Sally A. Marik

Significance: Perceptual learning is a form of memory involving improvement in the ability to detect or discriminate between sensory stimuli. Encoding learned information requires plasticity of cortical circuits. Physiological studies have suggested that even the earliest stages in sensory cortical processing show functional changes associated with perceptual improvements. Previously, we have shown experience-dependent change in cortical circuits associated with retinal lesions that can account for functional adaptation to CNS lesions. Here, we have studied whether these changes are also associated with normal visual experience, specifically with perceptual learning. We found that during the course of perceptual learning axon collaterals in primary visual cortex (V1) undergo sprouting and pruning, suggesting how V1 is engaged in encoding learned information.

The cerebral cortex is a learning engine. The ability to encode information about sensory experience or practiced movements is a universal property of all cortical areas. This capacity, known as cortical plasticity, is seen in experience dependent changes in the functional properties of cortical neurons and in the alteration of cortical circuits. Certain properties are mutable only during a short period in postnatal life, which is known as the critical period, while others retain the ability to change throughout life. The same changes associated with assimilating normal experiences can be implemented for functional recovery following lesions of the central nervous system.

Significance: Amyloid precursor protein (APP) has long been implicated in Alzheimer’s disease, but its normal physiological role has only recently come to light. Here we demonstrate that APP plays a key role in axonal pruning after experience-dependent plasticity in the adult. Furthermore, we show that APP operates in a cell-autonomous fashion in the cortex to induce axonal pruning after sensory loss. APP is therefore important for the normal process of adult cortical plasticity through its role in the sculpting of axonal arbors.

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.

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 andin vivotwo-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.

Sensory experience alters cortical circuitry by parallel processes of axon outgrowth and pruning, but the mechanisms that control these rearrangements are poorly understood. Usingin vivo2-photon longitudinal imaging, we found a marked reduction in axonal pruning in somatosensory cortex of mice with a knock-out of theDR6gene, 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.

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. The adult brain is capable of learning new tasks and being shaped by new experiences. Evidence for experience-dependent plasticity of the adult cerebral cortex is seen in the functional rearrangement of cortical maps of sensory input and in the formation of new connections following alteration of sensory experience. The barrel cortex of the rodent receives sensory input from the whiskers and is an ideal model for examining the influence of experience on cortical function and circuitry. In the current study, we asked how experience alters cortical circuitry by examining excitatory and inhibitory axons within the adult whisker barrel cortex before and after plucking of a whisker and hence removal of its sensory input. By combining delivery of genes encoding fluorescent proteins, under the control of cell-type specific promoters, with two-photon imaging, we were able to directly examine subpopulations of axons and to determine when and to what extent experience altered specific connections in the adult living brain. Following whisker plucking we observed both the retraction of existing connections and an exuberant amount of growth of new axons. Axonal restructuring occurred rapidly and continued to undergo changes over the following weeks, with reciprocal sprouting of axons of excitatory neurons located in non-deprived cortex and of inhibitory neurons located in deprived cortex. The changes in the inhibitory circuits preceded those seen for excitatory connections.

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.