Brain, Behavior, and the Environment
Name of lab:
Brain, Behavior and the Environment Laboratory
Environmental Health Sciences (EHS)
The overall research focus of the Brain, Behavior, and the Environment laboratory is to understand the role of environmental pollutants on neurological and neurodegenerative diseases and mental health. Our work uses behavioral, cellular and molecular approaches, ranging from studies using primary culture of brain cells to the application of brain imaging technologies. Major projects include:
Effects of early life lead (Pb2+) exposure on cognitive function and molecular mechanisms:
Our laboratory was one of two research labs that initially showed that Pb2+ is a potent inhibitor of the NMDA receptor. This initial finding was followed by a series of studies showing that early life Pb2+ exposure disrupts the normal ontogeny of NMDA receptor subunits in the hippocampus leading to impairments of synaptic plasticity in the form of long-term potentiation and deficits in spatial learning. This work also showed that early life Pb2+ exposure impairs adult neurogenesis in the hippocampus. Our lab was the first to show that environmental enrichment can reverse the Pb2+-induced deficits in spatial learning and normalize the deficits in NMDA receptor subunits. This worked formed the basis for developing a working model of the molecular mechanisms by which Pb2+ exposure alters synapse development and function. During the last five years, our work has shown that early life Pb2+ exposure may be a risk factor for mental disorders, specifically schizophrenia, as well as substance abuse.
Environmental enrichment reverses cognitive and molecular deficits induced by developmental lead exposure. Guilarte TR, Toscano CD, McGlothan JL, Weaver SA (2003) Annals of Neurology 53: 50-56.
Chronic exposure of mutant DISC1 mice to lead produces sex-dependent abnormalities consistent with schizophrenia and related mental disorders: a gene-environment interaction study. Abazyan B, Dziedzic J, Hua K, Abazyan S, Yang C, Mori S, Pletnikov MV, Guilarte TR (2014) Schizophrenia Bulletin 40: 575-84.
Early life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopamine system hyperactivity present in schizophrenia. Stansfield KH, Ruby KN, Soares BD, McGlothan JL, Liu X, Guilarte TR (2015) Translational Psychiatry 5e522.
7,8-Dihydroxyflavone rescues lead-induced impairment of vesicular release: A novel therapeutic approach for lead-intoxicated children. Zhang XL, McGlothan JL, Miry O, Stansfield KH, Loth MK, Stanton PK, Guilarte TR (2018) Toxicological Sciences 161: 186-195.
Translocator Protein 18 kDa (TSPO): A Molecular Biomarker of Brain Injury & Inflammation:
Our laboratory has performed pioneering work in the validation and application of Translocator Protein 18 kDa (TSPO) as a biomarker of brain injury and inflammation. TSPO is currently being used in clinical and preclinical neuroimaging studies in major research institutions around the world. In the normal brain neuropil, TSPO levels are almost non-detectable, but following brain injury, TSPO levels increase markedly in microglia and astrocytes and this effect depends on the type and severity of the injury. More recent work in the lab relates to the function of TSPO in glial cells, specifically microglia and astrocytes. This work has recently shown that TSPO ligands induce reactive oxygen species production in microglia and this effect may be associated with the activation of NADPH oxidase. Further work has shown the utility of TSPO to detect inflammation in other organs systems besides the brain, for example myocardial inflammation.
Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair. Chen MK, Guilarte TR (2008) Pharmacology & Therapeutics 118:1-17.
TSPO finds NOX2 in microglia for redox homeostasis. Guilarte TR, Loth MK, Guariglia SR (2016) Trends in Pharmacological Sciences 37: 334-343.
Imaging of glial cell activation and white matter integrity in brains of active and recently retired National Football League players. Coughlin JM, Wang Y, Minn I, Bienko N, Ambinder EB, Xu X, Peters ME, Dougherty JW, Vranesic M, Lee M, Cottrell C, Sair HI, Sawa A, Munro CA, Nowinski CJ, Dannals RF, Lyketsos CG, Kassiou M, Guilarte TR, Pomper MG (2017) JAMA-Neurology 74: 67-74.
TSPO in diverse CNS pathologies and psychiatric disease: a critical review and a way forward. Guilarte TR (2018) Pharmacology & Therapeutics 194: 44-58.
Behavioral and Molecular Effects of Chronic Manganese Exposure in Non-Human Primates:
Our laboratory has been studying the effects of chronic manganese exposure on neurological health in non-human primates. This work, in collaboration with Dr. Jay Schneider (Thomas Jefferson) and Dr. Dean Wong (Johns Hopkins), utilizes behavioral, neuroimaging and neuropathological endpoints to determine the mechanisms of manganese-induced parkinsonism. This research was the first to show that manganese-induced parkinsonism differs from idiopathic Parkinson’s disease in that manganese-induced parkinsonism does not involve degeneration of dopamine neuron cell bodies in the substantia nigra pars compacta, but in fact, it is related to a marked inhibition of dopamine release in the dorsal striatum. We propose that the marked inhibition of striatal dopamine release by manganese in conjunction with degeneration of cells intrinsic to the basal ganglia (cholinergic interneurons) will form the basis for the movement abnormalities documented in humans and experimental animals. Using this same non-human primate model, our lab was the first to show that chronic manganese exposure results in beta-amyloid aggregation and neurodegeneration in the frontal cortex. This effect was associated with impairment of working memory and paired-associative learning in these same animals.
Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates. Guilarte TR, Chen MK, McGlothan JL, Verina T, Wong DF, Zhou Y, Alexander M, Rohde CA, Syversen T, Decamp E, Koser AJ, Fritz S, Gonczi H, Anderson DW, Schneider JS. (2006) Exp Neurol 202: 381-90.
Increased APLP1 expression and neurodegeneration in the frontal cortex of manganese-exposed non-human primates. Guilarte TR, Burton NC, Verina T, Prabhu VV, Becker KG, Syversen T, Schneider JS. (2008) J Neurochem 105: 1948-59.
Chronic manganese exposure impairs visuospatial associative learning in non-human primates. Schneider JS, Williams C, Ault M, Guilarte TR. (2013) Toxicol Lett 221: 146-51.
PET imaging of dopamine release in the frontal cortex of manganese-exposed non-human primates. Guilarte TR, Yeh CL, McGlothan JL, Perez J, Finley P, Zhou Y, Wong DF, Dydak U, Schneider JS. (2019) J Neurochem 150: 188-201.
Jennifer McGlothan Dziedzic,
Research associate and lab manager
Dr. Diana Azzam,
Dr. Damaris Albores-Garcia,
Dr. Monica Rodriguez-Silva,
Undergraduate research assistant