A Small Motor Cortex Lesion Abolished Ocular Dominance Plasticity in the Adult Mouse Primary Visual Cortex and Impaired Experience-Dependent Visual Improvements

It was previously shown that a small lesion in the primary somatosensory cortex (S1) prevented both cortical plasticity and sensory learning in the adult mouse visual system: While 3-month-old control mice continued to show ocular dominance (OD) plasticity in their primary visual cortex (V1) after monocular deprivation (MD), age-matched mice with a small photothrombotically induced (PT) stroke lesion in S1, positioned at least 1 mm anterior to the anterior border of V1, no longer expressed OD-plasticity. In addition, in the S1-lesioned mice, neither the experience-dependent increase of the spatial frequency threshold (“visual acuity”) nor of the contrast threshold (“contrast sensitivity”) of the optomotor reflex through the open eye was present. To assess whether these plasticity impairments can also occur if a lesion is placed more distant from V1, we tested the effect of a PT-lesion in the secondary motor cortex (M2). We observed that mice with a small M2-lesion restricted to the superficial cortical layers no longer expressed an OD-shift towards the open eye after 7 days of MD in V1 of the lesioned hemisphere. Consistent with previous findings about the consequences of an S1-lesion, OD-plasticity in V1 of the nonlesioned hemisphere of the M2-lesioned mice was still present. In addition, the experience-dependent improvements of both visual acuity and contrast sensitivity of the open eye were severely reduced. In contrast, sham-lesioned mice displayed both an OD-shift and improvements of visual capabilities of their open eye. To summarize, our data indicate that even a very small lesion restricted to the superficial cortical layers and more than 3mm anterior to the anterior border of V1 compromised V1-plasticity and impaired learning-induced visual improvements in adult mice. Thus both plasticity phenomena cannot only depend on modality-specific and local nerve cell networks but are clearly influenced by long-range interactions even from distant brain regions.     

Molecular basis for induction of ocular dominance plasticity.

The most dramatic example of experience-dependent cortical plasticity is the shift in ocular dominance that occurs in visual cortex as a consequence of monocular deprivation during early postnatal life. Many of the basic properties of this type of synaptic plasticity have been described in detail. The important challenge that remains is to understand the molecular basis for these properties. By combining theoretical analysis with experiments in vivo and in vitro, some of the elementary molecular mechanisms for visual cortical plasticity have now been uncovered.     

Pull-push neuromodulation of LTP and LTD enables bidirectional experience-induced synaptic scaling in visual cortex

Neuromodulatory input, acting on G protein-coupled receptors, is essential for the induction of experience-dependent cortical plasticity. Here we report that G-coupled receptors in layer II/III of visual cortex control the polarity of synaptic plasticity through a pull-push regulation of LTP and LTD. In slices, receptors coupled to Gs promote LTP while suppressing LTD; conversely, receptors coupled to Gq11 promote LTD and suppress LTP. In vivo, the selective stimulation of Gs- or Gq11-coupled receptors brings the cortex into LTP-only or LTD-only states, which allows the potentiation or depression of targeted synapses with visual stimulation. The pull-push regulation of LTP/LTD occurs via direct control of the synaptic plasticity machinery and it is independent of changes in NMDAR activation or neuronal excitability. We propose these simple rules governing the pull-push control of LTP/LTD form a general metaplasticity mechanism that may contribute to neuromodulation of plasticity in other cortical circuits.     

Extracellular matrix and visual cortical plasticity: freeing the synapse

The effects of monocular deprivation (MD) on the ocular dominance of visual cortical neurons are a paradigmatic example of experience-dependent plasticity. Here we review recent data showing that extracellular matrix (ECM) plays an important role in the control of experience-dependent plasticity both in the developing and adult visual cortex.     

Molecular mechanisms of experience-dependent plasticity in visual cortex

A remarkable amount of our current knowledge of mechanisms underlying experience-dependent plasticity during cortical development comes from study of the mammalian visual cortex. Recent advances in high-resolution cellular imaging, combined with genetic manipulations in mice, novel fluorescent recombinant probes, and large-scale screens of gene expression, have revealed multiple molecular mechanisms that underlie structural and functional plasticity in visual cortex. We situate these mechanisms in the context of a new conceptual framework of feed-forward and feedback regulation for understanding how neurons of the visual cortex reorganize their connections in response to changes in sensory inputs. Such conceptual advances have important implications for understanding not only normal development but also pathological conditions that afflict the central nervous system.     

