Layers Of Visual Cortex Research Articles

Recurrent inhibition refines mental templates to optimize perceptual decisions.

Translating sensory inputs to perceptual decisions relies on building internal representations of features critical for solving complex tasks. Yet, we still lack a mechanistic account of how the brain forms these mental templates of task-relevant features to optimize decision-making. Here, we provide evidence for recurrent inhibition: an experience-dependent plasticity mechanism that refines mental templates by enhancing γ-aminobutyric acid (GABA)-mediated (GABAergic) inhibition and recurrent processing in superficial visual cortex layers. We combine ultrahigh-field (7 T) functional magnetic resonance imaging at submillimeter resolution with magnetic resonance spectroscopy to investigate the fine-scale functional and neurochemical plasticity mechanisms for optimized perceptual decisions. We demonstrate that GABAergic inhibition increases following training on a visual (i.e., fine orientation) discrimination task, enhancing the discriminability of orientation representations in superficial visual cortex layers that are known to support recurrent processing. Modeling functional and neurochemical plasticity interactions reveals that recurrent inhibitory processing optimizes brain computations for perpetual decisions and adaptive behavior.

Influence of white-light-emitting diodes on primary visual cortex layer 5 pyramidal neurons (V1L5PNs) and remodeling by blue-light-blocking lenses

Studies have explored the consequences of excessive exposure to white-light-emitting diodes (LEDs) in the retina. Hence, we aimed to assess the implications of such exposure on structural alterations of the visual cortex, learning and memory, and amelioration by blue-light-blocking lenses (BBLs). Eight-week-old Wistar rats (n = 24) were used for the experiment and divided into four groups (n = 6 in each group) as control, white LED light exposure (LE), BBL Crizal Prevencia-1 (CP), and DuraVision Blue-2 (DB). Animals in the exposure group were exposed to white LED directly for 28 days (12:12-h light/dark cycle), whereas animals in the BBL groups were exposed to similar light with BBLs attached to the LEDs. Post-exposure, a Morris water maze was performed for memory retention, followed by structural analysis of layer 5 pyramidal neurons in the visual cortex. We observed a significant difference (P < 0.001) in the functional test on day 1 and day 2 of training in the LE group. Structural analysis of Golgi-Cox-stained visual cortex layer 5 pyramidal neurons showed significant alterations in the apical and basal branching points (p < 0.001) and basal intersection points (p < 0.001) in the LE group. Post hoc analysis revealed significant changes between (p < 0.001) LE and CP and (p < 0.001) CP and DB groups. Constant and cumulative exposure to white LEDs presented with structural and functional alterations in the visual cortex, which are partly remodeled by BBLs.

Modeling apical and basal tree contribution to orientation selectivity in a mouse primary visual cortex layer 2/3 pyramidal cell.

Pyramidal neurons, a mainstay of cortical regions, receive a plethora of inputs from various areas onto their morphologically distinct apical and basal trees. Both trees differentially contribute to the somatic response, defining distinct anatomical and possibly functional sub-units. To elucidate the contribution of each tree to the encoding of visual stimuli at the somatic level, we modeled the response pattern of a mouse L2/3 V1 pyramidal neuron to orientation tuned synaptic input. Towards this goal, we used a morphologically detailed computational model of a single cell that replicates electrophysiological and two-photon imaging data. Our simulations predict a synergistic effect of apical and basal trees on somatic action potential generation: basal tree activity, in the form of either depolarization or dendritic spiking, is necessary for producing somatic activity, despite the fact that most somatic spikes are heavily driven by apical dendritic spikes. This model provides evidence for synergistic computations taking place in the basal and apical trees of the L2/3 V1 neuron along with mechanistic explanations for tree-specific contributions and emphasizes the potential role of predictive and attentional feedback input in these cells.

