Rebecca D. Burwell - US grants

The proposed studies are initial experiments in a program that will examine the cognitive functions of the cortical regions surrounding the posterior rhinal sulcus in the rat. These regions include the perirhinal cortex and the newly defined postrhinal cortex. The P.I was a major contributor to neuroanatomical findings that led to more precise boundaries for the rat perirhinal cortex and provided the conceptual basis for defining the rat postrhinal cortex, a region that exhibits considerable homology with the monkey parahippocampal cortex. A role in recognition memory has already been identified for the perirhinal cortex. Electrophysiological studies provide evidence that this function may be mediated by the encoding of familiarity or recency. Other work suggests that the functions of this region may not be limited to recognition memory. The planned experiments will address the hypotheses that the perirhinal cortex also supports mnemonic processes by configuring multiple stimuli to form single representations as distinct from the individual elements and by permitting the association of stimuli across sensory modalities. These hypotheses will be addressed using behavioral tasks that require the configuration of stimuli within and across sensory modalities in combination with experimental lesion studies. Performance of animals with selective perirhinal lesions will be compared to that of animals with selective lesions of the adjacent postrhinal cortex as well as to normal and operated controls. The proposed experiments w\ill employ behavioral approaches aimed at further characterizing the contribution of the perirhinal cortex to mnemonic processes and at dissociating the function of the perirhinal cortex from that of the neighboring and newly defined postrhinal cortex. This work will provide the background for continued examination of the perirhinal cortex using electrophysiological methods in combination with the same behavioral protocols. These experiments hold the potential for broadening our understanding of the perirhinal cortex by discovering a role in cognitive functions other than recognition memory or familiarity judgement. This work may also shed light on the contributions of the postrhinal cortex to cognition.

Memory for the context in which daily life events occur is a hallmark of episodic memory, but how and where context is represented in the brain is an open question. Evidence in multiple species suggests that postrhinal cortex (POR) is critically involved. The PI will study the role of neural circuits in the rodent POR in processing information about contexts. The guiding hypothesis is that POR is necessary for forming representations of specific contexts and for updating such representations when changes occur. What part of the brain notices, for example, when an object has been moved for one place to another in a familiar room? The PI has compelling new data showing that neurons in the POR do, indeed, represent object-place associations, and thus have all the information to signal changes in object location. The proposed studies will employ state of the art techniques in behaving rats to address questions about how context changes are represented in the brain. This work will impact memory research and neuroscience at large in several ways. For example, these studies will advance our understanding of the neural basis of context and visual information processing. In addition to the scientific impact, the proposal will contribute to increasing diversity in neuroscience by recruiting summer research rotation students from historically black colleges including Tougaloo College in Jackson, MS, Spelman College in Atlanta, GA, and Dillard University in New Orleans, LA.

Research on memory and plasticity has focused on the hippocampus for some time. The cortical regions surrounding the hippocampus including the perirhinal, postrhinal, and entorhinal cortices have been appreciated primarily because they provide the major interface between cortical unimodal and polymodal sensory processing regions and the hippocampus. Whereas recent neuroanatomical findings have served to reinforce this view, the results of experimental lesion and electrophysiological studies now indicate that these regions may make unique contributions to memory, in addition to their connectional contributions to hippocampal functions. The rat and the monkey have traditionally provided the primary animal models for memory research, but mice are becoming more widely used, especially since the development of technologies for manipulating the mouse genome. Unfortunately, most of the neuroanatomy and much of the behavior providing the background for neuroscience approaches to memory research using mouse models are based on assumptions drawn from what is known about the rat. In particular, the organization of mouse hippocampal circuitry is largely assumed from findings in the rat. Additionally, spatial tasks commonly used in mice are drawn from a battery of spatial tasks at which rats are known to perform well. Yet, direct behavioral comparisons between laboratory rats and laboratory mice on similar tests of spatial processing ability indicate that there often substantial cross-species differences in performance measures. Available evidence suggests that mice may not perform spatial tasks as well as rats do, and that the discrepancy reflects differences in hippocampal processing of spatial or contextual information. If mice and rats process sensory information for its spatial content differently, this should be evident in the organization of the structures corticohippocampal systems in the two species. The guiding hypothesis of the proposed studies is that mice differ from rats in the processing of spatial information and that the differences are reflected in the functional architecture of corticohippocampal systems. Accordingly, a major objective of the proposed studies is to examine hypotheses about basic connectional principles of the mouse corticocortical and corticohippocampal circuitry. Neuroanatomical studies will be conducted using a mouse strain chosen to provide the best comparison with research conducted in the rat and to complement other ongoing research in the mouse. These experiments will include cytoarchitectonic, histochemical, and tract tracing studies of the hippocampal formation and the cortical regions that surround the hippocampus. Another major aim of the proposed studies is to use neuropsychological approaches within a comparative framework to investigate the function of specific target structures.

