Delayed plasticity of inhibitory neurons in developing visual cortex

During postnatal development, altered sensory experience triggers the rapid reorganization of neuronal responses and connections in sensory neocortex. This experience-dependent plasticity is disrupted by reductions of intracortical inhibition. Little is known about how the responses of inhibitory cells themselves change during plasticity. We investigated the time course of inhibitory cell plasticity in mouse primary visual cortex by using functional two-photon microscopy with single-cell resolution and genetic identification of cell type. Initially, local inhibitory and excitatory cells had similar binocular visual response properties, both favoring the contralateral eye. After 2 days of monocular visual deprivation, excitatory cell responses shifted to favor the open eye, whereas inhibitory cells continued to respond more strongly to the deprived eye. By 4 days of deprivation, inhibitory cell responses shifted to match the faster changes in their excitatory counterparts. These findings reveal a dramatic delay in inhibitory cell plasticity. A minimal linear model reveals that the delay in inhibitory cell plasticity potently accelerates Hebbian plasticity in neighboring excitatory neurons. These findings offer a network-level explanation as to how inhibition regulates the experience-dependent plasticity of neocortex.     

Experience-dependent regulation of CaMKII activity within single visual cortex synapses in vivo

Unbalanced visual input during development induces persistent alterations in the function and structure of visual cortical neurons. The molecular mechanisms that drive activity-dependent changes await direct visualization of underlying signals at individual synapses in vivo. By using a genetically engineered Förster resonance energy transfer (FRET) probe for the detection of CaMKII activity, and two-photon imaging of single synapses within identified functional domains, we have revealed unexpected and differential mechanisms in specific subsets of synapses in vivo. Brief monocular deprivation leads to activation of CaMKII in most synapses of layer 2/3 pyramidal cells within deprived eye domains, despite reduced visual drive, but not in nondeprived eye domains. Synapses that are eliminated in deprived eye domains have low basal CaMKII activity, implying a protective role for activated CaMKII against synapse elimination.     

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.     

Syngap1 regulates experience-dependent cortical ensemble plasticity by promoting in vivo excitatory synapse strengthening

A significant proportion of autism risk genes regulate synapse function, including plasticity, which is believed to contribute to behavioral abnormalities. However, it remains unclear how impaired synapse plasticity contributes to network-level processes linked to adaptive behaviors, such as experience-dependent ensemble plasticity. We found that Syngap1, a major autism risk gene, promoted measures of experience-dependent excitatory synapse strengthening in the mouse cortex, including spike-timing–dependent glutamatergic synaptic potentiation and presynaptic bouton formation. Synaptic depression and bouton elimination were normal in Syngap1 mice. Within cortical networks, Syngap1 promoted experience-dependent increases in somatic neural activity in weakly active neurons. In contrast, plastic changes to highly active neurons from the same ensemble that paradoxically weaken with experience were unaffected. Thus, experience-dependent excitatory synapse strengthening mediated by Syngap1 shapes neuron-specific plasticity within cortical ensembles. We propose that other genes regulate neuron-specific weakening within ensembles, and together, these processes function to redistribute activity within cortical networks during experience.

