Development and plasticity of the functional laminar mesoscale organization of the primary auditory cortex

Early sensory experience is fundamental for proper structural and functional organization of the brain. A brain region that particularly relies on sensory input during a critical period of development is the primary auditory cortex (A1). The functional architecture of A1 in adult mammals has been widely studied on a macroscale and single-cell level, and it is evident that this sensory area is characterized by a tonotopic gradient of frequency preference and that individual auditory neurons are tuned to complex features of acoustic stimuli. However, the development of microcircuits within A1 and how experience shapes this mesoscale organization during different plasticity windows is not known. The work in this dissertation uses in vivo two-photon calcium imaging in mice to investigate how the population dynamics of auditory neurons within thalamorecipient layer 4 and supragranular layers 2/3 change over development – from before ear opening, through the critical period for auditory spectral tuning, and on to mature adult circuitry. Furthermore, this dissertation explores how brief visual deprivation has the power to initiate compensatory, cross-modal plasticity mechanisms and restructure network circuitry in the adult auditory cortex, after the critical period for developmental plasticity has closed. Results from these studies fill crucial gaps in our understanding of experience-dependent cortical circuit development and refinement by showing that the spatial representation of sound frequency is shaped by sensory experience, teasing apart the underlying laminar-specific differences in microcircuitry changes, and indicating an overall dissociation of plasticity of single-cell, mesoscale, and macroscale network properties

Dissecting the Microvascular Contributions to Diffuse Correlation Spectroscopy Measurements of Cerebral Hemodynamics Using Optical Coherence Tomography Angiography

Significance: Diffuse correlation spectroscopy (DCS) is an emerging noninvasive, diffuse optical modality that purportedly enables direct measurements of microvasculature blood flow. Functional optical coherence tomography angiography (OCT-A) can resolve blood flow in vessels as fine as capillaries and thus has the capability to validate key attributes of the DCS signal. Aim: To characterize activity in cortical vasculature within the spatial volume that is probed by DCS and to identify populations of blood vessels that are most representative of the DCS signals. Approach: We performed simultaneous measurements of somatosensory-evoked cerebral blood flow in mice in vivo using both DCS and OCT-A. Results: We resolved sensory-evoked blood flow in the somatosensory cortex with both modalities. Vessels with diameters smaller than 10μm role= presentation style= box-sizing: inherit; display: inline-block; line-height: 0; font-size: 19.04px; overflow-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; margin: 0px; padding: 1px 0px; color: rgb(33, 33, 33); font-family: BlinkMacSystemFont, -apple-system, Segoe UI , Roboto, Oxygen, Ubuntu, Cantarell, Fira Sans , Droid Sans , Helvetica Neue , sans-serif; position: relative; \u3e10μm10μm featured higher peak flow rates during the initial poststimulus positive increase in flow, whereas larger vessels exhibited considerably larger magnitude of the subsequent undershoot. The simultaneously recorded DCS waveforms correlated most highly with flow in the smallest vessels, yet featured a more prominent undershoot. Conclusions: Our direct, multiscale, multimodal cross-validation measurements of functional blood flow support the assertion that the DCS signal preferentially represents flow in microvasculature. The significantly greater undershoot in DCS, however, suggests a more spatially complex relationship to flow in cortical vasculature during functional activation

Longitudinal Functional Assessment of Brain Injury Induced by High-Intensity Ultrasound Pulse Sequences

Exposure of the brain to high-intensity stress waves creates the potential for long-term functional deficits not related to thermal or cavitational damage. Possible sources of such exposure include overpressure from blast explosions or high-intensity focused ultrasound (HIFU). While current ultrasound clinical protocols do not normally produce long-term neurological deficits, the rapid expansion of potential therapeutic applications and ultrasound pulse-train protocols highlights the importance of establishing a safety envelope beyond which therapeutic ultrasound can cause neurological deficits not detectable by standard histological assessment for thermal and cavitational damage. In this study, we assessed the neuroinflammatory response, behavioral effects, and brain micro-electrocorticographic (microECoG) signals in mice following exposure to a train of transcranial pulses above normal clinical parameters. We found that the HIFU exposure induced a mild regional neuroinflammation not localized to the primary focal site, and impaired locomotor and exploratory behavior for up to 1 month post-exposure. In addition, low frequency (delta) and high frequency (beta, gamma) oscillations recorded by ECoG were altered at acute and chronic time points following HIFU application. ECoG signal changes on the hemisphere ipsilateral to HIFU exposure are of greater magnitude than the contralateral hemisphere, and persist for up to three months. These results are useful for describing the upper limit of transcranial ultrasound protocols, and the neurological sequelae of injury induced by high-intensity stress waves