Leah Krubitzer - US grants

DESCRIPTION (provided by applicant): While area 5 has been considered a posterior parietal field involved exclusively in processing somatic inputs, recent evidence from our laboratory in both New World and Old World monkeys, as well as work from other laboratories, indicate that this cortical area is also involved in processing visual inputs, and is closely associated with the motor system. Accumulating evidence indicates that area 5 may be a "central planner" critical for monitoring limb location during intended reaching and grasping, converting sensory locations into motor coordinates for intentional movement, and in perceiving the movements of the body in extra personal space. The goal of the present investigation is to determine the role of posterior parietal area 5 in visually guided and non-visually guided reaching and grasping, object manipulation, bilateral coordination of the hands, and information transfer across the' cerebral hemispheres. To accomplish this, we will make electrophysiologically targeted unilateral lesions in the hand and forearm representation of area 5 in macaque monkeys, and examine the effects of these lesions on these behaviors. We expect that ablations of area 5 will result in a variety of deficits involving manual dexterity, reaching, grasping, and bilateral coordination of the hands. The proposed studies are broken into three major groups of experiments. The first series of experiments will examine the cortical, callosal, and subcortical connections of area 5 and adjacent somatosensory area 2, in macaque monkeys. The second group of experiments will examine the consequences of precisely targeted lesions in area 5 on directed reaching and grasping, bilateral coordination of the hands, shape discrimination abilities and interhemispheric transfer. The tasks include reaching and grasping under visually guided and non-visually guided conditions, bilateral manipulation of objects, and object identification under both ipsilateral and bilateral hand use conditions. The final series of experiments will examine the cortical substrate for behavioral recovery by determining if changes in both functional organization and anatomical cortical connectivity have occurred in cortical area 2 as a consequence of the lesion. This study represents one of the first attempts to combine modern neuroanatomical, electrophysiological, and lesioning techniques to determine the contribution of a single cortical field involved in generating sophisticated hand use. Further, it is one of the few studies that utilizes electrophysiological and neuroanatomical techniques to examine the long-term cortical changes that occur after cortical damage, followed by behavioral training. These studies will ultimately allow us to better understand the role of area 5 in reaching, grasping, object manipulation, and bilateral coordination of the hands, the time course of behavioral plasticity following lesions in area 5, and the cortical mechanisms that contribute to recovery after brain injury.

Significance To determine the anatomical substrate for higher level functions such a manual dexterity and bilateral coordination of the hands. Objectives Using electrophysiological recording techniques, areas of the lateral sulcus and posterior parietal cortex will be explored so that the functional organization of distinct areas can be ascertained. The connections of these regions with the thalamus, ipsilateral areas of the cortex, and with the contralateral hemisphere will be determined by injecting small amounts of anatomical tracers into electrophysiologically defined areas. After the tracers have transported, the regions that are connected to the area injected will be explored electrophysiologically so that the exact nature of topographic and non-topographic connections can be better understood. One would expect that these higher order fields would integrate information across the hand, and thus non-topographic connections should be present. In addition, we expect dense connections with areas in the contralateral hemisphere, since information from both hands must be integrated to coordinate movements across the body. Finally, connections with motor cortex, needed to subserve sensorimotor integration and direct future movements would also be expected. Results Preliminary results demonstrate that areas of the lateral sulcus do have strong connections with the opposite hemisphere, particularly hand representations in the second somatosensory area, SII, and parietal ventral area, PV. Another important finding is that there are relatively dense connections between posterior parietal cortex and motor cortex. Finally, we have found that connections from the thalamus are both topographically matched and mismatched. This finding is particularly important for studies of cortical plasticity, in which the anatomical substrate for functional changes in the cortex has yet to be determined. Future Directions Goals are to compare the present results with studies in humans utilizing functional imaging techniques, such as fMRI and MEG in both humans and non-human primates. KEYWORDS second somatosensory area, parietal ventral area, posterior parietal cortex, sensorimotor integration

touch; nervous system; Mammalia;

Ablation; Acquired brain injury; Area; Behavior; Behavioral; Bilateral; Body Buffer Zone; Brain Hemisphere; Brain Injuries; CRISP; Cercopithecidae; Cerebral Hemisphere; Cerebral hemisphere structure (body structure); Cognitive Discrimination; Computer Retrieval of Information on Scientific Projects Database; Condition; Discrimination; Discrimination (Psychology); Extremities; Forearm; Funding; Goals; Grant; Grips; Hand; Hand functions; Institution; Investigation; Investigators; Ipsilateral; Laboratories; Lesion; Limb structure; Limbs; Location; Macaca; Macaque; Manuals; Methods and Techniques; Methods, Other; Monitor; Monkeys; Monkeys, Old World; Motor; Movement; NIH; National Institutes of Health; National Institutes of Health (U.S.); Non-Trunk; Parietal; Personal Space; Privacy of Space; Process; Recovery; Research; Research Personnel; Research Resources; Researchers; Resources; Role; Sensory; Series; Shapes; Somatosensory Cortex; Source; System; System, LOINC Axis 4; Techniques; Thalamic structure; Thalamus; Time; Training; United States National Institutes of Health; Using hands; Work; body movement; brain damage; brain lesion (from injury); experiment; experimental research; experimental study; grasp; interhemispheric transfer; research study; social role; somatosensory; somesthetic sensory cortex; thalamic; visual process; visual processing

