Primate V2 Receptive Fields Derived from Anatomically Identified Large-Scale V1 Inputs.

In the primate visual system, visual object recognition involves a series of cortical areas arranged hierarchically along the ventral visual pathway. As information flows through this hierarchy, neurons become progressively tuned to more complex image features. The circuit mechanisms and computations underlying the increasing complexity of these receptive fields (RFs) remain unidentified. To understand how this complexity emerges in the secondary visual area (V2), we investigated the functional organization of inputs from the primary visual cortex (V1) to V2 by combining retrograde anatomical tracing of these inputs with functional imaging of feature maps in macaque monkey V1 and V2. We found that V1 neurons sending inputs to single V2 orientation columns have a broad range of preferred orientations, but are strongly biased towards the orientation represented at the injected V2 site. For each V2 site, we then constructed a feedforward model based on the linear combination of its anatomically-identified large-scale V1 inputs, and studied the response proprieties of the generated V2 RFs. We found that V2 RFs derived from the linear feedforward model were either elongated versions of V1 filters or had spatially complex structures. These modeled RFs predicted V2 neuron responses to oriented grating stimuli with high accuracy. Remarkably, this simple model also explained the greater selectivity to naturalistic textures of V2 cells compared to their V1 input cells. Our results demonstrate that simple linear combinations of feedforward inputs can account for the orientation selectivity and texture sensitivity of V2 RFs.

Primate V2 Receptive Fields Derived from Anatomically Identified Large-Scale V1 Inputs.

In the primate visual system, visual object recognition involves a series of cortical areas arranged hierarchically along the ventral visual pathway. As information flows through this hierarchy, neurons become progressively tuned to more complex image features. The circuit mechanisms and computations underlying the increasing complexity of these receptive fields (RFs) remain unidentified. To understand how this complexity emerges in the secondary visual area (V2), we investigated the functional organization of inputs from the primary visual cortex (V1) to V2 by combining retrograde anatomical tracing of these inputs with functional imaging of feature maps in macaque monkey V1 and V2. We found that V1 neurons sending inputs to single V2 orientation columns have a broad range of preferred orientations, but are strongly biased towards the orientation represented at the injected V2 site. For each V2 site, we then constructed a feedforward model based on the linear combination of its anatomically-identified large-scale V1 inputs, and studied the response proprieties of the generated V2 RFs. We found that V2 RFs derived from the linear feedforward model were either elongated versions of V1 filters or had spatially complex structures. These modeled RFs predicted V2 neuron responses to oriented grating stimuli with high accuracy. Remarkably, this simple model also explained the greater selectivity to naturalistic textures of V2 cells compared to their V1 input cells. Our results demonstrate that simple linear combinations of feedforward inputs can account for the orientation selectivity and texture sensitivity of V2 RFs.

Antioxidant Behavioural Phenotype in the Immp2l Gene Knock-Out Mouse.

Mitochondrial dysfunction is strongly associated with autism spectrum disorder (ASD) and the Inner mitochondrial membrane protein 2-like (IMMP2L) gene is linked to autism inheritance. However, the biological basis of this linkage is unknown notwithstanding independent reports of oxidative stress in association with both IMMP2L and ASD. To better understand IMMP2L's association with behaviour, we developed the Immp2lKD knockout (KO) mouse model which is devoid of Immp2l peptidase activity. Immp2lKD -/- KO mice do not display any of the core behavioural symptoms of ASD, albeit homozygous Immp2lKD -/- KO mice do display increased auditory stimulus-driven instrumental behaviour and increased amphetamine-induced locomotion. Due to reports of increased ROS and oxidative stress phenotypes in an earlier truncated Immp2l mouse model resulting from an intragenic deletion within Immp2l, we tested whether high doses of the synthetic mitochondrial targeted antioxidant (MitoQ) could reverse or moderate the behavioural changes in Immp2lKD -/- KO mice. To our surprise, we observed that ROS levels were not increased but significantly lowered in our new Immp2lKD -/- KO mice and that these mice had no oxidative stress-associated phenotypes and were fully fertile with no age-related ataxia or neurodegeneration as ascertained using electron microscopy. Furthermore, the antioxidant MitoQ had no effect on the increased amphetamine-induced locomotion of these mice. Together, these findings indicate that the behavioural changes in Immp2lKD -/- KO mice are associated with an antioxidant-like phenotype with lowered and not increased levels of ROS and no oxidative stress-related phenotypes. This suggested that treatments with antioxidants are unlikely to be effective in treating behaviours directly resulting from the loss of Immp2l/IMMP2L activity, while any behavioural deficits that maybe associated with IMMP2L intragenic deletion-associated truncations have yet to be determined.

