The work proposed here aims to address a key question in AD: how does amyloid deposition impact the function of sensory cortex involved in linking reward-predictive auditory stimuli with the correct motor actions. In AD, patients exhibit a profound inability to use sensory cues to trigger relevant emotions, memories or action sequences. Sensory regions of the brain have received less attention then higher-order regions involved in cognitive flexibility (e.g. PFC) or regions involved in memory consolidation and recall (e.g. hippocampus). Sensory systems in the brain, however, are critical intermediaries allowing us to perceive the outside world and interact with the external environment. Recent evidence supports the idea that the auditory cortex (AC) serves both as an acoustic ?filter? of the environment but also as an integrative hub that uses contextual signals to prime downstream circuits for action. In this framework, deficits in sensory processing and behavioral modulation triggered by AD-related pathology directly in the auditory cortex may have profound effects on cognition, limiting the ability to exploit learned stimulus-action associations. In order to address this question appropriately, we need to conduct foundational work looking first at core sensory processing in mice with amyloid pathology and then explore how behavioral modulation of sensory responses are impacted. To that end, we have sequenced this supplement to provide useful data in understanding how amyloid deposition 1) disrupts tonotopic maps, 2) impacts short-term sensory memory formation via stimulus specific adaptation, and finally 3) disrupts context-related modulation of cortical activity in a behaviorally-relevant manner. These studies organize around the idea that inhibitory circuits may be particularly sensitive to amyloid deposition. The work proposed here builds on the principle findings of the work in the active grant. During the period of that grant, we have shown how inhibitory networks in the auditory cortex are critical for gating behaviorally relevant information in the response of excitatory neurons in A1. In particular, we showed how cell-type specific modes of inhibition suppress (through direct suppression via PV+ and SOM+ interneurons) or facilitate (through disinhibitory VIP+ interneurons) sub-populations of excitatory neurons. This bidirectional modulation is critical for animals as they move from a passive state, when they do not use that information, to an active state, when they use the sensory stimuli as cues for reward. Here, we aim to use a similar framework to the study of sensorimotor behavior but in the context of AD and amyloid deposition.
The work proposed here aims to address a key question in AD: how does amyloid deposition impact the function of sensory cortex involved in linking reward-predictive auditory stimuli with the correct motor actions. In AD, patients exhibit a profound inability to use sensory cues to trigger relevant emotions, memories or action sequences. To that end, we have sequenced this supplement to provide powerful data in understanding how amyloid deposition 1) disrupts tonotopic maps, 2) impacts short-term sensory memory formation via stimulus specific adaptation, and finally 3) disrupts context-related modulation of cortical activity in a behaviorally-relevant manner.
| Kuchibhotla, Kishore V; Gill, Jonathan V; Lindsay, Grace W et al. (2017) Parallel processing by cortical inhibition enables context-dependent behavior. Nat Neurosci 20:62-71 |