The neocortex is involved in perception, cognition, reasoning, and other abilities generally associated with intelligence. It has increased in size and in the complexity of its organization, and in humans these changes are particularly dramatic. How have these changes emerged in humans and other animals? What is the contribution of genes versus the environment to the development of the neocortex and ultimately to human's special cognitive abilities? This project addresses these questions using molecular techniques combined with anatomical techniques to examine the developing neocortex in three different animal species that have a unique type of neocortex. In some of these animals, how information from the environment accesses the brain during development will be altered. The project has two goals. (1) To determine if there are differences in gene expression that can account for the variable patterns of cortical organization in mammals. (2) To understand how differences in sensory information from the environment that reaches the brain during development affect the organization of the brain, and in turn the behavior of the animal. These studies will be carried out by a post-doc and graduate student in the laboratory, under the supervision of the PI, and will provide an excellent training opportunity for both. There are two broad expectations. (1) All three animals will have some similarities in how genes are expressed in the neocortex, and these similarities form the basic framework of how the brain is organized, and gets connected during development. (2) Changes in the types and amount of information that the brain has access to during development can significantly alter this basic blueprint laid down by genes. These results are critical for understanding the precise interaction between genes and the environment in creating a unique cortical phenotype which functions optimally in a given environment.

DESCRIPTION (provided by applicant): The emergence of a six-layered neocortex is one of the hallmarks of mammalian brain evolution. An important feature of the neocortex is its ability to change throughout a lifetime. This plasticity is especially pronounced during development. Developmental plasticity is a highly adaptive process that allows the neocortex to functionally optimize both its organization and connectivity to match the physical parameters of the environment in which an animal develops. While we appreciate that the developing cortex is highly malleable, the limits to which it can be altered and recover following injury, or extreme environmental rearing conditions is still not fully understood. The goals of this R21 proposal are to: 1) determine the extent to which the entire cortical sheet can re-organize and recover following severe loss of tissue very early in development;2) determine the developmental stage at which the cortex loses, or has a reduced capacity to recover following a lesion;and 3) quantify the extent to which prolonged exposure to a highly specified visual environment can influence the organization and connectivity of the developing cortex, and ultimately the behavior in normal and brain lesioned individuals. In these experiments in short-tailed opossums, bilateral ablations of visual cortex will be made just before thalamocortical afferents reach the cortex or just after thalamocortical innervation of the cortex has occurred. Animals will be reared in either a neutral or visually enhanced environment until adulthood. To determine the effects of this environment in both normal and lesioned animals, behavioral tests will be administered and the functional organization and connectivity of spared cortex will be determined in these same animals. These experiments will allow us to probe the limits of plasticity in normally developing systems as well as to appreciate the extent to which individuals can recover from large early lesions to the neocortex. The results of our studies will have a significant clinical impact in terms of prognosis for recovery from injuries that occur at different developmental time points, and rehabilitation strategies that facilitate recovery in children with early cortical insult. PUBLIC HEALTH RELEVANCE: The goal of the present investigation is to determine the extent to which the cortex and the behavior it generates can recover following neonatal lesions to visual cortex. By rearing animals in an enhanced visual environment, we hope to push the limits of recovery in brain lesioned animals, and ultimately generate normal visually mediated behavior in these individuals. These studies have important implications for children who sustain early cortical lesions or trauma and will aid in prognosis, and impact rehabilitation strategies that facilitate recovery.

