Novel stimuli evoke excess activity in the mouse primary visual cortex

To explore how neural circuits represent novel versus familiar inputs, we presented mice with repeated sets of images with novel images sparsely substituted. Using two-photon calcium imaging to record from layer 2/3 neurons in the mouse primary visual cortex, we found that novel images evoked excess activity in the majority of neurons. This novelty response rapidly emerged, arising with a time constant of 2.6 ± 0.9 s. When a new image set was repeatedly presented, a majority of neurons had similarly elevated activity for the first few presentations, which decayed to steady state with a time constant of 1.4 ± 0.4 s. When we increased the number of images in the set, the novelty response’s amplitude decreased, defining a capacity to store ∼15 familiar images under our conditions. These results could be explained quantitatively using an adaptive subunit model in which presynaptic neurons have individual tuning and gain control. This result shows that local neural circuits can create different representations for novel versus familiar inputs using generic, widely available mechanisms.

Because the behavioral consequences of a sensory stimulus can depend on whether that stimulus is novel or familiar, sensory systems can benefit from employing different representations of novel versus familiar stimuli. At the level of human psychophysics, stimulus novelty can enhance salience and capture attention (1–3), while familiarity can speed visual search (4). Novelty also affects aversive conditioning (5–7) and fear conditioning (8, 9). In human brain imaging, novel stimuli have been shown to generate the mismatch negativity (MMN) (10, 11) while repeated stimuli lead to repetition suppression (12). Explicit representation of novelty has been shown at higher stages of the sensory hierarchy, such as in the hippocampus (13) and inferotemporal cortex (14–16), and has been interpreted as a possible substrate of recognition memory (17). Lower in sensory hierarchies, the representation of novelty can be enhanced by stimulus-specific adaptation (SSA) (18–21) as well as by gain control (22, 23). Novelty signals are also prominently present in midbrain dopamine neurons (24).Explicit representation of stimulus novelty is also related to theories of predictive coding, in which neural circuits carry out computations that emphasize novel or surprising information. Theories of predictive coding have had a long history, starting with ideas about how the receptive field structure of retinal ganglion cells more efficiently encodes natural visual scenes by removing redundant data (25–28) and including the idea that active adaptation may aid in this process (18). Theories of predictive coding in the neocortex have typically focused on the idea that feedback from higher cortical areas encodes a prediction about lower-level sensory data (29) that is subtracted from the lower-level representation, so that the signals traveling up the cortical hierarchy represent surprise or novelty (30, 31). However, a recent study failed to find these signatures of predictive coding (32).Here, we investigate novelty processing in the mouse primary visual cortex. We repeatedly presented a set of images, each composed of a random superposition of Gabor functions, and then occasionally presented novel images drawn from the same ensemble. Using two-photon imaging of the Ca²⁺ sensor GCaMP6f to measure neural activity in layer 2/3 of awake, head-fixed mice (33), we found that the majority of neurons exhibited excess activity in response to a novel image. This distinction between novel versus familiar images was quickly reached, emerging with a time constant of 2.6 ± 0.9 s. Similarly, when we began presenting a new set of images, a majority of the neurons exhibited elevated firing that relaxed to a steady state with a time constant of 1.4 ± 0.4 s. When we presented novel images within larger image sets, the amplitude of novelty response decreased, defining a capacity of the system to encode ∼15 familiar images. All of these findings could be explained qualitatively using an adaptive subunit model in which neurons presynaptic to a recorded neuron have both individual tuning to visual stimuli and adaptive gain control.     

A theory of direction selectivity for macaque primary visual cortex

This paper offers a theory for the origin of direction selectivity (DS) in the macaque primary visual cortex, V1. DS is essential for the perception of motion and control of pursuit eye movements. In the macaque visual pathway, neurons with DS first appear in V1, in the Simple cell population of the Magnocellular input layer 4Cα. The lateral geniculate nucleus (LGN) cells that project to these cortical neurons, however, are not direction selective. We hypothesize that DS is initiated in feed-forward LGN input, in the summed responses of LGN cells afferent to a cortical cell, and it is achieved through the interplay of 1) different visual response dynamics of ON and OFF LGN cells and 2) the wiring of ON and OFF LGN neurons to cortex. We identify specific temporal differences in the ON/OFF pathways that, together with item 2, produce distinct response time courses in separated subregions; analysis and simulations confirm the efficacy of the mechanisms proposed. To constrain the theory, we present data on Simple cells in layer 4Cα in response to drifting gratings. About half of the cells were found to have high DS, and the DS was broadband in spatial and temporal frequency (SF and TF). The proposed theory includes a complete analysis of how stimulus features such as SF and TF interact with ON/OFF dynamics and LGN-to-cortex wiring to determine the preferred direction and magnitude of DS.

