ABSTRACT
Neuronal plasticity in the brain is greatly enhanced during critical periods early in life and was long thought to be rather limited thereafter. Studies in primary sensory areas of the neocortex have revealed a substantial degree of plasticity in the mature brain, too. Often, plasticity in the adult neocortex lies dormant but can be reactivated by modifications of sensory input or sensory-motor interactions, which alter the level and pattern of activity in cortical circuits. Such interventions, potentially in combination with drugs targeting molecular brakes on plasticity present in the adult brain, might help recovery of function in the injured or diseased brain.
Subject(s)
Brain/physiology , Neocortex/physiology , Neuronal Plasticity , Animals , Brain/cytology , Brain/growth & development , Critical Period, Psychological , Dominance, Ocular , Humans , Species SpecificityABSTRACT
The ability to categorize sensory stimuli is crucial for an animal's survival in a complex environment. Memorizing categories instead of individual exemplars enables greater behavioural flexibility and is computationally advantageous. Neurons that show category selectivity have been found in several areas of the mammalian neocortex1-4, but the prefrontal cortex seems to have a prominent role4,5 in this context. Specifically, in primates that are extensively trained on a categorization task, neurons in the prefrontal cortex rapidly and flexibly represent learned categories6,7. However, how these representations first emerge in naive animals remains unexplored, leaving it unclear whether flexible representations are gradually built up as part of semantic memory or assigned more or less instantly during task execution8,9. Here we investigate the formation of a neuronal category representation throughout the entire learning process by repeatedly imaging individual cells in the mouse medial prefrontal cortex. We show that mice readily learn rule-based categorization and generalize to novel stimuli. Over the course of learning, neurons in the prefrontal cortex display distinct dynamics in acquiring category selectivity and are differentially engaged during a later switch in rules. A subset of neurons selectively and uniquely respond to categories and reflect generalization behaviour. Thus, a category representation in the mouse prefrontal cortex is gradually acquired during learning rather than recruited ad hoc. This gradual process suggests that neurons in the medial prefrontal cortex are part of a specific semantic memory for visual categories.
Subject(s)
Learning/physiology , Models, Neurological , Pattern Recognition, Visual/physiology , Prefrontal Cortex/physiology , Animals , Female , Memory/physiology , Mice , Mice, Inbred C57BL , Neurons/physiology , Photic Stimulation , Prefrontal Cortex/cytology , Time FactorsABSTRACT
Pyramidal cells of neocortical layer 2/3 (L2/3 PyrCs) integrate signals from numerous brain areas and project throughout the neocortex. These PyrCs show pial depth-dependent functional and structural specializations, indicating participation in different functional microcircuits. However, whether these depth-dependent differences result from separable PyrC subtypes or whether their features display a continuum correlated with pial depth is unknown. Here, we assessed the stimulus selectivity, electrophysiological properties, dendritic morphology, and excitatory and inhibitory connectivity across the depth of L2/3 in the binocular visual cortex of mice. We find that the apical, but not the basal dendritic tree structure, varies with pial depth, which is accompanied by variation in subthreshold electrophysiological properties. Lower L2/3 PyrCs receive increased input from L4, while upper L2/3 PyrCs receive a larger proportion of intralaminar input. In vivo calcium imaging revealed a systematic change in visual responsiveness, with deeper PyrCs showing more robust responses than superficial PyrCs. Furthermore, deeper PyrCs are more driven by contralateral than ipsilateral eye stimulation. Importantly, the property value transitions are gradual, and L2/3 PyrCs do not display discrete subtypes based on these parameters. Therefore, L2/3 PyrCs' multiple functional and structural properties systematically correlate with their depth, forming a continuum rather than discrete subtypes.
