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Object detection is an essential function of the visual system. Although the visual cortex plays an important role in object detection, the superior colliculus can support detection when the visual cortex is ablated or silenced. Moreover, it has been shown that superficial layers of mouse SC (sSC) encode visual features of complex objects, and that this code is not inherited from the primary visual cortex. This suggests that mouse sSC may provide a significant contribution to complex object vision. Here, we use optogenetics to show that mouse sSC is involved in figure detection based on differences in figure contrast, orientation, and phase. Additionally, our neural recordings show that in mouse sSC, image elements that belong to a figure elicit stronger activity than those same elements when they are part of the background. The discriminability of this neural code is higher for correct trials than for incorrect trials. Our results provide new insight into the behavioral relevance of the visual processing that takes place in sSC., Competing Interests: JC, RH, TT, AH, MH, BP, LK, MS, PR, JH No competing interests declared, (© 2024, Cazemier et al.)

Experience-dependent plasticity in the adult visual system is generally thought of as a cortical process. However, several recent studies have shown that perceptual learning or monocular deprivation can also induce plasticity in the adult dorsolateral geniculate nucleus (dLGN) of the thalamus. How plasticity in the thalamus and cortex interact in the adult visual system is ill-understood. To assess the influence of thalamic plasticity on plasticity in primary visual cortex (V1), we made use of our previous finding that during the critical period ocular dominance (OD) plasticity occurs in dLGN and requires thalamic synaptic inhibition. Using multielectrode recordings we find that this is also true in adult mice, and that in the absence of thalamic inhibition and plasticity, OD plasticity in adult V1 is absent. To study the influence of V1 on thalamic plasticity, we silenced V1 and show that during the critical period, but not in adulthood, the OD shift in dLGN is partially caused by feedback from V1. We conclude that during adulthood the thalamus plays an unexpectedly dominant role in experience-dependent plasticity in V1. Our findings highlight the importance of considering the thalamus as a potential source of plasticity in learning events that are typically thought of as cortical processes., Competing Interests: YQ, MA, SS, PN, Ld, JH, CL No competing interests declared, (© 2023, Qin et al.)

Purpose: Human albinos have a low visual acuity. This is partially due to the presence of spontaneous erroneous eye movements called pendular nystagmus. This nystagmus is present in other albino vertebrates and has been hypothesized to be caused by aberrant wiring of retinal ganglion axons to the nucleus of the optic tract (NOT), a part of the accessory optic system involved in the optokinetic response to visual motion. The NOT in pigmented rodents is preferentially responsive to ipsiversive motion (i.e., motion in the contralateral visual field in the temporonasal direction). We compared the response to visual motion in the NOT of albino and pigmented mice to understand if motion coding and preference are impaired in the NOT of albino mice., Methods: We recorded neuronal spiking activity with Neuropixels probes in the visual cortex and NOT in C57BL/6JRj mice (pigmented) and DBA/1JRj mice with oculocutaneous albinism (albino)., Results: We found that in pigmented mice, NOT is retinotopically organized, and neurons are direction tuned, whereas in albino mice, neuronal tuning is severely impaired. Neurons in the NOT of albino mice do not have a preference for ipsiversive movement. In contrast, neuronal tuning in visual cortex was preserved in albino mice and did not differ significantly from the tuning in pigmented mice., Conclusions: We propose that excessive interhemispheric crossing of retinal projections in albinos may cause the disrupted left/right direction encoding we found in NOT. This, in turn, impairs the normal horizontal optokinetic reflex and leads to pendular albino nystagmus.

Neurophysiological studies depend on a reliable quantification of whether and when a neuron responds to stimulation. Simple methods to determine responsiveness require arbitrary parameter choices, such as binning size, while more advanced model-based methods require fitting and hyperparameter tuning. These parameter choices can change the results, which invites bad statistical practice and reduces the replicability. New recording techniques that yield increasingly large numbers of cells would benefit from a test for cell-inclusion that requires no manual curation. Here, we present the parameter-free ZETA-test, which outperforms t-tests, ANOVAs, and renewal-process-based methods by including more cells at a similar false-positive rate. We show that our procedure works across brain regions and recording techniques, including calcium imaging and Neuropixels data. Furthermore, in illustration of the method, we show in mouse visual cortex that (1) visuomotor-mismatch and spatial location are encoded by different neuronal subpopulations and (2) optogenetic stimulation of VIP cells leads to early inhibition and subsequent disinhibition., Competing Interests: JM, KS, MH, JC, MK, CL, JH No competing interests declared, (© 2021, Montijn et al.)

