GABAergic inhibitory interneurons are thought to play a powerful role in regulating the ongoing pattern of activity in the cortex. Interneurons can be divided into many classes based on their intrinsic properties, synaptic targets, and molecular markers. The two largest groups are the parvalbumin-expressing interneurons that target the soma and the somatostatin-expressing interneurons that target the dendrites. Identifying the mechanisms by which these two sources of synaptic inhibition regulate sensory processing is a critical step towards understanding the complex cellular interactions underlying active network function in the brain. However, little is known about the activity pattern or impact of these cells during wakefulness. Using the primary visual system as a model system, we will record the activity of many excitatory and inhibitory neurons in awake, moving animals. Using dense extracellular recordings of identified neurons, we will examine the temporal pattern of interneuron recruitment by sensory stimuli and the contrast-dependence of those activity patterns. We will use a combination of intracellular recordings and cell type-specific optogenetic manipulations to test the impact of parvalbumin and somatostatin interneurons on input integration and spike generation by their postsynaptic target excitatory neurons. Inhibition is thought to play a major role in facilitating the functional flexibility of cortical networks and allowing adaptive scaling of neuronal output to match the range of inputs present in the surrounding sensory environment. To understand the dynamic role that inhibitory interneurons play in regulating the input-output relationship of local cortical networks, we will test the impac of parvalbumin and somatostatin interneurons, as well as excitatory neurons, in modulating the sensitivity, or gain, of cortical responses to visual stimuli. We will further test the behavioral tate dependence of inhibitory gain modulation. These studies will reveal fundamental mechanisms of visual processing in the awake brain and lead to a more complete understanding of cortical network function. Results from our experiments will answer fundamental questions about key interneuron populations that have historically not been possible to target in vivo. Because input integration and gain control are global elements of neural function, our results will be applicable to systems throughout the brain and will elucidate the function and dysfunction of cortical circuits critical for information encoding, perception, and behavior.

Public Health Relevance

GABAergic inhibitory interneurons are a diverse group of brain cells critical for sensory processing and preventing runaway excitation. This proposal will determine how specific subtypes of interneurons with distinct properties regulate excitatory neurons in the visual cortex. Results from these studies will provide novel insight into fundamental cellular mechanisms of healthy brain activity and promote our understanding of interneuron classes whose dysfunction results in neurological diseases such as epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022951-02
Application #
8631088
Study Section
Special Emphasis Panel (SPC)
Program Officer
Steinmetz, Michael A
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$407,925
Indirect Cost
$162,925
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chuong, Amy S; Miri, Mitra L; Busskamp, Volker et al. (2014) Noninvasive optical inhibition with a red-shifted microbial rhodopsin. Nat Neurosci 17:1123-9