Immp2l knockdown in male mice increases stimulus-driven instrumental behaviour but does not alter goal-directed learning or neuron density in cortico-striatal circuits in a model of Tourette syndrome and autism spectrum disorder.

Cortico-striatal neurocircuits mediate goal-directed and habitual actions which are necessary for adaptive behaviour. It has recently been proposed that some of the core symptoms of autism spectrum disorder (ASD) and Gilles de la Tourette syndrome (GTS), such as tics and other repetitive behaviours, may emerge because of imbalances in these neurocircuits. We have recently developed a model of ASD and GTS by knocking down Immp2l, a mitochondrial gene frequently associated with these disorders. The current study sought to determine whether Immp2l knockdown (KD) in male mice alters flexible, goal- or cue- driven behaviour using procedures specifically designed to examine response-outcome and stimulus-response associations, which underlie goal-directed and habitual behaviour, respectively. Whether Immp2l KD alters neuron density in cortico-striatal neurocircuits known to regulate these behaviours was also examined. Immp2l KD mice and wild type-like mice (WT) were trained on Pavlovian and instrumental learning procedures where auditory cues predicted food delivery and lever-press responses earned a food outcome. It was demonstrated that goal-directed learning was not changed for Immp2l KD mice compared to WT mice, as lever-press responses were sensitive to changes in the value of the food outcome, and to contingency reversal and degradation. There was also no difference in the capacity of KD mice to form habitual behaviours compared to WT mice following extending training of the instrumental action. However, Immp2l KD mice were more responsive to auditory stimuli paired with food as indicated by a non-specific increase in lever response rates during Pavlovian-to-instrumental transfer. Finally, there were no alterations to neuron density in striatum or any prefrontal cortex or limbic brain structures examined. Thus, the current study suggests that Immp2l is not necessary for learned maladaptive goal or stimulus driven behaviours in ASD or GTS, but that it may contribute to increased capacity for external stimuli to drive behaviour. Alterations to stimulus-driven behaviour could potentially influence the expression of tics and repetitive behaviours, suggesting that genetic alterations to Immp2l may contribute to these core symptoms in ASD and GTS. Given that this is the first application of this battery of instrumental learning procedures to a mouse model of ASD or GTS, it is an important initial step in determining the contribution of known risk-genes to goal-directed versus habitual behaviours, which should be more broadly applied to other rodent models of ASD and GTS in the future.

Optogenetics in primate cortical networks.

The implementation of optogenetics in studies on non-human primates has generally proven quite difficult, but recent successes have paved the way for its rapid increase. Limitations in the genetic tractability in primates, have been somewhat overcome by implementing tailored vectors and promoters to maximize expression and specificity in primates. More recently, implantable devices, including microLED arrays, have made it possible to deliver light deeper into brain tissue, allowing targeting of deeper structures. However, the greatest limitation in applying optogenetics to the primate brain is the complex connections that exist within many neural circuits. In the past, relatively cruder methods such as cooling or pharmacological blockade have been used to examine neural circuit functions, though their limitations were well recognized. In some ways, similar shortcomings remain for optogenetics, with the ability to target a single component of complex neural circuits being the greatest challenge in applying optogenetics to systems neuroscience in primate brains. Despite this, some recent approaches combining Cre-expressing and Cre-dependent vectors have overcome some of these limitations. Here we suggest that optogenetics provides its greatest advantage to systems neuroscientists when applied as a specific tool to complement the techniques of the past, rather than necessarily replacing them.

Targeting the lateral hypothalamus with short hairpin RNAs reduces habitual behaviour following extended instrumental training in rats.