Autism risk genes converge on several neurobiological functions, including the regulation of synapse biology (1–3). Synapse processes directly controlled by autism spectrum disorder (ASD) risk genes include de novo synapse formation, synapse maturation, and activity-driven changes in synapse function (i.e., synapse plasticity). Synapse plasticity, especially in cortical excitatory neurons, is a process enabling neural circuits to store new information, which is essential for experience-dependent modifications of behavior to promote survival (4, 5). Thus, risk genes are thought to contribute to ASD etiology by disrupting how neural circuits change in response to novel experiences, which in turn contributes to maladaptive behaviors. However, the study of risk gene biology and their relationship to neural plasticity is largely restricted to reduced biological preparations that focus on isolated changes to a small subset of synapses. Therefore, it is unclear how risk gene–driven regulation of synapse plasticity contributes to changes in neural dynamics within intact functional networks known to drive adaptive behaviors.Neuronal ensembles, or groups of coactivated neurons, are thought to be the direct neural substrate of cognitive processes and behavior (6). In cortex, ensemble plasticity is a multidimensional process that reflects the distribution of distinct cellular plasticity mechanisms across individual neuronal components within the assembly. For example, neurons within the same sensory-evoked cortical ensemble can undergo either increases or decreases in activity in response to the same sensory experience (7–9). While this general phenomenon has been observed in multiple contexts, it is unclear how neurons within the same functional network can have opposing changes to enduring neuronal activity in response to the same sensory experience. One way that this may occur is through the simultaneous activation of distinct forms of experience-dependent plasticity that are differentially distributed throughout neurons that comprise a functional network. Indeed, sensory experience drives the induction of Hebbian-type synaptic plasticity that can strengthen or weaken excitatory synaptic input onto sensory-responsive neurons (10). Experience-dependent circuit plasticity is not limited to changes in excitatory synaptic strength. Robust changes to the function and connectivity of GABAergic interneurons within cortical microcircuits also occurs in response to novel experience, which in turn regulates the output of pyramidal neurons (11–13). Moreover, intrinsic changes to neuronal excitability have also been observed, and in combination with changes to GABAergic function, these collective processes are thought to maintain a set firing rate within networks even as activity is redistributed among individual neurons (8, 14, 15).We propose that experience induces heterogenous changes in activity within neurons of a cortical assembly through cellular processes controlled, at least in part, by genetic mechanisms linked to ASD risk. This hypothesis originates from the clear overrepresentation of ASD risk genes that regulate the neurobiology of synapses and synapse plasticity (1–3). However, because of the multidimensional nature of cortical network plasticity, one cannot infer how a gene influences experience-dependent changes in distributed network dynamics when the function of the gene has only been studied in isolated subcellular structures, such as synapses. It is therefore important to study major ASD risk genes in the context of intact functional networks. Doing so will help to elucidate how their influence over molecular and cellular functions contribute to intermediate network-level processes more directly linked to behaviors, such as cortical ensemble plasticity.In this study, we investigated how a major ASD risk gene, SYNGAP1/Syngap1 (HUMAN/mouse–mouse only from now on), regulates specific aspects of cellular plasticity in vivo and how this process shapes experience-dependent ensemble plasticity with sensory-responsive cortical networks. The Syngap1 gene, which is a major autism risk factor (16), is a robust regulator of various forms of long-term potentiation (LTP) (17), a cellular model of Hebbian plasticity. It regulates LTP through control of excitatory synapse structure and function by gating NMDA receptor-dependent regulation of AMPA receptor trafficking and dendritic spine size (18–20). The role of Syngap1 in regulating synapse plasticity has been observed by various researchers across distinct neuronal subtypes in a variety of in vitro and ex vivo preparations (21–24). Based on this past work in reduced preparations, we hypothesized that Syngap1 regulates experience-dependent ensemble plasticity by promoting the strengthening of excitatory synapses within functional cortical networks. We found that Syngap1 was required for spike-timing-dependent (STD) synaptic potentiation and experience-mediated synapse bouton formation in layer (L) 2/3 of somatosensory cortex (SSC) but not synaptic depression or synapse bouton elimination. Syngap1 heterozygosity in mice disrupted experience-dependent potentiation of neuronal activity within a subpopulation of L2/3 SSC neurons. Syngap1 loss of function had no effect on plasticity of neurons within the same ensemble that weakens with experience. These findings indicate that disruptions to synapse-level strengthening mechanisms in Syngap1 mice contribute to imbalanced cortical ensemble plasticity driven by novel sensory experience. We propose that a key function of Syngap1 is to promote complex network-level plasticity through the strengthening of excitatory connections within cortical circuits.     