Investigation of layer-specific BOLD signal in the human visual cortex during visual attention

Directing spatial attention towards a particular stimulus location enhances cortical responses at corresponding regions in cortex. How attention modulates the laminar response profile within the attended region remains unclear, however. In this paper, we use high-field (7T) functional magnetic resonance imaging to investigate the effects of attention on laminar activity profiles in areas V1–V3 both when a stimulus was presented to the observer and in the absence of visual stimulation. Replicating previous findings, we find robust increases in the overall BOLD response for attended regions in cortex, both with and without visual stimulation. When analysing the BOLD response across the individual layers in visual cortex, we observed no evidence for laminar-specific differentiation with attention. We offer several potential explanations for these results, including theoretical, methodological and technical reasons. Additionally, we provide all data and pipelines openly in order to promote analytic consistency across layer-specific studies and improve reproducibility.

Maternal diabetes decreases the expression of GABAAα1, GABAB1, and mGlu2 receptors in the visual cortex of male rat neonates

AimsThis study examines the impact of maternal diabetes on the expression of GABAB1, GABAAα1, and mGlu2 receptors in the primary visual cortex layers of male rat newborns.Main Methods: In diabetic group (Dia), diabetes was induced in adult female rats using an intraperitoneal dose of Streptozotocin (STZ) 65 (mg/kg). Diabetes was managed by daily subcutaneous injection of NPH insulin in insulin-treated diabetic group (Ins). Control group (Con) received normal saline intraperitoneally rather than STZ. Male offspring born to each group of female rats were euthanized via CO2 inhalation at P0, P7, and P14 days after delivery and the expression of GABAB1, GABAAα1, and mGlu2 receptors in their primary visual cortex was determined using immunohistochemistry (IHC).Key Findings: The expression of GABAB1, GABAAα1, and mGlu2 receptors increased gradually with age in the male offspring born to Con group while the highest expression was detected in layer IV of the primary visual cortex. In Dia group newborns, the expression of these receptors was significantly reduced in all layers of the primary visual cortex at every three days. Insulin treatment in diabetic mothers restored the expression of these receptors to normal levels in their newborns. SignificanceThe study indicates that diabetes reduces the expression of GABAB1, GABAAα1, and mGlu2 receptors in the primary visual cortex of male offspring born to diabetic rats at P0, P7, and P14. However, insulin treatment can counteract these effects.

The L1 cell adhesion molecule constrains dendritic spine density in pyramidal neurons of the mouse cerebral cortex.

A novel function for the L1 cell adhesion molecule, which binds the actin adaptor protein Ankyrin was identified in constraining dendritic spine density on pyramidal neurons in the mouse neocortex. In an L1-null mouse mutant increased spine density was observed on apical but not basal dendrites of pyramidal neurons in diverse cortical areas (prefrontal cortex layer 2/3, motor cortex layer 5, visual cortex layer 4. The Ankyrin binding motif (FIGQY) in the L1 cytoplasmic domain was critical for spine regulation, as demonstrated by increased spine density and altered spine morphology in the prefrontal cortex of a mouse knock-in mutant (L1YH) harboring a tyrosine (Y) to histidine (H) mutation in the FIGQY motif, which disrupted L1-Ankyrin association. This mutation is a known variant in the human L1 syndrome of intellectual disability. L1 was localized by immunofluorescence staining to spine heads and dendrites of cortical pyramidal neurons. L1 coimmunoprecipitated with Ankyrin B (220 kDa isoform) from lysates of wild type but not L1YH forebrain. This study provides insight into the molecular mechanism of spine regulation and underscores the potential for this adhesion molecule to regulate cognitive and other L1-related functions that are abnormal in the L1 syndrome.

A three-photon head-mounted microscope for imaging all layers of visual cortex in freely moving mice

Advances in head-mounted microscopes have enabled imaging of neuronal activity using genetic tools in freely moving mice but these microscopes are restricted to recording in minimally lit arenas and imaging upper cortical layers. Here we built a 2-g, three-photon excitation-based microscope, containing a z-drive that enabled access to all cortical layers while mice freely behaved in a fully lit environment. The microscope had on-board photon detectors, robust to environmental light, and the arena lighting was timed to the end of each line-scan, enabling functional imaging of activity from cortical layer 4 and layer 6 neurons expressing jGCaMP7f in mice roaming a fully lit or dark arena. By comparing the neuronal activity measured from populations in these layers we show that activity in cortical layer 4 and layer 6 is differentially modulated by lit and dark conditions during free exploration.

