Cortical Auditory Adaptation in the Awake Rat and the Role of Potassium Currents

Responses to sound in the auditory cortex are influenced by the preceding history of firing. We studied the time course of auditory adaptation in primary auditory cortex (A1) from awake, freely moving rats. Two identical stimuli were delivered with different intervals ranging from 50 ms to 8 s. Single neuron recordings in the awake animal revealed that the response to a sound is influenced by sounds delivered even several seconds earlier, the second one usually yielding a weaker response. To understand the role of neuronal intrinsic properties in this phenomenon, we obtained intracellular recordings from rat A1 neurons in vitro and mimicked the same protocols of adaptation carried out in awake animals by means of depolarizing pulses of identical duration and intervals. The intensity of the pulses was adjusted such that the first pulse would evoke a similar number of spikes as its equivalent in vivo. A1 neurons in vitro adapted with a similar time course but less than in awake animals. At least two potassium currents participated in the in vitro adaptation: a Na +-dependent K + current and an apamin-sensitive K + current. Our results suggest that potassium currents underlie at least part of cortical auditory adaptation during the awake state.Fil: Abolafia, Juan M.. INSTITUTO DE INVESTIGACIONES BIOMEDICAS AUGUST PI I SUNYER (IDIBAPS);Fil: Vergara, Ramiro Oscar. INSTITUTO DE INVESTIGACIONES BIOMEDICAS AUGUST PI I SUNYER (IDIBAPS); . Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España. Universidad Nacional de Quilmes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Arnold, M. M.. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España. INSTITUTO DE INVESTIGACIONES BIOMEDICAS AUGUST PI I SUNYER (IDIBAPS);Fil: Reig, R.. INSTITUTO DE INVESTIGACIONES BIOMEDICAS AUGUST PI I SUNYER (IDIBAPS);Fil: Sanchez Vives, M. V.. INSTITUTO DE INVESTIGACIONES BIOMEDICAS AUGUST PI I SUNYER (IDIBAPS)

The cortical states of wakefulness

Cortical neurons process information on a background of spontaneous, ongoing activity with distinct spatiotemporal profiles defining different cortical states. During wakefulness, cortical states alter constantly in relation to behavioral context, attentional level or general motor activity. In this review article, we will discuss our current understanding of cortical states in awake rodents, how they are controlled, their impact on sensory processing, and highlight areas for future research. A common observation in awake rodents is the rapid change in spontaneous cortical activity from high-amplitude, low-frequency (LF) fluctuations, when animals are quiet, to faster and smaller fluctuations when animals are active. This transition is typically thought of as a change in global brain state but recent work has shown variation in cortical states across regions, indicating the presence of a fine spatial scale control system. In sensory areas, the cortical state change is mediated by at least two convergent inputs, one from the thalamus and the other from cholinergic inputs in the basal forebrain. Cortical states have a major impact on the balance of activity between specific subtypes of neurons, on the synchronization between nearby neurons, as well as the functional coupling between distant cortical areas. This reorganization of the activity of cortical networks strongly affects sensory processing. Thus cortical states provide a dynamic control system for the moment-by-moment regulation of cortical processing

Up and down states and memory consolidation across somatosensory, entorhinal, and hippocampal cortices

In the course of a day, brain states fluctuate, from conscious awake information-acquiring states to sleep states, during which previously acquired information is further processed and stored as memories. One hypothesis is that memories are consolidated and stored during "offline" states such as sleep, a process thought to involve transfer of information from the hippocampus to other cortical areas. Up and Down states (UDS), patterns of activity that occur under anesthesia and sleep states, are likely to play a role in this process, although the nature of this role remains unclear. Here we review what is currently known about these mechanisms in three anatomically distinct but interconnected cortical areas: somatosensory cortex, entorhinal cortex, and the hippocampus. In doing so, we consider the role of this activity in the coordination of "replay" during sleep states, particularly during hippocampal sharp-wave ripples. We conclude that understanding the generation and propagation of UDS may provide key insights into the cortico-hippocampal dialogue linking archi- and neocortical areas during memory formation

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

Multiplexed calcium imaging of single-synapse activity and astroglial responses in the intact brain

All-optical registration of neuronal and astrocytic activities within the intact mammalian brain has improved significantly with recent advances in optical sensors and biophotonics. However, relating single-synapse release events and local astroglial responses to sensory stimuli in an intact animal has not hitherto been feasible. Here, we present a multiplexed multiphoton excitation imaging approach for assessing the relationship between presynaptic Ca2+ entry at thalamocortical axonal boutons and perisynaptic astrocytic Ca2+ elevations, induced by whisker stimulation in the barrel cortex of C57BL/6 mice. We find that, unexpectedly, Ca2+ elevations in the perisynaptic astrocytic regions consistently precede local presynaptic Ca2+ signals during spontaneous brain activity associated with anaesthesia. The methods described here can be adapted to a variety of optical sensors and are compatible with experimental designs that might necessitate repeated sampling of single synapses over a longitudinal behavioural paradigm

Network Model of Spontaneous Activity Exhibiting Synchronous Transitions Between Up and Down States

Both in vivo and in vitro recordings indicate that neuronal membrane potentials can make spontaneous transitions between distinct up and down states. At the network level, populations of neurons have been observed to make these transitions synchronously. Although synaptic activity and intrinsic neuron properties play an important role, the precise nature of the processes responsible for these phenomena is not known. Using a computational model, we explore the interplay between intrinsic neuronal properties and synaptic fluctuations. Model neurons of the integrate-and-fire type were extended by adding a nonlinear membrane current. Networks of these neurons exhibit large amplitude synchronous spontaneous fluctuations that make the neurons jump between up and down states, thereby producing bimodal membrane potential distributions. The effect of sensory stimulation on network responses depends on whether the stimulus is applied during an up state or deeply inside a down state. External noise can be varied to modulate the network continuously between two extreme regimes in which it remains permanently in either the up or the down state

The (un)conscious mouse as a model for human brain functions: key principles of anesthesia and their impact on translational neuroimaging

In recent years, technical and procedural advances have brought functional magnetic resonance imaging (fMRI) to the field of murine neuroscience. Due to its unique capacity to measure functional activity non-invasively, across the entire brain, fMRI allows for the direct comparison of large-scale murine and human brain functions. This opens an avenue for bidirectional translational strategies to address fundamental questions ranging from neurological disorders to the nature of consciousness. The key challenges of murine fMRI are: (1) to generate and maintain functional brain states that approximate those of calm and relaxed human volunteers, while (2) preserving neurovascular coupling and physiological baseline conditions. Low-dose anesthetic protocols are commonly applied in murine functional brain studies to prevent stress and facilitate a calm and relaxed condition among animals. Yet, current mono-anesthesia has been shown to impair neural transmission and hemodynamic integrity. By linking the current state of murine electrophysiology, Ca(2+) imaging and fMRI of anesthetic effects to findings from human studies, this systematic review proposes general principles to design, apply and monitor anesthetic protocols in a more sophisticated way. The further development of balanced multimodal anesthesia, combining two or more drugs with complementary modes of action helps to shape and maintain specific brain states and relevant aspects of murine physiology. Functional connectivity and its dynamic repertoire as assessed by fMRI can be used to make inferences about cortical states and provide additional information about whole-brain functional dynamics. Based on this, a simple and comprehensive functional neurosignature pattern can be determined for use in defining brain states and anesthetic depth in rest and in response to stimuli. Such a signature can be evaluated and shared between labs to indicate the brain state of a mouse during experiments, an important step toward translating findings across species