Long-term training alters response dynamics in the aging auditory cortex.

Age-related auditory dysfunction, presbycusis, is caused in part by functional changes in the auditory cortex (ACtx) such as altered response dynamics and increased population correlations. Given the ability of cortical function to be altered by training, we tested if performing auditory tasks might benefit auditory function in old age. We examined this by training adult mice on a low-effort tone-detection task for at least six months and then investigated functional responses in ACtx at an older age (∼18 months). Task performance remained stable well into old age. Comparing sound-evoked responses of thousands of ACtx neurons using in vivo 2-photon Ca2+ imaging, we found that many aspects of youthful neuronal activity, including low activity correlations, lower neural excitability, and a greater proportion of suppressed responses, were preserved in trained old animals as compared to passively-exposed old animals. Thus, consistent training on a low-effort task can benefit age-related functional changes in ACtx and may preserve many aspects of auditory function.

Orbitofrontal cortex conveys stimulus and task information to the auditory cortex.

Auditory cortical neurons modify their response profiles in response to numerous external factors. During task performance, changes in primary auditory cortex (A1) responses are thought to be driven by top-down inputs from the orbitofrontal cortex (OFC), which may lead to response modification on a trial-by-trial basis. While OFC neurons respond to auditory stimuli and project to A1, the function of OFC projections to A1 during auditory tasks is unknown. Here, we observed the activity of putative OFC terminals in A1 in mice by using in vivo two-photon calcium imaging of OFC terminals under passive conditions and during a tone detection task. We found that behavioral activity modulates but is not necessary to evoke OFC terminal responses in A1. OFC terminals in A1 form distinct populations that exclusively respond to either the tone, reward, or error. Using tones against a background of white noise, we found that OFC terminal activity was modulated by the signal-to-noise ratio (SNR) in both the passive and active conditions and that OFC terminal activity varied with SNR, and thus task difficulty in the active condition. Therefore, OFC projections in A1 are heterogeneous in their modulation of auditory encoding and likely contribute to auditory processing under various auditory conditions.

Decreased Modulation of Population Correlations in Auditory Cortex Is Associated with Decreased Auditory Detection Performance in Old Mice.

Age-related hearing loss (presbycusis) affects one-third of the world's population. One hallmark of presbycusis is difficulty hearing in noisy environments. Presbycusis can be separated into two components: the aging ear and the aging brain. To date, the role of the aging brain in presbycusis is not well understood. Activity in the primary auditory cortex (A1) during a behavioral task is because of a combination of responses representing the acoustic stimuli, attentional gain, and behavioral choice. Disruptions in any of these aspects can lead to decreased auditory processing. To investigate how these distinct components are disrupted in aging, we performed in vivo 2-photon Ca2+ imaging in both male and female mice (Thy1-GCaMP6s × CBA/CaJ mice) that retain peripheral hearing into old age. We imaged A1 neurons of young adult (2-6 months) and old mice (16-24 months) during a tone detection task in broadband noise. While young mice performed well, old mice performed worse at low signal-to-noise ratios. Calcium imaging showed that old animals have increased prestimulus activity, reduced attentional gain, and increased noise correlations. Increased correlations in old animals exist regardless of cell tuning and behavioral outcome, and these correlated networks exist over a much larger portion of cortical space. Neural decoding techniques suggest that this prestimulus activity is predictive of old animals making early responses. Together, our results suggest a model in which old animals have higher and more correlated prestimulus activity and cannot fully suppress this activity, leading to the decreased representation of targets among distracting stimuli.SIGNIFICANCE STATEMENT Aging inhibits the ability to hear clearly in noisy environments. We show that the aging auditory cortex is unable to fully suppress its responses to background noise. During an auditory behavior, fewer neurons were suppressed in the old relative to young animals, which leads to higher prestimulus activity and more false alarms. We show that this excess activity additionally leads to increased correlations between neurons, reducing the amount of relevant stimulus information in the auditory cortex. Future work identifying the lost circuits that are responsible for proper background suppression could provide new targets for therapeutic strategies to preserve auditory processing ability into old age.

Altered Response Dynamics and Increased Population Correlation to Tonal Stimuli Embedded in Noise in Aging Auditory Cortex.

Age-related hearing loss (presbycusis) is a chronic health condition that affects one-third of the world population. One hallmark of presbycusis is a difficulty hearing in noisy environments. Presbycusis can be separated into two components: alterations of peripheral mechanotransduction of sound in the cochlea and central alterations of auditory processing areas of the brain. Although the effects of the aging cochlea in hearing loss have been well studied, the role of the aging brain in hearing loss is less well understood. Therefore, to examine how age-related central processing changes affect hearing in noisy environments, we used a mouse model (Thy1-GCaMP6s X CBA) that has excellent peripheral hearing in old age. We used in vivo two-photon Ca2+ imaging to measure the responses of neuronal populations in auditory cortex (ACtx) of adult (2-6 months, nine male, six female, 4180 neurons) and aging mice (15-17 months, six male, three female, 1055 neurons) while listening to tones in noisy backgrounds. We found that ACtx neurons in aging mice showed larger responses to tones and have less suppressed responses consistent with reduced inhibition. Aging neurons also showed less sensitivity to temporal changes. Population analysis showed that neurons in aging mice showed higher pairwise activity correlations and showed a reduced diversity in responses to sound stimuli. Using neural decoding techniques, we show a loss of information in neuronal populations in the aging brain. Thus, aging not only affects the responses of single neurons but also affects how these neurons jointly represent stimuli.SIGNIFICANCE STATEMENT Aging results in hearing deficits particularly under challenging listening conditions. We show that auditory cortex contains distinct subpopulations of excitatory neurons that preferentially encode different stimulus features and that aging selectively reduces certain subpopulations. We also show that aging increases correlated activity between neurons and thereby reduces the response diversity in auditory cortex. The loss of population response diversity leads to a decrease of stimulus information and deficits in sound encoding, especially in noisy backgrounds. Future work determining the identities of circuits affected by aging could provide new targets for therapeutic strategies.