A microcircuit model involving parvalbumin, somatostatin, and vasoactive intestinal polypeptide inhibitory interneurons for the modulation of neuronal oscillation during visual processing.

Various subtypes of inhibitory interneurons contact one another to organize cortical networks. Most cortical inhibitory interneurons express 1 of 3 genes: parvalbumin (PV), somatostatin (SOM), or vasoactive intestinal polypeptide (VIP). This diversity of inhibition allows the flexible regulation of neuronal responses within and between cortical areas. However, the exact roles of these interneuron subtypes and of excitatory pyramidal (Pyr) neurons in regulating neuronal network activity and establishing perception (via interactions between feedforward sensory and feedback attentional signals) remain largely unknown. To explore the regulatory roles of distinct neuronal types in cortical computation, we developed a computational microcircuit model with biologically plausible visual cortex layers 2/3 that combined Pyr neurons and the 3 inhibitory interneuron subtypes to generate network activity. In simulations with our model, inhibitory signals from PV and SOM neurons preferentially induced neuronal firing at gamma (30-80Hz) and beta (20-30Hz) frequencies, respectively, in agreement with observed physiological results. Furthermore, our model indicated that rapid inhibition from VIP to SOM subtypes underlies marked attentional modulation for low-gamma frequency (30-50Hz) in Pyr neuron responses. Our results suggest the distinct but cooperative roles of inhibitory interneuron subtypes in the establishment of visual perception.

Quantitative evaluation of the functional activity in multilayered brain structures using histological sections

Subject of study. We develop an algorithm and software to estimate optical density as a correlate of neural activity in multilayered brain structures. Aim of study. We develop a method and program algorithm for quantitative evaluation of the optical density in the layers of neural structures from images of histological brain preparations that correlates with the functional activity of the cells. Method. Optical density was measured locally in successive areas of a layer or several layers of the neural structure, which are curvilinear-shaped in the brain slices. An expert researcher selects the trajectory of optical density measurement in the digitized image of the slice in an interactive mode. The results of density measurements were plotted in an orthogonal coordinate system. Capabilities enabling automated curve smoothing, extremum seeking, and calculation of distances between extrema were developed. Results. An algorithm for implementing the developed program is presented. The successive stages of operation are illustrated through the evaluation of the optical density in the visual cortex layer from an image of a brain slice as an example. In addition, the evaluation results of the optical density in layers of a lateral geniculate body are presented. Practical significance. The developed method and program algorithm are required for reconstructing the functional activity of the curved layers of different brain structures to investigate and simulate the organization patterns of the neural networks of the human brain.

Deciphering functional roles of synaptic plasticity and intrinsic neural firing in developing mouse visual cortex layer IV microcircuit.

Between the onset of the critical period of mouse primary visual cortex and eye opening at postnatal day 14 is a complex process and that is vital for the cognitive function of vision. The onset of the critical period of mouse primary visual cortex involves changes of the intrinsic firing property of each neuron and short term plasticity of synapses. In order to investigate the functional role of each factor in regulating the circuit firing activity during the critical period plasticity, we adopted the Markram's model for short term plasticity and Wilson's model for intrinsic neuron firing activity, and construct a microcircuit for mouse visual cortex layer IV based on the connection probabilities from experimental results. Our results indicate that, during CP development, the most critical factors that regulate the firing pattern of microcircuit is the short term plasticity of the synapse from PC to PV and SST interneurons, which upregulates the PV interneuron firing and produces new balance between excitation and inhibition; the intrinsic firing activity of PC and PV during development downregulates the firing frequency of the circuits. In addition, we have investigated the function of feedforward excitatory thalamic-cortical projection to PC and PV interneuron during CP, and found that neural firing activity largely depends on the TC input and the results are similar to the local circuit with minor differences. We conclude that the short term plasticity development during critical period plays a crucial role in regulating the circuit behavior.

