Jeffrey S. Taube - US grants

This proposal describes a series of experiments which will examine will examine how spatial information is processed in the mammalian brain. In previous studies a population of neurons was identified in the postsubiculum (located within the hippocampal formation) which discharge as a function of the animal's head direction, independent of the animal's behavior and spatial location. This spatial signal provides a model system for examining how primary sensory information, entering through various sensory pathways, is transformed into a 'higher level cognitive signal" representing the organism's spatial relationship with its environment. The mechanisms which accomplish this transformation in the central nervous system are not known. The first aim of the proposal is to examine how the head direction cell signal is processed in the brain. To address this issue, three experimental approaches will be pursed. First, the anatomical connectivity of the postsubiculum will be identified using neural anatomical tracing techniques. Second, the electrophysiological properties and spatial sensitivities of single neurons in brain regions projecting to the postsubiculum will be examined. Finally, the processing of head direction cell activity will be monitored in rats in which lesions or chemical treatments have interrupted the circuit. Taken together, the results obtained from these studies will improve our understanding of the neural circuitry involved in the activation of head direction cells. A second line of investigation will focus on how an animal uses the head direction cell signal in behavior and spatial navigation. To date, head direction cell activity has been recorded only in rats moving freely in a cylindrical environment retrieving food pellets. The proposed studies will evaluate how different behavioral paradigms effect head direction cell activity. For example, head direction cell activity will be monitored while an animal performs a classical conditioning or visual discrimination task. Additional experiments will determine whether head direction cell activity can be modified by environmental manipulations. In these experiments, head direction cell activity will be observed as an animal learns its orientation in a novel, or previously familiar environment. Finally, the role of NMDA receptors in establishing an animal's spatial orientation in a novel environment will be explored. The results from the proposed experiments will provide insight into how spatial information is processed in the brain. These findings have implications from human health and behavior. It is common for elderly patients and patients with Alzheimer's disease, a disease often associated with marked pathology of the postsubiculum, to experience spatial disorientation to the extent that constant supervision is required. Learning how spatial information is processed in the rat brain will give us clues about the complex nature of spatial processes in humans.

Project Summary/Abstract The Research Plan describes a series of experiments that will examine how spatial information is processed in the mammalian brain. In previous studies a population of neurons was identified within the mammillary nuclei ? anterior thalamus ? hippocampal formation axis that discharge as a function of the animal's head direction (HD), independent of the animal's behavior and spatial location. This spatial signal provides a model system for examining how primary sensory information, entering through various sensory pathways, is transformed into a higher level cognitive signal representing the organism's spatial relationship with its environment. The mechanisms that accomplish this transformation in the central nervous system are not known. The first aim contains four experiments and is designed to determine how the HD signal is derived and processed from known sensory inputs. Studies will focus on subcortical areas in the brainstem and mammillary nuclei. The second aim will determine the brain areas involved in generating the grid cell signal in medial entorhinal cortex. The third aim addresses the role of two subcortical brain areas that are involved in generating the HD signal in performing a path integration spatial task. In sum, these studies will provide insight into how spatial information is organized and processed in the brain and will enhance our understanding of the functional role of HD cells during navigation. The results will have implications for human health and behavior. It is common for elderly patients and patients with Alzheimer?s disease, a disease often associated with marked pathology in limbic system structures, to experience spatial disorientation to the extent that constant supervision is required. Learning how spatial information is processed in the rat brain will give us clues about the complex nature of spatial processes in humans.

