Overview. Human fMRI and LFP recording studies suggest that the anterior insula encodes the salience of
stimuli and deviations from expectations. However, BOLD signals and LFPs have insufficient resolution to assess
how these codes are distributed across insular cells. Moreover, the origin and functional relevance of insular
codes is unclear. We will address these questions with multi-site single unit and LFP recordings as well as
optogenetic methods in rats. Critically, our pilot data indicates that presentation of salient stimuli elicits identical
LFP responses in rats and humans: bursts of high amplitude beta (13-30 Hz) oscillations.
Significance and approach. Because its volume is reduced in most psychiatric disorders, the insula is a
promising therapeutic target for transcranial or deep brain stimulation. However, progress in this field has been
hindered by a lack of high-resolution data about insula signaling. Thus, this proposal may facilitate the
development of novel therapies. To study the insula in rats, we developed a novel reinforcement learning task
that features a behavioral readout of the rats’ expectations (and their violations). This task will allow us to assess
how anterior insula neurons and their synaptic partners encode multiple variables and probe their role in learning.
Aim #1 Characterize the coding properties of neurons in the anterior insula and its synaptic partners.
We will perform multi-site unit and LFP recordings in the anterior insula and its synaptic partners. This will allow
us to: (1) test whether cells at these various sites encode outcome valence, magnitude, salience, and deviations
from expectations; (2) test whether valenced stimuli elicit bursts of beta oscillations in the anterior insula, as seen
in humans; (3) compare the entrainment of neurons at these various sites by oscillations of different frequencies;
(4) test whether the amplitude of insular beta bursts tracks stimulus salience and deviations from expectations.
Aim #2: Determine which inputs drive coding of different variables in anterior insula neurons. The data
obtained in Aim 1 will suggest which inputs convey information about different variables to insula neurons. Similar
hypotheses will arise regarding the origin and propagation of insular beta bursts. To test these hypotheses, we
will infuse AAVs driving the expression of an inhibitory opsin in projection-defined cell types. Then, we will inhibit
the candidate cell types and assess how these manipulations affect the coding properties of insula neurons as
well as the genesis and propagation of insular beta bursts.
Aim #3 Test whether reducing or enhancing insular beta bursts impairs or facilitates learning. We will
achieve real-time control over insular beta bursts by combining optogenetics with programmable multi-channel
signal processors, giving us unprecedented control over fast neuronal events. We will enhance or dampen
insular beta bursts by delivering low-intensity light stimuli that bias spike times in or out-of-phase with respect to
beta oscillations, without altering firing rates. If insular beta bursts facilitate learning, up- or down-regulating them
should respectively accelerate or slow down learning in the task.