1996 |
Semendeferi, Katerina |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Hominoid Frontal Lobe--Neuroimaging/Histological Studies |
0.976 |
2004 — 2006 |
Semendeferi, Katerina |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Doctoral Dissertation Improvement : Comparative Analysis of Two Anterior Neural Substrates of Language @ University of California-San Diego
The principal brain regions involved in language production include the inferior frontal gyrus and the anterior insula. To date, there have been few neuroanatomical investigations of these regions in humans and even fewer studies involving multiple species. Additional neuroanatomical data on humans and their closest relatives would enhance our scientific understanding of changes in cognition and language throughout human evolution. Similarly, additional cross-species data would enhance existing debates concerning possible differences in cognitive capabilities among primate species.
This study will analyze the inferior frontal gyrus and the anterior insula at microstructural and macrostructural levels in multiple primate species, including humans, chimpanzees and macaques. The data from this study will not only contribute to the understanding of human and primate evolution, but will also facilitate an understanding of how language is organized in the human brain. Greater understanding of language organization can aid in the study and treatment of speech pathologies such as stuttering. Furthermore, the data from additional species, such as the apes, will facilitate the interpretation of findings from human imaging studies and those from experimental studies of macaques.
A key component of the proposed project is the training of the co-principal investigator in a variety of techniques (including stereology, neurochemistry and magnetic resonance imaging) that are important in the study of neuroanatomy. This learning and training will take place in selected laboratories in the United States and Germany that have previously analyzed some of the regions of interest in individual species. These activities will not only serve to train the co-principal investigator, but will also serve to enhance collaborative networks and partnerships among several laboratories currently working on issues relating to primate brain evolution.
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2007 — 2009 |
Semendeferi, Katerina |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Doctoral Dissertation Improvement: Primate Social Behavior From An Evolutionary Neuroanatomical Perspective: a Comparative Analysis of the Amygdaloid Complex @ University of California-San Diego
It has been suggested that pressures inherent in the primate social environment have driven the elaboration of the human and nonhuman primate neocortex. Yet, functional studies of human and nonhuman primate behavior indicate that the neural systems subserving social behavior include both critical subcortical structures and specific neocortical areas. Unfortunately, a dearth of information exists for components of this functional system, making it difficult to address the evolutionary development of these structures which are so essential to human behavior. The proposed analysis specifically attempts to address this problem by providing information about an important subcortical structure, the amygdaloid complex. The amygdaloid complex in primates plays a key role in mediating social appraisal and interaction and is highly incorporated with cortical areas involved in social information processing. As such, the aims of this research also reflect a paradigm shift in the neurosciences which have come to stress the functional links between subcortical limbic structures and neocortex, underscoring the interdependence of emotion and higher order cognition. The proposed morphometric analysis will procure unbiased volumes and neuron counts for the amygdaloid complex and five of its constituent nuclei in all six hominoid species and three Old World monkey species. Because these five amygdaloid nuclei are differentially connected to brainstem, olfactory, and neocortical areas, they are expected to show differential expansion resulting in evolutionary reorganization of the amygdaloid complex. The intellectual merit of this project lay in its intended goal to increase understanding of the evolution of the human and ape brain, specifically for regions that may have adaptive significance. While the brain is an important locus for human adaptation, scant comparative neuroanatomical information is available for our closest living relatives, the five other species of hominoids (bonobos, chimpanzees, gorillas, orangutans, and gibbons). For example, previous analyses of the amygdaloid complex have only produced volumetric measures for only four individual apes. This dearth of information limits the testability of theories of brain evolution, including those focused on the interplay between social pressures and the evolution of cognition. The proposed analysis is well suited to address these problems given that the sample, which includes thirty-five hominoid specimens, is the largest to date. Furthermore, this project will broadly impact the scientific community, providing new data, student expertise, histological series, and laboratory facilities. It will contribute to the development of new wet lab facilities in the UCSD Anthropology Department, which will allow for the production of other invaluable histological series of ape brains. Experts from UCSD and the Salk Institute will teach the student researcher multiple staining techniques to process the brains of rare primate species donated by zoos and research institutes. Results of the morphometric analyses will be available in published form to other researchers, and the series produced from the analysis will also be available for use in other anatomical analyses. Overall, the results of this research are expected to have a clear, positive impact on biological anthropology and the neurosciences, as well as the greater scientific community.
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2013 |
Semendeferi, Katerina |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Project 3: Cellular Architectonics and Local Circuits
PROJECT III ABSTRACT Wlliams Syndrome is a rare neurodevelopmental disorder with a characteristic behavioral profile that includes an abundance of affectivity or hypersociability. Neuroimaging findings from Project IV indicate that the atypical affiliative behavior in WS is related to enhanced development of anterior regions including parts of the frontal lobe and the temporal lobe. However, no anatomical information is currently available at the microstructural level for any parts of the social brain circuitry in WS. Project 111 aims to identify the fundamental microstructural differences that account for the observed augmentation of the social brain in WS, including whether numbers of neurons, degree of arborization or distribution of specific neuronal subpopulations constitute the factors underlying the observed changes in the frontal lobe and the amygdala. Specifically, we will investigate: (1) the differences in the neuronal number and cell body size that contribute to observed changes in density, (2) the differences in connectivity inferred by cellular arrangement of neurons within cortical layers and (3) expressed by degree of arborizations and morphology of neurons, (4)differences in distribution of elemental factors associated with synaptic activity and cellular metabolism. Using a combination of well established techniques including stereology and the Golgi method, we will address fundamental questions of the microarchitecture in WS social brain regions. In additional, we employ a groundbreaking technique of synchrotron-based x-ray fluorescence imaging to explore the possibility of altered distribution of specific neuronal subpopulations in WS as compared to TD. Our findings will provide a crifical neuroanatomical foundation to this Program Project and are essential components to integrating across biological scales and forming our comprehensive picture of the WS social phenotype.