Subject(s)
Neocortex , Visual Cortex , Mice , Animals , Pyramidal Cells/physiology , Electrophysiological Phenomena , Visual Cortex/physiologyABSTRACT
The ability of the adult mammalian brain to compensate for neuronal loss caused by injury or disease is very limited. Transplantation aims to replace lost neurons, but the extent to which new neurons can integrate into existing circuits is unknown. Here, using chronic in vivo two-photon imaging, we show that embryonic neurons transplanted into the visual cortex of adult mice mature into bona fide pyramidal cells with selective pruning of basal dendrites, achieving adult-like densities of dendritic spines and axonal boutons within 4-8 weeks. Monosynaptic tracing experiments reveal that grafted neurons receive area-specific, afferent inputs matching those of pyramidal neurons in the normal visual cortex, including topographically organized geniculo-cortical connections. Furthermore, stimulus-selective responses refine over the course of many weeks and finally become indistinguishable from those of host neurons. Thus, grafted neurons can integrate with great specificity into neocortical circuits that normally never incorporate new neurons in the adult brain.
Subject(s)
Embryo, Mammalian/cytology , Neocortex/cytology , Neural Pathways , Neurons/physiology , Neurons/transplantation , Visual Cortex/cytology , Afferent Pathways , Animals , Axons/metabolism , Cell Differentiation , Cell Tracking , Dendritic Spines/metabolism , Efferent Pathways , Mice , Neocortex/physiology , Neurons/cytology , Presynaptic Terminals/metabolism , Pyramidal Cells/cytology , Pyramidal Cells/physiology , Visual Cortex/physiologyABSTRACT
Binocular disparity, the difference between the two eyes' images, is a powerful cue to generate the 3D depth percept known as stereopsis. In primates, binocular disparity is processed in multiple areas of the visual cortex, with distinct contributions of higher areas to specific aspects of depth perception. Mice, too, can perceive stereoscopic depth, and neurons in primary visual cortex (V1) and higher-order, lateromedial (LM) and rostrolateral (RL) areas were found to be sensitive to binocular disparity. A detailed characterization of disparity tuning across mouse visual areas is lacking, however, and acquiring such data might help clarifying the role of higher areas for disparity processing and establishing putative functional correspondences to primate areas. We used two-photon calcium imaging in female mice to characterize the disparity tuning properties of neurons in visual areas V1, LM, and RL in response to dichoptically presented binocular gratings, as well as random dot correlograms (RDC). In all three areas, many neurons were tuned to disparity, showing strong response facilitation or suppression at optimal or null disparity, respectively, even in neurons classified as monocular by conventional ocular dominance (OD) measurements. Neurons in higher areas exhibited broader and more asymmetric disparity tuning curves compared with V1, as observed in primate visual cortex. Finally, we probed neurons' sensitivity to true stereo correspondence by comparing responses to correlated RDC (cRDC) and anticorrelated RDC (aRDC). Area LM, akin to primate ventral visual stream areas, showed higher selectivity for correlated stimuli and reduced anticorrelated responses, indicating higher-level disparity processing in LM compared with V1 and RL.SIGNIFICANCE STATEMENT A major cue for inferring 3D depth is disparity between the two eyes' images. Investigating how binocular disparity is processed in the mouse visual system will not only help delineating the role of mouse higher areas for visual processing, but also shed light on how the mammalian brain computes stereopsis. We found that binocular integration is a prominent feature of mouse visual cortex, as many neurons are selectively and strongly modulated by binocular disparity. Comparison of responses to correlated and anticorrelated random dot correlograms (RDC) revealed that lateromedial area (LM) is more selective to correlated stimuli, while less sensitive to anticorrelated stimuli compared with primary visual cortex (V1) and rostrolateral area (RL), suggesting higher-level disparity processing in LM, resembling primate ventral visual stream areas.
Subject(s)
Vision Disparity/physiology , Vision, Binocular/physiology , Visual Cortex/physiology , Animals , Brain Mapping , Eye Movements/physiology , Female , Mice , Mice, Inbred C57BL , Neuroimaging , Photic Stimulation , Visual Fields , Visual Pathways/physiologyABSTRACT
In many regions of the developing brain, neuronal circuits undergo defined phases of enhanced plasticity, termed critical periods. Work in the rodent visual cortex has led to important insights into the cellular and molecular mechanisms regulating the timing of the critical period. Although there is little doubt that the maturation of specific inhibitory circuits plays a key role in the opening of the critical period in the visual cortex, it is less clear what puts an end to it. In this review, we describe the established mechanisms and point out where more experimental work is needed. We also show that plasticity in the visual cortex is present well before, and long after, the peak of the critical period.
