Schizophrenia is a severe mental illness affecting about 1% of the population in which disruptions in the physical connections of neural circuitry are unclear. Our goal is to further understand the underlying changes to neural circuitry that occur in schizophrenia to provide a foundation that is fundamental for better treatment. The nucleus accumbens is a region of convergence for afferents of many brain areas disrupted in schizophrenia, and is the major site of input into the basal ganglia from the mesolimbic dopamine system, making it a key area of interest for schizophrenia;dopamine hyperfunction in the dorsal striatum is a hallmark characteristic of the disorder, and the role of dopamine as central in schizophrenia is one of the most accepted hypotheses of the illness. Although there is evidence for the role of the ventral striatum in schizophrenia, the anatomical pathology of the nucleus accumbens in schizophrenia has largely been overlooked. The proposed research will test the hypothesis that subjects with schizophrenia have increased dopaminergic inputs in the nucleus accumbens compared to normal control cases using postmortem human tissue. The density of tyrosine hydroxylase immunolabeling, the rate limiting synthesizing enzyme of dopamine, will be determined in control subjects compared to groups of off- and on-drug schizophrenia subjects using optical densitometry and western blot assays. The proposed research will also determine the ultrastructural abnormalities present in the nucleus accumbens neurocircuitry of subjects with schizophrenia using 3- dimensional stereological counting at the electron microscopic level. Lastly, chronically antipsychotic drug- treated rats will provide a context for the interpretation of results from the postmortem human studies. Results from the proposed research will provide insight into the abnormal circuitry that may be a core feature of schizophrenia, further elucidate mechanisms of the illness, and offer insight into therapeutics which are not fully understood.

Public Health Relevance

There is a need to improve treatment for patients with schizophrenia which requires a better understanding of the underlying pathology of the neural circuitry in the disorder than is currently known. This project will determine if there are underlying neural circuitry disruptions in the nucleus accumbens core and shell in schizophrenia to help fill the gaps in this necessary foundation of schizophrenia treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31MH098566-02
Application #
8743623
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chavez, Mark
Project Start
2013-09-24
Project End
2015-09-23
Budget Start
2014-09-24
Budget End
2015-09-23
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Schoonover, Kirsten E; McCollum, Lesley A; Roberts, Rosalinda C (2017) Protein Markers of Neurotransmitter Synthesis and Release in Postmortem Schizophrenia Substantia Nigra. Neuropsychopharmacology 42:540-550
McCollum, Lesley A; McCullumsmith, Robert E; Roberts, Rosalinda C (2016) Tyrosine hydroxylase localization in the nucleus accumbens in schizophrenia. Brain Struct Funct 221:4451-4458
McCollum, Lesley A; Roberts, Rosalinda C (2015) Uncovering the role of the nucleus accumbens in schizophrenia: A postmortem analysis of tyrosine hydroxylase and vesicular glutamate transporters. Schizophr Res 169:369-373
McCollum, Lesley A; Walker, Courtney K; Roche, Joy K et al. (2015) Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study. Schizophr Bull 41:1123-32
McCollum, L A; Roberts, R C (2014) Ultrastructural localization of tyrosine hydroxylase in tree shrew nucleus accumbens core and shell. Neuroscience 271:23-34