Instrumental actions are initially goal-directed but with repeated performance can become habitual. Habitual actions are adaptive, learned behaviours that are automated in order to reduce cognitive load and to allow for efficient interaction with the environment. Goal-directed and habitual actions are mediated by distinct neurocircuits which centre on the dorsal striatum and involve different cortical and limbic inputs. The lateral hypothalamus (LH) has yet to be considered in this neurocircuitry despite its anatomical connections with these neurocircuits and its established role in motivated behaviour. The aim of the current study was to determine whether the LH has a role in the development of habitual actions in rats by knocking down protein expression in the LH with short hairpin RNAs (shRNA). Two shRNAs were utilised, both of which were shown to reduce the expression of two neuropeptides within the LH, orexin and melanin-concentrating hormone, compared to a saline-vehicle control. This was unexpected given that one shRNA was a control vector (i.e, scrambled sequence), and the other shRNA was supposed to selectively target orexin's precursor protein. Given this lack of specificity and that shRNA's are known to be neurotoxic, the current study examined the impact of non-selective dysfunction of the LH on habitual actions. Adult male Long-Evans rats were trained to press a lever for a food outcome and were tested for goal directed and habitual behaviour following devaluation of the food. The shRNA groups displayed goal-directed actions following moderate instrumental training, but did not develop habitual actions following extended training. That is, control rats developed the expected habitual behaviour where lever-response rates were insensitive to outcome value when tested, whilst the shRNA groups reduced rates of responding on the lever under devalued conditioned and hence remained goal-directed. This failure to demonstrate habitual actions was unlikely to be secondary to changes in motivation or arousal as the shRNA groups did not show altered food consumption, body weight, lever response rates, or motor performance on a rota rod or tapered balance beam. However, locomotor activity was reduced in an open field test, consistent with the proposed role of the LH in spontaneous locomotor activity. Therefore, this study implicates the LH in habitual learning, and adds to the emerging evidence that the LH has a role in associative learning processes. This finding has implications for human conditions where there is dysfunction or neurodegeneration in the LH, as well as altered habitual actions, such as in Parkinson's disease and drug addiction.

Habitual behaviour associated with exposure to high-calorie diet is prevented by an orexin-receptor-1 antagonist.

Habitual actions, which are associated with addictive behaviours, contribute to the loss of control of food seeking seen following exposure to calorie-dense foods in rats. Antagonism of orexin-receptor-1 (ORX-R1) has been shown to reduce a range of stimulus-driven feeding behaviours, but have yet to be implicated in the regulation of habitual actions. In the current study, male Long-Evans rats were given 'binge-like' access to high-calorie diet (HCD) or standard chow diet, and were subsequently trained to press a lever for food outcome. When lever responses were tested following outcome devaluation, chow-fed rats displayed goal-directed actions, whereas HCD-exposed rats displayed habitual actions. In study 1, it was shown that systemic administration of the ORX-R1 antagonist, SB-334867, prior to test restored goal-directed behaviour in HCD-exposed rats. In study 2, intra-nigral administration of SB-334867 similarly restored goal-directed behaviour, thereby implicating the substantia nigra as an important site for this effect. This study demonstrates that targeting ORX-R1 reduces habitual food seeking in male rats which may be important for understanding and treating compulsive feeding, obesity and binge eating disorder. This study also implicates the lateral hypothalamus, where ORX is produced, in mediating the expression of habits for the first time, and thus extends on the neurocircuits known to regulate habitual actions. Further investigation is required to determine whether the same effects are also seen in female rats, given that there are recognised sexual dimorphisms in feeding behaviour and a higher incidence of disordered eating in female than male populations.

Hippocampus-Prefrontal Coupling Regulates Recognition Memory for Novelty Discrimination.

Recognition memory provides the ability to distinguish familiar from novel objects and places, and is important for recording and updating events to guide appropriate behavior. The hippocampus (HPC) and medial prefrontal cortex (mPFC) have both been implicated in recognition memory, but the nature of HPC-mPFC interactions, and its impact on local circuits in mediating this process is not known. Here we show that novelty discrimination is accompanied with higher theta activity (4-10 Hz) and increased c-Fos expression in both these regions. Moreover, theta oscillations were highly coupled between the HPC and mPFC during recognition memory retrieval for novelty discrimination, with the HPC leading the mPFC, but not during initial learning. Principal neurons and interneurons in the mPFC responded more strongly during recognition memory retrieval compared with learning. Optogenetic silencing of HPC input to the mPFC disrupted coupled theta activity between these two structures, as well as the animals' (male Sprague Dawley rats) ability to differentiate novel from familiar objects. These results reveal a key role of monosynaptic connections between the HPC and mPFC in novelty discrimination via theta coupling and identify neural populations that underlie this recognition memory-guided behavior.SIGNIFICANCE STATEMENT Many memory processes are highly dependent on the interregional communication between the HPC and mPFC via neural oscillations. However, how these two brain regions coordinate their oscillatory activity to engage local neural populations to mediate recognition memory for novelty discrimination is poorly understood. This study revealed that the HPC and mPFC theta oscillations and their temporal coupling is correlated with recognition memory-guided behavior. During novel object recognition, the HPC drives mPFC interneurons to effectively reduce the activity of principal neurons. This study provides the first evidence for the requirement of the HPC-mPFC pathway to mediate recognition memory for novelty discrimination and describes a mechanism for how this memory is regulated.

