Major depressive disorder (MDD) is predicted to be the most burdensome disease worldwide by the year 2030. Improved understanding of the neural circuits mediating key psychological processes that go awry in the disorder will facilitate development of novel treatments for MDD. Reduced interest in pursuing previously rewarding stimuli (anhedonia) is a core symptom of MDD. The mesolimbic dopamine (DA) system is critical to the pursuit of rewards under normal conditions, and clinical neuroimaging studies suggest this system to be hypoactive in MDD. The unpredictable chronic mild stress (UCMS) animal model has been a useful means to study this phenomenon in rodents. Following UCMS, animals show decreased motivated behavior, which can be restored with DA system excitation. An important question that remains unanswered, however, is why the DA system is functioning improperly in MDD. Our lab has recently shown that the DA system is hypoactive in animals that have undergone UCMS (as well as learned helplessness), due to enhanced afferent inhibition of DA neurons located in the ventral tegmental area (VTA). We have delineated a circuit whereby increased basolateral amygdala (BLA) drive of the ventral pallidum (VP) following UCMS leads to a potent reduction in VTA DA neuron population activity (number of active DA neurons), and this appears to be critical to the mechanism whereby UCMS reduces DA system tone. However, this circuit presently omits two regions proposed to be important nodes in MDD circuitry in humans: the subgenual cingulate cortex (BA25), whose rodent homologue is the infralimbic prefrontal cortex (ILPFC), and the lateral habenula (LHb). Human studies have shown BA25 to be overactive in MDD, as is also seen for the BLA, and thus a known projection from the ILPFC to the BLA may be driving the BLA over-activation that is critical to diminished DA activity seen following UCMS. Alternatively, the LHb has a more proximal projection to the VTA DA neurons and therefore over- activation of this region may, via the rostromedial tegmentum (RMTg), inhibit VTA DA neurons. We will therefore investigate the relative roles of these two regions in UCMS-induced DA system down-regulation, via the following aims: 1) To determine the impact on the DA system of activating efferent projections from ILPFC- >BLA and LHb->RMTg in normal rats using electrophysiological and behavioral readouts, 2) To assess whether inactivating the ILPFC->BLA or LHb->RMTg projections improves DA system function in animals that exhibit impaired motivation after undergoing UCMS, 3) To define the time course for the development of alterations in regional activity level in potential circuit nodes, including the ILPFC, BLA, LHb, RMTg, VP, and VTA. With greater understanding of the afferent structures potentially down-regulating the DA system in MDD, novel therapeutic interventions could specifically target aberrantly functioning nodes in this neural circuit.

Public Health Relevance

The purpose of my research proposal is to identify the regions of the brain that contribute to the reduced motivation experienced by individuals with depression; an important topic given that there is currently little understanding of how specific brain regions that are malfunctioning in depression contribute to the specific symptoms a patient is experiencing, and as a result current treatments are not optimal. Since dopamine is a neurotransmitter that is key to the pursuit and enjoyment of reward, determining the brain pathways leading to its down-regulation in depression can potentially allow for discovery of new medications targeting these pathways. Such research can facilitate the development of novel approaches to the treatment of depression through rationally designed therapeutics selected for a given patient based on that patient's specific set of symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30MH105199-02
Application #
9011382
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Van'T Veer, Ashlee V
Project Start
2015-02-06
Project End
2019-02-05
Budget Start
2016-02-06
Budget End
2017-02-05
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Moreines, Jared L; Owrutsky, Zoe L; Grace, Anthony A (2016) Involvement of Infralimbic Prefrontal Cortex but Not Lateral Habenula in Dopamine Attenuation after Chronic Mild Stress. Neuropsychopharmacology :