An animal's response to external stimuli is critical to its survival; inaction to threatening stimuli could result in death. These responses are dependent on both the external world and the internal brain state of the animal, which itself is influenced by how attentive that animal is to features in its surroundings. Previous work has shown that increased attention is associated with increased desynchrony in the cortex, which is characterized by low-amplitude, fast oscillations reflective of populations of neurons firing at different rates. Less attention is associated with a synchronized state, characterized by high-amplitude, slow oscillations that reflect more similarity in neuronal population activity. The desynchronization driven by increases in attention are largely due to neuromodulatory input, including increased cholinergic drive to the cortex from the basal forebrain. In contrast, the mechanisms underlying resynchronization after desynchronization remain almost completely unknown. Recent work, however, suggests that this resynchronization may be actively regulated by non-neuronal cell populations (astrocytes) in cortex. If true, this finding could fundamentally alter the framework with which we conceptualize mechanisms of attention and behavior. The overall goal of the current proposal is to investigate whether astrocytes are active players in cortical resynchronization following acetylcholine (ACh)-driven increases in attention. To address this, I will quantify astrocyte activity, biological correlates of attention, and cortical state during periods of increased arousal and cholinergic activity in the primary visual cortex of awake, head-fixed mice.
In Aim 1, I will test the hypothesis that astrocytes respond to increased arousal via cholinergic signaling mechanisms.
In Aim 2, I will test the hypothesis that this astrocyte response is necessary for cortical resynchronization. Together, this proposal will determine the function of astrocyte signaling following ACh-driven increases in attention. These results will allow us to dissect the mechanisms of cortical resynchronization, and gain novel insight into this phenomenon that is critical for proper behavioral performance. Many disorders, such as autism and schizophrenia, are associated with impaired cortical state regulation and sensory processing, and thus results from this proposal will have further implications for treating attention-related disorders. The Poskanzer lab at UCSF is an ideal place to carry out the experiments outlined in this proposal. Dr. Poskanzer is an expert in in vivo recording of astrocytic and population-level activity, with extensive knowledge of the techniques and concepts necessary for successful completion of the proposed experiments. Additionally, I will receive expert training in cortical physiology and neuromodulatory integration from my Co-Sponsor Dr. Stryker, who has also been a leader in dissecting the role of ACh in attention-related visual circuits. Lastly, I have assembled a Scientific Committee with experts in several aspects of the project, and they will provide excellent scientific support during all aspects of the proposed research.
Abnormal regulation of brain oscillations?or brain state?underlies many cognitive disorders. This proposal seeks to understand how astrocytes contribute to attention-specific oscillatory state via integration of cholinergic signals in the cortex. Results from the experiments in this proposal will provide a greater understanding of the mechanisms underlying cortical state transitions that are critical for animal behavior and survival.