This paper proposes a solution to a longstanding question in visual neuroscience, namely, the origin of direction selectivity (DS) in the visual cortex of macaque monkeys. Motion perception is a vital visual capability well developed in primates. As perceiving motion requires perceiving the direction in which a target moves, DS, the ability of visual neurons to sense the direction of movement, is essential for motion perception (1) and for the control of pursuit eye movements (2). For these reasons, understanding DS is an important first step toward understanding how the cortex processes motion signals.DS in cortical neurons was first documented in the cat (3). Since then, it has been found in neurons all along the visual dorsal stream (an area associated with motion processing) in primates like macaque monkeys (4–7), whose vision is like that of humans. Neurons with DS are, in fact, present across species; they are widespread among visual mammals, an experimental fact that testifies to their biological significance.In the visual pathway of macaques, DS appears first in the primary visual cortex (V1), in the Simple cell population of the input layer 4Cα (8). These neurons provide feed-forward direction-selective signals to subsequent cortical layers and brain regions in the dorsal pathway. Thus, to discover the origin of DS, one is led to examining how neurons in layer 4Cα acquire their DS—and that is where it gets interesting: The neurons that provide visual signals to layer 4Cα, the Magnocellular cells in the lateral geniculate nucleus (LGN), are not direction selective (9–12). Yet many of the cells in the input layer of V1 to which they project are direction selective. A fundamental scientific question, therefore, is how 4Cα neurons acquire their DS. That is the question we would like to answer in this paper.Although many papers have been written on DS since its discovery over half a century ago, and there is continued interest in the subject (13–16), no satisfactory mechanistic explanation for the origin of DS in primate cortex has been proposed before now: Early conceptual models of how DS may arise, such as the Reichardt multiplier (17) or the motion energy model (18), were not concerned with biological mechanisms. Later work proposed neural mechanisms for the motion energy model (19), but they are not sufficient for explaining DS in primate cortex. See Discussion for comparisons of different model mechanisms.It is widely accepted that the DS computation requires spatiotemporal inseparability (STI); that is, different subregions of the receptive field have different time courses of response (18, 20, 21). What were lacking were biological mechanisms that could produce STI, and a clear understanding of how DS depends on the interaction between STI and the spatial and temporal character of the visual stimulus. These are the issues we address in this paper.We hypothesize that a plausible biological mechanism is the interplay between 1) the different dynamics of ON and OFF LGN cells and 2) the specific wiring that connects ON and OFF cells to V1. Item 2 refers here to the well-known fact that OFF and ON LGN cells are wired to segregated V1 receptive field subregions (3, 22, 23). Our main contribution is item 1: We identify, in Results, dynamic differences in the ON/OFF pathways that, together with item 2, produce distinct response time courses in separated receptive-field subregions. The mechanisms we propose are biologically grounded, and, as we show, they are sufficient for initiating DS in the feed-forward LGN input to cortical cells.To constrain our theory, we present experimental results on the responses of macaque 4Cα Simple cells to drifting gratings. Most Simple cells we recorded in 4Cα were unambiguously direction selective, preferring, consistently, the same direction over their entire visible ranges of spatial frequency (SF) and temporal frequency (TF); about half of the cells had high DS. Our data reveal also an important characteristic of neurons with DS, namely, the approximate invariance of DS with SF and TF. Explaining the broadband character of DS (in TF and SF) is a challenge for all previous theories. Our theory includes a complete analysis of how stimulus features like SF and TF interact with ON/OFF dynamics and LGN-to-cortex wiring to explain the broadband character of DS. The theoretical predictions are in good agreement with data.With regard to broader implications, although the theory as described in this paper is specifically about DS, an important message is that, when combining information from multiple channels, slight biases in their temporal filters can greatly enhance the capability of a system. Thus, it may be possible to exploit the temporal axis further in the processing of biological and nonbiological signals, especially in the neural processing of sensory inputs and, possibly, in computer vision.     