DESCRIPTION (provided by applicant): The goal of this project is to develop a miniaturized microfluidic thermal regulator to reversibly deactivate one or multiple areas of the neocortex through thermal regulation. This device, or cooling chip, includes indwelling microthermocouples and recording microelectrodes to monitor temperature and neural response and make online adjustments of cooling parameters to reach a desired cortical temperature. The cooling chip is being designed, assembled and tested as a multi-disciplinary collaboration between four different laboratories at the University of California Davis spanning three different departments. Although previous cooling devices have been used to reduce brain activity, the significance of our new design lies in its smaller size and the presence of indwelling electrodes/thermocouple ensemble, which will greatly expand the range of animals and experiments in which it can be used. Design criteria for the cooling chip include biocompatibility with brain tissue and a structure that accommodates the geometry of the cortical area where it is placed. Innovative soft lithography fabrication of elastomeric material (i.e., polydimethylsilane, or PDMS) offers excellent biomechanical flexibility and compliance; compact device dimensions (< 9 mm3) as well as desired heat transfer properties, which have been characterized at the tissue interface. The current prototype absorbs ~ 2 kCal/min, and produces a highly localized temperature drop from 370C to 200C within a minute. This device is highly innovative because its flexibility in size and shape allow it to be used in different animal models from rats to monkeys. A primary application for the cooling chip will be to probe cortical macrocircuitry and the specific behaviors that cortical areas generate. Further, this device can be generalized easily across a number of neuroscience disciplines for studies of sensory and motor systems as well as cognitive systems such as long-term memory (e.g., hippocampus), working memory (e.g., prefrontal cortex), and attention (e.g., parietal lobe). Its user-friendly interface with commercially available hardware and software running on a laboratory PC will make it adaptable for use in any number of laboratories. Finally, questions regarding the neural basis of complex behaviors that are currently conducted almost exclusively in non-primates can now be addressed in the more ubiquitous rodent model.

DESCRIPTION (provided by applicant): A distinguishing feature of the mammalian neocortex is its remarkable ability to change over a lifetime, especially during early development. Thus, the functional organization and connectivity of each individual's brain is tailored to the physical parameters of a specific environment, permitting behavior to be uniquely optimized for a given sensory milieu. Such plasticity plays an integral role in shaping the brains of normal humans as well those who suffer from severe visual impairments due to retinal abnormalities or cortical lesions that occur at various stages of development. This proposal will investigate the extent of cortical plasticity following experimentally induced manipulations to the visual system during development. Our first objective is to examine the alterations in sensory mediated behavior, as well as changes in the functional organization, connectivity and cellular composition of the neocortex that result from one of two induced neural insults: 1) loss of neocortex that would normally develop into visual cortex; 2) loss of visual input normally provided by the retina. The second objective is to determine if early, pervasive sensory enhancement can be used to direct the functional reorganization of the neocortex and optimize sensory mediated behavior. Manipulations will be made at one of three developmental milestones: 1) Before retinal ganglion cell axons enter the diencephalon and before thalamocortical afferents have reached the cortex. 2) Before eye opening, after thalamocortical afferents have innervated the neocortex, but before axonal pruning and the completion of cortical development. 3) Just after the eyes have opened, when retinofugal and thalamocortical development is established and the subventricular zone and all six cortical layers are present. These animals will be exposed to either a normal or to a tactilely (for bilateral enucleates) or visually (for cortical lesions) enhanced environment. Our animal model, the short-tailed opossum (Monodelphis domestica) is born prematurely, allowing ex-utero manipulations to the nervous system at developmental time points that would be in-utero in other mammals. After the animals have reached maturity we will use behavioral testing combined with electrophysiological and neuroanatomical techniques to examine sensory discrimination, the functional organization and neural response properties of re-organized cortex, cortical and thalamic connectivity, and the cellular composition including neuronal number and density of re-organized cortex. These studies, which are novel in their scope, provide an opportunity to translate detailed knowledge gained at the cellular and systems level to produce significant therapeutic interventions designed to direct multisensory plasticity, and optimize sensory mediated behavior following loss of vision.

DESCRIPTION (provided by applicant): The first goal of these experiments is to delineate how brain areas in posterior parietal cortex of New World cebus monkeys operate within a cortical network that is critical for reaching, grasping and bimanual behaviors. The second goal is to extend our ongoing collaboration with faculty at the Instituto de Biofisica Carlos Chagas Filho (IBCCF; Drs. Franca, Gattass, Fiorani and Soares) at the Federal University of Rio de Janeiro, Brazil by introducing a new technology that was developed as a joint project between laboratories at the Center for Neuroscience (Krubitzer) and Department of Biomedical Engineering (Simon) at UC Davis. Cebus monkeys, like humans, have an opposable thumb, utilize a precision grip and engage in a variety of complex manual behaviors. Their use of tools in both the wild and laboratory settings make cebus monkeys an excellent model for understanding the neural basis of complex manual abilities in humans, more so than the commonly used macaque monkey, which rarely uses tools. The new technology that this international consortium will introduce to IBCCF is the microfluidic cooling device. This is an indwelling and biocompatible device that can selectively and reversibly deactivate one or more brain areas in awake animals performing a trained task. This is equivalent to reversibly 'lesioning' a brain area and will enable us to probe the function of the affected area by detection of specific deficits in behavior during deactivation. Using this device we can compare similarities in cortical circuits between Old World macaque monkeys and New World cebus monkeys that are involved in coordinated hand use, and define differences in circuits that have arisen in conjunction with tool use in cebus monkeys. These studies have important clinical relevance because they will reveal the relationship between the size of a deactivated area and the extent of behavioral dysfunction and recovery that is possible. Application of this device simulates a calibrated clinical lesion and provides a novel approach to assess the effects of progressively larger lesions such as can occur during stroke in humans.