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0.976 |
2014 — 2015 |
Semendeferi, Katerina |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Dissecting the Social Brain: Amygdala Changes in Williams Syndrome @ University of California San Diego
DESCRIPTION (provided by applicant): The amygdala plays a central role in human social behavior. Amygdala perturbations contribute to autism, social phobia, and other psychiatric disorders, but little is known about the neural basis of its function or the genetic determinants o its role in human neural circuitry. This proposal will address these gaps by defining the microstructural changes in the amygdala of human brains from individuals with Williams syndrome (WS). WS is a neurodevelopmental disorder with a well described genotype (Korenberg et al., 2000) and a consistently altered social phenotype that includes hyperaffiliative behavior combined with poor social judgment (Semel and Rosner, 2003). Significantly, evidence from fMRI and evoked potential studies directly implicates perturbations in amygdala function in WS during socially-oriented tasks (Meyer-Lindenberg et al., 2005; Haas et al., 2009, 2010). Thus, WS provides a unique opportunity to define the neural circuitry of the social brain at the cellular level and to link it to its genetic and developmental origins. The proposed studies pave the way for understanding the neural basis of social dysfunction and for ultimately developing therapies and treatments. Specific Aim Determine the relationship between total amygdala volume and the relative size of the four major nuclei (lateral, basal, accessory basal, central) in WS and typically developing controls. MRI studies in WS have shown increases in total amygdala volume (Reiss et al., 2004, Martens et al., 2009; Capitao, 2011), but individual nuclei have not been examined. We will examine the basolateral nuclei (lateral, basal, and accessory basal nuclei) because they have reciprocal and topographically organized connections with higher order sensory regions in the temporal lobe and with the orbitofrontal cortex (Stefanacci et al., 1996, Stefanacci and Amaral, 2002), important components of the social brain (Damasio et al., 2004, Semendeferi et al., 2010). We will also examine the central nucleus because of its importance in downstream connections to the brainstem and hypothalamus, which are key regions for marshalling species-specific behavior. Specific Aim 2 Identify changes in neuronal size, number, and density in four major amygdala nuclei (lateral, basal, accessory basal, and central) of Williams Syndrome individuals and typically developing controls. Changes in the number of neurons in the lateral nucleus of the amygdala have been identified in autism, another disorder characterized by disruptions in social behavior. While the number of neurons in the amygdala of WS is not known, changes in density and neuronal size were reported in selected locations in the cerebral cortex of WS individuals (Hollinger et al., 2005; Galaburda et al., 2002). Our findings will reveal how the microstructure of the amygdala is disrupted in individuals who demonstrate an altered social phenotype. More broadly, we will gain new insights into the genetic contributions to the detailed cytoarchitechtonic organization of the amygdala, an essential next step for drilling down to the neurobiological and genetic targets for therapeutics of disorders of social behavior.
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2016 |
Muotri, Alysson R. Semendeferi, Katerina |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
A Human Neurodevelopmental Model For Williams Syndrome @ University of California San Diego
? DESCRIPTION (provided by applicant): The main goal of this proposal is to define the contribution of specific genes to cellular and molecular phenotypes relevant to William's syndrome (WS). WS is a genetic neurodevelopmental disorder characterized by an unusual hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. WS is caused by a hemizygous deletion of approximately 25 genes in chromosome band 7q11.23. Treatment for this disorder is entirely symptomatic: there are no curative or disease modifying therapies. We used cellular reprogramming technologies to generate induced pluripotent stem cells (iPSCs) from WS and typically developing (TD) individuals. Our data revealed increased apoptosis in WS neural progenitor cells (NPCs) and a higher complexity of neuronal dendrites in WS cortical layer V/VI neurons. We also used structural imaging of the brains of living subjects and found that WS showed decreased cortical surface area compared to TD. Additionally, we performed a morphometric analysis of cortical neurons from postmortem human brains and, similar to the iPSC-derived neurons, we also revealed longer total dendrites and increased number of spines in WS. Thus, we hypothesize that deletion of certain genes in the WS region can lead too specific defects in human NPCs and neurons. To link genes to cellular and molecular phenotypes, we propose the following specific aims: Aim 1: Determine the impact of the FZD9 and GTF2I deletion cellular and molecular phenotypes in WS and Aim 2: Measure cortical neuronal morphology and density in WS and TD postmortem adult and developing brain tissue. These experiments will allow us to determine the impact of the FZD9 and GTF2I deletions on the WS cellular and molecular phenotypes. Our findings will connect these two genes to specific cellular defects that may contribute to WS social behaviors. Direct comparison of cellular phenotypes in vitro will come from postmortem brain tissue quantification. This information will be important not only for WS, but also for other developmental human conditions affecting the human social brain, such as autism spectrum disorders.
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