Shao-Pii Onn, Ph.D.
Assistant Professor, Dept. Neurobiology and Anatomy, Drexel University College of Medicine
Email: shao-pii.onn@drexel.edu

Dopamine modulation of the information outflow in limbic prefrontal-accumbens systems

Research and Interest

The primary research interest of my laboratory is dopamine (DA) modulation of the information processing in the prefrontal cortex (PFC) and the cortico-accumbens circuit and its relevance to psychiatric disorders, e.g., drug dependence and schizophrenia. It has been shown in humans that psychostimulants can precipitate psychotic episodes, with lower doses of drug in former drug addicts than in naïve individuals. Repeated exposure of monkey to amphetamine induces enduring cognitive and emotional deficits similar to that identified in chronic amphetamine abusers. In rats similarly treated with amphetamine for a period of 1 month, there exists enhanced synchronous activity between neurons in the prefrontal cortex and in the n. accumbens via augmenting bistable membrane potentials and gap junctional conductances (Onn & Grace, 2000). This suggests enhanced synchrony across limbic prefrontal-accumbens circuits in a DA-compromised state, e.g., drug dependence. Current research projects, using complementary in vivo intracellular sharp-electrode and in vitro whole-cell recordings in conjunction with confocal microscopy, are to evaluate the type of cortical abnormalities associated with distinct interneuronal subclass(es) and output neurons in amphetamine- or nicotine-dependent rats. In addition, in conjunction with iontophoretic application of DA or synaptic activation of DA fibers, we hope to address the cortical pathophysiology in specific afferent input to the PFC, possibly contributing to what some clinicians have reported as hypofrontality in drug dependence. Another series of ongoing work using in vitro intracellular/whole cell recordings is to characterize the involvement of DA receptors (e.g., D4 receptor subtype) in regulating excitatory synaptic potentials/currents in PFC or accumbens neurons in living brain slices to better understand the interdependency between hypofrontality and subcortical hyperdopaminergic activity in diseases like drug dependence.

Projects currently under study include:

1) Recording from PFC neurons using in vivo extracellular/intracellular recordings in conjunction with intracellular staining in amphetamine-dependent rats, to evaluate the relative role of different cortical afferent input in controlling the activity level of PFC neurons in drug-dependent rats (Onn et al., 2003).

2) Employing confocal microscopy to examine anatomical alterations associated with distinct subsets of GABA interneurons linking to presynaptic variocosities containing corticotrophin-releasing factors during amphetamine withdrawal (Mohila and Onn, 2003), to understand how psychostimulants regulate inhibitory connections between distinct subsets of cortical inhibitory interneurons.

3) Employing whole cell patch recordings assisted with differential infrared-assisted videomicroscopy to target GABA interneuronal subclasses to characterize inhibitory postsynaptic potentials/currents in living brain slices taken from nicotine-exposed rats. Collectively, we hope to understand the interdependency between cortical intrinsic GABA deficits and cortical output neuron synchronization that may underlie subsequent subcortical hyperdopaminergic activity manifested as drug-seeking behavior.

4) Using intracellular/whole cell recordings from cortical or accumbens slices, in collaboration with Drs. Allen Fienberg, Paul Greengard (Rockefeller University) and Dr. Anthony Grace (University of Pittsburgh), to address the pharmacological roles of DA receptors in the regulation of dye coupling between cortical or accumbens output neurons in DARPP-32 knockout mice (Onn et al., 2003).

Biography

Shao-Pii Onn graduated from the University of Pittsburgh with a PhD in Neuroscience (mentor: Dr. Michael Zigmond). She did her post-doctoral fellowships at the University of Pittsburgh, Department of Psychiatry and Neuroscience (Mentors: Drs. Anthony Grace and Theodore Berger). She continued to serve as a research faculty at the University of Pittsburgh (1995-2000) before joining the Department of Neurobiology and Anatomy at Drexel University College of Medicine, in September 2000.