Study on the mechanism of visual aging in cats’ primary visual cortex based on BDNF-TrkB signal pathway

To explore the expression of brain-derived neurotrophic factor (BDNF) and specific receptor tyrosine kinase receptor B (TrkB) in the primary visual cortex of young and old cats, especially to reveal the age-related differences in the mediating mechanism of BDNF-TrkB signaling pathway in cats’ visual cortex and their possible effects on synaptic plasticity, Nissl staining was used to display neurons in each layer of cats’ primary visual cortex, and immunohistochemical ABC method was used to label BDNF and TrkB immunopositive cells in each layer of cats’ primary visual cortex. The BDNF and TrkB receptor immunoreactive neurons and non-neurons were observed and photographed. Their density and immunoreactive intensity were measured. Results showed that BDNF and TrkB were widely expressed in all layers of visual cortex in young and old cats. Compared with the young group, the density and intensity of BDNF and TrkB positive cells in each layer of primary visual cortex in the old group decreased significantly (P < 0.01). The findings indicate that the expression levels of BDNF and TrkB in the primary visual cortex of cats decrease with age, suggesting that the change of BDNF-TrkB signal pathway caused by the weakening of brain-derived neurotrophic factor activity may be one of the important reasons for the decline of visual function.

Blue Light-Induced Retinal Neuronal Injury and Amelioration by Commercially Available Blue Light-Blocking Lenses.

Blue light exposure-induced retinal damage has been extensively studied. Although many in vitro studies have shown the benefits of blue light-blocking lenses (BBL) there have been few comprehensive in vivo studies to assess the effects of BBL. We investigated the influence of blue light exposure using light-emitting diodes on retinal histology and visual cortex neurons in rodents. We also considered whether retinal and cortical changes induced by blue light could be ameliorated with blue light-blocking lenses. A total of n = 24 (n = 6 in each group; control, light exposure without lenses, two different BBLs)) male Wistar rats were subjected to blue light exposure (LEDs, 450–500 lux) without or with BBLs (400–490 nm) for 28 days on a 12:12 h light–dark cycle. Histological analysis of retinae revealed apoptosis and necrosis of the retinal pigment epithelium (RPE), photoreceptors, and inner retina in the light exposure (LE) group, along with increase caspase-3 immunostaining in the ganglion cell layer (p < 0.001). BBL groups showed less caspase-3 immunostaining compared with the LE group (p < 0.001). V1-L5PNs (primary visual cortex layer 5 pyramidal neurons) demonstrated reduced branching and intersections points for apical (p < 0.001) and basal (p < 0.05) dendrites following blue light exposure. Blue light-blocking lenses significantly improved the number of basal branching points compared with the LE group. Our study shows that prolonged exposure to high levels of blue light pose a significant hazard to the visual system resulting in damage to the retina with the associated remodeling of visual cortex neurons. BBL may offer moderate protection against exposure to high levels of blue light.

Visual cortex damage in a ferret model of ocular hypertension.

We aimed to analyze the changes in the visual cortex of a ferret model of ocular hypertension (OH) using cytochrome oxidase (CO) staining. Experimental. OH was induced in 9 ferrets by means of injection of cultured conjunctival cells into the anterior chamber of the right eye. Three ferrets were used as the controls. CO staining was performed to assess the metabolic intensity at the II-III and IVC layers of the visual cortex. The intensities of CO staining in the right and left II-III layers of the primary visual cortex (V1) in the OH ferrets were 39.8 ± 10.3 and 41.9 ± 9.2 arbitrary units, respectively. In the control ferrets, the intensity was 88.1 ± 8.1 arbitrary units. The intensity of CO staining of the II-III layers obtained from the OH eyes was significantly lower than that from the control eyes (unpaired t test, P < .01). The intensities of CO staining in the right and left IVC layers of V1 in the OH ferrets were 60.3 ± 12.8 and 60.0 ± 13.5 arbitrary units, respectively. In the control ferrets, the intensity was 111.4 ± 9.6 arbitrary units. The CO staining intensity of the IVC layer obtained from the OH eyes was significantly lower than that from the control eyes (unpaired t test, P < .01). The CO staining intensity was reduced in the visual cortex from OH eyes. This study revealed that OH causes metabolic change in the visual cortex.

