The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

The aim of this thesis was to investigate the input-specificity of sensory-induced plasticity in humans. This was achieved by varying the characteristics of sine gratings so that they selectively targeted distinct populations of neurons in the visual cortex. In Experiments 1-3, specificity was investigated with electroencephalography using horizontally- and vertically-oriented sine gratings (Experiment 1) or gratings of differing spatial frequency (Experiments 2 & 3). Increases in the N1b potential were observed only for sine gratings that were the same in orientation or spatial frequency as that used as the tetanus, suggesting that the potentiation is specific to the visual pathways stimulated during the induction of the tetanus. However, the increase in the amplitude of the N1b in Experiment 1 was not maintained when tested again at 50 minutes post-tetanus. This may have been due to depotentiation caused by the temporal frequency of stimulus presentation in the first post-tetanus block. To try to circumvent this potential confound, immediate and maintained (tested 30 minutes post-tetanus) spatial-frequency-specific potentiation were tested separately in Experiments 2 and 3, respectively. Experiment 3 demonstrated that the increased N1b was maintained for up to half an hour post-tetanus. In addition, the findings from Experiment 1, as well as the pattern of results from Experiments 2 and 3, indicate that the potentiation must be occurring in the visual cortex rather than further upstream at the lateral geniculate nucleus. In Experiment 4 functional magnetic resonance imaging was used to more accurately localise where these plastic changes were taking place using sine gratings of differing spatial frequency. A small, focal post-tetanic increase in the blood-oxygen-level-dependent (BOLD) response was observed for the tetanised grating in the right temporo-parieto-occipital junction. For the non-tetanised grating, decreases in BOLD were found in the primary visual cortex and bilaterally in the cuneus and pre-cuneus. These decreases may have been due to inhibitory interconnections between neurons tuned to different spatial frequencies. These data indicate that tetanic sensory stimulation selectively targets and potentiates specific populations of neurons in the visual cortex.

Introdução: Apesar do grande impacto da ressonância magnética funcional em neurociências, a sua aplicabilidade clínica ainda é pequena. Um dos principais motivos é a falta de dados populacionais para dar suporte à decisão clínica. Esta tese teve por objetivo formar um banco de dados normais, representativo de pacientes do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP). Métodos: Foram estudados 64 acompanhantes normais dos pacientes do HCFMUSP. Cada indivíduo realizou tarefas quem envolviam função de linguagem, somatossensorial, motor, audiovisual e de memória em aparelho de 1,5 T. Foram colhidos dados demográficos, de desempenho e neuropsicológicos dos sujeitos e de controle de qualidade do magneto de RM. As imagens funcionais foram analisadas através do software XBAM para cada indivíduo, para os grupos e para análise de correlação comportamental. Resultados: A amostra teve uma distribução demográfica variada. Os resultados das análises de grupo mostraram padrões de acordo com a literatura. O paradigma motor mostrou efeito BOLD positivo nos giros pré e pós-centrais estendendo-se para regiões pré-motoras e parietais, área motora suplementar, áreas somatosensoriais secundárias, núcleos da base e tálamo contralaterais à mão avaliada e hemisférios cerebelares ipsilaterais. O paradigma somatossensorial das mãos demonstrou efeito BOLD positivo nos giros pré e pós-centrais, núcleos da base e tálamos contralaterais à mão estimulada, cerebelo ipsilateral à mão estimulada e o córtex somatossensorial secundário bilateralmente e o da face mostrou os giros pré e pós-centrais, o córtex parietal, regiões pré-motoras, regiões temporais posteriores e inferiores e área somatosensorial secundária bilateralmente. A análise de grupo dos paradigmas de linguagem mostrou efeito BOLD positivo no giro frontal inferior e ínsula bilateralmente, maiores à esquerda, giro frontal médio esquerdo, cíngulo anterior, área motora suplementar, cerebelo à direita e vermis cerebelar, núcleos da base e tálamos à esquerda e em particular na fluência verbal falada com apresentação de letras diferentes, lobo parietal esquerdo. No paradigma audiovisual a condição visual mostrou efeito BOLD positivo no córtex occipital, parietal e cerebelo bilateralmente e a condição auditiva, nos lobos temporais bilaterais, com extensão fronto-parietal à esquerda. A análise de grupo