Reorganization of columnar architecture in the growing visual cortex

Many cortical areas increase in size considerably during postnatal development, progressively displacing neuronal cell bodies from each other. At present, little is known about how cortical growth affects the development of neuronal circuits. Here, in acute and chronic experiments, we study the layout of ocular dominance (OD) columns in cat primary visual cortex during a period of substantial postnatal growth. We find that despite a considerable size increase of primary visual cortext, the spacing between columns is largely preserved. In contrast, their spatial arrangement changes systematically over this period. Whereas in young animals columns are more band-like, layouts become more isotropic in mature animals. We propose a novel mechanism of growth-induced reorganization that is based on the “zigzag instability,” a dynamical instability observed in several inanimate pattern forming systems. We argue that this mechanism is inherent to a wide class of models for the activity-dependent formation of OD columns. Analyzing one representative of this class, the Elastic Network model, we show that this mechanism can account for the preservation of column spacing and the specific mode of reorganization of OD columns that we observe. We conclude that column width is preserved by systematic reorganization of neuronal selectivities during cortical expansion and that this reorganization is well described by the zigzag instability. Our work suggests that cortical circuits may remain plastic for an extended period in development to facilitate the modification of neuronal circuits to adjust for cortical growth.     

Constitutively active H-ras accelerates multiple forms of plasticity in developing visual cortex

Experience-dependent cortical plasticity has been studied by using loss-of-function methods. Here, we take the complementary approach of using a genetic gain-of-function that enhances plasticity. We show that a constitutively active form of H-ras (H-ras(G12V)), expressed presynaptically at excitatory synapses in mice, accelerates and enhances multiple, mechanistically distinct forms of plasticity in the developing visual cortex. In vivo, H-ras(G12V) not only increased the rate of ocular dominance change in response to monocular deprivation (MD), but also accelerated recovery from deprivation by reverse occlusion. In vitro, H-ras(G12V) expression decreased baseline presynaptic release probability and enhanced presynaptically expressed long-term potentiation (LTP). H-ras(G12V) expression also accelerated the increase following MD in the frequency of miniature excitatory potentials, mirroring accelerated plasticity in vivo. These findings demonstrate accelerated neocortical plasticity, which offers an avenue toward future therapies for many neurological and neuropsychiatric disorders.     

Metabotropic glutamate receptor signaling is required for NMDA receptor-dependent ocular dominance plasticity and LTD in visual cortex

A feature of early postnatal neocortical development is a transient peak in signaling via metabotropic glutamate receptor 5 (mGluR5). In visual cortex, this change coincides with increased sensitivity of excitatory synapses to monocular deprivation (MD). However, loss of visual responsiveness after MD occurs via mechanisms revealed by the study of long-term depression (LTD) of synaptic transmission, which in layer 4 is induced by acute activation of NMDA receptors (NMDARs) rather than mGluR5. Here we report that chronic postnatal down-regulation of mGluR5 signaling produces coordinated impairments in both NMDAR-dependent LTD in vitro and ocular dominance plasticity in vivo. The data suggest that ongoing mGluR5 signaling during a critical period of postnatal development establishes the biochemical conditions that are permissive for activity-dependent sculpting of excitatory synapses via the mechanism of NMDAR-dependent LTD.Temporary monocular deprivation (MD) sets in motion synaptic changes in visual cortex that result in impaired vision through the deprived eye. The primary cause of visual impairment is depression of excitatory thalamocortical synaptic transmission in layer 4 of visual cortex (1–3). The study of long-term depression (LTD) of synapses, elicited in vitro by electrical or chemical stimulation, has revealed many of the mechanisms involved in deprived-eye depression (4). In slices of visual cortex, LTD in layer 4 is induced by NMDA receptor (NMDAR) activation and expressed by posttranslational modification and internalization of AMPA receptors (AMPARs) (5, 6). MD induces identical NMDAR-dependent changes in AMPARs, and synaptic depression induced by deprivation in vivo occludes LTD in visual cortex ex vivo (6–8). Manipulations of NMDARs and AMPAR trafficking that interfere with LTD also prevent the effects of MD (7, 9–11).Although NMDAR-dependent LTD is widely expressed in the brain (12, 13), it is now understood that different circuits use different mechanisms for long-term homosynaptic depression (14). For example, in the CA1 region of hippocampus, synaptic activation of either NMDARs or metabotropic glutamate receptor 5 (mGluR5) induces LTD. In both cases, depression is expressed postsynaptically as a reduction in AMPARs, but these forms of LTD are not mutually occluding and have distinct signaling requirements (15). A defining feature of mGluR5-dependent postsynaptic LTD in CA1 is a requirement for the immediate translation of synaptic mRNAs (16). In visual cortex, there is evidence that induction of LTD in layers 2–4 requires NMDAR activation, whereas induction of LTD in layer 6 requires activation of mGluR5 (17, 18).The hypothesis that mGluRs, in addition to NMDARs, play a key role in visual cortical plasticity can be traced back more than 25 y to observations that glutamate-stimulated phosphoinositide turnover, mediated in visual cortex by mGluR5 coupled to phospholipase C, is elevated during the postnatal period of heightened sensitivity to MD (19). Early attempts to test this hypothesis were inconclusive owing to the use of weak and nonselective orthosteric compounds (20–22); however, subsequent experiments did confirm that NMDAR-dependent LTD occurs normally in layers 2/3 of visual cortex in Grm5 knockout mice (23).The idea that mGluR5 is critically involved in visual cortical plasticity in vivo was rekindled with the finding that deprived-eye depression fails to occur in layer 4 of Grm5^+/− mutant mice (24). This finding was unexpected because, as reviewed above, a considerable body of evidence has implicated the mechanism of NMDAR-dependent LTD in deprived-eye depression. In the present study, we reexamined the role of mGluR5 in LTD and ocular dominance plasticity in layer 4, using the Grm5^+/− mouse and a highly specific negative allosteric modulator, 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP), that has proven suitable for chronic inhibition of mGluR5 (25, 26). Our data show that NMDAR-dependent LTD and deprived-eye depression in layer 4 require mGluR5 signaling during postnatal development.     

