Throughout the brain, specialized systems carry out different but complementary functions, sometimes
independently but often in cooperation. However, we do not understand how their activity is dynamically
coordinated, and dysregulation of this is associated with many mental health conditions. Neuronal
oscillations, which are detectable in local field potentials (LFPs) at various frequencies, are a promising
target for this coordination. Gamma oscillations (40-100 Hz) in particular have been singled out since
they enhance stimulus responses, facilitate interactions between brain regions, and are expressed
ubiquitously across cortical and subcortical regions. Indeed, gamma oscillations occur in the basolateral
nucleus of the amygdala (BL), an important regulator of emotional behaviors. BL gamma oscillations are
enhanced during periods of heightened vigilance during a foraging task, following emotionally salient
experiences, and upon presentation of socially-relevant stimuli. The variety of circumstances that engage
it make it a promising target for interventions affecting emotional behaviors in general. However, technical
challenges abound because gamma manifests as brief intermittent oscillatory bursts, layered atop
numerous ongoing activities in other frequency bands. This precludes manipulating gamma exclusively
with traditional pharmacological, optogenetic, or chemogenetic approaches, since these have substantial
effects on ongoing non-gamma activities, and are delivered irrespective of whether gamma bursts are
present or absent. To overcome this, a closed-loop algorithm was developed that monitors the LFP in
real-time for gamma oscillations and delivers precisely timed optogenetic stimulation capable of
enhancing or suppressing gamma strength on a cycle-by-cycle basis. While this improves upon the status
quo,, further refinement is needed. Aim 1 of this proposal seeks to clarify how the gamma modulation
technique operates via biophysically detailed modeling of the local circuits in the BL that generate gamma,
the effects of optogenetic stimulation, and the closed-loop algorithm. Aim 2 designs better signal
processing routines for detecting and parameterizing gamma in real-time. Aim 3 develops an approach to
create customized biophysical models that reproduce the properties of gamma observed in individual
subjects, which when combined with the results of Aims 1 and 2 should allow for optimized control over
gamma oscillations in individual subjects.
RELEVANCE (See instructions):
Gamma oscillations occur in the basolateral amygdala, a brain region implicated in emotional regulation.
By developing improved methods to manipulate these oscillations, we hope to better understand their
function and improve our ability to control emotional states and behaviors.