Associative memory of phase-coded spatiotemporal patterns in leaky Integrate and Fire networks

We study the collective dynamics of a Leaky Integrate and Fire network in which precise relative phase relationship of spikes among neurons are stored, as attractors of the dynamics, and selectively replayed at differentctime scales. Using an STDP-based learning process, we store in the connectivity several phase-coded spike patterns, and we find that, depending on the excitability of the network, different working regimes are possible, with transient or persistent replay activity induced by a brief signal. We introduce an order parameter to evaluate the similarity between stored and recalled phase-coded pattern, and measure the storage capacity. Modulation of spiking thresholds during replay changes the frequency of the collective oscillation or the number of spikes per cycle, keeping preserved the phases relationship. This allows a coding scheme in which phase, rate and frequency are dissociable. Robustness with respect to noise and heterogeneity of neurons parameters is studied, showing that, since dynamics is a retrieval process, neurons preserve stablecprecise phase relationship among units, keeping a unique frequency of oscillation, even in noisy conditions and with heterogeneity of internal parameters of the units

Mecanismos biofísicos y fuentes de los potenciales extracelulares en el hipocampo

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Físicas, Departamento de Física Aplicada III (Electricidad y Electrónica), leída el 20-11-2015Depto. de Estructura de la Materia, Física Térmica y ElectrónicaFac. de Ciencias FísicasTRUEunpu

Parallel and convergent processing in grid cell, head-direction cell, boundary cell, and place cell networks.

The brain is able to construct internal representations that correspond to external spatial coordinates. Such brain maps of the external spatial topography may support a number of cognitive functions, including navigation and memory. The neuronal building block of brain maps are place cells, which are found throughout the hippocampus of rodents and, in a lower proportion, primates. Place cells typically fire in one or few restricted areas of space, and each area where a cell fires can range, along the dorsoventral axis of the hippocampus, from 30 cm to at least several meters. The sensory processing streams that give rise to hippocampal place cells are not fully understood, but substantial progress has been made in characterizing the entorhinal cortex, which is the gateway between neocortical areas and the hippocampus. Entorhinal neurons have diverse spatial firing characteristics, and the different entorhinal cell types converge in the hippocampus to give rise to a single, spatially modulated cell type-the place cell. We therefore suggest that parallel information processing in different classes of cells-as is typically observed at lower levels of sensory processing-continues up into higher level association cortices, including those that provide the inputs to hippocampus. WIREs Cogn Sci 2014, 5:207-219. doi: 10.1002/wcs.1272 Conflict of interest: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website

The role of medial entorhinal cortex activity in hippocampal CA1 spatiotemporally correlated sequence generation and object selectivity for memory function

The hippocampus is crucial for episodic memory and certain forms of spatial navigation. Firing activity of hippocampal principal neurons contains environmental information, including the presence of specific objects, as well as the animal’s spatial and temporal position relative to environmental and behavioral cues. The organization of these firing correlates may allow the formation of memory traces through the integration of object and event information onto a spatiotemporal framework of cell assemblies. Characterizing how external inputs guide internal dynamics in the hippocampus to enable this process across different experiences is crucial to understanding hippocampal function. A body of literature implicates the medial entorhinal cortex (MEC) in supplying spatial and temporal information to the hippocampus. Here we develop a protocol utilizing bilaterally implanted custom designed triple fiber optic arrays and the red-shifted inhibitory opsin JAWS to transiently inactivate large volumes of MEC in freely behaving rats. This was coupled with extracellular tetrode recording of ensembles in CA1 of the hippocampus during a novel memory task involving temporal, spatial and object related epochs, in order to assess the importance of MEC activity for hippocampal feature selectivity during a rich and familiar experience. We report that inactivation of MEC during a mnemonic temporal delay disrupts the existing temporal firing field sequence in CA1 both during and following the inactivation period. Neurons with firing fields prior to the inactivation on each trial remained relatively stable. The disruption of CA1 temporal firing field sequences was accompanied by a behavioral deficit implicating MEC activity and hippocampal temporal field sequences in effective memory across time. Inactivating MEC during the object or spatial epochs of the task did not significantly alter CA1 object selective or spatial firing fields and behavioral performance remained stable. Our findings suggest that MEC is crucial specifically for temporal field organization and expression during a familiar and rich experience. These results support a role for MEC in guiding hippocampal cell assembly sequences in the absence of salient changing stimuli, which may extend to the navigation of cognitive organization in humans and support memory formation and retrieval

