term depression (LTD) evoked in the somatosensory cortex after cathodal tDCS.
  • Publication
    EFFECTS OF TRANSCRANIAL DIRECT CURRENT STIMULATION (tDCS) ON CORTICAL ACTIVITY: A COMPUTATIONAL MODELING STUDY
    (Elsevier Inc., 2013-01) B. Molaee-Ardekani, J. Márquez-Ruiz, I. Merlet, R. Leal-Campanario, A. Gruart, R. Sánchez-Campusano, G. Birot, G. Ruffini, J.M. Delgado-García, and F. Wendling; Leal Campanario, Rocío; Gruart, Agnès; Sánchez-Campusano, Raudel
    Although it is well-admitted that transcranial Direct Current Stimulation (tDCS) allows for interacting with brain endogenous rhythms, the exact mechanisms by which externally-applied fields modulate the activity of neurons remain elusive. In this study a novel computational model (a neural mass model including subpopulations of pyramidal cells and inhibitory interneurons mediating synaptic currents with either slow or fast kinetics) of the cerebral cortex was elaborated to investigate the local effects of tDCS on neuronal populations based on an in-vivo experimental study. Model parameters were adjusted to reproduce evoked potentials (EPs) recorded from the somatosensory cortex of the rabbit in response to air-puffs applied on the whiskers. EPs were simulated under control condition (no tDCS) as well as under anodal and cathodal tDCS fields. Results first revealed that a feed-forward inhibition mechanism must be included in the model for accurate simulation of actual EPs (peaks and latencies). Interestingly, results revealed that externally-applied fields are also likely to affect interneurons. Indeed, when interneurons get polarized then the characteristics of simulated EPs become closer to those of real EPs. In particular, under anodal tDCS condition, more realistic EPs could be obtained when pyramidal cells were depolarized and, simultaneously, slow (resp. fast) interneurons became de- (resp. hyper-) polarized. Geometrical characteristics of interneurons might provide some explanations for this effect.
  • Publication
    BEHAVIORAL CHARACTERISTICS, ASSOCIATIVE LEARNING CAPABILITIES AND DYNAMIC ASSOCIATION MAPPING IN AN ANIMAL MODEL OF CEREBELLAR DEGENERATION
    (The American Physiological Society, 2010-07-01) E. Porras-García*, R. Sánchez-Campusano*, D. Martínez-Vargas, E. Domínguez-del-Toro, J. Cendelín, F. Vozeh, and J.M. Delgado-García; Sánchez-Campusano, Raudel
    Young adult heterozygous Lurcher mice constitute an excellent model for studying the role of the cerebellar cortex in motor performance—including the acquisition of new motor abilities— because of the early postnatal degeneration of almost all of their Purkinje and granular cells. Wild-type and Lurcher mice were classically conditioned for eyelid responses using a delay paradigm with or without an electrolytic lesion in the interpositus nucleus. Although the late component of electrically evoked blink reflexes was smaller in amplitude and had a longer latency in Lurcher mice than that in controls, the two groups of animals presented similar acquisition curves for eyeblink conditioning. The lesion of the interpositus nucleus affected both groups of animals equally for the generation of reflex and conditioned eyelid responses. Furthermore, we recorded the multiunitary activity at the red and interpositus nuclei during the same type of associative learning. In both nuclei, the neural firing activity lagged the beginning of the conditioned response (determined by orbicularis oculi muscle response). Although red nucleus neurons and muscle activities presented a clear functional coupling (strong correlation and low asymmetry) across conditioning, the coupling between interpositus neurons and either red nucleus neurons or muscle activities was slightly significant (weak correlation and high asymmetry). Lurcher mice presented a nonlinear coupling (high asymmetry) between red nucleus neurons and muscle activities, with an evident compensatory adjustment in the correlation of firing between interpositus and red nuclei neurons (a coupling with low asymmetry), aimed probably at compensating the absence of cerebellar cortical neurons. *These authors contributed equally to this work: E. Porras-García and R. Sánchez-Campusano.
  • Publication
    PRESYNAPTIC GABAB RECEPTORS REGULATE HIPPOCAMPAL SYNAPSES DURING ASSOCIATIVE LEARNING IN BEHAVING MICE
    (Public Library of Science, 2016-02-05) M.T. Jurado-Parras, J.M. Delgado-García, R. Sánchez-Campusano, M. Gassmann, B. Bettler, A. Gruart; Sánchez-Campusano, Raudel; Gruart, Agnès
    GABAB receptors are the G-protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the central nervous system. Pharmacological activation of GABAB receptors regulates neurotransmission and neuronal excitability at pre- and postsynaptic sites. Electrophysiological activation of GABAB receptors in brain slices generally requires strong stimulus intensities. This raises the question as to whether behavioral stimuli are strong enough to activate GABAB receptors. Here we show that GABAB1a -/- mice, which constitutively lack presynaptic GABAB receptors at glutamatergic synapses, are impaired in their ability to acquire an operant learning task. In vivo recordings during the operant conditioning reveal a deficit in learning-dependent increases in synaptic strength at CA3-CA1 synapses. Moreover, GABAB1a -/- mice fail to synchronize neuronal activity in the CA1 area during the acquisition process. Our results support that activation of presynaptic hippocampal GABAB receptors is important for acquisition of a learning task and for learning-associated synaptic changes and network dynamics.
  • Publication
    AN AGONIST-ANTAGONIST CEREBELLAR NUCLEAR SYSTEM CONTROLLING EYELID KINEMATICS DURING MOTOR LEARNING
    (Frontiers Media, 2012-03-14) Sánchez-Campusano, Raudel; Gruart, Agnès; Fernández-Mas, R.
    The presence of two antagonistic groups of deep cerebellar nuclei neurons has been reported as necessary for a proper dynamic control of learned motor responses. Most models of cerebellar function seem to ignore the biomechanical need for a double activation–deactivation system controlling eyelid kinematics, since most of them accept that, for closing the eyelid, only the activation of the orbicularis oculi muscle (via the red nucleus to the facial motor nucleus) is necessary, without a simultaneous deactivation of levator palpebrae motoneurons (via unknown pathways projecting to the perioculomotor area). We have analyzed the kinetic neural commands of two antagonistic types of cerebellar posterior interpositus neuron (types A and B), the electromyographic activity of the orbicularis oculi muscle, and eyelid kinematic variables in alert behaving cats during classical eyeblink conditioning, using a delay paradigm. We addressed the hypothesis that the interpositus nucleus can be considered an agonist–antagonist system controlling eyelid kinematics during motor learning. To carry out a comparative study of the kinetic–kinematic relationships, we applied timing and dispersion pattern analyses. We concluded that, in accordance with a dominant role of cerebellar circuits for the facilitation of flexor responses, type A neurons fire during active eyelid downward displacements ─ i.e., during the active contraction of the orbicularis oculi muscle. In contrast, type B neurons present a high tonic rate when the eyelids are wide open, and stop firing during any active downward displacement of the upper eyelid. From a functional point of view, it could be suggested that type B neurons play a facilitative role for the antagonistic action of the levator palpebrae muscle. From an anatomical point of view, the possibility that cerebellar nuclear type B neurons project to the perioculomotor area ─ i.e., more or less directly onto levator palpebrae motoneurons ─ is highly appealing.