? DESCRIPTION (provided by applicant): Why do our early interactions, particularly those with our parents, have such an enormous impact on subsequent social behavior and how we rear our own children? There is overwhelming and unequivocal evidence that aberrant parent-offspring interactions during early life, including maltreatment and abuse, negatively impact adolescent behavioral outcomes and perpetuate a continuing cycle of abuse or maltreatment. However, there are few, if any, studies that have directly linked these early experiences to changes in brain organization and connectivity. Further, the underlying genetic and epigenetic mechanisms present during development that generate these anatomical changes to the brain are only poorly understood. The overarching goal of this proposal is to determine how early social interactions, mediated by somatosensory and olfactory systems, impact the development of specific patterns of connectivity to produce individual differences within a population. We use a unique animal model, the prairie vole, which is one of only a small proportion of mammals that are monogamous, pair-bonded and that rear their young bi-parentally. Pair-bonded parents show remarkable variability in rearing styles, particularly in behaviors requiring close physical contact such as nursing, huddling, and non-huddling contact, all of which profoundly shape tactile and olfactory experience. We have quantified these differences in rearing style, and have demonstrated significant differences in cortical connectivity and social behaviors of the offspring of high contact (HC) and low contact (LC) parents. In addition, LC and HC offspring adopt a similar rearing style to that of their parents, perpetuating these two distinct phenotypes. Cross-fostering of offspring demonstrates that these changes in behavior are culturally transmitted rather than inherited. This opens up the intriguing possibility that, in large part, experience generates the differences in cortical connectivity associated with the different behaviors. In othe words, some aspects of brain organization may be culturally transmitted. However, a direct relationship between differential sensory experience, parental rearing styles, and cortical connectivity of the brain has never been established. In humans, rodents and many other mammals, early tactile and olfactory experience is critical for forming filial relationships betwee the mother and the offspring and for establishing normal social behavior later in life. Thus, results from our studies in voles have broad implications for mammals in general, including humans. In these studies we will cross-foster HC and LC offspring; in some of these litters we will induce anosmia. In all groups we will compare cross-fostered offspring with their in-fostered siblings and their biological siblings on several measures including: olfactory and tactile discrimination, social behavior, and density and distribution of connections of somatosensory (S1), olfactory (orbitofrontal cortex, OFC), and anterior cingulate (ACC) cortical areas. Finally, we will determine the period in development when alterations in connectivity occur, and explore some of the genetic and epigenetic mechanisms that drive these changes in cortical connectivity. With this design we will reveal the mechanisms that translate early sensory experiences into a cortical phenotype that generates adaptive, and complex social behavior later in life.

The emergence of the neocortex and its capacity to be shaped by early sensory and motor experience is the hallmark of mammalian brain evolution. This remarkable plasticity allows the neocortex to be constructed for a multi-sensory context, and to generate flexible behavior throughout a lifetime. While it is well established that early sensory experience can alter the functional organization of sensory and motor cortex, most studies have focused on either the somatosensory or the motor system in isolation, and almost exclusively studied animals reared in relatively restricted laboratory environments. Thus, the extent to which the sensory complexity, variability, and affordances of the early environment impact neural and behavioral development is unknown. Also, whether these types of dynamic environments can increase the capacity for behavioral plasticity throughout a lifetime has never been explored. In the current proposal, rats will be born and reared in two distinct environments; a laboratory cage, or in a large, highly enriched, semi-natural outdoor enclosure. We will determine if the speed with which an animal learns a sensory motor task, the accuracy of performance, and strategy by which novel tasks are learned correlate with, and can predict, differences in the functional organization, neural response properties and connections of the neocortex. We focus on areas involved in sensorimotor integration and motor control that we believe will be highly impacted by rearing condition: the primary somatosensory cortex (S1) and motor cortex (M1). We will use electrophysiological recording techniques to examine the somatotopic organization and neural response properties of S1, and intracortical microstimulation techniques to determine how muscle synergies are represented in M1 and S1. We will also quantify differences in the neuroanatomical connections of M1 and S1 with other cortical fields within and across hemispheres, as well as with the dorsal thalamus and spinal cord. Finally, to determine when these distinct environments have the greatest impact on the functional organization and connections of S1 and M1, we will examine animals at 4 important developmental time points and as adults. These studies will uncover when and how early sensory experience coupled with diverse motor opportunities impact cortical organization and connectivity in the developing brain to generate context-appropriate behavior; and if dynamic and complex sensorimotor environments generate brains and bodies capable of a larger degree of behavioral plasticity throughout a lifetime.