Ph.D. Georgetown University, 2007
Circuit neurophysiology of substance use
Our lab investigates how behavioral signatures of substance use are represented by activity of cells and networks within the brain. A broad range of legal and illicit substances can lead to compulsive use despite prominently negative physical, psychological, or social consequences. The behaviors associated with substance use disorders are intuitive: craving, spending effort to obtain the drug, distress in the drug’s absence. The question of why such symptoms develop from initial curiosity or a chance encounter with a drug to an overwhelming presence in all daily activities, however, is much more difficult.
We are interested in the idea that behavioral similarities shared by all substance use disorders occur on the background of dissimilar and heterogeneous cellular adaptations. Much like the histories of individual users differ from one another, so do the cellular events underlying such histories. A person driven to drug use to escape depression is different from a person resorting to drugs to fight daily stress who is different still from a thrill-seeker escaping from the mundane. We use a rat self-administration model of cocaine seeking to explore potential mechanisms representing disparate behavioral histories of drug exposure. A prominent focus of early work in the lab has been on the role of excitatory glutamate receptor-mediated signaling in the nucleus accumbens. We have shown, for example, that the strength of excitatory synaptic signaling in this brain area depends on duration of withdrawal from cocaine and availability of endogenous cannabinoids.
Our more recent studies focused on molecules regulating action potential output of accumbens neurons following extinction of cocaine seeking. Building on this and other findings, current studies in the lab focus on three broad topics: 1) impact of astroglial signaling on neuronal network response to cocaine; 2) regulation of motivational effort to pursue reward by intrinsic conductances in the nucleus accumbens; 3) mechanisms responsible for cognitive deficits following psychostimulant exposure. To address these questions, we rely on electrophysiological recordings in brain slices, Ca2+ imaging in brain slices and in vivo, operant conditioning and other behavioral paradigms, as well as an array of molecular techniques. The overarching goal of research in the lab is to integrate genomic, cellular, and network levels of analysis into a conceptual framework that accomodates diverse substance use etiologies.
1. Ortinski, P.I.*, Dong, J.*, Mungenast, A., Takano, H., Watson, D.J., Haydon, P.G., Coulter, D.A.: Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nature Neuroscience 13: 548-591, 2010 (* co-authors).
2. Takano, H., McCartney, M., Ortinski, P.I., Yue, C., Putt, M.E., Coulter, D.A. Deterministic and Stochastic Neuronal Contributions to Distinct Synchronous CA3 Network Bursts. Journal of Neuroscience 32:4743-52, 2012.
3. Ortinski P.I., Vassoler F.M., Carlson G.C., and Pierce R.C.: Temporally dependent changes in cocaine-induced synaptic plasticity in the nucleus accumbens shell are reversed by D1-like dopamine receptor stimulation. Neuropsychopharmacology, 2012, 37:1671-82.
4. Mietlicki-Baase E.G., Ortinski P.I., Reiner D.J., Sinon C.G., McCutcheon J.E., Pierce R.C., Roitman M.F., Hayes M.R. Glucagon-like peptide-1 receptor activation in the nucleus accumbens core suppresses feeding by increasing glutamatergic AMPA/kainate signaling. Journal of Neuroscience, 2014, 34:6985-92.
5. Zhou L., Andersen H., Arreola A.C., Turner J.R., Ortinski P.I. Behavioral history of withdrawal influences regulation of cocaine seeking by glutamate re-uptake. PLoS One, 2016, 11:e0163784.
6. Zhou L., Fisher M.L., Cole R.D., Gould T.J., Parikh V., Ortinski P.I., Turner J.R. Neuregulin 3 signaling mediates nicotine-dependent synaptic plasticity in the orbitofrontal cortex and cognition. Neuropsychopharmacology, 2018, 43:1343-54.
7. Galloway A., Adeluyi A., O'Donovan B., Fisher M.L., Rao C.N., Critchfield P., Sajish M., Turner J.R., Ortinski P.I. Dopamine triggers CTCF-dependent morphological and genomic remodeling of astrocytes. Journal of Neuroscience, 2018, 38:4846-58.
8. Hernandez N.S., O'Donovan B., Ortinski P.I., Schmidt H.D. Activation of glucagon-like peptide-1 receptors in the nucleus accumbens attenuates cocaine seeking in rats. Addiction Biology, 2019 24:170-81. Epub 2017.
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