Global impairment and therapeutic restoration of visual plasticity mechanisms after a localized cortical stroke

We tested the influence of a photothrombotic lesion in somatosensory cortex on plasticity in the mouse visual system and the efficacy of anti-inflammatory treatment to rescue compromised learning. To challenge plasticity mechanisms, we induced monocular deprivation (MD) in 3-mo-old mice. In control animals, MD induced an increase of visual acuity of the open eye and an ocular dominance (OD) shift towards this eye. In contrast, after photothrombosis, there was neither an enhancement of visual acuity nor an OD-shift. However, OD-plasticity was present in the hemisphere contralateral to the lesion. Anti-inflammatory treatment restored sensory learning but not OD-plasticity, as did a 2-wk delay between photothrombosis and MD. We conclude that (i) both sensory learning and cortical plasticity are compromised in the surround of a cortical lesion; (ii) transient inflammation is responsible for impaired sensory learning, suggesting anti-inflammatory treatment as a useful adjuvant therapy to support rehabilitation following stroke; and (iii) OD-plasticity cannot be conceptualized solely as a local process because nonlocal influences are more important than previously assumed.     

Population receptive field analysis of the primary visual cortex complements perimetry in patients with homonymous visual field defects

Injury to the primary visual cortex (V1) typically leads to loss of conscious vision in the corresponding, homonymous region of the contralateral visual hemifield (scotoma). Several studies suggest that V1 is highly plastic after injury to the visual pathways, whereas others have called this conclusion into question. We used functional magnetic resonance imaging (fMRI) to measure area V1 population receptive field (pRF) properties in five patients with partial or complete quadrantic visual field loss as a result of partial V1+ or optic radiation lesions. Comparisons were made with healthy controls deprived of visual stimulation in one quadrant [“artificial scotoma” (AS)]. We observed no large-scale changes in spared-V1 topography as the V1/V2 border remained stable, and pRF eccentricity versus cortical-distance plots were similar to those of controls. Interestingly, three observations suggest limited reorganization: (i) the distribution of pRF centers in spared-V1 was shifted slightly toward the scotoma border in 2 of 5 patients compared with AS controls; (ii) pRF size in spared-V1 was slightly increased in patients near the scotoma border; and (iii) pRF size in the contralesional hemisphere was slightly increased compared with AS controls. Importantly, pRF measurements yield information about the functional properties of spared-V1 cortex not provided by standard perimetry mapping. In three patients, spared-V1 pRF maps overlapped significantly with dense regions of the perimetric scotoma, suggesting that pRF analysis may help identify visual field locations amenable to rehabilitation. Conversely, in the remaining two patients, spared-V1 pRF maps failed to cover sighted locations in the perimetric map, indicating the existence of V1-bypassing pathways able to mediate useful vision.Cortical damage of the visual pathway often results from posterior or middle cerebral artery infarcts, hemorrhages, and other brain injuries. The most common visual cortex lesions involve the primary visual cortex (V1), the chief relayer of visual information to higher visual areas. Damage to area V1 or its primary inputs leads to the loss of conscious vision in the corresponding region of the contralateral visual hemifield, producing a dense contralateral scotoma that often covers a hemifield (hemianopia) or a single visual field quadrant (quadrantanopia).A much-debated issue is whether the adult V1 is able to reorganize after injury. Reorganization refers to long-term changes in the neuronal circuit (1) and generally requires the growth of new anatomic connections or a permanent change in the strength of existing connections. Several studies report significant remapping in area V1 of patients suffering from macular degeneration and other retinal lesions (2–12). The extent of this remapping has recently been called into question, however (1, 13–19). Less is