The segregation of figures from the background is an important step in visual perception. In primary visual cortex, figures evoke stronger activity than backgrounds during a delayed phase of the neuronal responses, but it is unknown how this figure-ground modulation (FGM) arises and whether it is necessary for perception. Here, we show, using optogenetic silencing in mice, that the delayed V1 response phase is necessary for figure-ground segregation. Neurons in higher visual areas also exhibit FGM and optogenetic silencing of higher areas reduced FGM in V1. In V1, figures elicited higher activity of vasoactive intestinal peptide-expressing (VIP) interneurons than the background, whereas figures suppressed somatostatin-positive interneurons, resulting in an increased activation of pyramidal cells. Optogenetic silencing of VIP neurons reduced FGM in V1, indicating that disinhibitory circuits contribute to FGM. Our results provide insight into how lower and higher areas of the visual cortex interact to shape visual perception., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Innate defensive responses such as freezing or escape are essential for animal survival. Mice show defensive behaviour to stimuli sweeping overhead, like a bird cruising the sky. Here, we tested this in young male mice and found that mice reduced their defensive freezing after sessions with a stimulus passing overhead repeatedly. This habituation is stimulus specific, as mice freeze again to a novel shape. Habituation occurs regardless of the visual field location of the repeated stimulus. The mice generalized over a range of sizes and shapes, but distinguished objects when they differed in both size and shape. Innate visual defensive responses are thus strongly influenced by previous experience as mice learn to ignore specific stimuli., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Proprioceptive neurons (PNs) are essential for the proper execution of all our movements by providing muscle sensory feedback to the central motor network. Here, using deep single cell RNAseq of adult PNs coupled with virus and genetic tracings, we molecularly identify three main types of PNs (Ia, Ib and II) and find that they segregate into eight distinct subgroups. Our data unveil a highly sophisticated organization of PNs into discrete sensory input channels with distinct spatial distribution, innervation patterns and molecular profiles. Altogether, these features contribute to finely regulate proprioception during complex motor behavior. Moreover, while Ib- and II-PN subtypes are specified around birth, Ia-PN subtypes diversify later in life along with increased motor activity. We also show Ia-PNs plasticity following exercise training, suggesting Ia-PNs are important players in adaptive proprioceptive function in adult mice.

The perception of speed is influenced by visual contrast. In primary visual cortex (V1), an early stage in the visual perception pathway, the neural tuning to speed is directly related to the neural tuning to temporal frequency of stimulus changes. The influence of contrast on speed perception can be caused by the joint dependency of neural responses in V1 on temporal frequency and contrast. Here, we investigated how tuning to contrast and temporal frequency in V1 of anesthetized mice are related. We found that temporal frequency tuning is contrast-dependent. V1 was more responsive at lower temporal frequencies than the dLGN, consistent with previous work at high contrast. The temporal frequency tuning moves toward higher temporal frequencies with increasing contrast. The low half-maximum temporal frequency does not change with contrast. The Heeger divisive normalization equation provides a good fit to many response characteristics in V1, but does not fit the dependency of temporal frequency and contrast with set of parameters for all temporal frequencies. Different mechanisms for normalization in the visual cortex may predict different relationships between temporal frequency and contrast non-linearity. Our data could help to make a model selection., (Copyright © 2020 Camillo, Ahmadlou and Heimel.)

Neurofibromatosis type 1 (NF1) is a common monogenic neurodevelopmental disorder associated with physical and cognitive problems. The cognitive issues are thought to arise from increased release of the neurotransmitter GABA. Modulating the signaling pathways causing increased GABA release in a mouse model of NF1 reverts deficits in hippocampal learning. However, clinical trials based on these approaches have so far been unsuccessful. We therefore used a combination of slice electrophysiology, in vivo two-photon calcium imaging, and optical imaging of intrinsic signal in a mouse model of NF1 to investigate whether cortical development is affected in NF1, possibly causing lifelong consequences that cannot be rescued by reducing inhibition later in life. We find that, in NF1 mice of both sexes, inhibition increases strongly during the development of the visual cortex and remains high. While this increase in cortical inhibition does not affect spontaneous cortical activity patterns during early cortical development, the critical period for ocular dominance plasticity is shortened in NF1 mice due to its early closure but unaltered onset. Notably, after environmental enrichment, differences in inhibitory innervation and ocular dominance plasticity between NF1 mice and WT littermates disappear. These results provide the first evidence for critical period dysregulation in NF1 and suggest that treatments aimed at normalizing levels of inhibition will need to start at early stages of development. SIGNIFICANCE STATEMENT Neurofibromatosis type 1 is associated with cognitive problems for which no treatment is currently available. This study shows that, in a mouse model of neurofibromatosis type 1, cortical inhibition is increased during development and critical period regulation is disturbed. Rearing the mice in an environment that stimulates cognitive function overcomes these deficits. These results uncover critical period dysregulation as a novel mechanism in the pathogenesis of neurofibromatosis type 1. This suggests that targeting the affected signaling pathways in neurofibromatosis type 1 for the treatment of cognitive disabilities may have to start at a much younger age than has so far been tested in clinical trials., (Copyright © 2020 the authors.)