The PI has been involved in neuroscience research since 1980 and is currently a full-time faculty member at Dartmouth College. The PI wishes to develop a strong research career in behavioral/system neuroscience and make significant contributions to his field. His areas of interests center on the neurobiological mechanisms underlying higher cognitive processes in mammals, in particular learning/memory and spatial cognition. He currently has 5 full-time students in his laboratory. This award will provide relief from several teaching responsibilities and enable him to focus more time on his research and train students within the laboratory. The Award will also provide time for him to learn several new research techniques related to his studies and develop new venues of research interest. Dartmouth College has committed significant financial resources to Dr. Taube over the next 10 years and wants him to develop a strong neuroscience program at the College. Dartmouth College and its affiliated Medical School have all the resources necessary for Dr. Taube to pursue his research goals. The Research Plan describes a series of experiments which will examine how spatial information is process in the mammalian brain. In previous studies a population of neurons was identified within the hippocampal formation and anterior thalamic nuclei which discharge as a function of the animal's head direction, independent of the animal's behavior and spatial location. This spatial signal provides a model system for examining how primary sensory information, entering through various sensory pathways, is transformed into a "higher level cognitive signal" representing the organism's spatial relationship with its environment. The mechanisms which accomplish this transformation in the central nervous system are not known. The first aim of the proposal is to examine how the head direction (HD) cell signal is processed in the brain. To address this issue, four experimental approaches are pursued: anatomical, single-unit recordings, lesion studies, and electrical stimulation. A second line of investigation will focus on how animals use HD cells in behavior and spatial navigation. To date, head direction cell activity has been recorded only in rats moving freely in a cylindrical environment retrieving food pellets. The proposed studies will evaluate how different behavioral paradigms affect head direction cell activity. Additional experiments will determine l) whether HD cells require volitional motor input for activation, 2) the role of GABAergic interneurons in defining the HD cell's "tuning curve", and 3) the role of NMDA receptors in establishing an animal's spatial orientation in a novel environment. Finally the contributions of vestibular, kinesthetic, optic flow, and motor efferent copy cues on HD cell activity will be assessed. The results from the proposed experiments will provide insight into how spatial information is processed in the brain and have implications for human health and behavior. It is common for elderly patients and patients with Alzheimer's disease, a disease often associated with marked pathology in limbic system structures, to experience spatial disorientation to the extent that constant supervision is required. Learning how spatial information is processed in the rat brain will give us clues about the complex nature of spatial processes in humans.

This three-year award provides support for US-France cooperative research on the neural mechanisms underlying spatial cognition. The collaboration involves researchers, Jeffrey S. Taube at Dartmouth College, Patricia Sharp at Yale University, and Alain Berthoz, Director of the Laboratory for the Physiology of Perception at the College de France. The investigators will perform experimental studies to determine the respective roles and mechanisms for integrating sensory and motor information in head orientation. The US investigators bring to this collaboration expertise in the area of head direction cells. This is complemented by the French investigators' expertise on physiological methods, mechanism of navigation, and vestibular systems. The project will advance understanding of how internal sensory cues contribute to navigation and neural mechanisms of navigation.

DESCRIPTION (provided by applicant): The Research Plan describes a series of experiments that will examine how spatial information is processed in the mammalian brain. In previous studies a population of neurons was identified within the mammillary nuclei -->anterior thalamus -->hippocampal formation axis that discharge as a function of the animal's head direction (HD), independent of the animal's behavior and spatial location. This spatial signal provides a model system for examining how primary sensory information, entering through various sensory pathways, is transformed into a "higher level cognitive signal" representing the organism's spatial relationship with its environment. The mechanisms that accomplish this transformation in the central nervous system are not known. The first aim contains 5 experiments and is designed to determine how the head direction signal is derived and processed from known sensory inputs. The question being asked is: how is primary sensory information, entering over various sensory pathways, transformed into a signal which represents the animal's directional orientation with respect to its environment? The second aim will better define the underlying anatomical connections within the HD cell system. The third aim will determine how visual landmark spatial information is processed in the brain. The fourth aim seeks to understand the functional significance of the HD signals to the organism;that is, how does an animal use these cells for orientation and navigation? In sum, these studies will provide insight into how spatial information is organized and processed in the brain and will enhance our understanding of the functional role of HD cells during navigation. The results will have implications for human health and behavior. It is common for elderly patients and patients with Alzheimers disease, a disease often associated with marked pathology in limbic system structures, to experience spatial disorientation to the extent that constant supervision is required. Learning how spatial information is processed in the rat brain will give us clues about the complex nature of spatial processes in humans.