Intermittent and rhythmic exposure to melatonin in primary cultured adipocytes enhances the insulin and dexamethasone effects on leptin expression

Considering the cyclic characteristic of production and secretion of pineal melatonin, it is reasonable to assume that this oscillation might be important in determining the variety of its circadian and seasonal effects. To simulate this physiological condition in vitro, isolated adipocytes were exposed to melatonin in a circadian-like pattern by adding the hormone to the incubating medium during 12 hr (mimicking the night), followed by an equal period without melatonin (mimicking the day). This intermittent procedure was interrupted when three cycles with melatonin were fulfilled (60-hr incubation). Here, we report the effects of melatonin (1 nM) added intermittently or continuously to the incubating medium alone or in combination with insulin (5 nM) and/or dexamethasone (7 nM) on leptin release and expression by rat adipocytes. After acute 12-hr incubation neither melatonin nor insulin alone affected leptin expression, but together they increased it by 105%. Dexamethasone increased leptin mRNA content and release (70%) but this effect was not enhanced by melatonin. Nevertheless, after 60 hr under intermittent melatonin, we observed a synergism between melatonin and dexamethasone. This interaction promoted an increment (75% compared with dexamethasone alone) in leptin release and expression. Our results suggest that circadian-like exposure to melatonin potentiates the dexamethasone action and is important to the effects promoted by insulin on leptin expression. Based on an in vitro approach, this work helps to clarify the physiological relevance and the repercussions of the in vivo circadian pattern of melatonin secretion.     

Decoding stimulus features in primate somatosensory cortex during perceptual categorization

Neurons of the primary somatosensory cortex (S1) respond as functions of frequency or amplitude of a vibrotactile stimulus. However, whether S1 neurons encode both frequency and amplitude of the vibrotactile stimulus or whether each sensory feature is encoded by separate populations of S1 neurons is not known, To further address these questions, we recorded S1 neurons while trained monkeys categorized only one sensory feature of the vibrotactile stimulus: frequency, amplitude, or duration. The results suggest a hierarchical encoding scheme in S1: from neurons that encode all sensory features of the vibrotactile stimulus to neurons that encode only one sensory feature. We hypothesize that the dynamic representation of each sensory feature in S1 might serve for further downstream processing that leads to the monkey’s psychophysical behavior observed in these tasks.A vibrotactile stimulus is composed of both frequency and amplitude, indicating that there is dependency between the two sensory features. In principle, this dependency could be dissociated, by quantifying the psychophysical behavior and neuronal responses as functions of the stimulus amplitude while maintaining fixed the stimulus frequency and vice versa. For example, in a vibrotactile detection task, monkeys detected the stimulus amplitude and the recorded S1 neurons increased their firing rates as a function of the stimulus amplitude and correlated with the animal’s psychophysical performance (1). Also, in a vibrotactile discrimination task, monkeys discriminated the difference in frequency between two consecutive vibrotactile stimuli and the recorded S1 neurons increased their firing rates as a function of the stimulus frequency and correlated with the animal’s psychophysical performance (2). The question is: Do S1 neurons encode both stimulus amplitude and frequency of the vibrotactile stimulus, or is each stimulus feature encoded by separate populations of neurons?Although this question appears simple to address, complexities arise. For example, recent studies have suggested that S1 neurons encode the mean velocity of the vibrotactile stimulus, which is the product of both stimulus amplitude and frequency (3). Also, in psychophysical experiments, humans reported changes in the perceived intensity of the stimulus as a function of amplitude or frequency (4), and the recorded S1 neurons in anesthetized rats indicated that their responses are associated with the mean velocity of the stimulus (5). These results show that there is an interaction between the two stimulus features and suggest that for a certain range of frequencies, it is almost impossible to distinguish between two stimulus frequencies when the intensities of the two stimuli are perceived of the same magnitude (6–8).Therefore, we need further experiments in which S1 neurons are recorded when a subject performs a vibrotactile task as a function of the stimulus amplitude or as a function of the stimulus frequency. Such experiments could provide meaningful information on the encoding capacities of S1 neurons during these tasks. Also, it has been shown that the stimulus duration can bias discrimination performance, but it is not clear how this variable affects vibrotactile discrimination (9).In this work, we show the encoding capacities of single S1 neurons while trained monkeys categorized only one sensory feature of the vibrotactile stimulus: frequency, amplitude, or duration. The results suggest a hierarchical encoding scheme in S1: from neurons that encode all of the sensory features of the vibrotactile stimulus to neurons that encode only one sensory feature. Furthermore, the S1 neurons that encoded each sensory feature correlated with the animals’ categorization behavior.     

