Saturday, May 17, 2025
5/17/2025
Sensory-evoked adenosine release in cortical plasticity - Abstract Neural circuits in sensory cortices are plastic, i.e., their properties change as new environmental information is integrated based on its behavioral value. The capacity of acoustic stimuli alone to induce plasticity in the auditory cortex (ACx) abruptly declines with age. In adults, ACx plasticity is induced during attentive wakefulness or by pairing acoustic stimuli with the activation of neuromodulatory systems, such as the cholinergic nucleus basalis or dopaminergic ventral tegmental area. It can also be induced in adults by passive exposure to acoustic stimuli during experimental juvenile-like weakening of adenosine signaling in glutamatergic thalamocortical inputs to the ACx. How the neuromodulatory systems interact with adenosine to refine cortical circuits is unclear. Recently, we identified an event we have termed “sound-evoked adenosine release” (SEAR) in the ACx of awake adult mice as a key gatekeeper for auditory cortical plasticity and improvement in auditory frequency-discrimination acuity (perceptual plasticity). SEAR originates from the thalamocortical projections via ecto-5ʹ-nucleotidase activity and becomes transiently reduced when acoustic stimuli are tightly paired with the activation of cholinergic or dopaminergic circuits. These seconds-long low-adenosine conditions permit stimulus-specific associative cortical and perceptual plasticities to occur. We, therefore, hypothesize that transient low-adenosine periods triggered by activity in neuromodulatory circuits are prerequisites for sensory stimuli to produce behaviorally significant cortical plasticity in adults. In this proposal, we aim to elucidate the developmental and spatiotemporal characteristics of SEAR in the ACx by using fast-scanning cyclic voltammetry, which directly detects extracellular adenosine with sub-second temporal resolution and 2-photon imaging of the ACx using the genetically encoded fluorescent adenosine sensor GRABAdo. We also propose to test if the SEAR decrease driven by neuromodulatory activity affects cortical plasticity of inhibitory neurons in the ACx. These experiments are inspired by the notion that sensory and neuromodulatory conversion occurs at the level of the excitatory/inhibitory balance, as the neuromodulators act through disinhibition of local inhibitory microcircuits to enhance the excitability of the cortical excitatory neurons. Lastly, we propose to elucidate the mechanisms of SEAR decrease, which depend on neuromodulatory activity. Specifically, we will determine whether equilibrative nucleoside transporters in astroglia and thalamic adenosine production regulate the level of extracellular adenosine during neuromodulatory activities. Together, these experiments will enable us to characterize in detail the mechanisms of SEAR as a key gatekeeper of cortical and perceptual plasticities in adults.
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