DESCRIPTION (provided by applicant): One cognitive function often taken for granted is the ability to maintain a sense of direction and location while moving about in the environment. This awareness is essential for getting around and functioning normally in the world. When our sense of spatial orientation is compromised by central nervous system or vestibular disease, the seriousness and devastation of the disorder becomes readily apparent both to the patient and clinician. Common problems include dizziness, balance, and spatial disorientation. To develop effective treatments for these disorders, we will need to understand the neural processes underlying spatial orientation and what goes awry with these processes that brings about disorientation. Thus, the long-term goal of this proposal is to better understand the neural mechanisms contributing to spatial perception of one's orientation. Using an animal model and electrophysiological techniques we will record from a class of neurons in rats that encodes the animal's directional heading in allocentric coordinates. These neurons are referred to as 'head direction (HD) cells'and have been identified in non-human primates. Our aim is to understand how head direction cells respond under a variety of conditions that pertain to issues of spatial orientation and disorientation. The experiments investigate 1) the response of HD cells in three dimensions - in particular, how they respond when the animal is inverted and locomotes upside-down while performing a spatial memory task, 2) the role of the vestibular system, both the semi-circular canals and the otolith organs, in generating HD cell responses, 3) the role of motor/proprioceptive cues in the discharge of angular head velocity cells, 4) the role of limbic system circuitry in generating head direction cell responses in the striatum, and 5) the response of HD cells during periods of disorientation. In sum, the results we obtain will provide essential information for understanding the neurophysiological basis for spatial orientation disorientation, and enhance our understanding of how spatial information is organized and processed in the mammalian brain. PUBLIC HEALTH RELEVANCE The results from these experiments will provide key information in understanding the basic neural mechanisms underlying spatial orientation. Ultimately, we would like to develop a better neurophysiological understanding of disorientation and use this information to develop effective treatments for spatial disorders such as vertigo, motion sickness, navigational disorders. Further, it is common for patients with vestibular disorders, elderly patients, and patients with Alzheimer's disease, a disease often associated with marked pathology in limbic system structures, to experience spatial disorientation to the extent that constant supervision is required. Learning how spatial information is processed in the rat brain will provide clues about the complex nature of spatial processes in humans.

Project Summary/Abstract The Research Plan describes two experiments that will examine how spatial information is processed in the mammalian brain ? particularly in regards to navigation in three-dimensional (3-D) space. Previous studies have identified a population of neurons, referred to as head direction cells, that discharge as a function of the animal?s directional heading in the horizontal plane. HD cells have primarily been recorded in two-dimensional space. Different theories have postulated how they respond in 3-D space. Aim 1 will test these theories by recording HD cells as an animal locomotes different routes on the surface of a 3-D cube. In particular, we will determine whether cell firing is comutative as the animal travels different routes from the floor up the vertical walls to the top surface. Each theory makes different predictions as how the cells will fire when the animal reaches the top surface. A second spatial cell type are grid cells in the entorhinal cortex. These cells fire when the animal is at multiple locations; the locations form a regular, repeating hexagonal pattern that forms a grid. Aim 2 will assess how grid cells fire across two horizontal planes that occupy the same location in the environment, but are offset in the vertical plane. We will determine if the grid patterns between the two surfaces are in alignment or offset from one another. Knowing how grid cells respond under these conditions has important implications for understanding how the grid cell signal is generated. In sum, these studies will provide insight into how 3-D spatial information is organized and processed in the brain and will enhance our understanding of the functional role of HD and grid cells during navigation. The results have implications for human health and behavior. It is common for patients with vestibular disorders and patients with Alzheimer?s disease, a disease often associated with marked pathology in limbic system structures, to experience spatial disorientation to the extent that constant supervision is required. Learning how spatial information is processed in the rat brain will give us clues about the complex nature of spatial processes in humans.

Project Summary/Abstract The Research Plan describes a series of experiments that will examine how spatial information is processed in the mammalian brain. Previous studies have identified a population of cells that are tuned to a subject?s directional heading These so-called head direction cells are thought to underlie one?s sense of direction. The neural basis for this computation is believed to reside in an attractor network at subcortical levels. Further, this network is believed to integrate information about self-motion and visual landmarks to yield an internal model of one?s sense of orientation. To understand how this integration is accomplished, it is crucial to know what information is encoded by inputs into the head direction system. This system ultimately guides one?s navigational behavior. This Brain Initiative proposal contains three aims that collectively will uncover a detailed understanding of how the head direction signal is constructed and used to guide behavior. Specifically, Aim 1 will identify the specific self- motion information to the head direction system and determine whether those inputs are sufficient to update the head direction signal. The vast majority of head direction cell studies have been conduted in rodents. Aim 2 will seek to identify head direction cells in non-human primates and systematically dissociate the contributions of eye, head, and body direction to the head direction signal. The first two aims focus on understanding how self-motion signals are integrated at subcortical nuclei that are believed to generate the head direction signal. But it is well-known that the head direction system must combine visual landmark information that is derived in the cortex. Thus, Aim 3 will use calcium-imaging techniques in retrosplenial cortex to reveal how conflicts between visual landmarks and self-motion cues are resolved. All aims will test quantitative predictions from head direction circuit models and based on findings in the three aims will derive new and more detailed networks that account for how the signal is generated at the neuronal level. Five investigators from two institutions will combine their expertise in high density ensemble recording, calcium imaging, and modeling/data analysis in behaving animals to understand in detail how the brain implements a neural compass.