Aprendiendo de las consecuencias de los actos: estudio electrofisiológico del hipocampo, corteza prefrontal y núcleo accumbens

Programa de Doctorado en NeurocienciasLa presente Tesis Doctoral se ha centrado en el estudio del papel del hipocampo, la corteza prefrontal medial y el núcleo accumbens en la adquisición del condicionamiento instrumental, del aprendizaje por observación y de la ejecución de tareas instrumentales. Además, se ha estudiado la participación de las sinapsis CA3 ¿ CA1, CA1 ¿ corteza prefrontal medial, corteza prefrontal medial ¿ núcleo accumbens y núcleo accumbens ¿ corteza prefrontal medial en el aprendizaje instrumental. El diseño experimental incluye la implantación crónica de electrodos de registro y estimulación en el hipocampo, la corteza prefrontal medial y el núcleo accumbens. De esta manera se ha podido registrar la actividad electroencefalográfica, estudiar la eficacia de las sinapsis y aplicar diferentes protocolos de estimulación, a la vez que el animal adquiría el condicionamiento instrumental, aprendía por observación o ejecutaba la tarea instrumental. Los resultados obtenidos muestran que, una vez aprendida la tarea operante, se observan cambios en la eficacia de la sinapsis CA3 ¿ CA1 y en la actividad EEG de las neuronas del área CA1 del hipocampo acordes con el comportamiento que el animal estuviese realizando en el momento. Sin embargo, nuestros resultados muestran que, probablemente, los animales ejecutarían la tarea de la misma manera aunque se alterasen estos cambios a corto plazo en el hipocampo. Se ha comprobado, también, que aunque las sinapsis CA1 ¿ corteza prefrontal medial, corteza prefrontal medial ¿ núcleo accumbens, núcleo accumbens ¿ corteza prefrontal medial podrían no participar en el aprendizaje del condicionamiento instrumental, se requiere que la actividad natural de las neuronas de la corteza prefrontal medial y el núcleo accumbens permanezca inalterable para la correcta ejecución de la tarea instrumental. La estimulación de ambas estructuras durante la práctica de la tarea instrumental produce efectos perturbadores sobre la ejecución de la misma. Asimismo, se ha demostrado estos efectos no se deben a una afectación del sistema motor sino a una alteración de los procesos cognitivos. La estimulación de ambas estructuras durante el proceso de aprendizaje por observación causa efectos opuestos: por un lado, la estimulación de la corteza prefrontal medial impide que se produzca el aprendizaje por observación, y por el otro, la estimulación del núcleo accumbens favorece el mismo aprendizaje. Estos resultados sugieren que tanto la corteza prefrontal medial como el núcleo accumbens participan tanto en la ejecución de la tarea instrumental como en el aprendizaje por observación de la misma.Universidad Pablo de Olavide. Departamento de Fisiología, Anatomía y Biología Celula

Deep learning-based feature extraction for prediction and interpretation of sharp-wave ripples in the rodent hippocampus

Local field potential (LFP) deflections and oscillations define hippocampal sharp-wave ripples (SWRs), one of the most synchronous events of the brain. SWRs reflect firing and synaptic current sequences emerging from cognitively relevant neuronal ensembles. While spectral analysis have permitted advances, the surge of ultra-dense recordings now call for new automatic detection strategies. Here, we show how one-dimensional convolutional networks operating over highdensity LFP hippocampal recordings allowed for automatic identification of SWR from the rodent hippocampus. When applied without retraining to new datasets and ultra-dense hippocampus-wide recordings, we discovered physiologically relevant processes associated to the emergence of SWR, prompting for novel classification criteria. To gain interpretability, we developed a method to interrogate the operation of the artificial network. We found it relied in feature-based specialization, which permit identification of spatially segregated oscillations and deflections, as well as synchronous population firing typical of replay. Thus, using deep learning-based approaches may change the current heuristic for a better mechanistic interpretation of these relevant neurophysiological events.This work is supported by grants from Fundación La Caixa (LCF/PR/HR21/52410030; DeepCode). Access to the Artemisa high-performance computing infrastructure (NeuroConvo project) is supported by Universidad de Valencia and co-funded by the European Union through the 2014–2020 FEDER Operative Programme (IDIFEDER/2018/048). ANO and RA are supported by PhD fellowships from the Spanish Ministry of Education (FPU17/03268) and Universidad Autónoma de Madrid (FPI-UAM-2017), respectively. We thank Elena Cid for help with histological confirmation of the probe tracks and Pablo Varona for feedback and discussion. We also thank Aarón Cuevas for clarifications and support while developing the Open Ephys Plugin for online detection

Multimodal determinants of phase-locked dynamics across deep-superficial hippocampal sublayers during theta oscillations

Theta oscillations play a major role in temporarily defining the hippocampal rate code by translating behavioral sequences into neuronal representations. However, mechanisms constraining phase timing and cell-type-specific phase preference are unknown. Here, we employ computational models tuned with evolutionary algorithms to evaluate phase preference of individual CA1 pyramidal cells recorded in mice and rats not engaged in any particular memory task. We applied unbiased and hypothesis-free approaches to identify effects of intrinsic and synaptic factors, as well as cell morphology, in determining phase preference. We found that perisomatic inhibition delivered by complementary populations of basket cells interacts with input pathways to shape phase-locked specificity of deep and superficial pyramidal cells. Somatodendritic integration of fluctuating glutamatergic inputs defined cycle-by-cycle by unsupervised methods demonstrated that firing selection is tuneable across sublayers. Our data identify different mechanisms of phase-locking selectivity that are instrumental for flexible dynamical representations of theta sequences

Immature Dentate Granule Cells Require Ntrk2/Trkb for the Formation of Functional Hippocampal Circuitry