do paradigma memória mostrou áreas no cerebelo, córtex occipital, giro frontal médio, região frontal mesial anterior e lobo parietal, com predomínio à direita. Nos mapas individuais foram detectadas muitas regiões em cada paradigma e houve grande variabilidade, sendo as regiões cerebrais que apresentaram efeito BOLD positivo com maior frequência ( 85%): giro pré-central esquerdo (95%) e cerebelo superior direito (87%) no movimento da mão direita; giro pré-central direito (88%) no movimento da mão esquerda; giro pós-central esquerdo (88%) no estímulo somatosensorial da mão direita; giro pós-central direito (89%) no estímulo somatosensorial da mão esquerda; giro lingual direito (90%) e esquerdo (88%) no estímulo visual; e giro temporal médio direito (93%) e esquerdo (91%) na condição auditiva. As tarefas de memória e fluência verbal não tiveram nenhuma região com frequência acima de 80%. Conclusões: Os padrões de ativação cerebral obtidos nas imagens de RMf do grupo de participantes são semelhantes à literatura. A freqüência das regiões com efeito BOLD positivo foi maior nos córtices primários sensoriais e motores. As informações colhidas no trabalho constituem uma base de dados que pode ser utilizada para suporte à decisão clínica. / Introduction: Functional magnetic resonance imaging has had a great impact on neuroscience, but its clinical applicability is still small. One of the main reasons is the lack of populational databases to support clinical decision. The aim of this work was to constitute a local normal database, representative of the patients from the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP). Methods: The sample included 64 normal subjects who, at some point, accompanied patients from the HCFMUSP. They all performed motor, somatosensory, language, audiovisual and memory paradigms in a 1,5 T magnet. Demographic, neuropsychological and behavioral data were collected. Scanner quality control was also verified. Data was analyzed through XBAM software on individual and group basis, and for behavioral correlation. Results: The sample had a variable demographic distribution. Group analysis showed results in agreement with the literature. The motor paradigm elicited positive BOLD effect in the pre and postcentral gyri, extending to premotor and parietal regions, supplementary motor area, secondary somatosensory areas, basal ganglia and thalamus contralateral to the hand in question, and ipsilateral cerebellum. Group analysis of the hand somatosensory paradigm showed pre and postcentral gyri, basal ganglia and thalamus contralateral to the stimulated hand, ipsilateral cerebellum and bilateral secondary somatosensory areas. The group analysis of the somatosensory paradigm of the face showed pre and postcentral gyri, parietal cortex, premotor areas, inferior-posterior temporal cortex and secondary somatosensory areas bilaterally. Language paradigms showed positive BOLD effect in the inferior frontal gyrus and insula bilaterally, bigger on the left, left middle frontal gyrus, anterior cingulate, supplementary motor area, right cerebellum, cerebellar vermis, left basal ganglia and thalamus, and in particular, overt verbal fluency with presentation of different letters also showed the left parietal lobe. The audiovisual paradigm group analysis showed positive BOLD effect in the occipital and parietal cortex and cerebellum bilaterally during the visual condition, and bilateral temporal with left frontal and parietal extension during the auditory condition. Finally, working memory task showed activation in the occipital cortex, cerebellum, middle frontal gyri, parietal association cortex and mesial frontal region bilaterally, with right predominance. On individual basis we detected a multitude of brain areas in each paradigm with great variability, and those with the higher frequency ( 85%) were: left precentral gyrus (95%) and superior right cerebellum (87%) during the right hand movement; right precentral gyrus (88%) during the left hand movement; left postcentral gyrus (88%) for the somatosensory stimulus of the right hand; right postcentral gyrus (89%) for the somatosensory stimulus of the left hand; right (90%) and left (88%) lingual gyri during the visual stimulus; and right (93%) and left (91%) middle temporal gyrus for the auditory stimulus. Working memory and verbal fluency had no region with a frequency above 80%. Conclusions: The patterns of cerebral activations obtained in group analysis are in agreement with the literature. Individual analysis showed a higher frequency of positive BOLD effect in the primary and sensory cortices. The data collected during this work constitute a database that can be used to support clinical decision.