Subject(s)
Critical Period, Psychological , Neural Inhibition/physiology , Neuronal Plasticity/physiology , Visual Cortex/growth & development , Visual Cortex/physiology , Aging/physiology , Animals , Dominance, Ocular/physiology , Humans , Models, Neurological , Signal Transduction/physiology , Synaptic Transmission/physiologyABSTRACT
Experience-driven circuit changes underlie learning and memory. Monocular deprivation (MD) engages synaptic mechanisms of ocular dominance (OD) plasticity and generates robust increases in dendritic spine density on L5 pyramidal neurons. Here we show that the paired immunoglobulin-like receptor B (PirB) negatively regulates spine density, as well as the threshold for adult OD plasticity. In PirB(-/-) mice, spine density and stability are significantly greater than WT, associated with higher-frequency miniature synaptic currents, larger long-term potentiation, and deficient long-term depression. Although MD generates the expected increase in spine density in WT, in PirB(-/-) this increase is occluded. In adult PirB(-/-), OD plasticity is larger and more rapid than in WT, consistent with the maintenance of elevated spine density. Thus, PirB normally regulates spine and excitatory synapse density and consequently the threshold for new learning throughout life.
Subject(s)
Dominance, Ocular/physiology , Excitatory Postsynaptic Potentials/physiology , Learning/physiology , Long-Term Potentiation/physiology , Pyramidal Cells/metabolism , Receptors, Immunologic/metabolism , Animals , Mice , Mice, Knockout , Pyramidal Cells/cytology , Receptors, Immunologic/geneticsABSTRACT
Sensory experiences exert a powerful influence on the function and future performance of neuronal circuits in the mammalian neocortex. Restructuring of synaptic connections is believed to be one mechanism by which cortical circuits store information about the sensory world. Excitatory synaptic structures, such as dendritic spines, are dynamic entities that remain sensitive to alteration of sensory input throughout life. It remains unclear, however, whether structural changes at the level of dendritic spines can outlast the original experience and thereby provide a morphological basis for long-term information storage. Here we follow spine dynamics on apical dendrites of pyramidal neurons in functionally defined regions of adult mouse visual cortex during plasticity of eye-specific responses induced by repeated closure of one eye (monocular deprivation). The first monocular deprivation episode doubled the rate of spine formation, thereby increasing spine density. This effect was specific to layer-5 cells located in binocular cortex, where most neurons increase their responsiveness to the non-deprived eye. Restoring binocular vision returned spine dynamics to baseline levels, but absolute spine density remained elevated and many monocular deprivation-induced spines persisted during this period of functional recovery. However, spine addition did not increase again when the same eye was closed for a second time. This absence of structural plasticity stands out against the robust changes of eye-specific responses that occur even faster after repeated deprivation. Thus, spines added during the first monocular deprivation experience may provide a structural basis for subsequent functional shifts. These results provide a strong link between functional plasticity and specific synaptic rearrangements, revealing a mechanism of how prior experiences could be stored in cortical circuits.
Subject(s)
Dendrites/physiology , Neural Pathways/physiology , Pyramidal Cells/cytology , Visual Cortex/cytology , Visual Cortex/physiology , Animals , Mice , Mice, Inbred C57BL , Models, Neurological , Neuronal Plasticity/physiology , Vision, Binocular/physiology , Vision, Monocular/physiologyABSTRACT
Ocular dominance (OD) columns, alternating regions of left and right eye input in the visual cortex of higher mammals, have long been thought to develop from an initially intermingled state by an activity-dependent process. While indirect evidence points to potential alternative mechanisms based on molecular cues, direct proof for a molecular difference between left- and right eye columns is missing. Here, we show that heat shock protein 90 alpha (Hsp90α) is expressed in a clustered fashion in the developing cat visual cortex. Clusters of Hsp90α-positive cells are in register with OD columns of the ipsilateral eye as early as postnatal day 16, when OD columns have just appeared. Importantly, a periodic, clustered expression of Hsp90α is already present weeks before OD columns have started to form, suggesting that molecular differences between future left and right eye OD columns may contribute to the segregated termination of eye specific afferents in the developing visual cortex.