Microstimulation-evoked neural responses in visual cortex are depth dependent

BackgroundCortical visual prostheses often use penetrating electrode arrays to deliver microstimulation to the visual cortex. To optimize electrode placement within the cortex, the neural responses to microstimulation at different cortical depths must first be understood. ObjectiveWe investigated how the neural responses evoked by microstimulation in cortex varied with cortical depth, of both stimulation and response. MethodsA 32-channel single shank electrode array was inserted into the primary visual cortex of anaesthetized rats, such that it spanned all cortical layers. Microstimulation with currents up to 14 μA (single biphasic pulse, 200 μs per phase) was applied at depths spanning 1600 μm, while simultaneously recording neural activity on all channels within a response window 2.25–11 ms. ResultsStimulation elicited elevated neuronal firing rates at all depths of cortex. Compared to deep sites, superficial stimulation sites responded with higher firing rates at a given current and had lower thresholds. The laminar spread of evoked activity across cortical depth depended on stimulation depth, in line with anatomical models. ConclusionStimulation in the superficial layers of visual cortex evokes local neural activity with the lowest thresholds, and stimulation in the deep layers evoked the most activity across the cortical column. In conjunction with perceptual reports, these data suggest that the optimal electrode placement for cortical microstimulation prostheses has electrodes positioned in layers 2/3, and at the top of layer 5.

Naturalistic Spike Trains Drive State-Dependent Homeostatic Plasticity in Superficial Layers of Visual Cortex.

The history of neural activity determines the synaptic plasticity mechanisms employed in the brain. Previous studies report a rapid reduction in the strength of excitatory synapses onto layer 2/3 (L2/3) pyramidal neurons of the primary visual cortex (V1) following two days of dark exposure and subsequent re-exposure to light. The abrupt increase in visually driven activity is predicted to drive homeostatic plasticity, however, the parameters of neural activity that trigger these changes are unknown. To determine this, we first recorded spike trains in vivo from V1 layer 4 (L4) of dark exposed (DE) mice of both sexes that were re-exposed to light through homogeneous or patterned visual stimulation. We found that delivering the spike patterns recorded in vivo to L4 of V1 slices was sufficient to reduce the amplitude of miniature excitatory postsynaptic currents (mEPSCs) of V1 L2/3 neurons in DE mice, but not in slices obtained from normal reared (NR) controls. Unexpectedly, the same stimulation pattern produced an up-regulation of mEPSC amplitudes in V1 L2/3 neurons from mice that received 2 h of light re-exposure (LE). A Poisson spike train exhibiting the same average frequency as the patterns recorded in vivo was equally effective at depressing mEPSC amplitudes in L2/3 neurons in V1 slices prepared from DE mice. Collectively, our results suggest that the history of visual experience modifies the responses of V1 neurons to stimulation and that rapid homeostatic depression of excitatory synapses can be driven by non-patterned input activity.

High-Frequency Visual Stimulation Primes Gamma Oscillations for Visually Evoked Phase Reset and Enhances Spatial Acuity.

