The prefrontal cortex is important for controlling cognition, emotion and memory in animals ranging from rodents to primates. The importance of the prefrontal cortex is highlighted in multiple neurological diseases, including schizophrenia and drug addiction. Pyramidal neurons are the principal cells of the prefrontal cortex and integrate glutamatergic inputs from multiple brain regions. These excitatory neurons also receive extensive dopaminergic inputs from sub-cortical brain areas that modulate pyramidal neurons. Together, glutamatergic and dopaminergic inputs help to govern the physiological properties of pyramidal neurons and determine the function of the prefrontal cortex. The primary goal of this study is to understand how these inputs interact at the sub-cellular level in pyramidal neurons. A mechanistic approach will reveal the electrical and calcium (Ca) signals generated during synaptic transmission and integration. Ca signals control the induction of synaptic plasticity, gene expression and morphological stability of these neurons. A combination of 2-photon microscopy and 2-photon laser uncaging will be used to study these signals at individual dendrites and spines. The planned experiments will reveal the importance of different voltage-sensitive ion channels and glutamate receptors in generating Ca signals. Moreover, they will determine how dopamine receptor activation modulates these channels and receptors to influence local Ca signals. The results from these experiments will answer fundamental questions about how prefrontal pyramidal neurons integrate their synaptic inputs. Moreover, they will identify novel therapeutic targets for the debilitating neurological diseases that arise from dysfunction of these neurons.

Public Health Relevance

The prefrontal cortex is important for controlling cognition, emotion and memory in animals ranging from mice to humans. The importance of the prefrontal cortex is highlighted in multiple neurological diseases, including schizophrenia and drug addiction. The proposed experiments will determine how these neurons function and identify novel treatments for these and other debilitating neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085974-05
Application #
8595331
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Nadler, Laurie S
Project Start
2010-01-06
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$336,362
Indirect Cost
$113,612
Name
New York University
Department
Neurology
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
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Chalifoux, Jason R; Carter, Adam G (2011) Glutamate spillover promotes the generation of NMDA spikes. J Neurosci 31:16435-46
Chalifoux, Jason R; Carter, Adam G (2011) GABAB receptor modulation of synaptic function. Curr Opin Neurobiol 21:339-44
Chalifoux, Jason R; Carter, Adam G (2011) GABAB receptor modulation of voltage-sensitive calcium channels in spines and dendrites. J Neurosci 31:4221-32
Chalifoux, Jason R; Carter, Adam G (2010) GABAB receptors modulate NMDA receptor calcium signals in dendritic spines. Neuron 66:101-13