Subject(s)
Dominance, Ocular/physiology , HSP90 Heat-Shock Proteins/metabolism , Visual Cortex/growth & development , Animals , Cats , Visual Cortex/metabolism , Visual Perception/physiologyABSTRACT
Tactile sensation and vision are often both utilized for the exploration of objects that are within reach though it is not known whether or how these two distinct sensory systems combine such information. Here in mice, we used a combination of stereo photogrammetry for 3D reconstruction of the whisker array, brain-wide anatomical tracing and functional connectivity analysis to explore the possibility of tacto-visual convergence in sensory space and within the circuitry of the primary visual cortex (VISp). Strikingly, we find that stimulation of the contralateral whisker array suppresses visually evoked activity in a tacto-visual sub-region of VISp whose visual space representation closely overlaps with the whisker search space. This suppression is mediated by local fast-spiking interneurons that receive a direct cortico-cortical input predominantly from layer 6 neurons located in the posterior primary somatosensory barrel cortex (SSp-bfd). These data demonstrate functional convergence within and between two primary sensory cortical areas for multisensory object detection and recognition.
Subject(s)
Neurons , Touch , Mice , Animals , Neurons/physiology , Touch/physiology , Interneurons , Recognition, Psychology , Somatosensory Cortex/physiology , Vibrissae/physiologyABSTRACT
Amyloid-ß (Aß) plaque deposition plays a central role in the pathogenesis of Alzheimer's disease (AD). Post-mortem analysis of plaque development in mouse models of AD revealed that plaques are initially small, but then increase in size and become more numerous with age. There is evidence that plaques can grow uniformly over time; however, a complementary hypothesis of plaque development is that small plaques cluster and grow together thereby forming larger plaques. To investigate the latter hypothesis, we studied plaque formation in APPPS1 mice using in vivo two-photon microscopy and immunohistochemical analysis. We used sequential pre- and post-mortem staining techniques to label plaques at different stages of development and to detect newly emerged plaques. Post-mortem analysis revealed that a subset (22 %) of newly formed plaques appeared very close (<40 µm) to pre-existing plaques and that many close plaques (25 %) that were initially separate merged over time to form one single large plaque. Our results suggest that small plaques can cluster together, thus forming larger plaques as a complementary mechanism to simple uniform plaque growth from a single initial plaque. This study deepens our understanding of Aß deposition and demonstrates that there are multiple mechanisms at play in plaque development.
Subject(s)
Alzheimer Disease/pathology , Brain/pathology , Microscopy, Fluorescence, Multiphoton/methods , Plaque, Amyloid/pathology , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Brain/metabolism , Disease Models, Animal , Disease Progression , Humans , Male , Mice , Mice, Transgenic , Plaque, Amyloid/genetics , Plaque, Amyloid/metabolism , Presenilin-1/genetics , Presenilin-1/metabolism , Staining and Labeling/methodsABSTRACT
Stripe rearing, the restriction of visual experience to contours of only one orientation, leads to an overrepresentation of the experienced orientation among neurons in the visual cortex. It is unclear, however, how these changes are brought about. Are they caused by silencing of neurons tuned to non-experienced orientations, or do some neurons change their preferred orientation? To address this question, we stripe-reared juvenile mice using cylinder lens goggles. Following stripe rearing, the orientation preference of cortical neurons was determined with two-photon calcium imaging. This allowed us to sample all neurons in a given field of view, including the non-responsive ones, thus overcoming a fundamental limitation of extracellular electrophysiological recordings. Stripe rearing for 3 weeks resulted in a clear overrepresentation of the experienced orientation in cortical layer 2/3. Closer inspection revealed that the stripe rearing effect changed with depth in cortex: The fraction of responsive neurons decreased in upper layer 2/3, but changed very little deeper in this layer. At the same time, the overrepresentation of the experienced orientation was strongest in lower layer 2/3. Thus, diverse mechanisms contribute to the overall stripe rearing effect, but for neurons in lower layer 2/3 the effect is mediated by an instructive mechanism, which alters the orientation tuning of individual neurons.