ABSTRACT

Integration of Dynamic Sensing and Actuating of Neural Microcircuits
PI: Arto V. Nurmikko

The proposed EFRI program aims to develop transformative paradigms in our understanding of the complex nonlinear dynamics of brain microcircuits and their function, by developing and fusing a new generation biosensing (recording) and actuation (neurostimulation) techniques to a potent toolbox. The proposed research engages brain circuits with external photonic and microelectronic interfaces in animal models, in particular for the study of the so-called "working memory" - the brain's "random access memory". At the neuroengineering level, the proposed research integrates new set of neural sensing and actuation tools on the microscale that are applied to engage with specific sensing and planning action by the brain - in particular the dynamics of information processing in the prefrontal cortex. A key experimental driver is the development of a new micro-optical/photonic device technology that will enable precise spatio-temporal targeting through sensory pathways of cortical microcircuitry and the imaging of this circuitry in real time in specific animal models. The unique device technology elements in the sensor/actuator engineering integrate ultracompact multi-element arrays of light emitters and microelectronic chip-scale sensors for excitation and mapping of the brain microcircuitry in real-time, which has been rendered both stimulus responsive and recordable by cellular-level genetic and nanomaterial sensitizing. The goal of the development of sensing/actuation microtools with associated brain science paradigms is to pave way for microdevice interfaces for bidirectional access across a population of neurons in the brain. Bidirectionality requires that both neural recording and neural stimulation can be achieved simultaneously at cellular level for multiple neurons, and ultimately multiple brain sites, spatially and temporally. Development of a class of specific brain-interfaces probes which synergize approaches from contemporary photonics/optoelectronics for "reading" and "writing" neural information from/to brain's microcircuits is the contributing aim of this planned EFRI proposal.

In a broader context, the research aims to facilitate the implementation of a closed-loop feedback compact device technology that offers the promise of entirely new classes of neural interfaces for (i) advancing the understanding of the brain from sensing to actuation- with cellular level resolution of microcircuit dynamics, (ii) aim the application of the technology to potentially therapeutic and prosthetic applications. For example, the study of the working memory function in the brain is closely associated with neurological diseases such as schizophrenia, attention deficit disorder and has been linked to epilepsy. The team aims to leverage the research outcomes from this program in mammalian animal models (in vitro and in vivo) so that key brain science paradigms such as the fundamentally important "working memory" will find translation to human neuroscience and rehabilitative goals. By including within the team a clinical neurology interface, our proposed research is envisioned to contribute to our unraveling of neurological disease, pave way for elucidating and exploring the applicability the nature of the brain-like systems to other technologies, as well as improve U.S. competitiveness in the global economy through advanced technology development in a frontier area at the intersection of physical and life sciences. The research on these topics is also expected to create a generation of "neuroengineering" graduate students with true interdisciplinary education, as well as innovative businesses and entrepreneurs.