Learning reward timing in cortex through reward dependent expression of synaptic plasticity

The ability to represent time is an essential component of cognition but its neural basis is unknown. Although extensively studied both behaviorally and electrophysiologically, a general theoretical framework describing the elementary neural mechanisms used by the brain to learn temporal representations is lacking. It is commonly believed that the underlying cellular mechanisms reside in high order cortical regions but recent studies show sustained neural activity in primary sensory cortices that can represent the timing of expected reward. Here, we show that local cortical networks can learn temporal representations through a simple framework predicated on reward dependent expression of synaptic plasticity. We assert that temporal representations are stored in the lateral synaptic connections between neurons and demonstrate that reward-modulated plasticity is sufficient to learn these representations. We implement our model numerically to explain reward-time learning in the primary visual cortex (V1), demonstrate experimental support, and suggest additional experimentally verifiable predictions.     

Visual cortex changes in children with sickle cell disease and normal visual acuity: a multimodal magnetic resonance imaging study

The visual system is primarily affected in sickle cell disease (SCD), and eye examination is recommended starting in late childhood. So far, to our knowledge, all studies have focused on the retina, neglecting the changes that might be present in the cortical portion of the visual system. We performed a multimodal magnetic resonance imaging (MRI) evaluation of the visual cortex in 25 children with SCD (mean age: 12·3 ± 1·9 years) and 31 controls (mean age: 12·7 ± 1·6 years). At ophthalmologic examination, 3/25 SCD children had mild visual acuity deficits and 2/25 had mild tortuosity of the retinal vessels. None showed optic pathway infarcts at MRI or Transcranial Doppler abnormal blood velocities, and 6/25 disclosed posterior cerebral artery stenosis (five mild and one severe) at MR‐angiography. Compared to controls, SCD children had increased posterior pericalcarine cortical thickness, with a different trajectory of cortical maturation and decreased connectivity within medial and ventral visual neural networks. Our findings suggest that SCD affects the development and the tuning of the visual cortex, leading to anatomical and functional changes in childhood even in the absence of retinopathy, and set the basis for future studies to determine if these changes can represent useful predictors of visual impairment in adulthood, biomarkers of disease progression or treatment response.     

Rapid recurrent processing gates awareness in primary visual cortex

Visual awareness has been proposed to depend on recurrent processing in early visual cortex areas including the primary visual cortex (V1). Here, we address this hypothesis with high spatiotemporal resolution magnetoencephalographic recordings in subjects performing a substitution masking paradigm. Neural activity reflecting awareness is assessed by directly comparing the neuromagnetic response elicited by effectively and ineffectively masked targets after the proportion of trials leading to masking was individually adjusted to match the proportion of trials without masking. This revealed a modulation of recurrent activity in the primary visual cortex rapidly after the onset of the feedforward sweep of processing in striate and extrastriate areas but significantly before the onset of attention-dependent recurrent modulations in V1. Our data provide direct support for the notion that (i) recurrent processing in V1 correlates with visual awareness and (ii) that attention and awareness involve distinct recurrent processing operations.     

Visual grouping in human parietal cortex

To efficiently extract visual information from complex visual scenes to guide behavior and thought, visual input needs to be organized into discrete units that can be selectively attended and processed. One important such selection unit is visual objects. A crucial factor determining object-based selection is the grouping between visual elements. Although human lesion data have pointed to the importance of the parietal cortex in object-based representations, our understanding of these parietal mechanisms in normal human observers remains largely incomplete. Here we show that grouped shapes elicited lower functional MRI (fMRI) responses than ungrouped shapes in inferior intraparietal sulcus (IPS) even when grouping was task-irrelevant. This relative ease of representing grouped shapes allowed more shape information to be passed onto later stages of visual processing, such as information storage in superior IPS, and may explain why grouped visual elements are easier to perceive than ungrouped ones after parietal brain lesions. These results are discussed within a neural object file framework, which argues for distinctive neural mechanisms supporting object individuation and identification in visual perception.     

