Principal Investigator:  David G. Amaral, Ph.D.

The primate amygdaloid complex is an important component of the brain system involved in mediating appropriate species-specific behaviors such as threat and defense.  This program of studies uses sophisticated neurobiological and behavioral methods to reassess the role of the primate amygdala in normal social interaction.  The research is carried out in the context of a long-standing program of neuroanatomy which has demonstrated that the amygdala receives sensory information from widespread regions of the cortex.  Over the last ten years, my laboratory has carried out neuroanatomical analyses of the macaque monkey amygdala.  More recently both behavioral and electrophysiological studies of the macaque monkey amygdala have been inaugurated.  These studies have been focused on the amygdala's role in social behavior and in the interpretation of facial expressions.  This research program has been expanded to include investigations of the brain systems associated with autism. These studies will provide important insights into the neurobiology of normal social behavior and may contribute to an understanding of the pathologies of social communication in disorders such as autism.

Principal Investigator:  David G. Amaral, Ph.D.

The hippocampal formation and its interconnected structures comprise a distributed neural network that supports memory formation in the mammalian brain.  Our ongoing research program on the medial temporal lobe memory system has involved both neuroanatomical and behavioral studies of the hippocampal formation and related structures such as the perirhinal and parahippocampal cortices and the retrosplenial cortex.  We have completed a series of studies that substantially redefines the organization of the entorhinal cortex and its projection to the hippocampus.  These studies demonstrate segregated anatomical domains within the entorhinal cortex that connect sub regions within the entorhinal cortex with specific domains within the hippocampus.  These findings demonstrate that relatively independent processing streams, similar to cortical-striatal-thalamic loops, define cortical-entorhinal-hippocampal organization.  This structural redefinition of entorhinal-hippocampal anatomy has important implications for not only neuroanatomical analysis, but for conceptual and computational theories of hippocampal function.  Importantly, it provides a new schemata for assessing the connectivity of the hippocampal formation to the neocortex.

Principal Investigator:   Prabhakara Choudary, Ph.D.
Multiple lines of recent evidence implicate glial cells in the etiology of major depression. For example, lowered astrocyte counts have been documented in the frontal cortex, in regions important for cognition, mood and motivation. Neuroimaging studies and postmortem histological and morphometric studies of depressed individuals who died young by suicide suggest a possible role for astroglia. Yet, hypotheses concerning depression etiology dogmatically approach major depression as a disorder of neurons, and ignore glia. To resolve this paradox, we profiled gene expression pattern in postmortem frontal cortex of depressed individuals using high density oligonucleotide microarrays. To our dismay, we found significant downregulation of glutamatergic genes, e.g., glial high-affinity glutamate transporters (SLC1A2 and SLC1A3) and glutamine synthetase (GS), concomitant with upregulation of the genes encoding glutamate (NMDA) and GABA receptor subunits (GABA-A receptor α1 and GABA-A receptor β3). These results provide further compelling evidence for the role of astroglia in major depression, since astrocytes are the site of biosynthesis of SLC1A2, SLC1A3 and GS. They also raise several tantalizing questions, e.g., (i) what changes in these genes (DNA) cause their transcript levels to drop?; (ii) do translational changes corroborate the transcriptional changes observed?; and (iii) will these genes potentially be useful as biomarkers of major depression? We are addressing these questions using a variety of tools and techniques, including: Laser Capture Microdissection (LCM); miRNA; and immunochemical and biological assays of functional activities. We anticipate the results will lead to the development of early detection screens with increased sensitivity and specificity. Similarly, the abnormal molecules/ circuits identified here could serve as targets for novel drugs, e.g., NMDA receptor antagonists or agents that can selectively restore the balance between inhibitory and excitatory synaptic transmission, and curtail excessive excitatory activity, ushering in an era of pathophysiological mechanism-targeted rather than symptom-based therapeutics. These studies are a part of an interdisciplinary multi-investigator study, carried out in close collaboration with fellow members of the Conte Center and Pritzker Consortium (of five US universities); Dr. Edward Jones leads the UC Davis component. In parallel, in collaboration with Dr. Cam Carter, we are initiating attempts to ask similar phenomics questions about schizophrenia, using whole genome scanning to identify SNPs.

Principal Investigator:   David Hessl, Ph.D.

Principal Investigator:   Karl Murray, Ph.D.

Dr Murray's research focuses on understanding the molecular and cellular mechanisms that form specific brain pathways and how these mechanisms are disrupted in neuropsychiatric disorders. Virtually all sensory-motor information is channeled through the thalamus where it is modulated via a network of neuronal connections derived from local and extrinsic sources, including the cortex. The mechanisms required to establish this complex system are investigated using a combination of functional genomics with modern molecular neurobiological tools that include laser capture microscopy, mouse genomics, and in vitro culture assays. With Dr. Edward G. Jones, and in collaboration with members of the NIH-funded Conte Center and the Pritzker Neuropsychiatric Disorders Consortium, we are addressing how molecular and cellular aspects of thalamocortical circuitry relate to neuropsychiatric disorders. Using laser capture microscopy and functional genomics on human postmortem brain tissue the transcriptional profile of classes of neurons that comprise thalamic circuits in the brains or normal individuals and schizophrenic and depressed patients is being determined. The overall goal of this research is to understand what molecular mechanisms are necessary for the proper formation and maintenance of anatomical pathways required for normal perception and cognition.

Principal Investigator:  Tony J. Simon, Ph.D.

The focus of research in our lab  is the neurocognitive basis of developmental disability in children with genetic disorders. We have carried out most of our investigations with children who have chromosome 22q11.2 deletion syndrome (hereafter DS22q11.2) and more recently have begun to study children with Fragile X, Turner and Williams syndromes. Despite many differences, individuals in these populations typically exhibit seemingly common impairments in the visuospatial and numerical cognitive domains. In these genetic disorders there is also reduced volume in many areas of the brain, including the parietal cortex, an area linked to visuospatial and numerical cognition. We hypothesize that some key aspects of visuospatial function are disturbed by this abnormal development and that a characterization of the changes to these basic processes will generate explanations of, and possibly indicate treatments for, a range of cognitive impairments in children with these disorders. We use a range of converging methods to test hypotheses about the neurocognitive bases of the aforementioned impairments and also of other behavioral manifestations in the realm of psychopathology. These include:

• characterizing the cognitive processing impairments by employing a set of experimental tests
• specifying the volumetric changes in whole brain in terms of the tissue involved (i.e. gray matter, white matter, cerebrospinal fluid)
• determining, through the use of Diffusion Tensor Imaging, any anomalies in neural connectivity that might contribute to cognitive dysfunction
• directly measuring, through the use of functional magnetic resonance imaging (fMRI), neural activity in children as they carry out a range of cognitive processing tasks