Visual deprivation suppresses L5 pyramidal neuron excitability by preventing the induction of intrinsic plasticity

In visual cortex monocular deprivation (MD) during a critical period (CP) reduces the ability of the deprived eye to activate cortex, but the underlying cellular plasticity mechanisms are incompletely understood. Here we show that MD reduces the intrinsic excitability of layer 5 (L5) pyramidal neurons and enhances long-term potentiation of intrinsic excitability (LTP-IE). Further, MD and LTP-IE induce reciprocal changes in K(v)2.1 current, and LTP-IE reverses the effects of MD on intrinsic excitability. Taken together these data suggest that MD reduces intrinsic excitability by preventing sensory-drive induced LTP-IE. The effects of MD on excitability were correlated with the classical visual system CP, and (like the functional effects of MD) could be rapidly reversed when vision was restored. These data establish LTP-IE as a candidate mechanism mediating loss of visual responsiveness within L5, and suggest that intrinsic plasticity plays an important role in experience-dependent refinement of visual cortical circuits.     

Regular spiking and intrinsic bursting pyramidal cells show orthogonal forms of experience-dependent plasticity in layer V of barrel cortex

Most functional plasticity studies in the cortex have focused on layers (L) II/III and IV, whereas relatively little is known of LV. Structural measurements of dendritic spines in?vivo suggest some specialization among LV cell subtypes. We therefore studied experience-dependent plasticity in the barrel cortex using intracellular recordings to distinguish regular spiking (RS) and intrinsic bursting (IB) subtypes. Postsynaptic potentials and suprathreshold responses in?vivo revealed a remarkable dichotomy in RS and IB cell plasticity; spared whisker potentiation occurred in IB but not RS cells while deprived whisker depression occurred in RS but not IB cells. Similar RS/IB differences were found in the LII/III to V connections in brain slices. Modeling studies showed that subthreshold changes predicted the suprathreshold changes. These studies demonstrate the major functional partition of plasticity within a single cortical layer and reveal the LII/III to LV connection as a major excitatory locus of cortical plasticity.     

Adult visual cortical plasticity

The visual cortex has the capacity for experience-dependent change, or cortical plasticity, that is retained throughout life. Plasticity is invoked for encoding information during perceptual learning, by internally representing the regularities of the visual environment, which is useful for facilitating intermediate-level vision-contour integration and surface segmentation. The same mechanisms have adaptive value for functional recovery after CNS damage, such as that associated with stroke or neurodegenerative disease. A common feature to plasticity in primary visual cortex (V1) is an association field that links contour elements across the visual field. The circuitry underlying the association field includes a plexus of long-range horizontal connections formed by cortical pyramidal cells. These connections undergo rapid and exuberant sprouting and pruning in response to removal of sensory input, which can account for the topographic reorganization following retinal lesions. Similar alterations in cortical circuitry may be involved in perceptual learning, and the changes observed in V1 may be representative of how learned information is encoded throughout the cerebral cortex.     

Developmental and Visual Input-Dependent Regulation of the CB1 Cannabinoid Receptor in the Mouse Visual Cortex

The mammalian visual system exhibits significant experience-induced plasticity in the early postnatal period. While physiological studies have revealed the contribution of the CB1 cannabinoid receptor (CB1) to developmental plasticity in the primary visual cortex (V1), it remains unknown whether the expression and localization of CB1 is regulated during development or by visual experience. To explore a possible role of the endocannabinoid system in visual cortical plasticity, we examined the expression of CB1 in the visual cortex of mice. We found intense CB1 immunoreactivity in layers II/III and VI. CB1 mainly localized at vesicular GABA transporter-positive inhibitory nerve terminals. The amount of CB1 protein increased throughout development, and the specific laminar pattern of CB1 appeared at P20 and remained until adulthood. Dark rearing from birth to P30 decreased the amount of CB1 protein in V1 and altered the synaptic localization of CB1 in the deep layer. Dark rearing until P50, however, did not influence the expression of CB1. Brief monocular deprivation for 2 days upregulated the localization of CB1 at inhibitory nerve terminals in the deep layer. Taken together, the expression and the localization of CB1 are developmentally regulated, and both parameters are influenced by visual experience.     