Microstimulation reveals specialized subregions for different complex movements in posterior parietal cortex of prosimian galagos

Posterior parietal cortex of prosimian galagos consists of a caudal half characterized by connections with visual cortex and a rostral half connected with motor, premotor, and visuomotor areas of frontal cortex. When 500-ms trains of electrical pulses were used to stimulate microelectrode sites throughout posterior parietal cortex, movements were elicited only from the rostral half. The movement zone reflected an overall pattern of somatotopy, from eye and face movements most ventrally to hindlimb movements most dorsally. In addition, subregions or zones of this movement cortex seemed to be devoted to components of different, ethologically significant behaviors. Thus, microstimulation within separate zones of cortex elicited reaching, hand-to-mouth, defensive, or aggressive movements. The finding of similar classes of elicited movement patterns from frontal and more recently intraparietal cortex of macaques suggests that multiareal circuits for biologically significant behaviors are components of all primate brains and that these circuits can be activated by long trains of current pulses at rostral locations in posterior parietal cortex.     

Active encoding of decisions about stimulus absence in primate prefrontal cortex neurons

Judging the presence or absence of a stimulus is likely the most basic perceptual decision. A fundamental difference of detection tasks in contrast to discrimination tasks is that only the stimulus presence decision can be inferred from sensory evidence, whereas the alternative decision about stimulus absence lacks sensory evidence by definition. Detection decisions have been studied in an intentional, action-based framework, in which decisions were regarded as intentions to pursue particular actions. These studies have found that only stimulus-present decisions are actively encoded by neurons, whereas the decision about the absence of a stimulus does not affect default neuronal responses. We tested whether this processing mechanism also holds for abstract detection decisions that are dissociated from motor preparation. We recorded single-neuron activity from the prefrontal cortex (PFC) of monkeys performing a visual detection task that forced a report-independent decision. We not only found neurons that actively encoded the subjective decision of monkeys about the presence of a stimulus, but also cells responding actively for the decision about the absence of stimuli. These results suggest that abstract detection decisions are processed in a different way compared with the previously reported action-based decisions. In a report-independent framework, neuronal networks seem to generate a second set of neurons actively encoding the absence of sensory stimulation, thus translating decisions into abstract categories. This mechanism may allow the brain to "buffer" a decision in a nonmovement-related framework.     

Spatiotemporal object continuity in human ventral visual cortex

Coherent visual experience requires that objects be represented as the same persisting individuals over time and motion. Cognitive science research has identified a powerful principle that guides such processing: Objects must trace continuous paths through space and time. Little is known, however, about how neural representations of objects, typically defined by visual features, are influenced by spatiotemporal continuity. Here, we report the consequences of spatiotemporally continuous vs. discontinuous motion on perceptual representations in human ventral visual cortex. In experiments using both dynamic occlusion and apparent motion, face-selective cortical regions exhibited significantly less activation when faces were repeated in continuous vs. discontinuous trajectories, suggesting that discontinuity caused featurally identical objects to be represented as different individuals. These results indicate that spatiotemporal continuity modulates neural representations of object identity, influencing judgments of object persistence even in the most staunchly "featural" areas of ventral visual cortex.     

Large-scale dissociations between views of objects,scenes, and reachable-scale environments in visual cortex

Space-related processing recruits a network of brain regions separate from those recruited in object processing. This dissociation has largely been explored by contrasting views of navigable-scale spaces to views of close-up, isolated objects. However, in naturalistic visual experience, we encounter spaces intermediate to these extremes, like the tops of desks and kitchen counters, which are not navigable but typically contain multiple objects. How are such reachable-scale views represented in the brain? In three human functional neuroimaging experiments, we find evidence for a large-scale dissociation of reachable-scale views from both navigable scene views and close-up object views. Three brain regions were identified that showed a systematic response preference to reachable views, located in the posterior collateral sulcus, the inferior parietal sulcus, and superior parietal lobule. Subsequent analyses suggest that these three regions may be especially sensitive to the presence of multiple objects. Further, in all classic scene and object regions, reachable-scale views dissociated from both objects and scenes with an intermediate response magnitude. Taken together, these results establish that reachable-scale environments have a distinct representational signature from both scene and object views in visual cortex.     

Effects of cholinergic deafferentation of the rhinal cortex on visual recognition memory in monkeys

Excitotoxic lesion studies have confirmed that the rhinal cortex is essential for visual recognition ability in monkeys. To evaluate the mnemonic role of cholinergic inputs to this cortical region, we compared the visual recognition performance of monkeys given rhinal cortex infusions of a selective cholinergic immunotoxin, ME20.4-SAP, with the performance of monkeys given control infusions into this same tissue. The immunotoxin, which leads to selective cholinergic deafferentation of the infused cortex, yielded recognition deficits of the same magnitude as those produced by excitotoxic lesions of this region, providing the most direct demonstration to date that cholinergic activation of the rhinal cortex is essential for storing the representations of new visual stimuli and thereby enabling their later recognition.     