Made available in DSpace on 2016-08-17T14:52:43Z (GMT). No. of bitstreams: 1 Andre Borges Cavalcante.pdf: 1739525 bytes, checksum: 2073615c7df203b086d5c76276905a35 (MD5) Previous issue date: 2008-02-25 / Efficient coding of natural images yields filters similar to the Gabor-like receptive fields of simple cells of primary visual cortex. However, natural and man-made images have different statistical proprieties. Here we show that a simple theoretical analysis of power spectra in a sparse model suggests that natural and man-made images would need specific filters for each group. Indeed, when applying sparse coding to man-made scenes, we found both Gabor and Haar wavelet-like filters. Furthermore, we found that man-made images when projected on those filters yielded smaller mean squared error than when projected on Gabor-like filters only. Thus, as natural and man-made images require different filters to be efficiently represented, these results suggest that besides Gabor, the primary visual cortex should also have cells with Haar-like receptive fields. / A codificação eficiente de imagens naturais gera filtros similares às wavelets de Gabor que relembram os campos receptivos de células simples do córtex visual primário. No entanto, imagens naturais e urbanas tem características estatísticas diferentes. Será mostrado que uma simples análise do espectro de potência em um modelo eficiente sugere que imagens naturais e urbanas requerem filtros específicos para cada grupo. De fato, aplicando codificação eficiente à imagens urbanas, encontramos filtros similares às wavelets de Gabor e de Haar. Além disso, observou-se que imagens urbanas quando projetadas nesses filtros geraram um menor erro médio quadrático do que quando projetadas somente em filtros de similares a Gabor. Desta forma, como imagens naturais e urbanas requerem filtros diferentes para serem representadas de forma eficiente, estes resultados sugerem que além de Gabor, o córtex visual primário também deve possuir células com campos receptivos similares às wavelets de Haar.

L’objectif de cette thèse est la validation fonctionnelle d’implants rétiniens pour la restauration fonctionnelle de la vision chez des patients non voyants suite à la perte de leurs photorécepteurs. Ce travail a été réalisé sur modèle animal et a évalué expérimentalement de nouveaux protocoles de stimulation. Tout d’abord nous avons utilisé la technique de spectroscopie d’impédance pour simuler mathématiquement l’interface tissu-implantafin de caractériser la présence d’un espace entre le tissu et l’implant. La seconde partie compare par imagerie optique (IO) les caractéristiques de la réponse corticale évoquée par stimulation visuelle ou électrique de la rétine par prothèse sous rétinienne. Nous avons retrouvé que la taille de l’activation par l’implant rétinien est beaucoup plus grande que son correspondant visuel. Dans une troisième partie, est réalisée une évaluation in vitro de la performance des stimulations sur rétine isolée pour définir comment les cellules ganglionnaires réagissent à différents modes de stimulations. Ce travail a permis d’établir la courbe des réponses en fonction de l’intensité des stimulations électriques. Enfin, la thèse décrit un modèle animal de dégénérescence rétinienne qui présente des désorganisations de la rétine externe. Une analyse en IO a été réalisée sur ce modèle afin d’évaluer la réponse corticale aux stimuli visuels et électriques. Ce travail de thèse, par des approches physiques et physiologiques complémentaires, apporte un certain nombre de réponses qui devraient permettre d’améliorer l’utilisation de futures prothèses rétiniennes par une adaptation physique des matrices d’électrodes ou des patrons de stimulations utilisées / The aim of this thesis is the functional validation of retinal implants used for vision restoration in blind patients due to the loss of photoreceptors. This work was designed to develop an animal model to experimentally validate prototypes of new implants and new stimulation protocols pattern. Firstly we used the technique of impedance spectroscopy to simulate mathematically the tissue/implant interface. These data confirm the importance of reducing the space between the stimulating electrodes and retinal tissue, as well as the importance of physical characteristics of the electrical stimulus used. In a second approach, we have compared responses of visual cortical neuronal population using optical imaging (OI), evoked either by visual or electric retinal stimulation through subretinal prosthesis. This approach has demonstrated that the stimulation of an electrode induces cortical activation that the size of the cortical response to the retinal implant stimulation is much larger than its corresponding visual stimulus. In the third part, I performed in vitro experiment to measure the performance of stimulation at the level of ganglion cells of isolated retina. We have quantified the response curve as a function of the intensity of the electrical stimulation. Finally, the thesis describes a new animal model of outter retinal degeneration. OI was also performed on this model to assess the response to the visual and retinal prosthesis stimulations. This thesis, through complementary physical and physiological approaches, provides a number of responses that can potentially improve the use of retinal prostheses through specification of their design or patterns of stimulation.