A direct interareal feedback-to-feedforward circuit in primate visual cortex.

The mammalian sensory neocortex consists of hierarchically organized areas reciprocally connected via feedforward (FF) and feedback (FB) circuits. Several theories of hierarchical computation ascribe the bulk of the computational work of the cortex to looped FF-FB circuits between pairs of cortical areas. However, whether such corticocortical loops exist remains unclear. In higher mammals, individual FF-projection neurons send afferents almost exclusively to a single higher-level area. However, it is unclear whether FB-projection neurons show similar area-specificity, and whether they influence FF-projection neurons directly or indirectly. Using viral-mediated monosynaptic circuit tracing in macaque primary visual cortex (V1), we show that V1 neurons sending FF projections to area V2 receive monosynaptic FB inputs from V2, but not other V1-projecting areas. We also find monosynaptic FB-to-FB neuron contacts as a second motif of FB connectivity. Our results support the existence of FF-FB loops in primate cortex, and suggest that FB can rapidly and selectively influence the activity of incoming FF signals.

Stream-specific feedback inputs to the primate primary visual cortex.

The sensory neocortex consists of hierarchically-organized areas reciprocally connected via feedforward and feedback circuits. Feedforward connections shape the receptive field properties of neurons in higher areas within parallel streams specialized in processing specific stimulus attributes. Feedback connections have been implicated in top-down modulations, such as attention, prediction and sensory context. However, their computational role remains unknown, partly because we lack knowledge about rules of feedback connectivity to constrain models of feedback function. For example, it is unknown whether feedback connections maintain stream-specific segregation, or integrate information across parallel streams. Using viral-mediated labeling of feedback connections arising from specific cytochrome-oxidase stripes of macaque visual area V2, here we show that feedback to the primary visual cortex (V1) is organized into parallel streams resembling the reciprocal feedforward pathways. This suggests that functionally-specialized V2 feedback channels modulate V1 responses to specific stimulus attributes, an organizational principle potentially extending to feedback pathways in other sensory systems.

Orientation Preference Maps in Microcebus murinus Reveal Size-Invariant Design Principles in Primate Visual Cortex.

Orientation preference maps (OPMs) are a prominent feature of primary visual cortex (V1) organization in many primates and carnivores. In rodents, neurons are not organized in OPMs but are instead interspersed in a "salt and pepper" fashion, although clusters of orientation-selective neurons have been reported. Does this fundamental difference reflect the existence of a lower size limit for orientation columns (OCs) below which they cannot be scaled down with decreasing V1 size? To address this question, we examined V1 of one of the smallest living primates, the 60-g prosimian mouse lemur (Microcebus murinus). Using chronic intrinsic signal imaging, we found that mouse lemur V1 contains robust OCs, which are arranged in a pinwheel-like fashion. OC size in mouse lemurs was found to be only marginally smaller compared to the macaque, suggesting that these circuit elements are nearly incompressible. The spatial arrangement of pinwheels is well described by a common mathematical design of primate V1 circuit organization. In order to accommodate OPMs, we found that the mouse lemur V1 covers one-fifth of the cortical surface, which is one of the largest V1-to-cortex ratios found in primates. These results indicate that the primate-type visual cortical circuit organization is constrained by a size limitation and raises the possibility that its emergence might have evolved by disruptive innovation rather than gradual change.

Age-Specific Retinal and Cerebral Immunodetection of Amyloid-ß Plaques and Oligomers in a Rodent Model of Alzheimer's Disease.