Laminar and columnar auditory cortex in avian brain

The mammalian neocortex mediates complex cognitive behaviors, such as sensory perception, decision making, and language. The evolutionary history of the cortex, and the cells and circuitry underlying similar capabilities in nonmammals, are poorly understood, however. Two distinct features of the mammalian neocortex are lamination and radially arrayed columns that form functional modules, characterized by defined neuronal types and unique intrinsic connections. The seeming inability to identify these characteristic features in nonmammalian forebrains with earlier methods has often led to the assumption of uniqueness of neocortical cells and circuits in mammals. Using contemporary methods, we demonstrate the existence of comparable columnar functional modules in laminated auditory telencephalon of an avian species (Gallus gallus). A highly sensitive tracer was placed into individual layers of the telencephalon within the cortical region that is similar to mammalian auditory cortex. Distribution of anterograde and retrograde transportable markers revealed extensive interconnections across layers and between neurons within narrow radial columns perpendicular to the laminae. This columnar organization was further confirmed by visualization of radially oriented axonal collaterals of individual intracellularly filled neurons. Common cell types in birds and mammals that provide the cellular substrate of columnar functional modules were identified. These findings indicate that laminar and columnar properties of the neocortex are not unique to mammals and may have evolved from cells and circuits found in more ancient vertebrates. Specific functional pathways in the brain can be analyzed in regard to their common phylogenetic origins, which introduces a previously underutilized level of analysis to components involved in higher cognitive functions.     

The time course and specificity of perceptual deterioration

Repeated within-day testing on a texture discrimination task leads to retinotopically specific decreases in performance. Although perceptual learning has been shown to be highly specific to the retinotopic location and characteristics of the trained stimulus, the specificity of perceptual deterioration has not been studied. We investigated the similarities between learning and deterioration by examining whether deterioration transfers to new distractor or target orientations or to the untrained eye. Participants performed a texture discrimination task in three one-hour sessions. We tested the specificity of deterioration in the final session by switching either the orientation of the background or the target elements by 90 degrees. We found that performance deteriorated steadily both within and across the first two sessions and was specific to the target but not the distractor orientation. In a separate experiment, we found that deterioration transferred to the untrained eye. Changes in performance were independent of reported sleepiness and awareness of stimulus changes, arguing against the possibility that perceptual deterioration is due to general fatigue. Rather, we hypothesize that perceptual deterioration may be caused by changes in the ability for attention to selectively enhance the responses of relatively low-level orientation-selective sensory neurons, possibly within the primary visual cortex. Further, the differences in specificity profiles between learning and deterioration suggest separate underlying mechanisms that occur within the same cortical area.     

Associative learning shapes the neural code for stimulus magnitude in primary auditory cortex

Since the dawn of experimental psychology, researchers have sought an understanding of the fundamental relationship between the amplitude of sensory stimuli and the magnitudes of their perceptual representations. Contemporary theories support the view that magnitude is encoded by a linear increase in firing rate established in the primary afferent pathways. In the present study, we have investigated sound intensity coding in the rat primary auditory cortex (AI) and describe its plasticity by following paired stimulus reinforcement and instrumental conditioning paradigms. In trained animals, population-response strengths in AI became more strongly nonlinear with increasing stimulus intensity. Individual AI responses became selective to more restricted ranges of sound intensities and, as a population, represented a broader range of preferred sound levels. These experiments demonstrate that the representation of stimulus magnitude can be powerfully reshaped by associative learning processes and suggest that the code for sound intensity within AI can be derived from intensity-tuned neurons that change, rather than simply increase, their firing rates in proportion to increases in sound intensity.     