Neuronal response to sensory stimuli depends on the context. The response in primary visual cortex (V1), for instance, is reduced when a stimulus is surrounded by a similar stimulus [1-3]. The source of this surround suppression is partially known. In mouse, local horizontal integration by somatostatin-expressing interneurons contributes to surround suppression [4]. In primates, however, surround suppression arises too quickly to come from local horizontal integration alone, and myelinated axons from higher visual areas, where cells have larger receptive fields, are thought to provide additional surround suppression [5, 6]. Silencing higher visual areas indeed decreased surround suppression in the awake primate by increasing responses to large stimuli [7, 8], although not under anesthesia [9, 10]. In smaller mammals, like mice, fast surround suppression could be possible without feedback. Recent studies revealed a small reduction in V1 responses when silencing higher areas [11, 12] but have not investigated surround suppression. To determine whether higher visual areas contribute to V1 surround suppression, even when this is not necessary for fast processing, we inhibited the areas lateral to V1, particularly the lateromedial area (LM), a possible homolog of primate V2 [13], while recording in V1 of awake and anesthetized mice. We found that part of the surround suppression depends on activity from lateral visual areas in the awake, but not anesthetized, mouse. Inhibiting the lateral visual areas specifically increased responses in V1 to large stimuli. We present a model explaining how excitatory feedback to V1 can have these suppressive effects for large stimuli., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Many brain regions go through critical periods of development during which plasticity is enhanced. These critical periods are associated with extensive growth and retraction of thalamocortical and intracortical axons. Here, we investigated whether a signaling pathway that is central in Wallerian axon degeneration also regulates critical period plasticity in the primary visual cortex (V1). Wallerian degeneration is characterized by rapid disintegration of axons once they are separated from the cell body. This degenerative process is initiated by reduced presence of cytoplasmic nicotinamide mononucleotide adenylyltransferases (NMNATs) and is strongly delayed in mice overexpressing cytoplasmic NMNAT proteins, such as Wld S mutant mice producing a UBE4b-NMNAT1 fusion protein or NMNAT3 transgenic mice. Here, we provide evidence that in Wld S mice and NMNAT3 transgenic mice, ocular dominance (OD) plasticity in the developing visual cortex is reduced. This deficit is only observed during the second half of the critical period. Additionally, we detect an early increase of visual acuity in the V1 of Wld S mice. We do not find evidence for Wallerian degeneration occurring during OD plasticity. Our findings suggest that NMNATs do not only regulate Wallerian degeneration during pathological conditions but also control cellular events that mediate critical period plasticity during the physiological development of the cortex.

The largest targets of retinal input in mammals are the dorsal lateral geniculate nucleus (dLGN), a relay to the primary visual cortex (V1), and the superior colliculus. V1 innervates and influences the superior colliculus. Here, we find that, in turn, superior colliculus modulates responses in mouse V1. Optogenetically inhibiting the superior colliculus reduces responses in V1 to optimally sized stimuli. Superior colliculus could influence V1 via its strong projection to the lateral posterior nucleus (LP/Pulvinar) or its weaker projection to the dLGN. Inhibiting superior colliculus strongly reduces activity in LP. Pharmacologically silencing LP itself, however, does not remove collicular modulation of V1. The modulation is instead due to a collicular gain modulation of the dLGN. Surround suppression operating in V1 explains the different effects for differently sized stimuli. Computations of visual saliency in the superior colliculus can thus influence tuning in the visual cortex via a tectogeniculate pathway.

Inhibition in the cerebral cortex is delivered by a variety of GABAergic interneurons. These cells have been categorized by their morphology, physiology, gene expression and connectivity. Many of these classes appear to be conserved across species, suggesting that the classes play specific functional roles in cortical processing. What these functions are, is still largely unknown. The largest group of interneurons in the upper layers of mouse primary visual cortex (V1) is formed by cells expressing the calcium-binding protein calretinin (CR). This heterogeneous class contains subsets of vasoactive intestinal polypeptide (VIP) interneurons and somatostatin (SOM) interneurons. Here we show, using in vivo two-photon calcium imaging in mice, that CR neurons can be sensitive to stimulus orientation, but that they are less selective on average than the overall neuronal population. Responses of CR neurons are suppressed by a surrounding stimulus, but less so than the overall population. In rats and primates, CR interneurons have been suggested to provide disinhibition, but we found that in mice their in vivo activation by optogenetics causes a net inhibition of cortical activity. Our results show that the average functional properties of CR interneurons are distinct from the averages of the parvalbumin, SOM and VIP interneuron populations.

The formation, plasticity and maintenance of synaptic connections is regulated by molecular and electrical signals. β-Catenin is an important protein in these events and regulates cadherin-mediated cell adhesion and the recruitment of pre- and postsynaptic proteins in an activity-dependent fashion. Mutations in the β-catenin gene can cause cognitive disability and autism, with life-long consequences. Understanding its synaptic function may thus be relevant for the treatment of these disorders. So far, β-catenin's function has been studied predominantly in cell culture and during development but knowledge on its function in adulthood is limited. Here, we show that ablating β-catenin in excitatory neurons of the adult visual cortex does not cause the same synaptic deficits previously observed during development. Instead, it reduces NMDA-receptor currents and impairs visual processing. We conclude that β-catenin remains important for adult cortical function but through different mechanisms than during development.