Cette thèse démontre qu’une potentialisation cholinergique durant un conditionnement visuel typique permet de raffiner la réponse et la connectivité des neurones des aires corticales visuelles ainsi que des aires associatives supérieures via un phénomène plastique. Afin de déterminer cet effet sur un conditionnement visuel monoculaire sur la réponse corticale, nous avons utilisé un système d’imagerie calcique à large champ sur des souris adultes exprimant le rapporteur calcique GCaMP6s. La potentialisation cholinergique était causée par l’administration de donepezil (DPZ), un inhibiteur de l’acétylcholinestérase qui dégrade l’acétylcholine. Cette technique, possédant de bonnes résolutions spatiale et temporelle, a permis l’observation de l’activité neuronale dans les couches supra granulaires du cortex visuel primaire (V1), des aires secondaires (A, AL, AM, LM, PM, RL) ainsi que dans le cortex retrosplénial (RSC). Il a été alors possible de mesurer les modifications d’activité neuronale de ces aires au repos et lors de la présentation de stimulations visuelles, composées de réseaux sinusoïdaux d’orientation et de contraste varié. La réponse corticale des animaux naïfs est similaire en matière d’amplitude et de sensibilité au contraste pour chacune des orientations de stimulations visuelles présentées. Le conditionnement visuel accompagné de l’administration de DPZ diminue significativement la réponse neuronale évoquée par le stimulus conditionné dans la majorité des aires observés alors qu’il ne modifie pas la réponse à la stimulation non conditionnée. Cet effet n’est pas présent sans potentialisation cholinergique. Il est intéressant de noter qu’un effet sur la corrélation d’activation est observé exclusivement dans les aires de la voie visuelle ventrale. Finalement, le conditionnement monoculaire diminue la corrélation au repos entre les aires visuelles monoculaire et binoculaire de chacun des hémisphères, un effet qui disparaît lors de l’administration du DPZ durant le conditionnement. En conclusion, nos résultats démontrent une diminution de l’amplitude et de l’étalement de la réponse corticale dans les couches supra-granulaires de PM et de V1 en réponse à notre traitement. Nous suggérons que ces résultats démontrent une diminution de la réponse excitatrice causée par l’augmentation de l’activité inhibitrice en réponse à la stimulation conditionnée. / The cholinergic system of the basal forebrain modulates the visual cortex and enhances visual acuity and discrimination when activated during visual conditioning. As wide-field calcium imaging provides cortical maps with a fine regional and temporal resolution, we used this technique to determine the effects of the cholinergic potentiation of visual conditioning on cortical activity and connectivity in the visual cortex and higher associative areas. Mesoscopic calcium imaging was performed in head-fixed GCaMP6s adult mice during resting state or monocular presentation of conditioned (0.03 cpd, 30°, 100% contrast) or non-conditioned 1Hz-drifting gratings (30°, 50 and 75% contrast; 90°, 50, 75 and 100% contrast), before and after conditioning. The conditioned stimulus was presented 10 min daily for a week. Donepezil (DPZ, 0.3 mg/kg, s.c.), a cholinesterase inhibitor that potentiates cholinergic transmission, or saline were injected prior to each conditioning session and compared to a sham-conditioned group. Cortical maps were established, then amplitude, duration, and latency of the peak response, as well as size of activation were measured in the primary visual cortex (V1), secondary visual areas (AL, A, AM, PM, LM, RL), the retrosplenial cortex (RSC) , and higher cortical areas. Visual stimulation increased calcium signaling in all primary and secondary visual areas, but no other cortices (except RSC). The cortical responses were sensitive to contrast but not to grating orientation. There were no significant effects of sham-conditioning or conditioning alone, but DPZ treatment during conditioning significantly decreased the evoked neuronal activity response for the conditioned stimulus in V1, AL, PM, and LM. The size of activated area and signal-to-noise ratio were affected in some cortical areas. There was no effect for the non-conditioned stimuli. Interestingly, signal correlation appeared only between V1 and the ventral visual pathway and RSC and was decreased by DPZ administration. The resting state activity was slightly correlated and rarely affected by treatments, except between binocular and monocular V1 in both hemispheres. In conclusion, despite the previously observed enhancement of the cortical response of layer 4 after visual conditioning with cholinergic potentiation, mesoscale cortical calcium imaging showed that cholinergic potentiation diminished the cortical activation in layer 2/3 and sharpened the responses to the conditioned visual stimulus in V1 and PM, via a layer-dependent effect.

