Depression is the most prevalent of the psychiatric disorders, causing higher morbidity and mortality than any other psychiatric disorder. Nonetheless, the neurobiological underpinnings of this disorder are not known. Anhedonia, an inability to derive pleasure from the environment, is a major feature of depression. We focus on the neurobiological basis of anhedonia, which is also present in schizophrenia, bipolar disorder, drug withdrawal, and Parkinson's disease, thereby being consistent with the Research Domain Criteria approach. The dopamine (DA) system has been classically associated with anhedonia, and has been suggested to play a role in depression;however, direct experimental evidence for this association is lacking. Functional imaging studies have shown an association between hyperactivity in area 25 (homologous to rodent infralimbic prefrontal cortex) and hyper-excitability of the amygdala in patients with depression. We have found in our preliminary studies that activation of the infralimbic prefrontal cortex decreases DA neuron activity states, which can be reversed by inactivation of the basolateral amygdala. Moreover, in animal models of depression we found that there is also a decrease in DA neuron activity states that also can be reversed by inactivation of the basolateral amygdala. These data are consistent with a model in which depression-induced hyperactivity of the ilPFC drives an amygdala-dependent down-regulation of DA neuron responsivity, leading to anhedonia. Moreover, ketamine, which has been found clinically to elicit rapid anti-depressant responses, reverses both the decrease in DA neuron activity and the helplessness state specifically in rats showing learned helplessness behavior. This could lead to insights into novel mechanisms of treatment for depression and other disorders in which anhedonia plays a major role. However, to do this we will need a better understanding of the circuitry involved, in particular the circuit by which the basolateral amygdala down-modulates DA neuron activity states. To address our overarching hypothesis, which is in disorders with a negative affective state, hyperactivity within the ilPFC causes an overdrive of the BLA, resulting in an attenuation of VTA DA neuron activity and anhedonia, we will perform experiments to address the following Specific Aims: 1) To examine how infralimbic prefrontal cortical activation affects DA neuron activity states, 2) To examine the pathways through which basolateral amygdala activation attenuates DA neuron activity patterns, 3) To evaluate the involvement of these systems in animal models of depression and anhedonia, and 4) to evaluate how ketamine can reverse the attenuated DA neuron activity and anhedonia in animal models. This will be done using an integrated systems-oriented approach focused on in vivo electrophysiology, optogenetics and behavior. By providing a better understanding of pathways that may underlie anhedonia in depression and other disorders, we will be in a better position to identify drugs with novel and specific mechanisms that may alleviate this crippling disorder.

Public Health Relevance

Depression is the most common psychiatric disorder, afflicting 15% of the population over their lifetimes;nonetheless, the neurobiology of this disorder is not well-understood. We propose to use a systems-oriented approach to study the neurobiology of anhedonia, a major feature of depression and related disorders, and which is often associated with the neurotransmitter dopamine. By using data derived from human imaging studies, we will examine how the dopamine system may be down-regulated in depression, the neural pathways that are likely involved in this down-regulation, and how the rapidly acting antidepressant effects of ketamine act to normalize this system. This will provide insights both into the neurobiology of anhedonia and depression, and point the way to new drug development for this devastating condition.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Meinecke, Douglas L
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University of Pittsburgh
Schools of Arts and Sciences
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Bortz, David M; Grace, Anthony A (2018) Medial septum differentially regulates dopamine neuron activity in the rat ventral tegmental area and substantia nigra via distinct pathways. Neuropsychopharmacology 43:2093-2100
Rincón-Cortés, Millie; Gagnon, Kimberly G; Dollish, Hannah K et al. (2018) Diazepam reverses increased anxiety-like behavior, social behavior deficit, and dopamine dysregulation following withdrawal from acute amphetamine. Neuropsychopharmacology 43:2418-2425
Rincón-Cortés, Millie; Grace, Anthony A (2017) Sex-Dependent Effects of Stress on Immobility Behavior and VTA Dopamine Neuron Activity: Modulation by Ketamine. Int J Neuropsychopharmacol 20:823-832
Belujon, Pauline; Grace, Anthony A (2017) Dopamine System Dysregulation in Major Depressive Disorders. Int J Neuropsychopharmacol 20:1036-1046
Grace, Anthony A (2017) Gilles de la Tourette's and the Disruption of Interneuron-Mediated Synchrony : Comments on: Hashemiyoon, R., Kuhn, J., Visser-Vandewalle, V. Brain Topography (2016). DOI 10.1007/s10548-016-0525-z. Brain Topogr 30:1-2
Moreines, Jared L; Owrutsky, Zoe L; Grace, Anthony A (2017) Involvement of Infralimbic Prefrontal Cortex but not Lateral Habenula in Dopamine Attenuation After Chronic Mild Stress. Neuropsychopharmacology 42:904-913
Myrga, John M; Juengst, Shannon B; Failla, Michelle D et al. (2016) COMT and ANKK1 Genetics Interact With Depression to Influence Behavior Following Severe TBI: An Initial Assessment. Neurorehabil Neural Repair 30:920-930
Zimmerman, Eric C; Grace, Anthony A (2016) The Nucleus Reuniens of the Midline Thalamus Gates Prefrontal-Hippocampal Modulation of Ventral Tegmental Area Dopamine Neuron Activity. J Neurosci 36:8977-84
Harun, Rashed; Hare, Kristin M; Brough, Elizabeth M et al. (2016) Fast-scan cyclic voltammetry demonstrates that L-DOPA produces dose-dependent, regionally selective bimodal effects on striatal dopamine kinetics in vivo. J Neurochem 136:1270-1283
Grace, Anthony A (2016) Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci 17:524-32

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