Subject(s)
Neuronal Plasticity/physiology , Orientation/physiology , Photic Stimulation/methods , Space Perception/physiology , Visual Cortex/physiology , Animals , Male , Mice , Mice, Inbred C57BLABSTRACT
In the visual cortex of higher mammals, neurons are arranged across the cortical surface in an orderly map of preferred stimulus orientations. This map contains 'orientation pinwheels', structures that are arranged like the spokes of a wheel such that orientation changes continuously around a centre. Conventional optical imaging first demonstrated these pinwheels, but the technique lacked the spatial resolution to determine the response properties and arrangement of cells near pinwheel centres. Electrophysiological recordings later demonstrated sharply selective neurons near pinwheel centres, but it remained unclear whether they were arranged randomly or in an orderly fashion. Here we use two-photon calcium imaging in vivo to determine the microstructure of pinwheel centres in cat visual cortex with single-cell resolution. We find that pinwheel centres are highly ordered: neurons selective to different orientations are clearly segregated even in the very centre. Thus, pinwheel centres truly represent singularities in the cortical map. This highly ordered arrangement at the level of single cells suggests great precision in the development of cortical circuits underlying orientation selectivity.
Subject(s)
Neurons/cytology , Neurons/physiology , Visual Cortex/cytology , Visual Cortex/physiology , Animals , Cats , Electrophysiology , Models, Neurological , Morphogenesis , Photic Stimulation , Visual Cortex/growth & developmentABSTRACT
The functional properties of neocortical pyramidal cells (PCs), such as direction and orientation selectivity in visual cortex, predominantly derive from their excitatory and inhibitory inputs. For layer 2/3 (L2/3) PCs, the detailed relationship between their functional properties and how they sample and integrate information across cortical space is not fully understood. Here, we study this relationship by combining functional in vivo two-photon calcium imaging, in vitro functional circuit mapping, and dendritic reconstruction of the same L2/3 PCs in mouse visual cortex. Our work reveals direct correlations between dendritic morphology and functional input connectivity and the orientation as well as direction tuning of L2/3 PCs. First, the apical dendritic tree is elongated along the postsynaptic preferred orientation, considering the representation of visual space in the cortex as determined by its retinotopic organization. Additionally, sharply orientation-tuned cells show a less complex apical tree compared with broadly tuned cells. Second, in direction-selective L2/3 PCs, the spatial distribution of presynaptic partners is offset from the soma opposite to the preferred direction. Importantly, although the presynaptic excitatory and inhibitory input distributions spatially overlap on average, the excitatory input distribution is spatially skewed along the preferred direction, in contrast to the inhibitory distribution. Finally, the degree of asymmetry is positively correlated with the direction selectivity of the postsynaptic L2/3 PC. These results show that the dendritic architecture and the spatial arrangement of excitatory and inhibitory presynaptic cells of L2/3 PCs play important roles in shaping their orientation and direction tuning.
Subject(s)
Neural Inhibition , Visual Cortex , Animals , Dendrites , Mice , Neural Inhibition/physiology , Neurons/physiology , Pyramidal Cells/physiology , Visual Cortex/physiologyABSTRACT
Experience-dependent plasticity is crucial for the precise formation of neuronal connections during development. It is generally thought to depend on Hebbian forms of synaptic plasticity. In addition, neurons possess other, homeostatic means of compensating for changes in sensory input, but their role in cortical plasticity is unclear. We used two-photon calcium imaging to investigate whether homeostatic response regulation contributes to changes of eye-specific responsiveness after monocular deprivation (MD) in mouse visual cortex. Short MD durations decreased deprived-eye responses in neurons with binocular input. Longer MD periods strengthened open-eye responses, and surprisingly, also increased deprived-eye responses in neurons devoid of open-eye input. These bidirectional response adjustments effectively preserved the net visual drive for each neuron. Our finding that deprived-eye responses were either weaker or stronger after MD, depending on the amount of open-eye input a cell received, argues for both Hebbian and homeostatic mechanisms regulating neuronal responsiveness during experience-dependent plasticity.