<p><a></a><a>The visual system is capable of interpreting immense sensory complexity, allowing us to quickly identify behaviorally relevant stimuli in the environment. It performs this task with a hierarchical organization that works to detect, relay, and integrate visual stimulus features into an interpretable form. To understand the complexities of this system, visual neuroscientists have benefited from the many advantages of using mice as visual models. Despite their poor visual acuity, these animals possess surprisingly complex visual systems, and have been instrumental in understanding how visual features are processed in the primary visual cortex (V1). However, a growing body of literature has shown that primary sensory areas like V1 are capable of more than basic feature detection, but can express neural activity patterns related to learning, memory, categorization, and prediction. </a></p> <p>Visual experience fundamentally changes the encoding and perception of visual stimuli at many scales, and allows us to become familiar with environmental cues. However, the neural processes that govern visual familiarity are poorly understood. By exposing awake mice to repetitively presented visual stimuli over several days, we observed the emergence of low frequency oscillations in the primary visual cortex (V1). The oscillations emerged in population level responses known as visually evoked potentials (VEPs), as well as single-unit responses, and were not observed before the perceptual experience had occurred. They were also not evoked by novel visual stimuli, suggesting that they represent a new form of visual familiarity in the form of low frequency oscillations. The oscillations also required the muscarinic acetylcholine receptors (mAChRs) for their induction and expression, highlighting the importance of the cholinergic system in this learning and memory-based phenomenon. Ongoing visually evoked oscillations were also shown to increase the VEP amplitude of incoming visual stimuli if the stimuli were presented at the high excitability phase of the oscillations, demonstrating how neural activity with unique temporal dynamics can be used to influence visual processing.</p> <p>Given the necessity of perceptual experience for the strong expression of these oscillations and their dependence on the cholinergic system, it was clear we had discovered a phenomenon grounded in visual learning or memory. To further validate this, we characterized this response in a mouse model of Fragile X syndrome (FX), the most common inherited form of autism and a condition with known visual perceptual learning deficits. Using a multifaceted experimental approach, a number of neurophysiological differences were found in the oscillations displayed in FX mice. Extracellular recordings revealed shorter durations and lower power oscillatory activity in FX mice. Furthermore, we found that the frequency of peak oscillatory activity was significantly decreased in FX mice, demonstrating a unique temporal neural impairment not previously reported in FX. In collaboration with Dr. Christopher J. Quinn at Purdue, we performed functional connectivity analysis on the extracellularly recorded spikes from WT and FX mice. This analysis revealed significant impairments in functional connections from multiple layers in FX mice after the perceptual experience; some of which were validated by another graduate student (Qiuyu Wu) using Channelrhodopsin-2 assisted circuit mapping (CRACM). Together, these results shed new light on how visual stimulus familiarity is differentially encoded in FX via persistent oscillations, and allowed us to identify impairments in cross layer connectivity that may underlie these differences. </p> <p>Finally, we asked whether these oscillations are observable in other brain areas or are intrinsic to V1. Furthermore, we sought to determine if the oscillating unit populations in V1 possess uniform firing dynamics, or contribute differentially to the population level response. By performing paired recordings, we did not find prominent oscillatory activity in two visual thalamic nuclei (dLGN and LP) or a nonvisual area (RSC) connected to V1, suggesting the oscillations may not propagate with similar dynamics via cortico-thalamic connections or retrosplenial connections, <a>but may either be uniquely distributed across the visual hierarchy or predominantly</a> restricted to V1. Using K-means clustering on a large population of oscillating units in V1, we found unique temporal profiles of visually evoked responses, demonstrating distinct contributions of different unit sub-populations to the oscillation response dynamics.</p>

<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>