Fractured columnar small-world functional network organization in volumes of L2/3 of mouse auditory cortex.

The sensory cortices of the brain exhibit large-scale functional topographic organization, such as the tonotopic organization of the primary auditory cortex (A1) according to sound frequency. However, at the level of individual neurons, layer 2/3 (L2/3) A1 appears functionally heterogeneous. To identify if there exists a higher-order functional organization of meso-scale neuronal networks within L2/3 that bridges order and disorder, we used in vivo two-photon calcium imaging of pyramidal neurons to identify networks in three-dimensional volumes of L2/3 A1 in awake mice. Using tonal stimuli, we found diverse receptive fields with measurable colocalization of similarly tuned neurons across depth but less so across L2/3 sublayers. These results indicate a fractured microcolumnar organization with a column radius of ∼50 µm, with a more random organization of the receptive field over larger radii. We further characterized the functional networks formed within L2/3 by analyzing the spatial distribution of signal correlations (SCs). Networks show evidence of Rentian scaling in physical space, suggesting effective spatial embedding of subnetworks. Indeed, functional networks have characteristics of small-world topology, implying that there are clusters of functionally similar neurons with sparse connections between differently tuned neurons. These results indicate that underlying the regularity of the tonotopic map on large scales in L2/3 is significant tuning diversity arranged in a hybrid organization with microcolumnar structures and efficient network topologies.

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.

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.

Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors.

Optimally orchestrating complex behavioral states, such as the pursuit and consumption of food, is critical for an organism's survival. The lateral hypothalamus (LH) is a neuroanatomical region essential for appetitive and consummatory behaviors, but whether individual neurons within the LH differentially contribute to these interconnected processes is unknown. Here, we show that selective optogenetic stimulation of a molecularly defined subset of LH GABAergic (Vgat-expressing) neurons enhances both appetitive and consummatory behaviors, whereas genetic ablation of these neurons reduced these phenotypes. Furthermore, this targeted LH subpopulation is distinct from cells containing the feeding-related neuropeptides, melanin-concentrating hormone (MCH), and orexin (Orx). Employing in vivo calcium imaging in freely behaving mice to record activity dynamics from hundreds of cells, we identified individual LH GABAergic neurons that preferentially encode aspects of either appetitive or consummatory behaviors, but rarely both. These tightly regulated, yet highly intertwined, behavioral processes are thus dissociable at the cellular level.