Lab Personnel

Postdoctoral Fellows (at Drexel University)
-Dr. George Yu, PhD/MD; -Dr. Kevin Wang, PhD; -Dr. Min Lin, PhD; -Dr. X-B Wang, PhD
-Dr. Gong S-Y (to be joining)

Graduate Students (at the Drexel University):
-Carrie A. Mohila (PhD/MD graduated in 2005; Dartmouth Medical School Resident)
-Ivy Li (M.S. graduated in 2004; Texas Medical School Medical Student)
-Nalini Govindarajan (M.S. graduated in 2005; University of Illinois Medical School Stuent)
-J-J Liu (B.S. Yale University; Stanford Medical School Stuent)

Collaborators & Colleagues

-Dr. Anthony A Grace (University of Pittsburgh)
-Dr. Allen Fienberg (Rockefeller University)
-Dr. Paul Greengard (Rockefeller University)

Selected Publication

1. Onn, S-P., X-B Wang (2005a) Differential modulation of prefrontal cortical activity by afferents from ventral tegmental area and mediodorsal thalamus. Eur J Neurosci 21(11)2975-2992.

2. Onn, S-P., X-B Wang, M. Lin, Grace, AA (2005b) Dopamine receptor subtypes differentially modulate recurrent excitatory synapses in prefrontal cortical pyramidal neurons. Neuropsychopharmacology, in press (journal issue cover page).

3. Mohila, C.A. and Onn, S-P. (2005c) Increases in the density of parvalbumin-immunoreactive neurons in anterior cingulate cortex of amphetamine-withdrawn rats: evidence for corticotropin-releasing factor in sustained elevation. Cerebral Cortex, 15: 250-261(journal issue cover page)

4. Liu, J-J, , Mohila, C.A., Govindarajan N., Gong Y., Onn, S-P. (2005d) Adolescent nicotine exposure differentially influences calcium binding proteins in adult rat anterior cingulated cortex. In 2nd review.

5. Onn, S-P, M. Lin, X-B Wang , M. Assing (2005e) Alterations in recurrent excitatory synapses in anterior cingulate cortex of nicotine-exposed rat brains. Submitted.

6. Onn, S-P., X-B Wang, C.A. Mohila (2005f) Altered mesocortical modulation of limbic thalamic input to the anterior cingulate cortex during amphetamine abuse. Submitted.

7. Onn, S-P., Fienberg A., Greengard, P., Grace A.A. (2003) Dopamine modulation of membrane excitability in striatal spiny neurons is altered in DARPP-32 knockout mice. Journal Pharmacology and Experimental Therapeutics306: 870-879.

8. Onn, S-P., West, A. R., Grace, A.A. (2000b) Dopamine-mediated regulation of striatal neuronal and network interactions. Trends in Neuroscience 23(10) 48-56.

9. Onn, S-P. and Grace, A.A. (2000a) Amphetamine withdrawal alters bistable states and cellular coupling in rat prefrontal cortex and nucleus accumbens neurons recorded in vivo. Journal of Neuroscience 20:2332- 2345.

10. Onn, S-P. and Grace, A. A (1999) Alterations in electrophysiological activity and dye coupling of striatal spiny and aspiny neurons in dopamine-denervated adult striatum recorded in vivo Synapse 33:1- 15 (journal issue cover page).

11. Fienberg, A.A. Hiroi, N., Mermelstein, P., Song, W.J., Snyder, G.L., Nishi, A., Cheramy, A., O’Callaghan, J.P., Cooper, D.C., Onn, S-P., Grace, A.A., Quimet, C.C., White,F.J., Hyman, S.E., Surmeier, D. J., Girault, J.A.,Nestler, E. J., and Greengard, P. (1998) DARPP-32, regulator of the efficacy of dopaminergic neurotransmission. Science 281:838-842.

12. Onn, S-P., and Grace, A.A. (1995) Repeated treatment with haloperidol and clozapine exerts differential effects on dye coupling between neurons in subregions of striatum and nucleus accumbens. Journal of Neuroscience 15: 7024-7036.