Dopamine (DA) plays a central role in the function of the prefrontal cortex (PFC). While the majority of dopamine receptors in PFC are D1-type, D2-receptors (D2Rs) play a vital role both as a counterbalance to D1 activation in working memory and in modulating behavior during set-shifting tasks. Additionally, dysfunction of the D2R system has been hypothesized to underlie a number of psychiatric diseases, most notably schizophrenia, and D2Rs are a major target of drug therapies. Recently, with collaborators in the Sohal laboratory, I have studied D2R-expressing neurons in mouse PFC and discovered two major results: (1) The population of D2R-expressing pyramidal cells in layer V PFC is coincident with a previously identified population of thick-tufted, subcortically projecting neuron. (2) Applying D2R agonists to these cells leads to a calcium-activated non-specific ion channel mediated afterdepolarization that is dependent on calcium entry through NMDR receptors and dendritic L-type calcium channels. These findings, taken together with studies showing that thick-tufted PFC neurons form a highly recurrent network in layer V of PFC suggest the following hypothesis: DA can lead to epochs of persistent network activity in D2R-expressing cell networks analogous to the activity that has been observed with D1R activation, and the amount and type of DA stimulation can modulate the stability of patterns of activity in these cells. This hypothesis will be tested through a combination of experimental and computational modeling aims. Experimentally, I will test the precise response of D2R-expressing neurons to synaptic and dopaminergic stimuli using optogenetic techniques to stimulate different types of axon terminals. This data will then be integrated into a biophysical model of networks of D2R-expressing neurons to discover the precise conditions under which persistent activity can occur among these cells and the extent to which patterns of persistent activity are stable against different types of synaptic input. This study will help to illuminate the role of D2R-expressing cells in the function of the PFC by providing an explicit model of these cells. In addition, this model may be used to gain insight into perturbations of normal D2R function that have been hypothesized to underlie psychiatric diseases such as schizophrenia.

Public Health Relevance

Dopamine has an important role in the normal function of the cortex. Dysfunction of the dopamine system is thought to underlie a number of psychiatric diseases including schizophrenia. A detailed model of dopamine's effect on cortical networks could lead to new insights into the diagnosis and treatment of these diseases.

Agency
National Institute of Health (NIH)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01MH097841-03
Application #
8687743
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Rosemond, Erica K
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143