Assessing Neuronal Interactions of Cell Assemblies during General Anesthesia

Understanding the way in which groups of cortical neurons change their individual and mutual firing activity during the induction of general anesthesia may improve the safe usage of many anesthetic agents. Assessing neuronal interactions within cell assemblies during anesthesia may be useful for understanding the neural mechanisms of general anesthesia. Here, a point process generalized linear model (PPGLM) was applied to infer the functional connectivity of neuronal ensembles during both baseline and anesthesia, in which neuronal firing rates and network connectivity might change dramatically. A hierarchical Bayesian modeling approach combined with a variational Bayes (VB) algorithm is used for statistical inference. The effectiveness of our approach is evaluated with synthetic spike train data drawn from small and medium-size networks (consisting of up to 200 neurons), which are simulated using biophysical voltage-gated conductance models. We further apply the analysis to experimental spike train data recorded from rats' barrel cortex during both active behavior and isoflurane anesthesia conditions. Our results suggest that that neuronal interactions of both putative excitatory and inhibitory connections are reduced after the induction of isoflurane anesthesia.National Institutes of Health (U.S.) (NIH Grants DP1-OD003646

Perioperative Neurocognitive Disorder: State of the Preclinical Science.

The purpose of this article is to provide a succinct summary of the different experimental approaches that have been used in preclinical postoperative cognitive dysfunction research, and an overview of the knowledge that has accrued. This is not intended to be a comprehensive review, but rather is intended to highlight how the many different approaches have contributed to our understanding of postoperative cognitive dysfunction, and to identify knowledge gaps to be filled by further research. The authors have organized this report by the level of experimental and systems complexity, starting with molecular and cellular approaches, then moving to intact invertebrates and vertebrate animal models. In addition, the authors' goal is to improve the quality and consistency of postoperative cognitive dysfunction and perioperative neurocognitive disorder research by promoting optimal study design, enhanced transparency, and "best practices" in experimental design and reporting to increase the likelihood of corroborating results. Thus, the authors conclude with general guidelines for designing, conducting and reporting perioperative neurocognitive disorder rodent research

State Dependence of Stimulus-Induced Variability Tuning in Macaque MT

Behavioral states marked by varying levels of arousal and attention modulate some properties of cortical responses (e.g. average firing rates or pairwise correlations), yet it is not fully understood what drives these response changes and how they might affect downstream stimulus decoding. Here we show that changes in state modulate the tuning of response variance-to-mean ratios (Fano factors) in a fashion that is neither predicted by a Poisson spiking model nor changes in the mean firing rate, with a substantial effect on stimulus discriminability. We recorded motion-sensitive neurons in middle temporal cortex (MT) in two states: alert fixation and light, opioid anesthesia. Anesthesia tended to lower average spike counts, without decreasing trial-to-trial variability compared to the alert state. Under anesthesia, within-trial fluctuations in excitability were correlated over longer time scales compared to the alert state, creating supra-Poisson Fano factors. In contrast, alert-state MT neurons have higher mean firing rates and largely sub-Poisson variability that is stimulus-dependent and cannot be explained by firing rate differences alone. The absence of such stimulus-induced variability tuning in the anesthetized state suggests different sources of variability between states. A simple model explains state-dependent shifts in the distribution of observed Fano factors via a suppression in the variance of gain fluctuations in the alert state. A population model with stimulus-induced variability tuning and behaviorally constrained information-limiting correlations explores the potential enhancement in stimulus discriminability by the cortical population in the alert state.Comment: 36 pages, 18 figure

Ongoing Spontaneous Activity Controls Access to Consciousness: A Neuronal Model for Inattentional Blindness

Even in the absence of sensory inputs, cortical and thalamic neurons can show structured patterns of ongoing spontaneous activity, whose origins and functional significance are not well understood. We use computer simulations to explore the conditions under which spontaneous activity emerges from a simplified model of multiple interconnected thalamocortical columns linked by long-range, top-down excitatory axons, and to examine its interactions with stimulus-induced activation. Simulations help characterize two main states of activity. First, spontaneous gamma-band oscillations emerge at a precise threshold controlled by ascending neuromodulator systems. Second, within a spontaneously active network, we observe the sudden “ignition” of one out of many possible coherent states of high-level activity amidst cortical neurons with long-distance projections. During such an ignited state, spontaneous activity can block external sensory processing. We relate those properties to experimental observations on the neural bases of endogenous states of consciousness, and particularly the blocking of access to consciousness that occurs in the psychophysical phenomenon of “inattentional blindness,” in which normal subjects intensely engaged in mental activity fail to notice salient but irrelevant sensory stimuli. Although highly simplified, the generic properties of a minimal network may help clarify some of the basic cerebral phenomena underlying the autonomy of consciousness

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

PRINCIPLES OF INFORMATION PROCESSING IN NEURONAL AVALANCHES

How the brain processes information is poorly understood. It has been suggested that the imbalance of excitation and inhibition (E/I) can significantly affect information processing in the brain. Neuronal avalanches, a type of spontaneous activity recently discovered, have been ubiquitously observed in vitro and in vivo when the cortical network is in the E/I balanced state. In this dissertation, I experimentally demonstrate that several properties regarding information processing in the cortex, i.e. the entropy of spontaneous activity, the information transmission between stimulus and response, the diversity of synchronized states and the discrimination of external stimuli, are optimized when the cortical network is in the E/I balanced state, exhibiting neuronal avalanche dynamics. These experimental studies not only support the hypothesis that the cortex operates in the critical state, but also suggest that criticality is a potential principle of information processing in the cortex. Further, we study the interaction structure in population neuronal dynamics, and discovered a special structure of higher order interactions that are inherent in the neuronal dynamics

On a Simple General Principle of Brain Organization

A possible framework to characterize nervous system dynamics and its organization in conscious and unconscious states is introduced, derived from a high level perspective on the coordinated activity of brain cell ensembles. Some questions are best addressable in a global framework and here we build on past observations about the structure of configurations of brain networks in conscious and unconscious states and about neurophysiological results. Aiming to bind some results together into some sort of coherence with a central theme, the scenario that emerges underscores the crucial importance of the creation and dissipation of energy gradients in brain cellular ensembles resulting in maximization of the configurations in the functional connectivity among those networks that favor conscious awareness and healthy conditions. These considerations are then applied to indicate approaches that can be used to improve neuropathological syndromes.Fil: Perez Velazquez, Jose L.. Ronnin Institute; Estados UnidosFil: Mateos, Diego Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Matemática Aplicada del Litoral. Universidad Nacional del Litoral. Instituto de Matemática Aplicada del Litoral; ArgentinaFil: Guevara Erra, Ramon. Laboratoire Psychologie de la Perception, Cnrs; Franci