Research

Brain Tissue Research

Dallas Brain Collection (DBC)

The biologic basis of mental illnesses is largely unknown. In recent years, the development of newer and better technology has provided scientists greater opportunities to study the pathophysiology of these devastating illnesses. Human post-mortem brain tissue is an essential resource that facilitates translational research. It serves as a bridge allowing for discoveries in animals to feed forward into the clinical setting and vice versa. With the advent of modern neuroscience tools, human post-mortem research is becoming increasingly important in translation neuroscience. Recognizing this, the Neuropsychiatry Research Program was established in 2003 and is an integral part of the Division of Translational Neuroscience Research in Schizophrenia (DTNRS) at UT Southwestern.

Contact: Kelly Gleason, 214-645-2527

Human Post-Mortem Brain Collection

The Brain Tissue Program is designed to collect human post-mortem from cases of all major psychiatric disorders including schizophrenia, major depressive disorder, bipolar disorder, substance abuse, and healthy controls after obtaining consent from next of kin. Priority is placed on the collection of high quality tissue determined by assessing RNA and protein measures. Tissue is collected from recently deceased persons who come to the Dallas County Medical Examiner’s Office, UT Southwestern Transplant Service Center, or the UT Southwestern Willed Body Program. Once procured, the brain tissue is rapidly processed, frozen, and stored at -80°C for future use. Each brain provides tissue for hundreds of potential experiments and is an invaluable resource. Clinical history is obtained from interviews with caregivers and from medical records. Using structured and semi-structured interviews, we are able to create a rich clinical database. Panels of board certified psychiatrists review the clinical information and make independent diagnoses using DSM IV criteria. This is followed by establishing a consensus diagnosis for each case. In addition we determine the risk gene profiles on each case.

Quantitative Examination of the Limbic Cortex in Schizophrenia (Limbic)

This study seeks to identify and characterize the nature and localization of anatomic and chemical abnormalities in the limbic cortex of schizophrenic (hippocampus, entorhinal cortex, and anterior cingulated) contributing to the pathophysiology of the disease.

Several laboratories have generated data suggesting limbic pathology in schizophrenia; our own in vivo imaging and post-mortem studies suggest a limbic focus as well. Recently, data from Csernansky et al. have suggested that pathology in the hippocampus and the medial aspect of the body (subiculum); this might explain the variability of outcomes reported across studies in post-mortem analyses, because few studies control for hippocampal axis. To answer this question, we have paired anatomic and neurochemical measures within the hippocampus, entorhinal cortex, and anterior cingulated from anterior to posterior extent, quantifying markers of neuronal structure and transmission which may be abnormal in schizophrenic limbic cortex.

The hypothesis driving this work is based on our in vivo imaging data from patient studies and our animal model work, which are extensively in agreement with the published literature. We have raised the speculative hypothesis that positive symptoms in schizophrenia are associated with reduced glutamatergic hippocampal efferent signal to its projection fields, including entorhinal cortex, anterior thalamus, and anterior cingulated may underlie the generation of psychotic symptoms in schizophrenia.

Twenty-four post-mortem schizophrenia brains with paired EC, hippocampi, and cingulates will be compared to the same structures in 24 matched healthy and 12 matched psychotic control brains. We will study neuronal number, sympatic and dendritic density, along with neurochemical measures of the glutamate and GABA, systems along with the A-P-extent of these structures. We postulate that only certain regions of hippocampus will be affected (lateral head and medial body), and that the neurochemical abnormalities in these regions will colocalize with neuronal number and/or sympatic and dendritic changes, and that related regions of hippo, EC, and ACC will be affected. These data will have implications for understanding the mechanisms of the illness and for directing future new discovery for schizophrenia therapeutics.

Neural Substrates of Appetitive Behavior in Mood and Motivation (CONTE)

The timely translation of molecular hypotheses based on animal models to the human syndrome of depression is one of the primary goals of our Conte Center. Based on the tight focus of our Center on the brain's reward circuitry, the task of translation is advantaged in two main ways. First, the anatomy of this circuit, which has been well described in animals as discussed elsewhere in this application, has direct analogues in humans, which have been validated increasingly by brain imaging.

Second, much is already known about the anatomy of these circuits in humans and, to a lesser degree, their neurochemistry. Nevertheless, brain reward circuits in humans remain largely uncharacterized in human depression, which is similar to the relative lack of attention to these circuits in animal models. Indeed, the raison d'etre of this Conte Center is to correct this relative inattention. The most direct and feasible methodology with which to query reward circuits in human brain for molecular changes in depression is the analysis of post-mortem brain. This is because virtually all of the proteins implicated in reward circuits in animal models cannot yet be investigated by brain imaging, given the lack of suitable radioligands.

In contrast, analysis of these proteins and their encoding genes and mRNAs is straightforward in human post-mortem brain – assuming high quality tissue, detailed clinical information, and customized, accurate brain dissections. As described in General Description of Overall Center, the major reward circuit in the brain arises in dopaminergic neurons of the VTA (ventral tegmental area) and the regions in limbic forebrain to which these neurons project, in particular, the NAc (nucleus accumbens). This Project, like Projects 1-4, therefore, focuses on these two regions in human brain. In addition, we will analyze particular hypothalamic nuclei, given the important role played by these nuclei in appetitive behavior, and their strong projections to the VTA-NAc.