Deficits in reward function, including impaired reward valuation, effort valuation and reward responsiveness, are core features of psychiatric disorders, such as schizophrenia and major depressive disorder. These reward deficits contribute significantly to the functional disability evident in these disorders. These reward processes correspond to approach/motivation constructs within the Positive Valence Domain of the NIMH Research Domain Criteria (RDoC) Program. The neurobiology underlying reward deficits is not completely understood and, as a result, there are currently no therapeutics that effectively alleviate reward deficits in psychiatric disorders. Schizophrenia and depression are both associated with abnormalities in glutamate and GABA neurotransmission. The GABAergic system is essential in regulating correct glutamatergic transmission that maintains optimal cortical balance. Importantly, postnatal glutamate transmission is critical for the normal development of the GABAergic system. The overarching goal of this R01 application is to investigate how disrupting early postnatal glutamate transmission leads to reward deficits in adulthood. To address this experimental question, we will employ translational behavioral procedures in rats, optogenetics and immunohistochemical techniques to identify the role of altered glutamate and/or GABA transmission in brain regions associated with reward processing.
Specific Aim 1 will determine whether administering the N-methyl- D-aspartate (NMDA) glutamate receptor antagonist phencyclidine (PCP) during the early postnatal period to male and female rats impairs reward valuation, effort valuation and/or reward responsiveness.
Specific Aim 2 will use optogenetics to either increase or decrease glutamate activity in the orbitofrontal cortex (OFC) or anterior cingulate cortex (ACC) to determine whether such changes in glutamate activity impact reward valuation, effort valuation or reward responsiveness. Specifically, we will determine whether increased or decreased glutamate transmission impairs or improves reward processing in saline- or PCP-treated rats. These findings will provide evidence as to how changes in glutamate transmission lead to the regulation of multiple aspects of reward processing mediated by distinct brain regions.
Specific Aim 3 will determine whether the reward deficits resulting from neonatal PCP treatment are associated with alterations in parvalbumin (PV)-, somatostatin (SST)- and/or vasoactive intestinal polypeptide (VIP)-positive GABA interneurons, and glutamic acid decarboxylase isoform 67 (GAD67) content, in brain regions critical for reward function (i.e., OFC, prelimbic cortex, anterior cingulate cortex, dorsal striatum and/or ventral striatum). This multidisciplinary project will promote our understanding of how alterations in neurobiology resulting from neonatally disrupted glutamate transmission contribute to deficits in reward function in adulthood. The generated findings may identify mechanisms that could be targeted to attenuate reward deficits in neuropsychiatric disorders.

Public Health Relevance

Psychiatric disorders, such as schizophrenia and depression, are characterized by reward deficits that contribute significantly to the functional disability observed in these disorders and are unresponsive to currently available treatments. The neurobiological mechanisms that lead to reward deficits in schizophrenia and depression are not completely understood. Therefore, the overarching goal of the proposed research project is to investigate how disrupting early postnatal glutamate transmission leads to deficits in GABA function and reward deficits of relevance to disorders such as schizophrenia and depression.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Application #
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Rossi, Andrew
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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Barnes, Samuel A; Sheffler, Douglas J; Semenova, Svetlana et al. (2018) Metabotropic Glutamate Receptor 5 as a Target for the Treatment of Depression and Smoking: Robust Preclinical Data but Inconclusive Clinical Efficacy. Biol Psychiatry 83:955-962
Barnes, Samuel A; Der-Avakian, Andre; Young, Jared W (2017) Preclinical Models to Investigate Mechanisms of Negative Symptoms in Schizophrenia. Schizophr Bull 43:706-711