known about how the visual system remaps to cover the visual field after injury to area V1 or its input projection from the lateral geniculate nucleus (LGN). Enlarged receptive fields have been found in areas surrounding chronic V1 lesions in cats (20–22), and visual point spread functions were seen to enlarge over time in the areas surrounding focal V1 lesions in kittens (23). Smaller, short-term changes (2 d after the lesion) have been reported as well (24). As expected, reorganization is more extensive in young animals (23, 25) compared with adults (26). A change in the balance between excitation and inhibition may underlie this functional reorganization (27–31).In humans, V1 injury is typically followed by a brief period of spontaneous recovery, which rarely lasts beyond 6 mo (32). Whether this recovery is the result of true visual system plasticity or is related to the gradual resolution of perilesional edema and general clinical improvement of the patients is unclear. A recent study in an adult human subject suggested that large-scale reorganization occurs in area V1 after partial deafferentiation by an optic radiation lesion (33); however, quantitative measurements were not performed. To date, there has been no systematic study in humans investigating how spared V1 cortex covers the visual field after chronic V1 injury. The present work is an effort in this direction.We used the population receptive field (pRF) mapping method (34) to study how spared area V1 covers the visual field after chronic injury in five adult human subjects suffering from partial or complete quadrantanopia. Our findings suggest that there is at best a limited degree of reorganization in the spared part of area V1 after partial V1 injury. Interestingly, the pattern of coverage of the visual field measured in spared V1 cortex by functional magnetic resonance imaging (fMRI) typically does not match predictions derived from perimetry maps. Identifying the patterns of mismatch and how they relate to the capacity of early visual areas to reorganize after injury will eventually allow the adoption of more rational strategies for visual rehabilitation.     

A rich environmental experience reactivates visual cortex plasticity in aged rats

Brain aging is characterized by functional deterioration across multiple systems, associated to a progressive decay of neural plasticity. Here, we explored environmental enrichment (EE), a condition of enhanced sensory-motor and cognitive stimulation, as a strategy to restore plasticity processes in the old brain. Visual system is one of the paradigmatic models for studying experience-dependent plasticity. While reducing input from one eye through monocular deprivation induces a marked ocular dominance (OD) shift of neurons in the primary visual cortex during development, the same manipulation is totally ineffective after the closure of the critical period. We show that EE is able to reactivate OD plasticity in the visual cortex of aging rats, as assessed with both visual-evoked potentials and single-unit recordings. A marked reduction in intracortical GABAergic inhibition and a remodeling of extracellular matrix accompany this effect. The non-invasive nature of EE makes this paradigm eligible for human application.     

Dynamic development of the calyx of Held synapse

The calyx of Held is probably the largest synaptic terminal in the brain, forming a unique one-to-one connection in the auditory ventral brainstem. During early development, calyces have many collaterals, whose function is unknown. Using electrophysiological recordings and fast-calcium imaging in brain slices, we demonstrate that these collaterals are involved in synaptic transmission. We show evidence that the collaterals are pruned and that the pruning already begins 1 week before the onset of hearing. Using two-photon microscopy to image the calyx of Held in neonate rats, we report evidence that both axons and nascent calyces are structurally dynamic, showing the formation, elimination, extension, or retraction of up to 65% of their collaterals within 1 hour. The observed dynamic behavior of axons may add flexibility in the choice of postsynaptic partners and thereby contribute to ensuring that each principal cell eventually is contacted by a single calyx of Held.     