The temporal frequency of sensory stimulation is a decisive factor in the plasticity of perceptual detection thresholds. However, surprisingly little is known about how distinct temporal parameters of sensory input differentially recruit activity of neuronal circuits in sensory cortices. Here we demonstrate that brief repetitive visual stimulation induces long-term plasticity of visual responses revealed 24 h after stimulation and that the location and generalization of visual response plasticity is determined by the temporal frequency of the visual stimulation. Brief repetitive low-frequency stimulation (2 Hz) is sufficient to induce a visual response potentiation that is expressed exclusively in visual cortex layer 4 and in response to a familiar stimulus. In contrast, brief, repetitive high-frequency stimulation (HFS, 20 Hz) is sufficient to induce a visual response potentiation that is expressed in all cortical layers and transfers to novel stimuli. HFS induces a long-term suppression of the activity of fast-spiking interneurons and primes ongoing gamma oscillatory rhythms for phase reset by subsequent visual stimulation. This novel form of generalized visual response enhancement induced by HFS is paralleled by an increase in visual acuity, measured as improved performance in a visual detection task.

Depletion of microglia in developing cortical circuits reveals its critical role in glutamatergic synapse development, functional connectivity, and critical period plasticity

Microglia populate the early developing brain and mediate pruning of the central synapses. Yet, little is known on their functional significance in shaping the developing cortical circuits. We hypothesize that the developing cortical circuits require microglia for proper circuit maturation and connectivity, and as such, ablation of microglia during the cortical critical period may result in a long-lasting circuit abnormality. We administered PLX3397, a colony-stimulating factor 1 receptor inhibitor, to mice starting at postnatal day 14 and through P28, which depletes >75% of microglia in the visual cortex (VC). This treatment largely covers the critical period (P19-32) of VC maturation and plasticity. Patch clamp recording in VC layer 2/3 (L2/3) and L5 neurons revealed increased mEPSC frequency and reduced amplitude, and decreased AMPA/NMDA current ratio, indicative of altered synapse maturation. Increased spine density was observed in these neurons, potentially reflecting impaired synapse pruning. In addition, VC intracortical circuit functional connectivity, assessed by laser scanning photostimulation combined with glutamate uncaging, was dramatically altered. Using two photon longitudinal dendritic spine imaging, we confirmed that spine elimination/pruning was diminished during VC critical period when microglia were depleted. Reduced spine pruning thus may account for increased spine density and disrupted connectivity of VC circuits. Lastly, using single-unit recording combined with monocular deprivation, we found that ocular dominance plasticity in the VC was obliterated during the critical period as a result of microglia depletion. These data establish a critical role of microglia in developmental cortical synapse pruning, maturation, functional connectivity, and critical period plasticity.

Superficial Bound of the Depth Limit of Two-Photon Imaging in Mouse Brain.

Two-photon fluorescence microscopy has been used extensively to probe the structure and functions of cells in living biological tissue. Two-photon excitation generates fluorescence from the focal plane, but also from outside the focal plane, with out-of-focus fluorescence increasing as the focus is pushed deeper into tissue. It has been postulated that the two-photon depth limit, beyond which results become inaccurate, is where in-focus and out-of-focus fluorescence are equal, which we term the balance depth. Calculations suggest that the balance depth should be at ∼600 µm in mouse cortex. Neither the two-photon depth limit nor the balance depth have been measured in brain tissue. We found the depth limit and balance depth of two-photon excitation in mice with GCaMP6 indicator expression in all layers of visual cortex, by comparing near-simultaneous two-photon and three-photon excitation. Two-photon and three-photon results from superficial locations were almost identical. two-photon results were inaccurate beyond the balance depth, consistent with the depth limit matching the balance depth for two-photon excitation. However, the two-photon depth limit and balance depth were at 450 µm, shallower than predicted by calculations. Our results were from tissue with a largely homogenous distribution of fluorophores. The expected balance depth is deeper in tissue with fewer fluorophores outside the focal plane and our results therefore establish a superficial bound on the two-photon depth limit in mouse visual cortex.

Laminar Differences in Responses to Naturalistic Texture in Macaque V1 and V2.

