We perceive the world through sensory experience. Sensory information is registered and processed by our brain in a modality specific fashion. Interestingly, studies have shown that the visual cortex of early but not late blind subjects is able to respond to touch or sound (Sadato et al., 1996; Buchel et al., 1998; Weeks et al., 2000; Gougoux et al., 2009). Here, we investigated whether sensory parcellation in adult cortex is innate or is acquired during early postnatal life in an experience-dependent manner. Furthermore, we studied the anatomical substrates and molecular pathways possibly involved in cross-modal activation and its plasticity. First, mice were reared from birth in total darkness until adulthood (DR) to replicate the human blind condition. Cross-modal activity and the underlying circuitry were analyzed. We found that DR visual cortex was strongly activated by sound stimulation using functional imaging, single-unit recording, and c-Fos immunohistochemistry. Functional analysis was followed by anatomical tracing studies, which showed ectopic projections from the auditory thalamus and auditory cortex into the secondary visual area in DR animals. The second half of our study looked at how visual experience affects cross-modal plasticity. We found that cross-modal activity and ectopic connectivity is present in normally reared young mice (25 postnatal days: P25). Normal sensory experience through the first two months of postnatal life was sufficient to decrease the number of ectopic inputs. Interestingly, exposing DR mice to visual experience as adults established transient functional sensory specificity in the visual cortex without eliminating the ectopic anatomical inputs. Lastly, we tested several molecular pathways that can potentially regulate cross-modal plasticity. We found that myelin signaling and cholinergic modulation controls the duration of cross-modal plasticity and consolidates sensory modularization. Overall, our work proposes a model of how cross-modal inputs into early sensory areas are pruned or retained depending on early life experience. This study provides insight into how the cortex develops functional specificity, and help approach disorders that exhibit abnormal sensory integration and disrupted neuronal connectivity such as Autism Spectrum Disorder.

<p>My thesis revolves around neuronal circuit dynamics in health and disease. The first part of the thesis characterized cross-regional synchrony within the visual cortical network following visual perceptual experience in healthy mice. This work for the first time described inter-areal 4-8 Hz superficial layer LFP synchrony across mouse visual cortical regions persisting beyond visual stimulation time window, and revealed that the synchrony was expressed specifically between V1 and the higher-order visual area (HVA) with functional preference matching the entrained spatial frequency (SF) and temporal frequency (TF) content, in mice. The discovery of visual familiarity induced inter-areal 4-8 Hz synchrony extends the previous discovery of the 4-8 Hz oscillation in V1 after visual experience from our lab (Kissinger et al., 2018; Kissinger et al., 2020; Gao et al., 2021), and provided the first pivotal evidence supporting the role of 4-8 Hz oscillation in mediating cross-regional communication. Such 4-8 Hz visual cortical network synchrony has been mostly reported in primate studies in contexts of visual attention and working memory (Liebe et al., 2012; Spyropoulos et al., 2018), while our study extended the visual cortical network synchrony research scope to mouse models and in a new context of visual familiarity. The work is a key step for starting cortical network studies in mice, and for starting predictive coding theory study in the context of oscillations in mouse cortical network in the future. Additionally, unit spiking was more strongly modulated by 4-8 Hz oscillations in V1 and HVAs after visual experience. The visually-locked responsive units in V1 and HVAs exihibted either increased or decreased inter-areal spiking synchrony, while most post-stimulus responsive units in V1 and HVA exhibited higher spiking synchrony. </p> <p>The other parts of my dissertation looked at V1 activity in disease and following a novel CNS therapy. One project looked at recovery of visually evoked response in mouse V1 after ischemia through NeuroD1 mediated astrocyte-to-neuron conversion, where we characterized the formation of cortical laminated structure from the converted neurons, longitudinal recovery of visually evoked responses of unit populations in V1, and units’ selective responses to orientations. Another project looked at altered visual cortical activity in an Auxilin knockout mouse model, which demonstrated overall reduced visually evoked responses, less selective responses to orientations, impaired visual adaptive responses and mismatch responses, as well as slower visual experience induced oscillations. These projects utilized the high-density silicon probe recording technique to 1) characterize visual cortical function recovery following a therapy, which provided evidence for its high efficacy for recovering physiological functions, and to 2) phenotype visual cortical functional impairments in a mouse disease model, which provided more basic understanding in visual cortical physiology of Auxilin related disease.</p> <p>In sum, my dissertation work took advantage of the high-density silicon probe recording technique to probe neuronal circuits in health and disease. The discovery of visual experience induced inter-areal 4-8 Hz synchrony paves the way for studying 4-8 Hz activity in relation to stream-dependent visual processing and predictive coding in health and disease.</p>