Fast-spiking cells (FS) are the most common interneuron type in the neocortex, and their activity is widely regarded as a key regulator of pyramidal neuron (PYR) function in health and disease. FS are highly active, connected at high probability to PYR, and generate rapid and strong hyperpolarization, supporting the view that FS activity is crucial for suppression of PYR. Here, we test the hypothesis that changes in FS activity can also enhance PYR sensitivity, specifically that FS synchrony can drive increased PYR responses to weak or even subthreshold sensory input. Based on the robust interconnectivity between FS and RS, and our Preliminary Data, we hypothesize that individual FS synchrony events can enhance PYR sensitivity. We also predict that FS synchrony increases across the local population for epochs lasting on order of hundreds of milliseconds, and that PYR sensitivity is enhanced during these events.
In Aim I, we will directly measure the endogenous expression of FS synchrony and its relation to PYR sensitivity using new chronic tetrode arrays we have developed that allow tolerance of high-electrode numbers in behaving mice. In addition to directly measuring the natural correlations between FS activity and PYR sensitivity, we will also use external input (selective optogenetic stimulation of FS) to directly test our variable of interest, independent of the co-variants that natural co-occur with FS synchrony expression. We will also conduct three closely related Aims.
In Aim II, we will quantify in detail the spatial and temporal expression of FS synchrony. Despite significant theorization as to the import of this dynamic, such measures have never been systematically made in awake behaving neocortex.
In Aim III, we will test two mechanisms that could lead FS synchrony to enhance PYR sensitivity. We will test the subthreshold impact of this phenomenon on PYR, and the network level impact, specifically whether FS synchrony leads to disinhibition through more efficacious suppression of FS.
In Aim I V, we will directly test the hypothesis that FS synchrony and increased sensitivity can enhance sensory processing, specifically the performance of vibrissal detection.
These Aims will directly test the FS synchrony hypothesis. They will also, independent of the outcome of hypothesis testing, generate important new data at several levels as to the impact of FS synchrony, a dynamic that has been widely hypothesized to be important for information processing and healthy network function.
In this proposal, we systematically examine the way that fast-spiking cells in mammalian neocortex control local neural activity. These cells are believed to be crucial for brain health, as their failure to properly regulate network activity is directly indicaed in diseases ranging from epilepsy to schizophrenia. In awake mice, we will record and image populations of neocortical cells with single or sub-neuronal resolution, and will control their activity using recent innovations in optogenetics while assessing impact on behavioral and neural metrics.