? DESCRIPTION (provided by applicant): Memory for the context in which life's events occur is a fundamental component of episodic memory. Also, the use of context representations for memory retrieval, decision-making, and other cognitive functions is disrupted in a number of neurological and neuropsychiatric diseases. Yet, many questions remain about how and where context is represented in the brain. A widespread view of the medial temporal lobe (MTL) memory system posits that object information reaches the hippocampus (HC) via the perirhinal cortex (PER) and spatial information arrives to the hippocampus from the postrhinal cortex (POR). The PER and POR each project to the HC both directly and indirectly through the lateral and medial entorhinal areas. By one view, the spatial pathway conveys both spatial and contextual information to the HC. By another view, the HC, itself, configures spatial and object information into representations of context. Neither view takes into account the robust, multilevel connections across the so-called object and spatial pathways. The proposed studies will resolve these open questions and potentially change how we view information processing in the MTL. The PI will study how MTL structures interact to represent and use object and context information in the service of cognition and behavior. The guiding hypotheses are 1) the POR represents the local spatial context, including the spatial layout of objects, patterns, and featurs of the environment, 2) object and pattern information necessary for context representations arrives to the POR directly from the PER, 3) object-context conjunctive encoding in the HC requires object information from the PER and context representations from the POR, and 4) oscillatory synchrony in the theta frequency band modulates transmission of information among these regions based on task demands, i.e. when spatial, contextual, or object-context conjunctive information is required for task performance. The PI will combine a novel behavioral approach with multisite electrophysiology and optogenetic manipulation in behaving rodents to address these hypotheses. By simultaneously recording and modulating single unit activity and local field potentials in the PER, POR and HC, this work can determine how these structures interact to represent contexts and objects, laying the ground work for understanding how context is represented in the brain and how such representations are used to guide cognition and behavior. The use of contextual representations is disrupted in neuropsychiatric disorders including depression and schizophrenia, and there is associated pathology in the hippocampus and parahippocampal cortex. Understanding how context is represented in the brain and how parahippocampal structures contribute to such representations is important for understanding and treating human mental disorders. These studies will elucidate the neural bases of context and establish an excellent model system for studying context information processing, a core function in human and nonhuman primate brains.

Mammals, including rats and humans, naturally explore novel items and situations. Exploratory behavior, however, is not optimal in all settings. For example, a hungry animal may avoid exploring a novel item when navigating toward a food source or being pursued by a predator. The perirhinal cortex, part of the medial temporal lobe memory system, is known to be important for identifying novelty. However, how do we know when it is appropriate or safe to explore a novel item or situation? Substantial evidence indicates that such cognitive control relies on the prefrontal cortex. Cells in the prefrontal as well as the perirhinal cortex respond to novelty by changing their activity levels. The mechanisms by which these two, distant brain regions interact in novelty-guided exploration are unknown. Recent work suggests that brain regions communicate by large, low-frequency oscillations, and results from the investigator's laboratory suggest that the particular frequency of oscillation in the perirhinal cortex transmits specific abstract information about the novelty and familiarity of individual items. The present research program addresses the overarching hypothesis that this signaling mechanism between brain regions is used in perirhinal-prefrontal interactions during novelty-guided behavior in rats. The work will impact memory research, neuroscience, and the community at large in several ways. First, the studies promise to delineate the neural mechanisms and brain circuitry underlying recognition memory and novelty-guided behavior. Second, the studies advance our understanding of the role of the prefrontal cortex and of prefrontal-perirhinal interactions in novelty-guided exploration. Finally, the studies hold the promise of revealing a new category of temporal coding in which the frequency of the oscillation enhances the transmission of specific abstract information across brain regions. In addition, the project provides opportunity for students from Historically Black Colleges and Universities to engage in intensive summer research training, and for local middle and high school students to learn about neuroscience research.

This research project includes a series of experiments that combine electrophysiology, optogenetics, transgenic animals, and behavior to elucidate the mechanisms and circuits by which synchronous neuronal activity guides appropriate exploration of novelty and familiarity. The experiments test the hypothesis that perirhinal-prefrontal interactions are necessary for novelty-guided exploration and modulated by synchronous neuronal activity in specific frequency bands. In vivo experiments employ multiple measures of rhythmic, synchronous activity to understand the temporal codes relaying information within and between the brain regions as a function of behavior, e.g., changes in local field potential (LFP) power in a given region at particular frequencies, changes in LFP coherence between any given pair of regions at particular frequencies, and phase-locking of cells in one region to the LFP in the same region or in other regions. Complimentary in vitro experiments employ state-of the-art optogenetic tools to interrogate the cellular mechanisms that underlie synchronous activity, focusing in particular on the differential roles of interneurons and pyramidal cells. The results from this work advances our understanding of the underlying circuitry of novelty-guided behavior and cognition, as well as of how brain oscillations modulate cognitive processes.