Morphological disruption and visual tuning alterations in the primary visual cortex in glaucoma(DBA/2J)mice

Glaucoma is a leading cause of irreve rsible blindness wo rldwide,and previous studies have shown that,in addition to affecting the eyes,it also causes abnormalities in the brain.However,it is not yet clear how the primary visual cortex(V1)is altered in glaucoma.This study used DBA/2J mice as a model for spontaneous secondary glaucoma.The aim of the study was to compare the electrophysiological and histomorphological chara cteristics of neurons in the V1between 9-month-old DBA/2J mice and age-matched C57BL/6J mice.We conducted single-unit recordings in the V1 of light-anesthetized mice to measure the visually induced responses,including single-unit spiking and gamma band oscillations.The morphology of layerⅡ/Ⅲneurons was determined by neuronal nuclear antigen staining and Nissl staining of brain tissue sections.Eighty-seven neurons from eight DBA/2J mice and eighty-one neurons from eight C57BL/6J mice were examined.Compared with the C57BL/6J group,V1 neurons in the DBA/2J group exhibited weaker visual tuning and impaired spatial summation.Moreove r,fewer neuro ns were observed in the V1 of DBA/2J mice compared with C57BL/6J mice.These findings suggest that DBA/2J mice have fewer neurons in the VI compared with C57BL/6J mice,and that these neurons have impaired visual tuning.Our findings provide a better understanding of the pathological changes that occur in V1 neuron function and morphology in the DBA/2J mouse model.This study might offer some innovative perspectives regarding the treatment of glaucoma.

AB072.Functional impact of the lateral posterior nucleus on the mouse primary visual cortex

Background:Information about the visual world is processed by an ensemble of cortical visual areas,which follow a hierarchical organization.The primary visual cortex(V1)first receives most of this information through the lateral geniculate nucleus(LGN),before being conveyed to higher-order cortical areas.Aside from this connectional route,there is also a complex network of bilateral connections between areas of the visual cortex and the pulvinar,considered as the largest extrageniculate visual thalamic nucleus.Despite an increasing number of studies on pulvinar,the exact function of this thalamic complex remains unknown.In this study,we investigated the functional impact of the lateral posterior(LP)nucleus,the homologue of the primate pulvinar,on the activity of neurons in the primary visual cortex in mice using optogenetic stimulation.Methods:A channel rhodopsin-2 gene-carrying viral vector(AAV5.CaMKII.hChR2-eYFP.WPRE)was injected into the LP of wild-type(C57BL/6)mice.Extracellular recordings of the activity of V1 neurons were carried out using 16-and 32-channel silicon probes.The stimulation of LP was achieved with light pulses(470 nm,20 pulse trains of 5 ms each at 10 Hz)delivered by a 4-channel optrode,which also recorded the thalamic activity.Visual stimuli consisted on drifting sinewave gratings of varying parameters(direction,contrast,spatial or temporal frequency and size).Results:Our preliminary data shows that LP stimulation performed in conjunction with the visual stimulation decreases the amplitude of neuronal responses up to 50%.To date,results indicate that this inhibitory effect is only observed in neurons in the infragranular layers.The response profiles of V1 neurons to size-increasing stimuli were also affected.Conclusions:These findings suggest that the pulvinar nucleus can exert layer-dependent contextual modulation on the activity of neurons in the mouse primary visual cortex.

AB009.Learning dynamics in a neural network model of the primary visual cortex

Background:The primary visual cortex(V1)is a key component of the visual system that builds some of the first levels of coherent visual representations from sparse visual inputs.While the study of its dynamics has been the focus of many computational models for the past years,there is still relatively few research works that put an emphasis on both synaptic plasticity in V1 and biorealism in the context of learning visual inputs.Here,we present a recurrent spiking neural network that is capable of spike timing dependent plasticity(STDP)and we demonstrate its capacity to discriminate spatio-temporal orientation patterns in noisy natural images.Methods:A two stage model was developed.First,natural images flux(be it videos/gratings/camera)were converted into spikes,using a difference of gaussians(DOG)approach.This transformation approximates the retina-lateral geniculate nucleus(LGN)organization.Secondly,a spiking neural network was build using PyNN simulator,mimicking cortical neurons dynamics and plasticity,as well as V1 topology.This network was then fed with spikes generated by the first model and its ability to build visual representations was assessed using control gratings inputs.Results:The neural network exhibited several interesting properties.After a short period of learning,it was capable of learning multiples orientations and reducing noise in such learned feature,compared to the inputs.These learned features were stable even after increasing the noise in inputs and were found to not only encoding the spatial properties of the input,but also its temporal aspects(i.e.,the time of each grating presentation Conclusions:Our work shows that topological structuring of the cortical neural networks,combined with simple plasticity rules,are sufficient to drive strong learning dynamics of natural images properties.This computational model fits many properties found in the literature and provides some theoritical explanations for the shape of tuning curve of certain layers of V1.Further investigations are now conducted to validate its properties against the neuronal responses of rodents,using identical visual stimuli.