Cortical plasticity induced by transplantation of embryonic somatostatin or parvalbumin interneurons

GABAergic inhibition has been shown to play an important role in the opening of critical periods of brain plasticity. We recently have shown that transplantation of GABAergic precursors from the embryonic medial ganglionic eminence (MGE), the source of neocortical parvalbumin- (PV⁺) and somatostatin-expressing (SST⁺) interneurons, can induce a new period of ocular dominance plasticity (ODP) after the endogenous period has closed. Among the diverse subtypes of GABAergic interneurons PV⁺ cells have been thought to play the crucial role in ODP. Here we have used MGE transplantation carrying a conditional allele of diphtheria toxin alpha subunit and cell-specific expression of Cre recombinase to deplete PV⁺ or SST⁺ interneurons selectively and to investigate the contributions of each of these types of interneurons to ODP. As expected, robust plasticity was observed in transplants containing PV⁺ cells but in which the majority of SST⁺ interneurons were depleted. Surprisingly, transplants in which the majority of PV⁺ cells were depleted induced plasticity as effectively as those containing PV⁺ cells. In contrast, depleting both cell types blocked induction of plasticity. These findings reveal that PV⁺ cells do not play an exclusive role in ODP; SST⁺ interneurons also can drive cortical plasticity and contribute to the reshaping of neural networks. The ability of both PV⁺ and SST⁺ interneurons to induce de novo cortical plasticity could help develop new therapeutic approaches for brain repair.Critical periods of activity-dependent plasticity shape the early development of many cortical areas. GABAergic inhibition has been shown to play an important role in the opening of a critical period in the developing visual cortex during which monocular visual deprivation (MD) rapidly alters the balance of responses to the two eyes (1–3). This ocular dominance plasticity (ODP) takes place with a well-defined beginning and end. The majority of GABAergic interneurons in the neocortex are derived from the medial ganglionic eminence (MGE) (4–8). Transplantation of embryonic inhibitory neuronal precursors from the MGE into the visual cortex of postnatal animals can induce a second window of plasticity (9). The transplanted interneurons, consisting primarily of parvalbumin-expressing (PV⁺) and somatostatin-expressing (SST⁺) cells, disperse, mature, and integrate into local visual cortical circuit (10–12). Evidence to date links only the PV⁺ interneurons to ODP (13–15). SST⁺ interneurons have scarcely been studied in the context of ODP despite their abundance in the visual cortex and their powerful influence on the apical dendrites of pyramidal cells (16, 17). Here we take advantage of MGE transplantation to dissect the contributions of different types of cortical interneuron cells to plasticity. We genetically ablated PV⁺ or SST⁺ cells in the transplants and tested whether the transplanted cells induced a second critical period in the recipients. Removing either PV⁺ or SST⁺ cells did not hinder the ability of MGE transplants to induce ODP, but removing both eliminated the plasticity. These results demonstrate that PV⁺ cells do not play an exclusive role in ODP; SST⁺ cells also can drive plasticity and reshape neural circuits when the majority of PV⁺ cells are eliminated. Furthermore, the ODP induced by MGE transplants resembled the plasticity in the normal critical period and differed from the plasticity observed in older animals in its magnitude, its sensitivity to brief MD, and in the weakening of response to the deprived eye. These findings reveal specific cortical GABAergic-inhibitory cell types that mediate plasticity.     