Early in brain development, impaired neuronal signaling during time-sensitive windows triggers the onset of neurodevelopmental disorders. GABA, through its depolarizing and excitatory actions, drives early developmental events including neuronal circuit formation and refinement. BDNF/TrkB signaling cooperates with GABA actions. How these developmental processes influence the formation of neural circuits and affect adult brain function is unknown. Here, we show that early deletion of Ntrk2/Trkb from immature mouse hippocampal dentate granule cells (DGCs) affects the integration and maturation of newly formed DGCs in the hippocampal circuitry and drives a premature shift from depolarizing to hyperpolarizing GABAergic actions in the target of DGCs, the CA3 principal cells of the hippocampus, by reducing the expression of the cation-chloride importer Nkcc1. These changes lead to the disruption of early synchronized neuronal activity at the network level and impaired morphological maturation of CA3 pyramidal neurons, ultimately contributing to altered adult hippocampal synaptic plasticity and cognitive processes

An update to Hippocampome.org by integrating single-cell phenotypes with circuit function in vivo

Understanding brain operation demands linking basic behavioral traits to cell-type specific dynamics of different brain-wide subcircuits. This requires a system to classify the basic operational modes of neurons and circuits. Single-cell phenotyping of firing behavior during ongoing oscillations in vivo has provided a large body of evidence on entorhinal-hippocampal function, but data are dispersed and diverse. Here, we mined literature to search for information regarding the phase-timing dynamics of over 100 hippocampal/entorhinal neuron types defined in . We identified missing and unresolved pieces of knowledge (e.g., the preferred theta phase for a specific neuron type) and complemented the dataset with our own new data. By confronting the effect of brain state and recording methods, we highlight the equivalences and differences across conditions and offer a number of novel observations. We show how a heuristic approach based on oscillatory features of morphologically identified neurons can aid in classifying extracellular recordings of single cells and discuss future opportunities and challenges towards integrating single-cell phenotypes with circuit function.Peer reviewe

Local or Not Local: Investigating the Nature of Striatal Theta Oscillations in Behaving Rats

International audienceVisual Abstract In the cortex and hippocampus, neuronal oscillations of different frequencies can be observed in local field potentials (LFPs). LFPs oscillations in the theta band (6-10 Hz) have also been observed in the dorsolateral striatum (DLS) of rodents, mostly during locomotion, and have been proposed to mediate behaviorally-relevant interactions between striatum and cortex (or between striatum and hippocampus). However, it is unclear if these theta oscillations are generated in the striatum. To address this issue, we recorded LFPs and spiking activity in the DLS of rats performing a running sequence on a motorized treadmill. We observed an increase in rhythmical activity of the LFP in the theta-band during run compared to rest periods. However, several observations suggest that these oscillations are mainly generated outside of the striatum. First, theta oscillations disappeared when Significance Statement In the cortex and hippocampus, neuronal network oscillations can be observed in the local field potentials (LFPs) and contribute to information transfer between brain regions. LFP oscillations can also be recorded in the striatum, even if, unlike the cortex and hippocampus, this brain region's anatomic organization does not favor the generation of dipolar sources. It is therefore unclear if these striatal oscillations are locally generated or reflect volume-conducted signals generated distally from the striatum. Here, we provide evidence that striatal theta oscillations of the LFPs recorded while rats performed a running sequence are largely contaminated by volume-conducted signals. We propose that theta LFP oscillations in the striatum do not accurately reflect local cellular activity and should be interpreted with caution

Learning capabilities and CA1-prefrontal synaptic plasticity in a mice model of accelerated senescence

Abstract SAMP8 mice represent a suitable model of accelerated senescence as compared with SAMR1 animals presenting normal aging. Five-month-old SAMP8 mice presented reflex eyelid responses like those of SAMR1 controls, but were incapable of acquiring classicallyconditioned eye blink responses in a trace (230 milliseconds [ms] of interstimulus interval) paradigm. Although SAMP8 mice presented a normal paired-pulse facilitation of the hippocampal CA1-medial prefrontal synapse, an input/output curve study revealed smaller field excitatory postsynaptic potentials (fEPSPs) in response to strong stimulations of the CA1-prefrontal pathway. Moreover, SAMP8 mice did not show any activity-dependent potentiation of the CA1-prefrontal synapse across the successive conditioning sessions shown by SAMR1 animals. In addition, SAMP8 mice presented a functional deficit during an object recognition test, continuing to explore the familiar object when controls moved to the novel one. Alert behaving SAMP8 mice presented a significant deficit in long-term potentiation (LTP) at the CA1-medial prefrontal synapse. According to the present results, SAMP8 mice present noticeable functional deficits in hippocampal and prefrontal cortical circuits directly related with the acquisition and storage of new motor and cognitive abilities

The Dorsal Striatum Energizes Motor Routines

International audienceThe dorsal striatum (dS) has been implicated in storing procedural memories and controlling movement kinematics. Since procedural memories are expressed through movements, the exact nature of the dS function has proven difficult to delineate. Here we challenged rats in complementary locomotion-based tasks designed to alleviate this confound. Surprisingly, dS lesions did not impair the rats' ability to remember the procedure for the successful completion of motor routines. However, the speed and initiation of the rewardoriented phase of the routines were irreversibly altered by the dS lesion. Further behavioral analyses combined with modeling in the optimal control framework indicated that these kinematic alterations were well-explained by an increased sensitivity to effort. Our work provides evidence supporting a primary role of the dS in modulating the kinematics of reward-oriented actions, a function that may be related to the optimization of the energetic costs of moving

Presynaptic GABAB Receptors Regulate Hippocampal Synapses during Associative Learning in Behaving Mice

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

Turning the body into a clock: Accurate timing is facilitated by simple stereotyped interactions with the environment

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