Most single units recorded from macaque secondary visual cortex (V2) respond with higher firing rates to synthetic texture images containing "naturalistic" higher-order statistics than to spectrally matched "noise" images lacking these statistics. In contrast, few single units in V1 show this property. We explored how the strength and dynamics of response vary across the different layers of visual cortex by recording multiunit (defined as high-frequency power in the local field potential) and gamma-band activity evoked by brief presentations of naturalistic and noise images in V1 and V2 of anesthetized macaque monkeys of both sexes. As previously reported, recordings in V2 showed consistently stronger responses to naturalistic texture than to spectrally matched noise. In contrast to single-unit recordings, V1 multiunit activity showed a preference for images with naturalistic statistics, and in gamma-band activity this preference was comparable across V1 and V2. Sensitivity to naturalistic image structure was strongest in the supragranular and infragranular layers of V1, but weak in granular layers, suggesting that it might reflect feedback from V2. Response timing was consistent with this idea. Visual responses appeared first in V1, followed by V2. Sensitivity to naturalistic texture emerged first in V2, followed by the supragranular and infragranular layers of V1, and finally in the granular layers of V1. Our results demonstrate laminar differences in the encoding of higher-order statistics of natural texture, and suggest that this sensitivity first arises in V2 and is fed back to modulate activity in V1.SIGNIFICANCE STATEMENT The circuit mechanisms responsible for visual representations of intermediate complexity are largely unknown. We used a well validated set of synthetic texture stimuli to probe the temporal and laminar profile of sensitivity to the higher-order statistical structure of natural images. We found that this sensitivity emerges first and most strongly in V2 but soon after in V1. However, sensitivity in V1 is higher in the laminae (extragranular) and recording modalities (local field potential) most likely affected by V2 connections, suggesting a feedback origin. Our results show how sensitivity to naturalistic image structure emerges across time and circuitry in the early visual cortex.

Disruption of NMDAR Function Prevents Normal Experience-Dependent Homeostatic Synaptic Plasticity in Mouse Primary Visual Cortex.

Homeostatic regulation of synaptic strength allows for maintenance of neural activity within a dynamic range for proper circuit function. There are largely two distinct modes of synaptic plasticity that allow for homeostatic adaptation of cortical circuits: synaptic scaling and sliding threshold (BCM theory). Previous findings suggest that the induction of synaptic scaling is not prevented by blocking NMDARs, whereas the sliding threshold model posits that the synaptic modification threshold of LTP and LTD readjusts with activity and thus the outcome of synaptic plasticity is NMDAR dependent. Although synaptic scaling and sliding threshold have been considered two distinct mechanisms, there are indications from recent studies that these two modes of homeostatic plasticity may interact or that they may operate under two distinct activity regimes. Here, we report using both sexes of mouse that acute genetic knock-out of the obligatory subunit of NMDAR or acute pharmacological block of NMDAR prevents experience-dependent homeostatic regulation of AMPAR-mediated miniature EPSCs in layer 2/3 of visual cortex. This was not due to gross changes in postsynaptic neuronal activity with inhibiting NMDAR function as determine by c-Fos expression and two-photon Ca2+ imaging in awake mice. Our results suggest that experience-dependent homeostatic regulation of intact cortical circuits is mediated by NMDAR-dependent plasticity mechanisms, which supports a sliding threshold model of homeostatic adaptation.SIGNIFICANCE STATEMENT Prolonged changes in sensory experience lead to homeostatic adaptation of excitatory synaptic strength in sensory cortices. Both sliding threshold and synaptic scaling models can account for the observed homeostatic synaptic plasticity. Here we report that visual experience-dependent homeostatic plasticity of excitatory synapses observed in superficial layers of visual cortex is dependent on NMDAR function. In particular, both strengthening of synapses induced by visual deprivation and the subsequent weakening by reinstatement of visual experience were prevented in the absence of functional NMDARs. Our results suggest that sensory experience-dependent homeostatic adaptation depends on NMDARs, which supports the sliding threshold model of plasticity and input-specific homeostatic control observed in vivo.