Subject(s)
Dominance, Ocular , Eye/innervation , Neuronal Plasticity/physiology , Neurons/physiology , Visual Cortex/cytology , Action Potentials/radiation effects , Animals , Animals, Newborn , Brain Mapping , Calcium/metabolism , Eyelids/innervation , Eyelids/physiology , Mice , Mice, Inbred C57BL , Photic Stimulation/methods , Sensory Deprivation/physiology , Time Factors , Vision, Binocular/physiology , Vision, Monocular/physiology , Visual Pathways/physiologyABSTRACT
Most binocular neurons in the mammalian visual cortex show matched selectivity for light stimuli presented through either eye. A recent study tracked the responses of individual neurons in early visual cortex over time, revealing that matched binocular selectivity develops through major rearrangements of binocular visual circuits.
Subject(s)
Neurons/physiology , Vision, Binocular/physiology , Visual Cortex/cytology , Visual Cortex/physiology , Animals , Humans , Neural Pathways , Photic StimulationABSTRACT
Associative memories are stored in distributed networks extending across multiple brain regions. However, it is unclear to what extent sensory cortical areas are part of these networks. Using a paradigm for visual category learning in mice, we investigated whether perceptual and semantic features of learned category associations are already represented at the first stages of visual information processing in the neocortex. Mice learned categorizing visual stimuli, discriminating between categories and generalizing within categories. Inactivation experiments showed that categorization performance was contingent on neuronal activity in the visual cortex. Long-term calcium imaging in nine areas of the visual cortex identified changes in feature tuning and category tuning that occurred during this learning process, most prominently in the postrhinal area (POR). These results provide evidence for the view that associative memories form a brain-wide distributed network, with learning in early stages shaping perceptual representations and supporting semantic content downstream.
Subject(s)
Learning/physiology , Visual Cortex/physiology , Visual Perception/physiology , Animals , Brain Mapping , Calcium Signaling/physiology , Conditioning, Operant , Discrimination, Psychological , GABA Agonists/pharmacology , Generalization, Psychological , Male , Memory , Mice , Mice, Inbred C57BL , Muscimol/pharmacology , Neocortex/physiology , Neuronal Plasticity/physiology , Photic Stimulation , Recruitment, NeurophysiologicalABSTRACT
Larval zebrafish (Danio rerio) are an ideal organism for studying color vision, as their retina possesses four types of cone photoreceptors, covering most of the visible range and into the UV.1,2 Additionally, their eye and nervous systems are accessible to imaging, given that they are naturally transparent.3-5 Recent studies have found that, through a set of wavelength-range-specific horizontal, bipolar, and retinal ganglion cells (RGCs),6-9 the eye relays tetrachromatic information to several retinorecipient areas (RAs).10-13 The main RA is the optic tectum, receiving 97% of the RGC axons via the neuropil mass termed arborization field 10 (AF10).14,15 Here, we aim to understand the processing of chromatic signals at the interface between RGCs and their major brain targets. We used 2-photon calcium imaging to separately measure the responses of RGCs and neurons in the brain to four different chromatic stimuli in awake animals. We find that chromatic information is widespread throughout the brain, with a large variety of responses among RGCs, and an even greater diversity in their targets. Specific combinations of response types are enriched in specific nuclei, but there is no single color processing structure. In the main interface in this pathway, the connection between AF10 and tectum, we observe key elements of neural processing, such as enhanced signal decorrelation and improved chromatic decoding.16,17 A richer stimulus set revealed that these enhancements occur in the context of a more distributed code in tectum, facilitating chromatic signal association in this small vertebrate brain.