Development and plasticity of the primary visual cortex

Hubel and Wiesel began the modern study of development and plasticity of primary visual cortex (V1), discovering response properties of cortical neurons that distinguished them from their inputs and that were arranged in a functional architecture. Their findings revealed an early innate period of development and a later critical period of dramatic experience-dependent plasticity. Recent studies have used rodents to benefit from biochemistry and genetics. The roles of spontaneous neural activity and molecular signaling in innate, experience-independent development have been clarified, as have the later roles of visual experience. Plasticity produced by monocular visual deprivation (MD) has been dissected into stages governed by distinct signaling mechanisms, some of whose molecular players are known. Many crucial questions remain, but new tools for perturbing cortical cells and measuring plasticity at the level of changes in connections among identified neurons now exist. The future for the study of V1 to illuminate cortical development and plasticity is bright.     

Possible role of cooperative action of NMDA receptor and GABA function in developmental plasticity

The maturation of cortical circuits is strongly influenced by sensory experience during a restricted critical period. The developmental alteration in the subunit composition of NMDA receptors (NMDARs) has been suggested to be involved in regulating the timing of such plasticity. However, this hypothesis does not explain the evidence that enhancing GABA inhibition triggers a critical period in the visual cortex. Here, to investigate how the NMDAR and GABA functions influence synaptic organization, we examine an spike-timing-dependent plasticity (STDP) model that incorporates the dynamic modulation of LTP, associated with the activity- and subunit-dependent desensitization of NMDARs, as well as the background inhibition by GABA. We show that the competitive interaction between correlated input groups, required for experience-dependent synaptic modifications, may emerge when both the NMDAR subunit expression and GABA inhibition reach a sufficiently mature state. This may suggest that the cooperative action of these two developmental mechanisms can contribute to embedding the spatiotemporal structure of input spikes in synaptic patterns and providing the trigger for experience-dependent cortical plasticity.     

Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex

The receptive fields of visual cortical neurons are bidirectionally modified by sensory deprivation and experience, but the synaptic basis for these changes is unknown. Here we demonstrate bidirectional, experience-dependent regulation of the composition and function of synaptic NMDA receptors (NMDARs) in visual cortex layer 2/3 pyramidal cells of young rats. Visual experience decreases the proportion of NR2B-only receptors, shortens the duration of NMDAR-mediated synaptic currents, and reduces summation of synaptic NMDAR currents during bursts of high-frequency stimulation. Visual deprivation exerts an opposite effect. Although the effects of experience and deprivation are reversible, the rates of synaptic modification vary. Experience can induce a detectable change in synaptic transmission within hours, while deprivation-induced changes take days. We suggest that experience-dependent changes in NMDAR composition and function regulate the development of receptive field organization in visual cortex.     

Experience-dependent development of perineuronal nets and chondroitin sulfate proteoglycan receptors in mouse visual cortex

Perineuronal nets (PNNs) are extracellular matrix structures consisting of chondroitin sulfate proteoglycans (CSPGs), hyaluronan, link proteins and tenascin-R (Tn-R). They enwrap a subset of GABAergic inhibitory interneurons in the cerebral cortex and restrict experience-dependent cortical plasticity. While the expression profile of PNN components has been widely studied in many areas of the central nervous system of various animal species, it remains unclear how these components are expressed during the postnatal development of mouse primary visual cortex (V1). In the present study, we characterized the developmental time course of the formation of PNNs in the mouse primary visual cortex, using the specific antibodies against the two PNN component proteins aggrecan and tenascin-R, or the lectin Wisteria floribunda agglutinin (WFA) that directly binds to glycosaminoglycan chains of chondroitin sulfate proteoglycans (CSPGs). We found that the fluorescence staining signals of both the WFA staining and the antibody against aggrecan rapidly increased in cortical neurons across layers 2–6 during postnatal days (PD) 10–28 and reached a plateau around PD42, suggesting a full construction of PNNs by the end of the critical period. Co-staining with antibodies to Ca^2 + binding protein parvalbumin (PV) demonstrated that the majority of PNN-surrounding cortical neurons are immunoreactive to PV. Similar expression profile of another PNN component tenascin-R was observed in the development of V1. Dark rearing of mice from birth significantly reduced the density of PNN-surrounding neurons. In addition, the expression of two recently identified CSPG receptors — Nogo receptor (NgR) and leukocyte common antigen-related phosphatase (LAR), showed significant increases from PD14 to PD70 in layer 2–6 of cortical PV-positive interneurons in normal reared mice, but decreased significantly in dark-reared ones. Taken together, these results suggest that PNNs form preferentially in cortical PV-positive interneurons in an experience-dependent manner, and reach full maturation around the end of the critical period of V1 development.     

