Axonal plasticity associated with perceptual learning in adult macaque primary visual cortex.

Perceptual learning is associated with changes in the functional properties of neurons even in primary sensory areas. In macaque monkeys trained to perform a contour detection task, we have observed changes in contour-related facilitation of neuronal responses in primary visual cortex that track their improvement in performance on a contour detection task. We have previously explored the anatomical substrate of experience-dependent changes in the visual cortex based on a retinal lesion model, where we find sprouting and pruning of the axon collaterals in the cortical lesion projection zone. Here, we attempted to determine whether similar changes occur under normal visual experience, such as that associated with perceptual learning. We labeled the long-range horizontal connections in visual cortex by virally mediated transfer of genes expressing fluorescent probes, which enabled us to do longitudinal two-photon imaging of axonal arbors over the period during which animals improve in contour detection performance. We found that there are substantial changes in the axonal arbors of neurons in cortical regions representing the trained part of the visual field, with sprouting of new axon collaterals and pruning of preexisting axon collaterals. Our findings indicate that changes in the structure of axonal arbors are part of the circuit-level mechanism of perceptual learning, and further support the idea that the learned information is encoded at least in part in primary visual cortex.

Physiological role for amyloid precursor protein in adult experience-dependent plasticity.

Changes in neural circuits after experience-dependent plasticity are brought about by the formation of new circuits via axonal growth and pruning. Here, using a combination of electrophysiology, adeno-associated virus-delivered fluorescent proteins, analysis of mutant mice, and two-photon microscopy, we follow long-range horizontally projecting axons in primary somatosensory cortex before and after selective whisker plucking. Whisker plucking induces axonal growth and pruning of horizontal projecting axons from neurons located in the surrounding intact whisker representations. We report that amyloid precursor protein is crucial for axonal pruning and contributes in a cell autonomous way.

Adult cortical plasticity studied with chronically implanted electrode arrays.

The functional architecture of adult cerebral cortex retains a capacity for experience-dependent change. This is seen after focal binocular lesions as rapid changes in receptive field (RF) of the lesion projection zone (LPZ) in the primary visual cortex (V1). To study the dynamics of the circuitry underlying these changes longitudinally, we implanted microelectrode arrays in macaque (Macaca mulatta) V1, eliminating the possibility of sampling bias, which was a concern in previous studies. With this method, we observed a rapid initial recovery in the LPZ and, during the following weeks, 63-89% of the sites in the LPZ showed recovery of visual responses with significant position tuning. The RFs shifted ∼3° away from the scotoma. In the absence of a lesion, visual stimulation surrounding an artificial scotoma did not elicit visual responses, suggesting that the postlesion RF shifts resulted from cortical reorganization. Interestingly, although both spikes and LFPs gave consistent prelesion position tuning, only spikes reflected the postlesion remapping.

Large-scale axonal reorganization of inhibitory neurons following retinal lesions.

The functional properties of adult cortical neurons are subject to alterations in sensory experience. Retinal lesions lead to remapping of cortical topography in the region of primary visual cortex representing the lesioned part of the retina, the lesion projection zone (LPZ), with receptive fields shifting to the intact parts of the retina. Neurons within the LPZ receive strengthened input from the surrounding region by growth of the plexus of excitatory long-range horizontal connections. Here, by combining cell type-specific labeling with a genetically engineered recombinant adeno-associated virus and in vivo two-photon microscopy in adult macaques, we showed that the remapping was also associated with alterations in the axonal arbors of inhibitory neurons, which underwent a parallel process of pruning and growth. The axons of inhibitory neurons located within the LPZ extended across the LPZ border, suggesting a mechanism by which new excitatory input arising from the peri-LPZ is balanced by reciprocal inhibition arising from the LPZ.

Death receptor 6 regulates adult experience-dependent cortical plasticity.

Sensory experience alters cortical circuitry by parallel processes of axon outgrowth and pruning, but the mechanisms that control these rearrangements are poorly understood. Using in vivo 2-photon longitudinal imaging, we found a marked reduction in axonal pruning in somatosensory cortex of mice with a knock-out of the DR6 gene, which codes for Death Receptor 6. This effect was seen for both long-range horizontal excitatory connections and for the axons of inhibitory neurons. These results identify a new pathway governing axonal plasticity associated with experience-dependent changes in cortical maps.

Axonal dynamics of excitatory and inhibitory neurons in somatosensory cortex.

Cortical topography can be remapped as a consequence of sensory deprivation, suggesting that cortical circuits are continually modified by experience. To see the effect of altered sensory experience on specific components of cortical circuits, we imaged neurons, labeled with a genetically modified adeno-associated virus, in the intact mouse somatosensory cortex before and after whisker plucking. Following whisker plucking we observed massive and rapid reorganization of the axons of both excitatory and inhibitory neurons, accompanied by a transient increase in bouton density. For horizontally projecting axons of excitatory neurons there was a net increase in axonal projections from the non-deprived whisker barrel columns into the deprived barrel columns. The axon collaterals of inhibitory neurons located in the deprived whisker barrel columns retracted in the vicinity of their somata and sprouted long-range projections beyond their normal reach towards the non-deprived whisker barrel columns. These results suggest that alterations in the balance of excitation and inhibition in deprived and non-deprived barrel columns underlie the topographic remapping associated with sensory deprivation.

Rapid axonal sprouting and pruning accompany functional reorganization in primary visual cortex.

The functional architecture of adult cerebral cortex retains a capacity for experience-dependent change. This is seen following focal binocular lesions, which induce rapid changes in receptive field size and position. To follow the dynamics of the circuitry underlying these changes, we imaged the intrinsic long-range horizontal connections within the lesion projection zone (LPZ) in adult macaque primary visual cortex. To image the same axons over time, we combined viral vector-mediated EGFP transfer and two-photon microscopy. The lesion triggered, within the first week, an approximately 2-fold outgrowth of axons toward the center of the LPZ. Over the subsequent month, axonal density declined due to a parallel process of pruning and sprouting but maintained a net increase relative to prelesion levels. The rate of turnover of axonal boutons also increased. The axonal restructuring recapitulates the pattern of exuberance and pruning seen in early development and correlates well with the functional changes following retinal lesions.

Plasticity of horizontal connections at a functional border in adult rat somatosensory cortex.

Horizontal connections in superficial cortical layers integrate information across sensory maps by connecting related functional columns. It has been hypothesized that these connections mediate cortical reorganization via synaptic plasticity. However, it is not known if the horizontal connections from discontinuous cortical regions can undergo plasticity in the adult. Here we located the border between two discontinuous cortical representations in vivo and used either pairing or low-frequency stimulation to induce synaptic plasticity in the horizontal connections surrounding this border in vitro. Individual neurons revealed significant and diverse forms of synaptic plasticity for horizontal connections within a continuous representation and discontinuous representations. Interestingly, both enhancement and depression were observed following both plasticity paradigms. Furthermore, plasticity was not restricted by the border's presence. Depolarization in the absence of synaptic stimulation also produced synaptic plasticity, but with different characteristics. These experiments suggest that plasticity of horizontal connections may mediate functional reorganization.