Primary sensory cortices analyze sensory information and store information about learned sensory experiences. The auditory cortex (ACx) acquires and retains memory traces about the behavioral significance of selected sounds. During learning, the tuning properties of ACx neurons undergo activity-dependent changes. This cortical map plasticity, which is believed to be a substrate of auditory memory, is characterized by the facilitation of responses to behaviorally important tones. In juvenile animals, cortical map plasticity in the ACx can be induced by passive environmental enrichment with a certain sound. In rodents, juvenile cortical map plasticity is limited to a few postnatal days (i.e., the early critical period). In mature animals, cortical map plasticity can be induced only if tones are behaviorally important or paired with the activation of modulatory (e.g., cholinergic, dopaminergic, noradrenergic) projections. During the previous funding period, we determined that cortical map plasticity is encoded by the same mechanisms as long-term potentiation (LTP) and long-term depression (LTD) at thalamocortical (TC) excitatory synapses. TC projections are the major sensory input to the neocortex and contribute to the formation of cortical maps. In brain slices, we showed that TC synaptic plasticity is not lost after the early critical period, instead a gating mechanism is acquired that can be released by activating cholinergic receptors on presynaptic terminals. Once gating is released, LTP/LTD at TC synapses and cortical map plasticity in vivo occur in animals aged beyond the early critical period. Adenosine machinery, consisting of adenosine-producing ecto-5'-nucleotidase (Nt5e) and A1 adenosine receptors (A1Rs), provides the gating. Juvenile plasticity can be reestablished in adults, if acoustic stimuli are paired with disruption of Nt5e or A1R signaling in the auditory thalamus. This plasticity occurs in cortical maps and individual ACx neurons of awake adult mice and is associated with long-term improvement in tone-discrimination abilities. In this competitive renewal, we propose to test our hypothesis that the adenosine machinery in the thalamus is the master mediator that transmits information from modulatory projections to the thalamus during ACx map plasticity in adults.
In Aim 1, we will induce cortical map plasticity in adults by pairing sounds with activation of modulatory projections while activating or deactivating the gating mechanism.
In Aim 2, we will explore the molecular mechanisms of terminating the early critical period by investigating age dependency of adenosine production.
In Aim 3, we will determine time scales of the gating mechanisms. Using fast-scan cyclic voltammetry in awake mice, we found that adenosine is transiently released in the auditory thalamus and cortex in response to sound. We propose to elucidate the mechanisms and kinetics of this sound-evoked adenosine release before and after the early critical period and determine how it affects spiking in thalamic relay and cortical neurons during sound stimulation. Knowledge gained from these studies will provide the basis for future elucidation of the cellular and molecular mechanisms of auditory memory.

Public Health Relevance

Synaptic plasticity is a key cellular mechanism of learning and memory. Cortical maps in the auditory cortex undergo substantial changes during learning of behaviorally important sounds. During the previous funding period, we identified the thalamic locus and mechanisms of cortical plasticity in the auditory cortex. In this proposal, we will investigate the properties of sound-evoked adenosine release in the mouse auditory thalamus and determine how those properties affect cortical map plasticity in the auditory cortex. Our findings will be relevant to understanding sound processing and perceptual learning by the auditory system.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC012833-06A1
Application #
9651526
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Poremba, Amy
Project Start
2013-07-01
Project End
2023-08-31
Budget Start
2018-09-12
Budget End
2019-08-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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