Contextual Fear Learning and Extinction in the Primary Visual Cortex of Mice

Fear memory contextualization is critical for selecting adaptive behavior to survive.Contextual fear conditioning(CFC)is a classical model for elucidating related underlying neuronal circuits.The primary visual cortex(V1)is the primary cortical region for contextual visual inputs,but its role in CFC is poorly understood.Here,our experiments demonstrated that bilateral inactivation of V1 in mice impaired CFC retrieval,and both CFC learning and extinction increased the turnover rate of axonal boutons in V1.The frequency of neuronal Ca^(2+)activity decreased after CFC learning,while CFC extinction reversed the decrease and raised it to the naïve level.Contrary to control mice,the frequency of neuronal Ca^(2+)activity increased after CFC learning in microglia-depleted mice and was maintained after CFC extinction,indicating that microglial depletion alters CFC learning and the frequency response pattern of extinction-induced Ca^(2+)activity.These findings reveal a critical role of microglia in neocortical information processing in V1,and suggest potential approaches for cellular-based manipulation of acquired fear memory.

Modulation of Spike Count Correlations Between Macaque Primary Visual Cortex Neurons by Difficulty of Attentional Task

Studies have shown that spatial attention remarkably affects the trial-to-trial response variability shared between neurons.Difficulty in the attentional task adjusts how much concentration we maintain on what is currently important and what is filtered as irrelevant sensory information.However,how task difficulty mediates the interactions between neurons with separated receptive fields(RFs)that are attended to or attended away is still not clear.We examined spike count correlations between single-unit activities recorded simultaneously in the primary visual cortex(V1)while monkeys performed a spatial attention task with two levels of difficulty.Moreover,the RFs of the two neurons recorded were non-overlapping to allow us to study fluctuations in the correlated responses between competing visual inputs when the focus of attention was allocated to the RF of one neuron.While increasing difficulty in the spatial attention task,spike count correlations were either decreased to become negative between neuronal pairs,implying competition among them,with one neuron(or none)exhibiting attentional enhancement of firing rate,or increased to become positive,suggesting inter-neuronal cooperation,with one of the pair showing attentional suppression of spiking responses.Besides,the modulation of spike count correlations by task difficulty was independent of the attended locations.These findings provide evidence that task difficulty affects the functional interactions between different neuronal pools in V1 when selective attention resolves the spatial competition.

Directional tunings independent of orientation in the primary visual cortex of the cat

A family of moving ‘random-line' patterns was developed and used to study the directional tuning of 91 single units in cat primary visual cortex (V1). The results suggest that, in addition to the well-known orientation-dependent mechanism, there is also some kind of orientation-independent mechanism underlying the direction selectivity. The directional tuning of the neurons varies in accordance with the increase of orientation or non-orientation element in the stimulus.

Adaptation to visual stimulation modifies the burst firing property of V1 neurons

The mean firing rate of visual cortical neurons is reduced after prolonged visual stimulation,but the underlying process by which this occurs as well as the biological significance of this phenomenon remains unknown.Computational neuroscience studies indicate that high-frequency bursts in stimulus-driven responses can be transmitted across synapses more reliably than isolated spikes,and thus may carry accurate stimulus-related information.Our research examined whether or not adaptation affects the burst firing property of visual cortical neurons by examining changes in the burst firing changes of V1 neurons during adaptation to the preferred visual stimulus.The results show that adaptation to prolonged visual stimulation significantly decreased burst frequency(bursts/s)and burst length(spikes/burst),but increased burst duration and the interspike interval within bursts.These results suggest that the adaptation of V1 neurons to visual stimulation may result in a decrease of feedforward response gain but an increase of functional activities from lateral and/or feedback connections,which could lead to a reduction in the effectiveness of adapted neurons in transmitting information to its driven neurons.