BACKGROUND: Amyloid-ß soluble oligomers (Aßo) are believed to be the cause of the pathophysiology underlying Alzheimer's disease (AD) and are normally detected some two decades before clinical onset of the disease. Retinal pathology associated with AD pathogenesis has previously been reported, including ganglion cell loss, accumulation of Aß deposits in the retina, and reduction of nerve fiber layer thickness as well as abnormalities of the microvasculature. OBJECTIVE: This study's aim is to better understand the relationship between brain and retinal Aßo deposition and in particular to quantify levels of the toxic Aßo as a function of age in the retina of a rodent model of AD. METHODS: Retinas and brain tissue from 5×FAD mice were stained with Congo red, Thioflavin-T (Th-T), and Aß plaque-specific and Aßo-specific antibodies. RESULTS: We show that retinas displayed an age-dependent increase of Th-T-specific amyloid fibrils. Staining with anti-Aß antibody confirmed the presence of the Aß plaques in all 5×FAD retinas tested. In contrast, staining with anti-Aßo antibody showed an age-dependent decrease of retinal Aßo. Of note, Aßo was observed mainly in the retinal nuclear layers. Finally, we confirmed the localization of Aßo to neurons, typically accumulating in late endosomes, indicating possible impairment of the endocytic pathway. CONCLUSION: Our results demonstrate the presence of intraneuronal Aßo in the retina and its accumulation inversely correlated with retinal Aß plaque deposition, indicating an age-related conversion in this animal model. These results support the development of an early AD diagnostic test targeting Aßo in the eye.

Distinct Laminar Processing of Local and Global Context in Primate Primary Visual Cortex.

Visual perception is affected by spatial context. In visual cortex, neuronal responses to stimuli inside the receptive field (RF) are suppressed by stimuli in the RF surround. To understand the circuits and cortical layers processing spatial context, we simultaneously recorded across all layers of macaque primary visual cortex while presenting stimuli at increasing distances from the recorded cells' RF. We find that near versus far-surround stimuli activate distinct layers, thus revealing unique laminar contributions to the processing of local and global spatial context. Stimuli in the near-surround evoke the earliest subthreshold responses in superficial and upper-deep layers, and earliest suppression of spiking responses in superficial layers. Conversely, far-surround stimuli evoke the earliest subthreshold responses in feedback-recipient layer 1 and lower-deep layers, and earliest suppression of spiking responses almost simultaneously in all layers, except 4C, where suppression emerges last. Our results suggest distinct circuits for local and global signal integration.

Top-down feedback controls spatial summation and response amplitude in primate visual cortex.

Sensory information travels along feedforward connections through a hierarchy of cortical areas, which, in turn, send feedback connections to lower-order areas. Feedback has been implicated in attention, expectation, and sensory context, but the mechanisms underlying these diverse feedback functions are unknown. Using specific optogenetic inactivation of feedback connections from the secondary visual area (V2), we show how feedback affects neural responses in the primate primary visual cortex (V1). Reducing feedback activity increases V1 cells' receptive field (RF) size, decreases their responses to stimuli confined to the RF, and increases their responses to stimuli extending into the proximal surround, therefore reducing surround suppression. Moreover, stronger reduction of V2 feedback activity leads to progressive increase in RF size and decrease in response amplitude, an effect predicted by a recurrent network model. Our results indicate that feedback modulates RF size, surround suppression and response amplitude, similar to the modulatory effects of visual spatial attention.

Utah optrode array customization using stereotactic brain atlases and 3-D CAD modeling for optogenetic neocortical interrogation in small rodents and nonhuman primates.

As the optogenetic field expands, the need for precise targeting of neocortical circuits only grows more crucial. This work demonstrates a technique for using Solidworks® computer-aided design (CAD) and readily available stereotactic brain atlases to create a three-dimensional (3-D) model of the dorsal region of area visual cortex 4 (V4D) of the macaque monkey (Macaca fascicularis) visual cortex. The 3-D CAD model of the brain was used to customize an [Formula: see text] Utah optrode array (UOA) after it was determined that a high-density ([Formula: see text]) UOA caused extensive damage to marmoset (Callithrix jacchus) primary visual cortex as assessed by electrophysiological recording of spiking activity through a 1.5-mm-diameter through glass via. The [Formula: see text] UOA was customized for optrode length ([Formula: see text]), optrode width ([Formula: see text]), optrode pitch ([Formula: see text]), backplane thickness ([Formula: see text]), and overall form factor ([Formula: see text]). Two [Formula: see text] UOAs were inserted into layer VI of macaque V4D cortices with minimal damage as assessed in fixed tissue cytochrome oxidase staining in nonrecoverable surgeries. Additionally, two [Formula: see text] arrays were implanted in mice (Mus musculus) motor cortices, providing early evidence for long-term tolerability (over 6 months), and for the ability to integrate the UOA with a Holobundle light delivery system toward patterned optogenetic stimulation of cortical networks.

Circuits and Mechanisms for Surround Modulation in Visual Cortex.