MAPPING LOW-FREQUENCY FIELD POTENTIALS IN BRAIN CIRCUITS WITH HIGH-RESOLUTION CMOS ELECTRODE ARRAY RECORDINGS

Neurotechnologies based on microelectronic active electrode array devices are on the way to provide the capability to record electrophysiological neural activity from a thousands of closely spaced microelectrodes. This generates increasing volumes of experimental data to be analyzed, but also offers the unprecedented opportunity to observe bioelectrical signals at high spatial and temporal resolutions in large portions of brain circuits. The overall aim of this PhD was to study the application of high-resolution CMOS-based electrode arrays (CMOS-MEAs) for electrophysiological experiments and to investigate computational methods adapted to the analysis of the electrophysiological data generated by these devices. A large part of my work was carried out on cortico-hippocampal brain slices by focusing on the hippocampal circuit. In the history of neuroscience, a major technological advance for hippocampal research, and also for the field of neurobiology, was the development of the in vitro hippocampal slice preparation. Neurobiological principles that have been discovered from work on in vitro hippocampal preparations include, for instance, the identification of excitatory and inhibitory synapses and their localization, the characterization of transmitters and receptors, the discovery of long-term potentiation (LTP) and long-term depression (LTD) and the study of oscillations in neuronal networks. In this context, an initial aim of my work was to optimize the preparation and maintenance of acute cortico-hippocampal brain slices on planar CMOS-MEAs. At first, I focused on experimental methods and computational data analysis tools for drug-screening applications based on LTP quantifications. Although the majority of standard protocols still use two electrodes platforms for quantifying LTP, in my PhD I investigate the potential advantages of recording the electrical activity from many electrodes to spatiotemporally characterized electrically induced responses. This work also involved the collaboration with 3Brain AG and a CRO involved in drug-testing, and led to a software tool that was licensed for developing its exploitation. In a second part of my work I focused on exploiting the recording resolution of planar CMOS-MEAs to study the generation of sharp wave ripples (SPW-Rs) in the hippocampal circuit. This research activity was carried out also by visiting the laboratory of Prof. A. Sirota (Ludwig Maximilians University, Munich). In addition to set-up the experimental conditions to record SPW-Rs from planar CMOS-MEAs integrating 4096 microelectrodes, I also explored the implementation of a data analysis pipeline to identify spatiotemporal features that might characterize different type of in-vitro generated SPW-R events. Finally, I also contributed to the initial implementation of high-density implantable CMOS-probes for in-vivo electrophysiology with the aim of evaluating in vivo the algorithms that I developed and investigated on brain slices. With this aim, in the last period of my PhD I worked on the development of a Graphical User Interface for controlling active dense CMOS probes (or SiNAPS probes) under development in our laboratory. I participated to preliminary experimental recordings using 4-shank CMOS-probes featuring 1024 simultaneously recording electrodes and I contributed to the development of a software interface for executing these experiments

Optogenetic Interrogation of Hippocampal Circuit Stabilization

Understanding the response of excitatory and inhibitory populations to varying input is vital to understanding how a brain region transforms information. Optogenetics - the combined use of optics and genetics to control the activity of proteins, provides neuroscientists with a tool to interrogate neuronal circuits with high spatio-temporal resolution and targeted cell specificity. This thesis examines the effects of optogenetic manipulations on hippocampal circuit responses. The hippocampus is a structure required for the formation and retention of episodic memories and is comprised of anatomically distinct subregions including cornu ammonis 3 (CA3) and cornu ammonis 1 (CA1). Both regions, despite differences in local circuitry, contain excitatory cells that fire in a spatially selective manner as an animal explores an environment. Based on these differences in circuitry, studies have proposed different computational roles of each region. In order to gain insight into how distinct hippocampal networks respond to light-induced external drive we measured the responses of neurons in CA1 and CA3 to optogenetic perturbation. To date, no work has explored the differences in CA3 and CA1 network responses to acute optogenetic manipulation of the circuits. This thesis uses a combined approach of optogenetic perturbation with simultaneous high-density electrophysiological recordings to answer two fundamental questions related to the computational roles of region CA3 and CA1. The first question asks, what role does region CA3 play in shaping spiking activity in downstream CA1? To address this question, electrophysiological recordings of CA1 were combined with optogenetic silencing of CA3 using the light-driven proton pump ArchT in both freely moving and urethane-anesthetized rodents. Since the major projection from CA3 to CA1 is excitatory, our initial hypothesis predicted an overall decrease in CA1 activity due to the expected decrease in excitatory drive from CA3. Surprisingly, suppression of CA3 resulted in a robust and consistent increase in interneuron firing in CA1 (awake: 68\% increase, 10\% decrease, 22\% no response n = 87, anesthetized: 59\% increase, 26\% decrease, 15\% no response, n = 96). The second question asks, how do excitatory and inhibitory populations in CA3 and CA1 differentially respond to incoming signals? To address this question, integrated opto-electrode devices were used to simultaneously manipulate and measure the responses of CA3 and CA1 circuits to perturbations. We found that focal suppression of CA3 driven by both ArchT and the light-driven chloride channel stGtACR2 resulted in a paradoxical increase in firing of both inhibitory and excitatory cell at all distances from the site of photoinhibition. In contrast, CA1 cells responded to focal photoinhibition by showing nearly 100\% decrease in cell response at the site of illumination. Paradoxical increases in firing in response to external inhibitory input to interneurons can be a feature of networks with highly-recurrent excitatory connections that are unstable in the absence of inhibition (ISNs: inhibitory-stabilized networks. Broad (600 $\mu$m diameter) photoinhibition was applied and network responses were measured over a range of laser intensities to test whether differences in responses between CA3 and CA1 can be attributed to CA3 operating in an ISN-regime. Paradoxical increases in pyramidal cell or interneuron firing were not observed when inhibitory opsins were expressed in both pyramidal cells and interneurons. When external input was restricted to interneurons, CA1, and to a smaller extent, CA3 showed increased firing in response to varying intensities of photoinhibition, suggesting both CA1 and CA3 operate as ISNs. Taken together, these results indicate that perturbations of neuronal activity can produce paradoxical effects that affect both local and connected regions. The emerging patterns depend on the detailed interactions between excitatory and inhibitory subpopulations within a region, and can be broadly explained by network models of global stabilization through inhibition. Our results further highlight the need for simultaneous monitoring of cellular responses when using optogenetics or other manipulations that alter neuronal activities