We detect objects more readily if they differ from their surroundings in motion, color, or texture. This increased saliency is thought to be related to increased responses in the visual cortex. The superior colliculus is another brain area involved in vision and especially in directing gaze and attention. In this study, we show that differences in texture orientation also increase responses in the superficial layers of the superior colliculus that receive retinal and cortical input. We found that gratings evoke more neural response when surrounded by orthogonal gratings than when surrounded by parallel gratings, particularly in the awake mouse. This pop-out is not originating from the visual cortex, and silencing visual cortex increased the relative difference in response. A model shows that this can result from retinotopically matched excitation from visual cortex to the superior colliculus. We suggest that the perceptual saliency of a stimulus differing from its surround in a low-level feature like grating orientation could depend on visual processing in the superior colliculus., (© The Author 2017. Published by Oxford University Press.)

Mitochondria buffer intracellular Ca 2+ and provide energy [1]. Because synaptic structures with high Ca 2+ buffering [2-4] or energy demand [5] are often localized far away from the soma, mitochondria are actively transported to these sites [6-11]. Also, the removal and degradation of mitochondria are tightly regulated [9, 12, 13], because dysfunctional mitochondria are a source of reactive oxygen species, which can damage the cell [14]. Deficits in mitochondrial trafficking have been proposed to contribute to the pathogenesis of Parkinson's disease, schizophrenia, amyotrophic lateral sclerosis, optic atrophy, and Alzheimer's disease [13, 15-19]. In neuronal cultures, about a third of mitochondria are motile, whereas the majority remains stationary for several days [8, 20]. Activity-dependent mechanisms cause mitochondria to stop at synaptic sites [7, 8, 20, 21], which affects synapse function and maintenance. Reducing mitochondrial content in dendrites decreases spine density [22, 23], whereas increasing mitochondrial content or activity increases it [7]. These bidirectional interactions between synaptic activity and mitochondrial trafficking suggest that mitochondria may regulate synaptic plasticity. Here we investigated the dynamics of mitochondria in relation to axonal boutons of neocortical pyramidal neurons for the first time in vivo. We find that under these circumstances practically all mitochondria are stationary, both during development and in adulthood. In adult visual cortex, mitochondria are preferentially localized at putative boutons, where they remain for several days. Retinal-lesion-induced cortical plasticity increases turnover of putative boutons but leaves mitochondrial turnover unaffected. We conclude that in visual cortex in vivo, mitochondria are less dynamic than in vitro, and that structural plasticity does not affect mitochondrial dynamics., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Mutations in the Crumbs-homologue-1 (CRB1) gene lead to severe recessive inherited retinal dystrophies. Gene transfer therapy is the most promising cure for retinal dystrophies and has primarily been applied for recessive null conditions via a viral gene expression vector transferring a cDNA encoding an enzyme or channel protein, and targeting expression to one cell type. Therapy for the human CRB1 disease will be more complex, as CRB1 is a structural and signaling transmembrane protein present in three cell classes: Müller glia, cone and rod photoreceptors. In this study, we applied CRB1 and CRB2 gene therapy vectors in Crb1-retinitis pigmentosa mouse models at mid-stage disease. We tested if CRB expression restricted to Müller glial cells or photoreceptors or co-expression in both is required to recover retinal function. We show that targeting both Müller glial cells and photoreceptors with CRB2 ameliorated retinal function and structure in Crb1 mouse models. Surprisingly, targeting a single cell type or all cell types with CRB1 reduced retinal function. We show here the first pre-clinical studies for CRB1-related eye disorders using CRB2 vectors and initial elucidation of the cellular mechanisms underlying CRB1 function., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The superior colliculus is a layered structure important for body- and gaze-orienting responses. Its superficial layer is, next to the lateral geniculate nucleus, the second major target of retinal ganglion axons and is retinotopically organized. Here we show that in the mouse there is also a precise organization of orientation preference. In columns perpendicular to the tectal surface, neurons respond to the same visual location and prefer gratings of the same orientation. Calcium imaging and extracellular recording revealed that the preferred grating varies with retinotopic location, and is oriented parallel to the concentric circle around the centre of vision through the receptive field. This implies that not all orientations are equally represented across the visual field. This makes the superior colliculus different from visual cortex and unsuitable for translation-invariant object recognition and suggests that visual stimuli might have different behavioural consequences depending on their retinotopic location.