AB050.Neuronal response to visual contrast varies as function of the cortical layer

Background:For years,studies using several animal models have highlighted the predominant role of the primary visual area in visual information processing.Its six cortical layers have morphological,hodological and physiological differences,although their roles regarding the integration of visual contrast and the messages sent by the layers to other brain regions have been poorly explored.Given that cortical layers have distinct properties,this study aims to understand these differences and how they are affected by a changing visual contrast.Methods:A linear multi-channel electrode was placed in the primary visual cortex(V1)of the anesthetized mouse to record neuronal activity across the different cortical layers.The laminar position of the electrode was verified in real time by measuring the current source density(CSD)and the multi-unit activity(MUA),and confirmed post-mortem by histological analysis.Drifting gratings varying in contrast enabled the measurement of the firing rate of neurons throughout layers.We fitted this data to the Naka-Rushton equations,which generated the contrast response function(CRF)of neurons.Results:The analysis revealed that the baseline activity as well as the rate of change of neural discharges(the slope of the CRF)had a positive correlation across the cortical layers.In addition,we found a trend between the cortical position and the contrast evoking the semi-saturation of the activity.A significant difference in the maximum discharge rate was also found between layers II/III and IV,as well as between layers II/III and V.Conclusions:Since layers II/III and V process visual contrast differently,our results suggest that higher cortical visual areas,as well subcortical regions,receive different information regarding a change in visual contrast.Thus,a contrast may be processed differently throughout the different areas of the visual cortex.

In vivo imaging reveals a synchronized correlation among neurotransmitter dynamics during propofol and sevoflurane anesthesia

General anesthesia is widely applied in clinical practice.However,the precise mechanism of loss of consciousness induced by general anesthetics remains unknown.Here,we measured the dynamics of five neurotransmitters,includingγ-aminobutyric acid,glutamate,norepinephrine,acetylcholine,and dopamine,in the medial prefrontal cortex and primary visual cortex of C57BL/6 mice through in vivo fiber photometry and genetically encoded neurotransmitter sensors under anesthesia to reveal the mechanism of general anesthesia from a neurotransmitter perspective.Results revealed that the concentrations of γ-aminobutyric acid,glutamate,norepinephrine,and acetylcholine increased in the cortex during propofol-induced loss of consciousness.Dopamine levels did not change following the hypnotic dose of propofol but increased significantly following surgical doses of propofol anesthesia.Notably,the concentrations of the five neurotransmitters generally decreased during sevoflurane-induced loss of consciousness.Furthermore,the neurotransmitter dynamic networks were not synchronized in the non-anesthesia groups but were highly synchronized in the anesthetic groups.These findings suggest that neurotransmitter dynamic network synchronization may cause anesthetic-induced loss of consciousness.

Restoration of FMRP expression in adult V1 neurons rescues visual deficits in a mouse model of fragile X syndrome

Many people affected by fragile X syndrome(FXS)and autism spectrum disorders have sensory processing deficits,such as hypersensitivity to auditory,tactile,and visual stimuli.Like FXS in humans,loss of Fmr1 in rodents also cause sensory,behavioral,and cognitive deficits.However,the neural mechanisms underlying sensory impairment,especially vision impairment,remain unclear.It remains elusive whether the visual processing deficits originate from corrupted inputs,impaired perception in the primary sensory cortex,or altered integration in the higher cortex,and there is no effective treatment.In this study,we used a genetic knockout mouse model(Fmr1^(KO)),in vivo imaging,and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex(V1).Specifically,Fmr1^(KO) mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli.This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons.These effects were ameliorated by the acute application of GABAA receptor activators,which enhanced the activity of inhibitory neurons,or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice.Overall,V1 plays an important role in the visual abnormalities of Fmr1^(KO) mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.

In Vivo Two-photon Calcium Imaging in Dendrites of Rabies Virus-labeled V1 Corticothalamic Neurons

Monitoring neuronal activity in vivo is critical to understanding the physiological or pathological functions of the brain.Two-photon Ca^(2+)imaging in vivo using a cranial window and specific neuronal labeling enables realtime,in situ,and long-term imaging of the living brain.Here,we constructed a recombinant rabies virus containing the Ca^(2+)indicator GCaMP6 s along with the fluorescent protein DsRed2 as a baseline reference to ensure GCaMP6 s signal reliability.This functional tracer was applied to retrogradely label specific V1-thalamus circuits and detect spontaneous Ca^(2+)activity in the dendrites of V1 corticothalamic neurons by in vivo two-photon Ca^(2+)imaging.Notably,we were able to record single-spine spontaneous Ca2+activity in specific circuits.Distinct spontaneous Ca^(2+)dynamics in dendrites of V1 corticothalamic neurons were found for different V1-thalamus circuits.Our method can be applied to monitor Ca^(2+)dynamics in specific input circuits in vivo,and contribute to functional studies of defined neural circuits and the dissection of functional circuit connections.