Serotonin mediates cross-modal reorganization of cortical circuits

Loss of one type of sensory input can cause improved functionality of other sensory systems. Whereas this form of plasticity, cross-modal plasticity, is well established, the molecular and cellular mechanisms underlying it are still unclear. Here, we show that visual deprivation (VD) increases extracellular serotonin in the juvenile rat barrel cortex. This increase in serotonin levels facilitates synaptic strengthening at layer 4 to layer 2/3 synapses within the barrel cortex. Upon VD, whisker experience leads to trafficking of the AMPA-type glutamate receptors (AMPARs) into these synapses through the activation of ERK and increased phosphorylation of AMPAR subunit GluR1 at the juvenile age when natural whisker experience no longer induces synaptic GluR1 delivery. VD thereby leads to sharpening of the functional whisker-barrel map at layer 2/3. Thus, sensory deprivation of one modality leads to serotonin release in remaining modalities, facilitates GluR1-dependent synaptic strengthening, and refines cortical organization.     

Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity

Neural circuits are shaped by experience in early postnatal life. Distinct GABAergic connections within visual cortex determine the timing of the critical period for rewiring ocular dominance to establish visual acuity. We find that maturation of the parvalbumin (PV)-cell network that controls plasticity onset is regulated by a selective re-expression of the embryonic Otx2 homeoprotein. Visual experience promoted the accumulation of non-cell-autonomous Otx2 in PV-cells, and cortical infusion of exogenous Otx2 accelerated both PV-cell development and critical period timing. Conversely, conditional removal of Otx2 from non-PV cells or from the visual pathway abolished plasticity. Thus, the experience-dependent transfer of a homeoprotein may establish the physiological milieu for postnatal plasticity of a neural circuit.     

Homeostatic regulation of eye-specific responses in visual cortex during ocular dominance plasticity

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.     

A role for retinal brain-derived neurotrophic factor in ocular dominance plasticity

Visual deprivation is a classical tool to study the plasticity of visual cortical connections. After eyelid closure in young animals (monocular deprivation, MD), visual cortical neurons become dominated by the open eye, a phenomenon known as ocular dominance (OD) plasticity . It is commonly held that the molecular mediators of OD plasticity are cortically derived and that the retina is immune to the effects of MD . Recently, it has been reported that visual deprivation induces neurochemical, structural, and functional changes in the retina , but whether these retinal changes contribute to the effects of MD in the cortex is unknown. Here, we provide evidence that brain-derived neurotrophic factor (BDNF) produced in the retina influences OD plasticity. We found a reduction of BDNF expression in the deprived retina of young rats. We compensated this BDNF imbalance between the two eyes by either injecting exogenous BDNF in the deprived eye or reducing endogenous BDNF expression in the nondeprived eye. Both treatments were effective in counteracting the OD shift induced by MD. Retinal BDNF could also influence OD distribution in normal animals. These results show for the first time that OD plasticity is modulated by BDNF produced in the retina.     

Learning-induced plasticity in the barrel cortex is disrupted by inhibition of layer 4 somatostatin-containing interneurons

Gaba-ergic neurons are a diverse cell class with extensive influence over cortical processing, but their role in experience-dependent plasticity is not completely understood. Here we addressed the role of cortical somatostatin- (SOM-INs) and vasoactive intestinal polypeptide- (VIP-INs) containing interneurons in a Pavlovian conditioning where stimulation of the vibrissae is used as a conditioned stimulus and tail shock as unconditioned one. This procedure induces a plastic change observed as an enlargement of the cortical functional representation of vibrissae activated during conditioning. Using layer-targeted, cell-selective DREADD transductions, we examined the involvement of SOM-INs and VIP-INs activity in learning-related plastic changes. Under optical recordings, we injected DREADD-expressing vectors into layer IV (L4) barrels or layer II/III (L2/3) areas corresponding to the activated vibrissae. The activity of the interneurons was modulated during all conditioning sessions, and functional 2-deoxyglucose (2DG) maps were obtained 24 h after the last session.In mice with L4 but not L2/3 SOM-INs suppressed during conditioning, the plastic change of whisker representation was absent. The behavioral effect of conditioning was disturbed. Both L4 SOM-INs excitation and L2/3 VIP-INs inhibition during conditioning did not affect the plasticity or the conditioned response.We found the activity of L4 SOM-INs is indispensable in the formation of learning-induced plastic change. We propose that L4 SOM-INs may provide disinhibition by blocking L4 parvalbumin interneurons, allowing a flow of information into upper cortical layers during learning.