Matthew Hearing, Ph.D. Research Lab
Opioid-based drugs are mainstays for pain management. However, side effects such as euphoria and the development of tolerance and dependence contribute to an increasing diversion of these readily available compounds for non-therapeutic use. A major emphasis in my research is using ex vivo brain slice electrophysiology to study how repeated opiate exposure modifies glutamate and gamma-Aminobutyric Acid (GABA)-mediated synaptic strength in neurons of the prefrontal cortex and nucleus accumbens – two highly inter-connected brain regions involved in decision-making and reward. Current studies focus on identifying alterations in intrinsic cell membrane properties (i.e., excitability), presynaptic glutamate release and postsynaptic signaling mediated by ionotropic AMPA- and NMDA-type glutamate receptors in medium spiny neurons and pyramidal cells -- the two principal cell-types in the nucleus accumbens and prefrontal cortex respectively. Additional studies focus on drug-induced adaptations in prefrontal cortex inhibitory signaling mediated by GABA and dopamine and how these modifications alter activation of layer 5/6 pyramidal neurons.
Research in my laboratory primarily employs a model of drug self-administration in mice genetically altered to express fluorescent proteins in specific sub-populations of neurons. This behavioral approach is used in combination with slice electrophysiology and utilizes genetic incorporation of light-sensitive ion channels (optogenetics) and retrograde neuron-tract tracers that allows us to isolate discrete forms of plasticity occurring within select neural circuits. We also use in vivo optogenetic stimulation to modulate synaptic strength in order to assess the functional role these adaptations play in driving relapse and identify targets for pharmacotherapies aimed at mitigating this behavior.
A second research interest in my laboratory integrates electrophysiology, rodent models of cognitive flexibility, and a neurodevelopmental model of schizophrenia to examine changes in prefrontal cortex pyramidal neuron and GABAergic interneuron signaling in hopes of identifying cellular correlates of prefrontal cortical dysfunction responsible for cognitive impairments observed in neuropsychiatric disorders.
- Hearing M, Jedynak J, Ebner RS, Ingebretson, A, Asp AJ, Fischer RA, Schmidt C, Larson EB, Thomas MJ (2016) Reversal of morphine-induced cell-type specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement. Proc Natl Acad Sci 113(3):757-762.
- Jedynak J1, Hearing M1, Kelly M, Ingebretson AE, Fischer R, Ebner SR, Thomas MJ (2016) Cocaine and amphetamine induce overlapping but distinct patterns of AMPAR plasticity in nucleus accumbens medium spiny neurons. Neuropsychopharm 41(2):464-476. 1authors contributed equally
- Kotecki L, Hearing M, McCall N, Marron Fernandez de Velasco E, Pravetoni M, Arora D, Victoria NC, Muñoz MB, Xia Z, Slesinger PA, Weaver CD, Wickman K (2015) GIRK channels modulate opioid-induced motor activity in a cell type- and subunit-dependent manner. J Neurosci 35(18): 7131-7142.
- Marron-Fernandez de Velasco E, Hearing M, Xia Z, Victoria NC, Lujan R, Wickman K (2015) Sex differences in GABAB receptor-dependent signaling in layer 5/6 pyramidal neurons of the mouse prelimbic cortex. Neuropharmacology 95:353-360.
- Wydeven N, Maron Fernandez de Velasco E, Bennyworth MA, Hearing MC, Fischer RA, Thomas MJ, Weaver DC, Wickman K (2014) Mechanisms underlying the activation of G protein-gated inwardly-rectifying K+ (GIRK) channels by the novel anxiolytic drug ML297. Proc Natl Acad Sci 111:10755-10760.
- Liang B, Nissen JD, Laursen M, Wang X, Hearing MC, Andersen MN, Rasmussen HB, Morten Grunnet, Søren-Peter Olesen, Thomas Jespersen. G-protein coupled inward rectifier potassium current contributes to ventricular repolarization. Cardiovascular Research 101: 1750184.
- Hearing M, Kotecki L, Marron Fernandez de Velasco E, Fajardo-Serrano A, Luján R, Wickman K (2013) Repeated cocaine weakens GABAB-Girk signaling in Layer 5/6 pyramidal neurons in the prelimbic cortex. Neuron 80(1): 159-170.
- Gross A, Booker S, Althof D, Shigemoto R, Bettler B, Frotscher M, Hearing M, Wickman K, Watanabe M, Kulik A, and Vida I (2013) Dendritic GABAB receptors contribute to the modulation of perisomatic-targeting parvalbumin interneuron networks. J Neurosci 33:7961-74.
- Hearing M, Rupp-Moody A, Wickman K (2012) Cocaine-induced adaptations in metabotropic inhibitory signaling in the mesocorticolimbic system. Rev Neurosci 23(4): 325-351.
- Arora D1, Hearing MC1, Haluk DM, Mirkovic K, Fajardo-Serrano A, Wessendorf MW, Watanabe M, Luján R, Wickman K (2011) Acute cocaine exposure weakens GABAB receptor-dependent Girk signaling in dopamine neurons of the ventral tegmental area. J Neurosci 34:12251-12257. 1authors contributed equally
- Hearing MC, Schwendt M, McGinty JF (2010) Suppression of activity-regulated cytoskeleton-associated gene expression in the dorsal striatum attenuates extinction of cocaine-seeking. Int J Neuropsychopharmacol 14:1-12.
- Hearing MC, Schochet TL, See RE, McGinty JF (2010) Context-driven cocaine-seeking in abstinent rats increases activity-regulated gene expression in the basolateral amydala and dorsal hippocampus differentially following short and long periods of abstinence. Neuroscience 170: 570-9.
- Hearing MC, Miller SW, See RE, McGinty JF (2008a) Relapse to cocaine seeking increases activity-related gene expression differentially in the prefrontal cortex of abstinent rats. Psychopharmacology 198(1):77-91.
- Hearing MC, See RE, McGinty JF (2008b) Relapse to cocaine-seeking increases activity-regulated gene expression differentially in the striatum and cerebral cortex of rats following short or long periods of abstinence. Brain Struct Funct 213(1-2):215-27.
- Mulholland PJ, Carpenter-Hyland EP, Hearing MC, Becker HC, Woodward JJ, Chandler LJ (2008) Glutamate transporters regulate extrasynaptic NMDA receptor modulation of Kv2.1 potassium channels. J Neurosci 28(35):8801-9.
- Schwendt M, Hearing MC, See RE, McGinty JF (2007) Chronic cocaine reduces RGS4 mRNA in rat prefrontal cortex and dorsal striatum. Neuroreport 18(12):1261-5.
- Madayag A, Lobner D, Kau KS, Mantsch JR, Abdulhameed O, Hearing M, Grier MD, Baker DA (2007) Repeated N-acetylcysteine administration alters plasticity-dependent effects of cocaine. J Neurosci 27(51):13968-76.