From the Cover: Seasonal plasticity in the adult somatosensory cortex

Seasonal cycles govern life on earth, from setting the time for the mating season to influencing migrations and governing physiological conditions like hibernation. The effect of such changing conditions on behavior is well-appreciated, but their impact on the brain remains virtually unknown. We investigate long-term seasonal changes in the mammalian brain, known as Dehnel’s effect, where animals exhibit plasticity in body and brain sizes to counter metabolic demands in winter. We find large seasonal variation in cellular architecture and neuronal activity in the smallest terrestrial mammal, the Etruscan shrew, Suncus etruscus. Their brain, and specifically their neocortex, shrinks in winter. Shrews are tactile hunters, and information from whiskers first reaches the somatosensory cortex layer 4, which exhibits a reduced width (−28%) in winter. Layer 4 width (+29%) and neuron number (+42%) increase the following summer. Activity patterns in the somatosensory cortex show a prominent reduction of touch-suppressed neurons in layer 4 (−55%), the most metabolically active layer. Loss of inhibitory gating occurs with a reduction in parvalbumin-positive interneurons, one of the most active neuronal subtypes and the main regulators of inhibition in layer 4. Thus, a reduction in neurons in layer 4 and particularly parvalbumin-positive interneurons may incur direct metabolic benefits. However, changes in cortical balance can also affect the threshold for detecting sensory stimuli and impact prey choice, as observed in wild shrews. Thus, seasonal neural adaptation can offer synergistic metabolic and behavioral benefits to the organism and offer insights on how neural systems show adaptive plasticity in response to ecological demands.

Animals have evolved to display extraordinary ethological adaptations in response to the ecological variations they face. Monarch butterflies perform annual migration cycles, each of which is completed over several generations (1), while squirrels can hibernate for several months (2). The primary organ responsible for regulating behaviors, the brain, also exhibits the ability to change: In response to environmental changes, behavioral needs, injury, or to form new memories (3–6). While the consequences of such neural plasticity have been studied at the synaptic level, minute changes in neuronal and synaptic activity over short time-scales, the impact of longer-term behavioral variations on neural structure and activity is largely unknown. Notable exceptions are songbirds that display seasonal variation in song repertoire and correlated anatomical changes in song nuclei (7). Although seasonal brain plasticity has mostly been studied in birds, mammalian brains, including humans (8), also display such effects. However, the evolutionary relations between key bird and mammalian brain regions are disputed (9, 10). Some of the most drastic yet largely unexplored seasonal changes in brain structure have been observed in small mammals, like shrews and weasels (11, 12). This phenomenon is known as Dehnel’s effect and entails a reduction in body weight, skull, and brain size during autumn and winter (11–15). We explore this effect in Etruscan shrews and find that individual shrews exhibit seasonal changes in brain size, with the cerebral cortex shrinking in winter. We then determine the microanatomical substrate of such cortical volume changes and report evidence of seasonal changes in neural activity in the cerebral cortex.     

Expanding the primate body schema in sensorimotor cortex by virtual touches of an avatar

The brain representation of the body, called the body schema, is susceptible to plasticity. For instance, subjects experiencing a rubber hand illusion develop a sense of ownership of a mannequin hand when they view it being touched while tactile stimuli are simultaneously applied to their own hand. Here, the cortical basis of such an embodiment was investigated through concurrent recordings from primary somatosensory (i.e., S1) and motor (i.e., M1) cortical neuronal ensembles while two monkeys observed an avatar arm being touched by a virtual ball. Following a period when virtual touches occurred synchronously with physical brushes of the monkeys'' arms, neurons in S1 and M1 started to respond to virtual touches applied alone. Responses to virtual touch occurred 50 to 70 ms later than to physical touch, consistent with the involvement of polysynaptic pathways linking the visual cortex to S1 and M1. We propose that S1 and M1 contribute to the rubber hand illusion and that, by taking advantage of plasticity in these areas, patients may assimilate neuroprosthetic limbs as parts of their body schema.     

Lentivirus-based genetic manipulations of cortical neurons and their optical and electrophysiological monitoring in vivo

It is becoming increasingly clear that single cortical neurons encode complex and behaviorally relevant signals, but efficient means to study gene functions in small networks and single neurons in vivo are still lacking. Here, we establish a method for genetic manipulation and subsequent phenotypic analysis of individual cortical neurons in vivo. First, lentiviral vectors are used for neuron-specific gene delivery from alpha-calcium/calmodulin-dependent protein kinase II or Synapsin I promoters, optionally in combination with gene knockdown by means of U6 promoter-driven expression of short-interfering RNAs. Second, the phenotypic analysis at the level of single cortical cells is carried out by using two-photon microscopy-based techniques: high-resolution two-photon time-lapse imaging is used to monitor structural dynamics of dendritic spines and axonal projections, whereas cellular response properties are analyzed electrophysiologically by two-photon microscopy directed whole-cell recordings. This approach is ideally suited for analysis of gene functions in individual neurons in the intact brain.     