Classic studies of lateral geniculate nucleus (LGN) and visual cortex (V1) in carnivores and primates have found that a majority of neurons in LGN exhibit a center-surround organization, while V1 neurons exhibit strong orientation selectivity and, in many species, direction selectivity. Recent work in the mouse and the monkey has discovered previously unknown classes of orientation- and direction-selective neurons in LGN. Furthermore, some recent studies in the mouse report that many LGN cells exhibit pronounced orientation biases that are of comparable strength to the subthreshold inputs to V1 neurons. These results raise the possibility that, in rodents, orientation biases of individual LGN cells make a substantial contribution to cortical orientation selectivity. Alternatively, the size and contribution of orientation- or direction-selective channels from LGN to V1 may vary across mammals. To address this question, we examined orientation and direction selectivity in LGN and V1 neurons of a highly visual diurnal rodent: the gray squirrel. In the representation of central vision, only a few LGN neurons exhibited strong orientation or direction selectivity. Across the population, LGN neurons showed weak orientation biases and were much less selective for orientation compared with V1 neurons. Although direction selectivity was weak overall, LGN layers 3abc, which contain neurons that express calbindin, exhibited elevated direction selectivity index values compared with LGN layers 1 and 2. These results suggest that, for central visual fields, the contribution of orientation- and direction-selective channels from the LGN to V1 is small in the squirrel. As in other mammals, this small contribution is elevated in the calbindin-positive layers of the LGN., (Copyright © 2015 the American Physiological Society.)

Background: To ensure that neuronal networks function in a stable fashion, neurons receive balanced inhibitory and excitatory inputs. In various brain regions, this balance has been found to change temporarily during plasticity. Whether changes in inhibition have an instructive or permissive role in plasticity remains unclear. Several studies have addressed this question using ocular dominance plasticity in the visual cortex as a model, but so far, it remains controversial whether changes in inhibition drive this form of plasticity by directly affecting eye-specific responses or through increasing the plasticity potential of excitatory connections., Results: We tested how three major classes of interneurons affect eye-specific responses in normally reared or monocularly deprived mice by optogenetically suppressing their activity. We find that in contrast to somatostatin-expressing or vasoactive intestinal polypeptide-expressing interneurons, parvalbumin (PV)-expressing interneurons strongly inhibit visual responses. In individual neurons of normal mice, inhibition and excitation driven by either eye are balanced, and suppressing PV interneurons does not alter ocular preference. Monocular deprivation disrupts the binocular balance of inhibition and excitation in individual neurons, causing suppression of PV interneurons to change their ocular preference. Importantly, however, these changes do not consistently favor responses to one of the eyes at the population level., Conclusions: Monocular deprivation disrupts the binocular balance of inhibition and excitation of individual cells. This disbalance does not affect the overall expression of ocular dominance. Our data therefore support a permissive rather than an instructive role of inhibition in ocular dominance plasticity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by impaired social interaction and communication, and restricted behavior and interests. A disruption in the balance of excitatory and inhibitory neurotransmission has been hypothesized to underlie these disorders. Here we demonstrate that genes of both pathways are affected by ASD, and that gene expression of inhibitory and excitatory genes is altered in the cerebral cortex of adult but not younger autistic individuals. We have developed a measure for the difference in the level of excitation and inhibition based on gene expression and observe that in this measure inhibition is decreased relative to excitation in adult ASD compared to control. This difference was undetectable in young autistic brains. Given that many psychiatric features of autism are already present at an early age, this suggests that the observed imbalance in gene expression is an aging phenomenon in ASD rather than its underlying cause.

Calretinin is a calcium-binding protein often used as a marker for a subset of inhibitory interneurons in the mammalian neocortex. We studied the labeled cells in offspring from a cross of a Cre-dependent reporter line with the CR-ires-Cre mice, which express Cre-recombinase in the same pattern as calretinin. We found that in the mature visual cortex, only a minority of the cells that have expressed calretinin and Cre-recombinase during their lifetime is GABAergic and only about 20% are immunoreactive for calretinin. The reason behind this is that calretinin is transiently expressed in many cortical pyramidal neurons during development. To determine whether neurons that express or have expressed calretinin share any distinct functional characteristics, we recorded their visual response properties using GCaMP6s calcium imaging. The average orientation selectivity, size tuning, and temporal and spatial frequency tuning of this group of cells, however, match the response profile of the general neuronal population, revealing the lack of functional specialization for the features studied.

The firing rates of neurons in primary visual cortex (V1) are suppressed by large stimuli, an effect known as surround suppression. In cats and monkeys, the strength of suppression is sensitive to orientation; responses to regions containing uniform orientations are more suppressed than those containing orientation contrast. This effect is thought to be important for scene segmentation, but the underlying neural mechanisms are poorly understood. We asked whether it is possible to study these mechanisms in the visual cortex of mice, because of recent advances in technology for studying the cortical circuitry in mice. It is unknown whether neurons in mouse V1 are sensitive to orientation contrast. We measured the orientation selectivity of surround suppression in the different layers of mouse V1. We found strong surround suppression in layer 4 and the superficial layers, part of which was orientation tuned: iso-oriented surrounds caused more suppression than cross-oriented surrounds. Surround suppression was delayed relative to the visual response and orientation-tuned suppression was delayed further, suggesting two separate suppressive mechanisms. Previous studies proposed that surround suppression depends on the activity of inhibitory somatostatin-positive interneurons in the superficial layers. To test the involvement of the superficial layers we topically applied lidocaine. Silencing of the superficial layers did not prevent orientation-tuned suppression in layer 4. These results show that neurons in mouse V1, which lacks orientation columns, show orientation-dependent surround suppression in layer 4 and the superficial layers and that surround suppression in layer 4 does not require contributions from neurons in the superficial layers., (Copyright © 2014 the authors 0270-6474/14/349290-15$15.00/0.)

