The overarching aim of thisgrant is to examine the role of glutamatergic neurotransmission,in particular that ofjgiutamatergic efferents rom the prefrontal cortex (RFC), in the functional abnormalities that may be ?elated to schizophrenia.One of our key findings during the past funding period has been that NMDA receptor hypofunction in b having animals increases the firing of RFC pyramidal cells consistent with the idea that cortical GABAint irneurons have a high level of NMDA tonic activation that drives the pyramidal neurons. Based on this progress, it is hypothesized that NMDA receptor hypofunction reduces the inhibitory influence of GABA interneurons on cortical pyramidal cells producing a tonic state of disinhibition at these neurons. We predict that tr is reduced inhibitory control (1) diminishes the capacity of RFC neurons to fire appropriately to task relevant stimuli, and (2) exaggeratesthe phasic impact of glutamate afferentson some pyramidal neurons leading to abnormal activity of RFC projections to dopamine cells resulting in excess dopamine release.The first prediction assumes a constant state of aberration, consistentwithsustained cognitive deficits in schizof: hrenia. The second prediction assumes interrupted changes in dopamine release th^t occur in response to p lasic activationof afferents from regions such as the thalamus and habenula consistent with episodic incidents of psychosis in schizophrenia. We further hypothesize that events at the excitatory afferent-GABAsynapse in the RFC are key for discovering drug targetsthat normalize the impact of jthe reduced inhibitory central on RFC efferents and, hence, may be useful for treatment of schizophrenia. We propose to test these hypotheses using ensemble recording and mierodialysis in behaving rodents. Public health relevance schizophrenia is a major public health concern. This project seeks to develop anew understanding of the pathophysiology of schizophrenia and evaluate novel treatment options for treatment of this disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH048404-22
Application #
8290236
Study Section
Special Emphasis Panel (NSS)
Program Officer
Winsky, Lois M
Project Start
1992-09-15
Project End
2013-07-31
Budget Start
2012-07-01
Budget End
2013-07-31
Support Year
22
Fiscal Year
2012
Total Cost
$373,599
Indirect Cost
$126,099
Name
University of Pittsburgh
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Simon, Nicholas W; Gregory, Timothy A; Wood, Jesse et al. (2013) Differences in response initiation and behavioral flexibility between adolescent and adult rats. Behav Neurosci 127:23-32
Volman, Susan F; Lammel, Stephan; Margolis, Elyssa B et al. (2013) New insights into the specificity and plasticity of reward and aversion encoding in the mesolimbic system. J Neurosci 33:17569-76
Matthews, Marguerite; Bondi, Corina; Torres, Gonzalo et al. (2013) Reduced presynaptic dopamine activity in adolescent dorsal striatum. Neuropsychopharmacology 38:1344-51
Totah, Nelson K B; Jackson, Mark E; Moghaddam, Bita (2013) Preparatory attention relies on dynamic interactions between prelimbic cortex and anterior cingulate cortex. Cereb Cortex 23:729-38
Moghaddam, Bita; Javitt, Daniel (2012) From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37:4-15
Kim, Yunbok; Wood, Jesse; Moghaddam, Bita (2012) Coordinated activity of ventral tegmental neurons adapts to appetitive and aversive learning. PLoS One 7:e29766
Sturman, David A; Moghaddam, Bita (2011) Reduced neuronal inhibition and coordination of adolescent prefrontal cortex during motivated behavior. J Neurosci 31:1471-8
Sturman, David A; Moghaddam, Bita (2011) The neurobiology of adolescence: changes in brain architecture, functional dynamics, and behavioral tendencies. Neurosci Biobehav Rev 35:1704-12
Moghaddam, Bita (2010) Dopamine in the thalamus: a hotbed for psychosis? Biol Psychiatry 68:3-4
Sturman, David A; Mandell, Daniel R; Moghaddam, Bita (2010) Adolescents exhibit behavioral differences from adults during instrumental learning and extinction. Behav Neurosci 124:16-25

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