Rapid plasticity of binocular connections in developing monkey visual cortex (V1)

The basic sets of cortical connections are present at birth in the primate visual system. The maintenance and refinement of these innate connections are highly dependent on normal visual experience, and prolonged exposure to binocularly uncorrelated signals early in life severely disrupts the normal development of binocular functions. However, very little is known about how rapidly these changes in the functional organization of primate visual cortex emerge or what are the sequence and the nature of the abnormal neural events that occur immediately after experiencing binocular decorrelation. In this study, we investigated how brief periods of ocular misalignment (strabismus) at the height of the critical period alter the cortical circuits that support binocular vision. After only 3 days of optically imposed strabismus, there was a striking increase in the prevalence of V1 neurons that exhibited binocular suppression, i.e., binocular responses were weaker than monocular responses. However, the sensitivity of these neurons to interocular spatial phase disparity was not significantly altered. These contrasting results suggest that the first significant change in V1 caused by early binocular decorrelation is binocular suppression, and that this suppression originates at a site(s) beyond where binocular signals are initially combined.     

A key mechanism underlying sensory experience-dependent maturation of neocortical GABAergic circuits in vivo

Mechanisms underlying experience-dependent refinement of cortical connections, especially GABAergic inhibitory circuits, are unknown. By using a line of mutant mice that lack activity-dependent BDNF expression (bdnf-KIV), we show that experience regulation of cortical GABAergic network is mediated by activity-driven BDNF expression. Levels of endogenous BDNF protein in the barrel cortex are strongly regulated by sensory inputs from whiskers. There is a severe alteration of excitation and inhibition balance in the barrel cortex of bdnf-KIV mice as a result of reduced inhibitory but not excitatory conductance. Within the inhibitory circuits, the mutant barrel cortex exhibits significantly reduced levels of GABA release only from the parvalbumin-expressing fast-spiking (FS) interneurons, but not other interneuron subtypes. Postnatal deprivation of sensory inputs markedly decreased perisomatic inhibition selectively from FS cells in wild-type but not bdnf-KIV mice. These results suggest that postnatal experience, through activity-driven BDNF expression, controls cortical development by regulating FS cell-mediated perisomatic inhibition in vivo.     

Unequal representation of cardinal and oblique contours in ferret visual cortex

We have measured the amount of cortical space activated by differently oriented gratings in 25 adult ferrets by optical imaging of intrinsic signal. On average, 7% more area of the exposed visual cortex was preferentially activated by vertical and horizontal contours than by contours at oblique angles. This anisotropy may reflect the real-world prevalence of contours in the cardinal axes and could explain the greater sensitivity of many animals to vertical and horizontal stimuli.     

Neuronal activity in the primate dorsomedial prefrontal cortex contributes to strategic selection of response tactics

The functional roles of the primate posterior medial prefrontal cortex have remained largely unknown. Here, we show that this region participates in the regulation of actions in the presence of multiple response tactics. Monkeys performed a forelimb task in which a visual cue required prompt decision of reaching to a left or a right target. The location of the cue was either ipsilateral (concordant) or contralateral (discordant) to the target. As a result of extensive training, the reaction times for the concordant and discordant trials were indistinguishable, indicating that the monkeys developed tactics to overcome the cue-response conflict. Prefrontal neurons exhibited prominent activity when the concordant and discordant trials were randomly presented, requiring rapid selection of a response tactic (reach toward or away from the cue). The following findings indicate that these neurons are involved in the selection of tactics, rather than the selection of action or monitoring of response conflict: (i) The response period activity of neurons in this region disappeared when the monkeys performed the task under the behavioral condition that required a single tactic alone, whereas the action varied across trials. (ii) The neuronal activity was found in the dorsomedial prefrontal cortex but not in the anterior cingulate cortex that has been implicated for the response conflict monitoring. These results suggest that the medial prefrontal cortex participates in the selection of a response tactic that determines an appropriate action. Furthermore, the observation of dynamic, task-dependent neuronal activity necessitates reconsideration of the conventional concept of cortical motor representation.