The anatomical basis of sensory tuning in auditory cortical microcircuits

Abstract

Unlike other sensory cortices, the auditory cortex receives inputs that have undergone extensive processing from the periphery and a number of subcortical nuclei. While sub-cortical auditory nuclei are well described, modelled and understood, the auditory cortex is relatively under-researched. Our understanding of the processing of simple and complex stimuli is incomplete. In addition, cortical connectivity and anatomy is still only sparsely described. This thesis aims to address some of the gaps in our understanding of auditory cortical processing. I first sought to investigate responses to pure tone stimuli (a fundamental building block of complex auditory stimuli) to understand how basic information is represented sub- threshold in auditory cortex. This involved performing in vivo whole cell recordings on neurons in mouse AI and quantifying responses to pure tone stimuli. My results demonstrate that AI neurons can exhibit complex frequency response profiles, where there is some indication that certain responses may be restricted to specific electrophysiological cell types. In order to understand in more detail how cortical responses are formed and also the transformations that occur, we need to understand how thalamic inputs are integrated and subsequent outputs computed. mGRASP is an exciting new technique that enables identification of synaptic contacts between spatially distinct but connected neuronal populations. I employed mGRASP to: 1) test it’s efficacy as a tool for assessing connectivity of disparate brain regions and subsequently 2) to measure and describe the spatial arrangement of synaptic inputs from thalamic projection cells onto cortical cells. Bulk viral labeling uncovered a somatocentric distribution of thalamic synapses onto neurons in AI, regardless of cell type and laminar location. In vivo whole cell transfection of individual cells was then performed, for the first time, in order to isolate the technique on a single cell level and correlate synaptic distributions with frequency response profiles. It has been suggested that cortex may play a critical role in the transformation of auditory responses from simple to complex representations. Comodulation-masking release (CMR) is an auditory phenomenon that uses cues of speech perception (a complex auditory stimulus) to allow the segregation of one sound from another (and its subsequent detection). It has been suggested that this high order processing occurs in auditory cortex. To test this I first demonstrated the presence of CMR in auditory cortex. I then applied optogenetics as a functional perturbation to measure the causal relationship between cortex and CMR processing. My results show that signal detection thresholds were lowest in broadband coherently modulated maskers, indicating that a correlate of across-channel CMR exists at the level of cortex. Furthermore the presence of noise history significantly improved sensitivity. In order to determine if this mechanism relies on cortical circuitry, AI was silenced during the noise history by activating ChR2-PV+ interneurons. This disruption resulted in increased thresholds, suggesting that circuitry in auditory cortex plays an integral role in detecting salient sounds in complex background noise.