(provided by candidate): The goal of this proposal is to investigate how inhibitory interneurons shape the response properties of cortical projection neurons. The great diversity of interneurons suggests that different subtypes play distinct roles in cortical processing. In addition, abnormal inhibitory circuitry may underlie several neurological and psychiatric disorders, such as epilepsy, schizophrenia, autism, and anxiety. However, thus far it has been difficult to specifically target and manipulate individual interneuronal classes. Recently, the use of cell-type-specific promoters has made it possible to express genes of interest in genetically-delimited groups of cells. I propose to use this technology, in conjunction with optical control of neural activity, to examine the function of specific interneuronal subtypes: those that express parvalbumin (PV+), and those that do not (PV-). My central hypothesis is that PV+ interneurons mediate fast sound-evoked synaptic inhibition, whereas PV- interneurons play a role in dendritic integration and plasticity. I will use Cre/LoxP technology to target the light-sensitive proteins channelrhodopsin-2 (ChR2) and halorhodopsin (Halo) to PV+ and PV- interneurons in auditory cortex, in separate populations of transgenic Cre driver mice, with viral delivery of loxP constructs. ChR2 will be used to optically """"""""tag"""""""" PV+ and PV- cells during physiological recordings, allowing me to characterize and compare their response properties. In a separate set of experiments, I will use Halo to selectively silence either PV+ or PV- cells, and observe how this affects sound-evoked activity in auditory cortex in awake mice. When PV+ cells are silenced, I expect auditory responses to be more sustained, less sparse, and less temporally precise. The silencing of PV- interneurons may affect synaptic summation and plasticity. Finally, mice expressing Halo will be trained on auditory tasks, and I will investigate how silencing PV+ o PV- interneurons affects auditory-driven behaviors.
better understanding of how different types of neurons work together will shed light on what can go wrong when brain circuits do not function properly. In particular, disorders such as epilepsy, schizophrenia, autism, and anxiety are thought to involve abnormalities of inhibitory networks in the cerebral cortex. Exploring the link between neural activity, perception, and behavior may guide the development of therapeutic strategies for a variety of brain disorders.
