Understanding the cellular and network mechanisms of attention is critical for the development of rational ther- apies for diseases with attention deficits. While neural correlates of attention have been identified in non- human primates, the underlying mechanisms are still unclear: attention increases the responsiveness of neu- rons encoding an attended visual stimulus, yet there is little direct evidence to explain this phenomenon. One possible mechanism could be that attention depolarizes neurons. This mechanism would set neurons' mem- brane potential (Vm) closer to action potential threshold, increasing the probability of spiking given an excitato- ry input. Indirect evidence studying extracellular waveforms supports this possibility but remains controversial because no study has been able to directly measure the Vm of neurons in primates performing an attention task due to extreme technical difficulties. To overcome these technical challenges, I propose to develop an attention task for mice. My sponsor's labora- tory specializes in performing 2-photon guided whole-cell recordings to measure the membrane potential of neurons in behaving mice. Using this technique, I will record visual cortical neurons' membrane potential as animals attend a visual stimulus and then ignore the same visual stimulus. My preliminary data show that I can readily train animals to do this task and obtain high quality whole-cell recordings in behaving animals. The re- sults of these recordings support my hypothesis and suggest that attention depolarizes neurons as a means to increase their responsiveness.
In Aim 1, I will develop and refine the attention task for mice by characterizing the strength, duration, and famil- iarity of stimuli necessary for animals to perform at an expert level.
In Aim 2, I will make 2-photon guided whole-cell recordings from excitatory neurons and inhibitory interneurons in layer 2/3 of the primary visual cor- tex in animals attending and ignoring visual stimuli. This will be the first stdy to directly investigate whether attention increases neural responsiveness via a depolarization mechanism. In the future, this paradigm will be coupled with two-photon calcium imaging and optogenetic stimulation to probe the sources of attention modu- lation. As a result, this new paradigm for studying attention will be an ideal system for making disease relevant mechanistic discoveries.
Deficits in attention play a major role in a number of neuropsychiatric disorders, but the neural mechanisms of attention are poorly understood. To design new and targeted therapeutics for diseases marked by attention deficits, it is critical to understand the cellular and network mech- anisms of attention. In this proposal I will develop a novel behavioral task for studying attention in mice, and use this task to understand the mechanisms of attention in the visual cortex.
| Einstein, Michael C; Polack, Pierre-Olivier; Tran, Duy T et al. (2017) Visually Evoked 3-5 Hz Membrane Potential Oscillations Reduce the Responsiveness of Visual Cortex Neurons in Awake Behaving Mice. J Neurosci 37:5084-5098 |