During development, cortical plasticity is associated with the rearrangement of excitatory connections. While these connections become more stable with age, plasticity can still be induced in the adult cortex. Here we provide evidence that structural plasticity of inhibitory synapses onto pyramidal neurons is a major component of plasticity in the adult neocortex. In vivo two-photon imaging was used to monitor the formation and elimination of fluorescently labeled inhibitory structures on pyramidal neurons. We find that ocular dominance plasticity in the adult visual cortex is associated with rapid inhibitory synapse loss, especially of those present on dendritic spines. This occurs not only with monocular deprivation but also with subsequent restoration of binocular vision. We propose that in the adult visual cortex the experience-induced loss of inhibition may effectively strengthen specific visual inputs with limited need for rearranging the excitatory circuitry., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Spontaneous network activity constitutes a central theme during the development of neuronal circuitry [1, 2]. Before the onset of vision, retinal neurons generate waves of spontaneous activity that are relayed along the ascending visual pathway [3, 4] and shape activity patterns in these regions [5, 6]. The spatiotemporal nature of retinal waves is required to establish precise functional maps in higher visual areas, and their disruption results in enlarged axonal projection areas (e.g., [7-10]). However, how retinal inputs shape network dynamics in the visual cortex on the cellular level is unknown. Using in vivo two-photon calcium imaging, we identified two independently occurring patterns of network activity in the mouse primary visual cortex (V1) before and at the onset of vision. Acute manipulations of spontaneous retinal activity revealed that one type of network activity largely originated in the retina and was characterized by low synchronicity (L-) events. In addition, we identified a type of high synchronicity (H-) events that required gap junction signaling but were independent of retinal input. Moreover, the patterns differed in wave progression and developmental profile. Our data suggest that different activity patterns have complementary functions during the formation of synaptic circuits in the developing visual cortex., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Many studies have been devoted to the identification of genes involved in experience-dependent plasticity in the visual cortex. To discover new candidate genes, we have reexamined data from one such study on ocular dominance (OD) plasticity in recombinant inbred BXD mouse strains. We have correlated the level of plasticity with the gene expression data in the neocortex that have become available for these same strains. We propose that genes with a high correlation are likely to play a role in OD plasticity. We have tested this hypothesis for genes whose inactivation is known to affect OD plasticity. The expression levels of these genes indeed correlated with OD plasticity if their levels showed strong differences between the BXD strains. To narrow down our candidate list of correlated genes, we have selected only those genes that were previously found to be regulated by visual experience and associated with pathways implicated in OD plasticity. This resulted in a list of 32 candidate genes. The list contained unproven, but not unexpected candidates such as the genes for IGF-1, NCAM1, NOGO-A, the gamma2 subunit of the GABA(A) receptor, acetylcholine esterase, and the catalytic subunit of cAMP-dependent protein kinase A. This demonstrates the viability of our approach. More interestingly, the following novel candidate genes were identified: Akap7, Akt1, Camk2d, Cckbr, Cd44, Crim1, Ctdsp2, Dnajc5, Gnai1, Itpka, Mapk8, Nbea, Nfatc3, Nlk, Npy5r, Phf21a, Phip, Ppm1l, Ppp1r1b, Rbbp4, Slc1a3, Slit2, Socs2, Spock3, St8sia1, Zfp207. Whether all these novel candidates indeed function in OD plasticity remains to be established, but possible roles of some of them are discussed in the article.

During brain development, the neocortex shows periods of enhanced plasticity, which enables the acquisition of knowledge and skills that we use and build on in adult life. Key to persistent modifications of neuronal connectivity and plasticity of the neocortex are molecular changes occurring at the synapse. Here we used isobaric tag for relative and absolute quantification to measure levels of 467 synaptic proteins in a well-established model of plasticity in the mouse visual cortex and the regulation of its critical period. We found that inducing visual cortex plasticity by monocular deprivation during the critical period increased levels of kinases and proteins regulating the actin-cytoskeleton and endocytosis. Upon closure of the critical period with age, proteins associated with transmitter vesicle release and the tubulin- and septin-cytoskeletons increased, whereas actin-regulators decreased in line with augmented synapse stability and efficacy. Maintaining the visual cortex in a plastic state by dark rearing mice into adulthood only partially prevented these changes and increased levels of G-proteins and protein kinase A subunits. This suggests that in contrast to the general belief, dark rearing does not simply delay cortical development but may activate signaling pathways that specifically maintain or increase the plasticity potential of the visual cortex. Altogether, this study identified many novel candidate plasticity proteins and signaling pathways that mediate synaptic plasticity during critical developmental periods or restrict it in adulthood.