Surround modulation (SM) is a fundamental property of sensory neurons in many species and sensory modalities. SM is the ability of stimuli in the surround of a neuron's receptive field (RF) to modulate (typically suppress) the neuron's response to stimuli simultaneously presented inside the RF, a property thought to underlie optimal coding of sensory information and important perceptual functions. Understanding the circuit and mechanisms for SM can reveal fundamental principles of computations in sensory cortices, from mouse to human. Current debate is centered over whether feedforward or intracortical circuits generate SM, and whether this results from increased inhibition or reduced excitation. Here we present a working hypothesis, based on theoretical and experimental evidence, that SM results from feedforward, horizontal, and feedback interactions with local recurrent connections, via synaptic mechanisms involving both increased inhibition and reduced recurrent excitation. In particular, strong and balanced recurrent excitatory and inhibitory circuits play a crucial role in the computation of SM.

Two projection streams from macaque V1 to the pale cytochrome oxidase stripes of V2.

In the primate visual cortex, areas V1 and V2 distribute information they receive from the retina to virtually all extrastriate cortex, parsing this information into dorsal and ventral streams. Therefore, understanding the connectivity between V1 and V2 is crucial to understand visual cortical processing. Cytochrome oxidase staining in V2 reveals a repeating pattern of pale-thick-pale-thin stripes. V1 sends parallel output pathways to distinct V2 stripes. Previous models proposed either three or two parallel V1-to-V2 pathways in macaque, but both models viewed the two pale stripes within a single stripe cycle as a single compartment. However, recent studies have suggested that the two pale stripes may be functionally distinct, and in marmosets they also differ anatomically in the laminar origin of projections they receive from V1. Here we have asked whether the two pale stripes are also anatomically distinct in macaque. We made small retrograde tracer injections in different pale stripe types. We found that while both pale stripes receive a predominant V1 input from layers 2/3, only one set of pale stripes (pale lateral) receives significant projections from layer 4B, while the other set (pale medial) receives few or no layer 4B projections. Moreover, different tracer injections in nearby pale stripe types revealed that 97-99% of layer 2/3 cells only project to a single pale stripe type. These results demonstrate that in macaque, the two pale stripes are anatomically distinct compartments, and support the notion of two distinct projection streams from V1 to the two pale stripes of V2.

Deletion of Ten-m3 induces the formation of eye dominance domains in mouse visual cortex.

The visual system is characterized by precise retinotopic mapping of each eye, together with exquisitely matched binocular projections. In many species, the inputs that represent the eyes are segregated into ocular dominance columns in primary visual cortex (V1), whereas in rodents, this does not occur. Ten-m3, a member of the Ten-m/Odz/Teneurin family, regulates axonal guidance in the retinogeniculate pathway. Significantly, ipsilateral projections are expanded in the dorsal lateral geniculate nucleus and are not aligned with contralateral projections in Ten-m3 knockout (KO) mice. Here, we demonstrate the impact of altered retinogeniculate mapping on the organization and function of V1. Transneuronal tracing and c-fos immunohistochemistry demonstrate that the subcortical expansion of ipsilateral input is conveyed to V1 in Ten-m3 KOs: Ipsilateral inputs are widely distributed across V1 and are interdigitated with contralateral inputs into eye dominance domains. Segregation is confirmed by optical imaging of intrinsic signals. Single-unit recording shows ipsilateral, and contralateral inputs are mismatched at the level of single V1 neurons, and binocular stimulation leads to functional suppression of these cells. These findings indicate that the medial expansion of the binocular zone together with an interocular mismatch is sufficient to induce novel structural features, such as eye dominance domains in rodent visual cortex.

Ten_m3 regulates eye-specific patterning in the mammalian visual pathway and is required for binocular vision.

Binocular vision requires an exquisite matching of projections from each eye to form a cohesive representation of the visual world. Eye-specific inputs are anatomically segregated, but in register in the visual thalamus, and overlap within the binocular region of primary visual cortex. Here, we show that the transmembrane protein Ten_m3 regulates the alignment of ipsilateral and contralateral projections. It is expressed in a gradient in the developing visual pathway, which is consistently highest in regions that represent dorsal visual field. Mice that lack Ten_m3 show profound abnormalities in mapping of ipsilateral, but not contralateral, projections, and exhibit pronounced deficits when performing visually mediated behavioural tasks. It is likely that the functional deficits arise from the interocular mismatch, because they are reversed by acute monocular inactivation. We conclude that Ten_m3 plays a key regulatory role in the development of aligned binocular maps, which are required for normal vision.