Dissecting cholinergic modulation of interneurons underlying state-dependent processing in mouse visual cortex

PROJECT SUMMARY
The visual cortex can process identical stimuli differently depending on context; behavioral states such as
locomotion or arousal can alter the magnitude and the specificity of visual responses. The neuromodulator
acetylcholine (ACh) is implicated in state-dependent processing and acts on diverse inhibitory interneurons in
cortical circuits, but it remains uncertain how interneuron classes contribute to state-dependence. Particular
controversy surrounds the role of the somatostatin-positive (SOM) cells, which shape circuit output by directly
inhibiting pyramidal cells. One model suggests that ACh action on upstream interneurons triggers suppression
of SOM cells via release of the inhibitory neurotransmitter γ-Aminobutyric acid (GABA). This disinhibits pyramidal
cells to increase gain in visual circuits during locomotion and potentially other states. However, contradictory
findings reveal that SOM cells, which can be directly facilitated by ACh through muscarinic receptors, are actually
more active during locomotion, indicating the disinhibitory model is not sufficient to explain context dependence.
This proposal tests the hypothesis that muscarinic and GABAergic action on SOM cells have
complementary effects on modulating visual cortex circuits and shaping in visual discrimination. I hypothesize
that muscarinic action on SOM cells contributes to tuning of the pyramidal population, while GABAergic action
on SOM cells contributes to pyramidal cell gain. I will dissect this utilizing unprecedented intersectional control
of specific receptors on specific cell types via the Drugs Acutely Restricted by Tethering (DART) methodology
coupled with 2-photon calcium imaging of mouse primary visual cortex.
In Aim 1, I will selectively antagonize muscarinic receptors on SOM cells and record activity of SOM cells
and nearby pyramidal cells as mice passively view visual stimuli. I will assess visual responses and how
responses are altered by locomotion and arousal, to reveal the direct impact of ACh on SOM cells in basal visual
processing and modulation by behavioral state. In Aim 2, I will selectively block GABA receptors on SOM cells,
again recording SOM and pyramidal cell activity during passive viewing. This will allow me to clarify how inhibition
onto SOM cells contributes to basal visual process and circuit modulation during locomotion and arousal. If, as
hypothesized, muscarinic and GABAergic control impact tuning and gain of pyramidal cells, this could
meaningfully impact visual discrimination. To assess how these two pathways act on animals' ability to perceive
and use visual information, in Aim 3 I will selectively antagonize muscarinic or GABAergic receptors on SOM
cells, and record activity of SOM and pyramidal cells, while mice perform an orientation change detection task.
Together these data will resolve longstanding questions around how neuromodulators imbue visual circuits with
context specificity.

Grant Number: 5F32EY034013-03
NIH Institute/Center: NIH
Principal Investigator: Celine Cammarata