During the last decade, we have gained much insight into the mechanisms that open and close a sensitive period of plasticity in the visual cortex. This brings the hope that novel treatments can be developed for brain injuries requiring renewed plasticity potential and neurodevelopmental brain disorders caused by defective synaptic plasticity. One of the central mechanisms responsible for opening the sensitive period is the maturation of inhibitory innervation. Many molecular and cellular events have been identified that drive this developmental process, including signaling through BDNF and IGF-1, transcriptional control by OTX2, maturation of the extracellular matrix, and GABA-regulated inhibitory synapse formation. The mechanisms through which the development of inhibitory innervation triggers and potentially closes the sensitive period may involve plasticity of inhibitory inputs or permissive regulation of excitatory synapse plasticity. Here, we discuss the current state of knowledge in the field and open questions to be addressed.

On bipolar cells are connected to photoreceptors via a sign-inverting synapse. At this synapse, glutamate binds to a metabotropic receptor which couples to the closure of a cation-selective transduction channel. The molecular identity of both the receptor and the G protein are known, but the identity of the transduction channel has remained elusive. Here, we show that the transduction channel in mouse rod bipolar cells, a subtype of On bipolar cell, is likely to be a member of the TRP family of channels. To evoke a transduction current, the metabotropic receptor antagonist LY341495 was applied to the dendrites of cells that were bathed in a solution containing the mGluR6 agonists L-AP4 or glutamate. The transduction current was suppressed by ruthenium red and the TRPV1 antagonists capsazepine and SB-366791. Furthermore, focal application of the TRPV1 agonists capsaicin and anandamide evoked a transduction-like current. The capsaicin-evoked and endogenous transduction current displayed prominent outward rectification, a property of the TRPV1 channel. To test the possibility that the transduction channel is TRPV1, we measured rod bipolar cell function in the TRPV1(-/-) mouse. The ERG b-wave, a measure of On bipolar cell function, as well as the transduction current and the response to TRPV1 agonists were normal, arguing against a role for TRPV1. However, ERG measurements from mice lacking TRPM1 receptors, another TRP channel implicated in retinal function, revealed the absence of a b-wave. Our results suggest that a TRP-like channel, possibly TRPM1, is essential for synaptic function in On bipolar cells.

Depriving one eye of visual experience during a sensitive period of development results in a shift in ocular dominance (OD) in the primary visual cortex (V1). To assess the heritability of this form of cortical plasticity and identify the responsible gene loci, we studied the influence of monocular deprivation on OD in a large number of recombinant inbred mouse strains derived from mixed C57BL/6J and DBA/2J backgrounds (BXD). The strength of imaged intrinsic signal responses in V1 to visual stimuli was strongly heritable as were various elements of OD plasticity. This has important implications for the use of mice of mixed genetic backgrounds for studying OD plasticity. C57BL/6J showed the most significant shift in OD, while some BXD strains did not show any shift at all. Interestingly, the increase in undeprived ipsilateral eye responses was not correlated to the decrease in deprived contralateral eye responses, suggesting that the size of these components of OD plasticity are not genetically controlled by only a single mechanism. We identified a quantitative trait locus regulating the change in response to the deprived eye. The locus encompasses 13 genes, two of which--Stch and Nrip1--contain missense polymorphisms. The expression levels of Stch and to a lesser extent Nrip1 in whole brain correlate with the trait identifying them as novel candidate plasticity genes.

How the visual cortex responds to specific stimuli is strongly influenced by visual experience during development. Monocular deprivation, for example, changes the likelihood of neurons in the visual cortex to respond to input from the deprived eye and reduces its visual acuity. Because these functional changes are accompanied by extensive reorganization of neurite morphology and dendritic spine turnover, genes regulating neuronal morphology are likely to be involved in visual plasticity. In recent years, Notch1 has been shown to mediate contact inhibition of neurite outgrowth in postmitotic neurons and implicated in the pathogenesis of various degenerative diseases of the CNS. Here, we provide the first evidence for the involvement of neuronal Notch1 signaling in synaptic morphology and plasticity in the visual cortex. By making use of the Cre/Lox system, we expressed an active form of Notch1 in cortical pyramidal neurons several weeks after birth. We show that neuronal Notch1 signals reduce dendritic spine and filopodia densities in a cell-autonomous manner and limit long-term potentiation in the visual cortex. After monocular deprivation, these effects of Notch1 activity predominantly affect responses to visual stimuli with higher spatial frequencies. This results in an enhanced effect of monocular deprivation on visual acuity.