Experience-dependent functional plasticity and visual response selectivity of surviving subplate neurons in the mouse visual cortex

Subplate neurons are early-born cortical neurons that transiently form neural circuits during perinatal development and guide cortical maturation. Thereafter, most subplate neurons undergo cell death, while some survive and renew their target areas for synaptic connections. However, the functional properties of the surviving subplate neurons remain largely unknown. This study aimed to characterize the visual responses and experience-dependent functional plasticity of layer 6b (L6b) neurons, the remnants of subplate neurons, in the primary visual cortex (V1). Two-photon Ca²⁺ imaging was performed in V1 of awake juvenile mice. L6b neurons showed broader tunings for orientation, direction, and spatial frequency than did layer 2/3 (L2/3) and L6a neurons. In addition, L6b neurons showed lower matching of preferred orientation between the left and right eyes compared with other layers. Post hoc 3D immunohistochemistry confirmed that the majority of recorded L6b neurons expressed connective tissue growth factor (CTGF), a subplate neuron marker. Moreover, chronic two-photon imaging showed that L6b neurons exhibited ocular dominance (OD) plasticity by monocular deprivation during critical periods. The OD shift to the open eye depended on the response strength to the stimulation of the eye to be deprived before starting monocular deprivation. There were no significant differences in visual response selectivity prior to monocular deprivation between the OD changed and unchanged neuron groups, suggesting that OD plasticity can occur in L6b neurons showing any response features. In conclusion, our results provide strong evidence that surviving subplate neurons exhibit sensory responses and experience-dependent plasticity at a relatively late stage of cortical development.

The mammalian cerebral cortex consists of six layers, with distinct roles in information processing (1, 2). At the bottom of the neocortex, on the boundary between the gray matter and white matter, there is a thin sheet of neurons called layer 6b (L6b) (3). Layer 6b neurons are thought to be remnants of subplate neurons based on their location and cell-type marker expression (4). During prenatal and early postnatal periods, subplate neurons form transient neuronal circuits that play key roles in cortical maturation (5–7). In the embryonic cortex, subplate neurons form short-lived synapses with early immature neurons to regulate radial migration (8). During perinatal development, subplate neurons transiently receive inputs from ingrowing thalamic axons and innervate layer 4 (L4) to guide thalamic inputs to the eventual target, L4 (5, 6). Thus, the circuits formed by subplate neurons at the perinatal developmental stage are essential to establish basic neuronal circuits before starting experience-dependent refinements (5–7). Subsequently, subplate neurons largely disappear due to programmed cell death, but some survive and reside in L6b (5, 6). In the adult cortex, L6b neurons form neuronal circuits with local and long-distance neurons, which are different from those formed during early development (9–12). Therefore, surviving subplate neurons may acquire a role in information processing after remodeling of neuronal connections. A recent study using three-photon Ca²⁺ imaging demonstrated that L6b neurons show visual responses with broad orientation/direction tuning in the adult mouse primary visual cortex (V1) (13). However, comparable evidence for L6b response properties with other layer neurons in V1 is lacking (14–20). Moreover, L6b neurons have diverse morphology and molecular expression (21–24). Neurons born during subplate neurogenesis show the different expression patterns of subplate markers in postnatal L6b (4). However, the response properties in each subtype of L6b neurons remain unknown.The sensory responsiveness of cortical neurons is considerably refined by sensory experience relatively late in development, referred to as the critical period (25, 26). Previous studies have demonstrated that sensory activities before the onset of the critical period affect the arrangement of subplate neuron neurites in the barrel cortex and local subplate circuits in the auditory cortex (27, 28). However, there is no direct evidence that the sensory responses of surviving subplate neurons are modified by sensory experience during the critical period. If experience-dependent plasticity occurs in subplate neuron responses, they will contribute to the experience-dependent development of sensory functions and possibly to the functions in the mature cortex. Ocular dominance (OD) plasticity in V1 is a canonical model used to examine experience-dependent refinement of sensory responses (25, 26, 29, 30). If one eye is occluded for several days during the critical period, neurons in V1 lose their response to the deprived eye. OD plasticity is robustly preserved across species and cell types. Therefore, OD plasticity is suitable for evaluating experience-dependent plasticity in L6b neurons.This study aimed to characterize the visual responses and OD plasticity of L6b neurons in V1. Toward this goal, two-photon Ca²⁺ imaging was performed in awake juvenile mice, followed by 3D immunohistochemistry with a subplate neuronal marker, connective tissue growth factor (CTGF) (4, 31). L6b neurons showed broader tuning to visual stimuli and lower binocular matching of orientation preference than did layer 2/3 (L2/3) and L6a neurons. Chronic two-photon imaging revealed significant OD plasticity in individual L6b neurons during the critical period. Our results provide strong evidence that L6b neurons, presumed to be subplate neuron remnants, exhibit sensory responses and experience-dependent functional plasticity at a relatively late stage of cortical development.