Aging; Alzheimer Disease; Behavioral Sciences; Psychology, Child; Mental Health; Neurobiology; Neurosciences; Stress Disorders, Post-Traumatic; Prefrontal Cortex; Cognitive Science
Public Health Interests
Aging; Alzheimer's Disease; Child Mental Health; Post-Traumatic Stress Disorder; Psychological Trauma; Schizophrenia
The Arnsten lab studies molecular influences on higher cognitive function, with the aim of developing rational therapies for mental illness and for age-related cognitive disorders such as Alzheimer's Disease. The work focuses on the prefrontal cortex, a highly evolved brain region that creates our "Mental Sketchpad", allowing us abstract reasoning, high order decision-making, working memory, and thoughtful regulation of attention, behavior and emotion (including inhibition of inappropriate thoughts, actions and feelings). The Arnsten lab has discovered powerful chemical signaling pathways that can impair prefrontal function, e.g. when we are stressed, as well as protective pathways that maintain strong cognitive function. These pathways are altered by normal aging, and can be genetically altered in mental illness. Based on research in the Arnsten lab, two medications have been developed for human use: guanfacine (Intuniv) for the treatment of Attention Deficit Hyperactivity Disorder, and prazosin for the treatment of Post-Traumatic Stress Disorder.
Specialized terms: Molecular influences on higher cognitive function
Extensive Research Description
The Arnsten Lab studies molecular influences on the higher cognitive functions of the prefrontal cortex (PFC), with the overarching goal of developing rational treatments for cognitive disorders and mental illness. The lab uses a multi-disciplinary approach to understand mechanisms influencing working memory at the cellular and behavioral levels. Research has focused on how the arousal pathways rapidly alter PFC network strength through intracellular signaling mechanisms, a process termed Dynamic Network Connectivity. Our data explain how exposure to stress causes the rapid loss of PFC cognitive abilities, and how genetic mutations in molecules that regulate these pathways can lead to symptoms of mental illness. Dysregulation of these pathways with advancing age leads to loss of neuronal firing, cognitive impairments,and increased vulnerability for degeneration. Understanding these mechanisms has led to successful new treatments for patients with PFC dysfunction, including medications for Attention Deficit Hyperactivity Disorder, Post-Traumatic Stress Disorder and a potential treatment for schizophrenia and bipolar disorder.
Nicotinic a7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex
Yang Y, Paspalas CD, Jin LE, Picciotto MR, Arnsten AF, Wang M. (2013) Nicotinic a7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. Proc Natl Acad Sci USA 110:12078-83.
NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex
Wang M, Yang Y, Wang CJ, Gamo NJ, Jin LE, Mazer JA, Morrison JH, Wang XJ, Arnsten AF. (2013) NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. Neuron 77:736-49.
Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses
Arnsten AF, Wang MJ, Paspalas CD. (2012) Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron 76:223-39.
Dynamic Network Connectivity: A new form of neuroplasticity
Arnsten AFT, Paspalas CD, Gamo NJ, Yang Y, Wang M. Dynamic Network Connectivity: A new form of neuroplasticity. Trends in Cognitive Sciences, 4: 365-75, 2010.
Stress signalling pathways that impair prefrontal cortex structure and function
Stress signalling pathways that impair prefrontal cortex structure and function. Arnsten AF. Nat Rev Neurosci. 2009 Jun;10(6):410-22. Review. PMID: 19455173 [PubMed - indexed for MEDLINE]
Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory
Vijayraghavan, S., Wang, M., Birnbaum, S.G., Bruce, C.J., Williams, G.V., and Arnsten, A.F.T. (2007). Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nature Neurosci. 10:376-84.
Alpha-2A-Adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex
Wang, M., et al. (2007). Alpha-2A-Adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129:397-410.
cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex.
Carlyle BC, Nairn AC, Wang M, Yang Y, Jin LE, Simen AA, Ramos BP, Bordner KA, Craft GE, Davies P, Pletikos M, Šestan N, Arnsten AF, Paspalas CD. Proc Natl Acad Sci U S A 111:5036-41, 2014.
Stress weakens prefrontal networks: molecular insults to higher cognition.
Arnsten AF. Nat Neurosci.;18:1376-85
Dopamine's Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders.
Arnsten AF, Wang M, Paspalas CD. Pharmacol Rev. 67:681-96