In the cerebral cortex of mammals, horizontal connections link cells up to several millimeters apart. In primary visual cortex (V1) of mammals with orientation maps, horizontal connections ramify in periodic patches across the cortical surface, connecting cells with similar orientation preferences. Rodents have orientation-selective cells but lack orientation maps, raising questions about relationships of horizontal connections to functional maps and receptive field properties. To address these questions, we studied anatomy of horizontal connections and characterized horizontal functional interactions in V1 of the gray squirrel, a highly visual rodent. Long-range intrinsic connections in squirrel V1 extended 1-2 mm but were not patchy or periodic. This result suggests that periodic and patchy connectivity is not a universal organizing principle of cortex, and the existence of patchy and periodic connectivity and functional maps may be linked. In multielectrode and intracellular recordings, we found evidence of unselective local interactions among cells, similar to pinwheel centers of carnivores. These data suggest that, in mammals with and without orientation maps, local connections link near neighbors without regard to orientation selectivity. In single-unit recordings, we found length-summing and end-stopped cells that were similar to those in other mammals. Length-summing cell surrounds were orientation selective, whereas surrounds of end-stopped cells were not. Receptive field response classes are quite similar across mammals, and therefore patchy and columnar connectivity may not be essential for these properties.

The gray squirrel (Sciurus carolinensis) is a diurnal highly visual rodent with a cone-rich retina. To determine which features of visual cortex are common to highly visual mammals and which are restricted to non-rodent species, we studied the laminar organization of response properties in primary visual area V1 of isoflurane-anesthetized squirrels using extra-cellular single-unit recording and sinusoidal grating stimuli. Of the responsive cells, 75% were tuned for orientation. Only 10% were directionally selective, almost all in layer 6, a layer receiving direct input from the dorsal lateral geniculate nucleus (LGN). Cone opponency was widespread but almost absent from layer 6. Median optimal spatial frequency tuning was 0.21 cycles/ degrees . Median optimal temporal frequency a high 5.3 Hz. Layer 4 had the highest percentage of simple cells and shortest latency (26 ms). Layers 2/3 had the lowest spontaneous activity and highest temporal frequency tuning. Layer 5 had the broadest spatial frequency tuning and most spontaneous activity. At the layer 4/5 border were sustained cells with high cone opponency. Simple cells, determined by modulation to drifting sinusoidal gratings, responded with shorter latencies, were more selective for orientation and direction, and were tuned to lower spatial frequencies. A comparison with other mammals shows that although the laminar organization of orientation selectivity is variable, the cortical input layers contain more linear cells in most mammals. Nocturnal mammals appear to have more orientation-selective neurons in V1 than diurnal mammals of similar size.

In mammalian neocortex, the orderly arrangement of columns of neurons is thought to be a fundamental organizing principle. In primary visual cortex (V1), neurons respond preferentially to bars of a particular orientation, and, in many mammals, these orientation-selective cells are arranged in a semiregular, smoothly varying map across the cortical surface. Curiously, orientation maps have not been found in rodents or lagomorphs. To explore whether this lack of organization in previously studied rodents could be attributable to low visual acuity, poorly differentiated visual brain areas, or small absolute V1 size, we examined V1 organization of a larger, highly visual rodent, the gray squirrel. Using intrinsic signal optical imaging and single-cell recordings, we found no evidence of an orientation map, suggesting that formation of orientation maps depends on mechanisms not found in rodents. We did find robust orientation tuning of single cells, and this tuning was invariant to stimulus contrast. Therefore, it seems unlikely that orientation maps are important for orientation tuning or its contrast invariance in V1. In vertical electrode penetrations, we found little evidence for columnar organization of orientation-selective neurons and little evidence for local anisotropy of orientation preferences. We conclude that an orderly and columnar arrangement of functional response properties is not a universal characteristic of cortical architecture.

Physiological studies of the lateral geniculate nucleus (LGN) have revealed three classes of relay neurons, called X, Y, and W cells in carnivores and parvocellular (P), magnocellular (M), and koniocellular (K) in primates. The homological relationships among these cell classes and how receptive field (RF) properties of these cells compare with LGN cells in other mammals are poorly understood. To address these questions, we have characterized RF properties and laminar organization in LGN of a highly visual diurnal rodent, the gray squirrel, under isoflurane anesthesia. We identified three classes of LGN cells. One class found in layers 1 and 2 showed sustained, reliable firing, center-surround organization, and was almost exclusively linear in spatial summation. Another class, found in layer 3, showed short response latencies, transient and reliable firing, center-surround organization, and could show either linear (76%) or nonlinear (24%) spatial summation. A third, heterogeneous class found throughout the LGN but primarily in layer 3 showed highly variable responses, a variety of response latencies and could show either center-surround or noncenter-surround receptive field organization and either linear (77%) or nonlinear (23%) spatial summation. RF sizes of all cell classes showed little dependency on eccentricity, and all of these classes showed low contrast gains. When compared with LGN cells in other mammals, our data are consistent with the idea that all mammals contain three basic classes of LGN neurons, one showing reliable, sustained responses, and center-surround organization (X or P); another showing transient but reliable responses, short latencies, and center-surround organization (Y or M); and a third, highly variable and heterogeneous class of cells (W or K). Other properties such as dependency of receptive field size on eccentricity, linearity of spatial summation, and contrast gain appear to vary from species to species.