The prefrontal cortex (PFC) plays a key role in aspects of cognition including working memory, behavioral flexibility, and decision making. Conversely, dysfunction of this brain region causes cognitive deficits, including major aspects of psychiatric disorders such as schizophrenia. Here, we will elucidate how the neuromodulator dopamine regulates activity in a specific class of neurons within the PFC. This is important because dopamine is believed to regulate both the normal and pathological function of the PFC. In fact, a major hypothesis in schizophrenia research is that abnormal dopaminergic modulation causes PFC dysfunction and some symptoms of schizophrenia. However, specific mechanisms through which prefrontal dopamine receptors exert their normal and pathological effects remain largely unknown. Our recent publication in the Journal of Neuroscience describes new effects of dopamine receptors on a specific population of neurons in the PFC. This proposal will focus on this subpopulation of prefrontal neurons, which we refer to as """"""""type A neurons."""""""" We propose that different classes of dopamine receptors produce opposing effects on the excitability of these neurons, and that aberrant activity in these neurons, which may be driven by excessive activation of certain dopamine receptors, can produce schizophrenia-like behaviors in mice. First, we will identify specific ion channels and other mechanisms that mediate the effects of dopamine receptors on type A neurons. Then, we will determine how, by altering the excitability of type A neurons, dopamine receptors can alter their responses to synaptic input. We will specifically determine whether dopamine receptors produce distinct effects on synaptic inputs that arise from different sources. Finally, we will deliver various patterns of stimulation to fibes that release dopamine in the PFC. These experiments will test the hypothesis that different patterns of activity in these fibers will activate different dopamine receptors, producing distinct effects on type A neurons. Many of our experiments will utilize new optogenetic technologies, which make it possible to stimulate specific neurons or neural connections, with light. This proposal will focus on how dopamine receptors modulate the activity of type A neurons. Our long-term goal is to relate these changes in type A neuron activity to effects on PFC-dependent behaviors, including pathological behaviors that occur in schizophrenia and other psychiatric disorders.
Schizophrenia affects approximately 1% of the population worldwide, causing distress for patients and their families, and in most cases, life-long disabilit. Many of the most disabling symptoms of schizophrenia are thought to involve dopamine and dysfunction of the prefrontal cortex. Here we propose to study how dopamine modulates the function of the prefrontal cortex in order to identify critical mechanisms that are likely to be disrupted in disease.
|Fazel Darbandi, Siavash; Robinson Schwartz, Sarah E; Qi, Qihao et al. (2018) Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity. Neuron 100:831-845.e7|
|Marton, Tobias; Seifikar, Helia; Luongo, Francisco J et al. (2018) Roles of prefrontal cortex and mediodorsal thalamus in task engagement and behavioral flexibility. J Neurosci :|
|Ellwood, Ian T; Patel, Tosha; Wadia, Varun et al. (2017) Tonic or Phasic Stimulation of Dopaminergic Projections to Prefrontal Cortex Causes Mice to Maintain or Deviate from Previously Learned Behavioral Strategies. J Neurosci 37:8315-8329|
|Robinson, Sarah E; Sohal, Vikaas S (2017) Dopamine D2 Receptors Modulate Pyramidal Neurons in Mouse Medial Prefrontal Cortex through a Stimulatory G-Protein Pathway. J Neurosci 37:10063-10073|
|Clarkson, Rebecca L; Liptak, Alayna T; Gee, Steven M et al. (2017) D3 Receptors Regulate Excitability in a Unique Class of Prefrontal Pyramidal Cells. J Neurosci 37:5846-5860|
|Marton, Tobias F; Sohal, Vikaas S (2016) Of Mice, Men, and Microbial Opsins: How Optogenetics Can Help Hone Mouse Models of Mental Illness. Biol Psychiatry 79:47-52|
|Cho, Kathleen K A; Hoch, Renee; Lee, Anthony T et al. (2015) Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6(+/-) mice. Neuron 85:1332-43|
|Vogt, Daniel; Cho, Kathleen K A; Lee, Anthony T et al. (2015) The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles. Cell Rep 11:944-956|