Major Research Areas
Frank A Middleton, PhD
- Associate Professor of Neuroscience and Physiology
- Associate Professor of Biochemistry and Molecular Biology
- Associate Professor of Psychiatry and Behavioral Sciences
Research Programs and Affiliations
- Biomedical Sciences Program
- Center for Neuropsychiatric Genetics
- Center for Psychiatric Neuroimaging
- Medical Genetics Research Center
- Neuroscience Program
- Neuroscience and Physiology
- Physiology Program
- Research Pillars
- Parkinson's disease
- Bipolar disorder
- Velocardiofacial syndrome
Molecular basis of cortical-basal ganglia and cortical-cerebellar circuit formation and dysfunction in neurological and psychiatric disease.
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High throughput genetic and genomic analysis of brain circuits involved in neurological and psychiatric disease.
The basal ganglia and cerebellum each contain discrete anatomical circuits that process information received from the cerebral cortex and other subcortical structures, and send the results of this processing back to the same cortical areas that they receive input from. Circuits involved in motor and cognitive function are largely separate, and appear to be selectively involved in certain neurological or psychiatric disorders. Using microarray technology, experiments are being carried out to identify the specific genes involved in the establishment and maturation of these circuits. These data are contrasted with those obtained from brain and peripheral biomarker tissues from individuals with neurological and psychiatric disorders known to affect these circuits, as well as genetic and environmental models of these disorders. Most of the work in the lab is focused on four disorders: schizophrenia, Parkinson's disease, attention deficit hyperactivity disorder (ADHD), and alcohol abuse. Each of these illnesses affects motor and cognitive behavior through actions on different components of the basal ganglia or cerebellum. Validation and follow-up studies utilize in situ hybridization, in situ transformation of cultured cells and tissue slices, as well as real time PCR, western blot, and immunohistochemistry.
The search for genes that cause neurological and psychiatric disorders.
The laboratory has also been extensively involved in the search for genes which cause schizophrenia, ADHD and Parkinson's disease, by comprehensive monitoring of gene expression, DNA methylation, copy number, and single nucleotide polymorphism (SNP) genotypes. Much of this work involves classical linkage and association analyses, but extends to include extensive functional characterization of candidate genes or sequence alterations that are identified.
Middleton FA, Fisher CM, Carrierfenster K, Mooney S, Youngentob SL (2009) Altered expression of neurotransmission genes in the olfactory bulb of adult rats prenatally exposed to ethanol. Brain Res. 2009; 1252:105-116.
DasBanerjee T, Middleton FA, Berger DF, Lombardo JP, Sagvolden T, Faraone SV (2008) A comparison of molecular alterations in environmental and genetic rat models of ADHD: a pilot study. Am. J. Medical Genetics Part B: Neuropsychiatric Genetics 147B:1554-1563.
Sagvolden T, Das-Banerjee T, Zhang-James Y, Middleton FA, Faraone SV (2008) Behavioral and genetic evidence for a novel animal model of attention-deficit/hyperactivity disorder predominantly inattentive subtype. Behavioral and Brain Functions 4:56.
Ross OA, Braithwaite AT, Skipper LM, Kachergus J, Hulihan MM, Middleton FA, Nishioka K, Fuchs J, Gasser T, Maraganore DM, Adler CH, Chartier-Harlin MC, Nilsson C, Langston JW, Gwinn-Hardy K, Hattori N, Farrer MJ (2008) Genomic investigation of alpha-synuclein multiplication and parkinsonism. Annals of Neurology 63:743-750.
International Schizophrenia Consortium (2008). Rare deletions at 22q11.2, 15q13.2 and 1q21.1 Identified as Schizophrenia Risk Loci. Nature 455:237-241.
Mick E, Neale B, Middleton FA, McGough J, Faraone S (2008) Genome-wide association study of response to methylphenidate in 185 children with attention-deficit/hyperactivity disorder. Am. J. Medical Genetics Part B: Neuropsychiatric Genetics. 2008; 147:1412-1418.
Middleton FA, Rosenow C, Vailaya A, Kuchinsky A, Pato MT, Pato CN (2007) Integrating genetic, functional genomic, and bioinformatic data in a systems biology approach to complex diseases: application to schizophrenia. Meth. Molec. Biol. 401:337-364.
Fuchs J, Nilsson C, Kachergus J, Munz M, Larsson E-M, Schüle B, Langston JW, Middleton FA, Ross OA, Hulihan M, Gasser T, Farrer MJ (2007) Variable phenotypes due to alpha-synuclein duplication and triplication in a single family. Neurology 68:916-922.
Miller MW, Mooney SM, Middleton FA (2006) Transforming growth factor beta and ethanol affect transcription of genes for cell adhesion proteins in B104 neuroblastoma cells. J. Neurochem. 97:1182-1190.
Vallano ML, Beaman-Hall CM, Bui CJ, Middleton FA (2006) Depolarization and Ca2+ downregulate CB1 receptors and CB1-mediated signaling in cerebellar granule neurons. Neuropharmacol. 50:651-660.
Zhang Y, James M, Middleton FA, Davis RL (2005) Transcriptional analysis of multiple brain regions in Parkinson's disease supports the involvement of specific protein processing, energy metabolism, and signaling pathways, and suggests novel disease mechanisms. Am. J. Medical Genetics Part B: Neuropsychiatric Genetics 137:5-16.
Middleton FA, Pato CN, Gentile KL, McGann L, Brown AM, Trauzzi M, Morley CP, Medeiros H, Azevedo MH, Pato MT (2005) Gene expression analysis of peripheral blood leukocytes from discordant sibpairs with schizophrenia and bipolar disorder reveals points of convergence between genetic and functional genomic approaches. Am. J. Medical Genetics Part B: Neuropsychiatric Genetics 136:12-25.
Petryshen TL, Middleton FA, Tahl AR, Rockwell GN, Purcell S, Aldinger KA, Kirby A, Morley CP, McGann L, Gentile KL, Waggoner SG, Medeiros HM, Carvalho C, Macedo A, Albus M, Maier W, Trixler M, Eichhammer P, Schwab SG, Wildenauer DB, Azevedo MH, Pato MT, Pato CN, Daly MJ, Sklar P. (2005) Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia. Molecular Psychiatry 10:1074-1088.
Middleton FA, Pato MT, Gentile KL, Morley CP, Zhao X, et al. (2004) Genome wide linkage analysis of bipolar subjects using high density single nucleotide polymorphisms (SNP) genotyping arrays: a comparison with microsatellite markers and finding of significant linkage to chromosome 6q22. Am. J. Human Genetics 74: 886-897.
Middleton FA, Mirnics K, Pierri JN, Lewis DA, Levitt P (2002) Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J. Neurosci., 22:2718-2729.
Mirnics K, Middleton FA, Lewis DA, Levitt P (2001) Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse. Trends Neurosci., 24:479-486.
Middleton FA and Strick PL (2001) Cerebellar projections to the prefrontal cortex of the primate. J. Neurosci., 21:700-712.
Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P (2000) Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron, 28:53-67.
Middleton FA and Strick PL (1996) The temporal lobe is a target of output from the basal ganglia. Proc. Natl. Acad. Sci., 93:8683-8687.
Middleton FA and Strick PL (1994) Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science, 266:458-461.