Activity-dependent Competition Research Articles

Using Motor Behavior during an Early Critical Period to Restore Skilled Limb Movement after Damage to the Corticospinal System during Development

This study investigated the requirements for restoring motor function after corticospinal (CS) system damage during early postnatal development. Activity-dependent competition between the CS tracts (CSTs) of the two hemispheres is imperative for normal development. Blocking primary motor cortex (M1) activity unilaterally during a critical period [postnatal week 5 (PW5) to PW7] produces permanent contralateral motor skill impairments, loss of M1 motor map, aberrant CS terminations, and decreases in CST presynaptic sites and spinal cholinergic interneuron numbers. To repair these motor systems impairments and restore function, we manipulated motor experience in three groups of cats after this CST injury produced by inactivation. One group wore a jacket restraining the limb ipsilateral to inactivation, forcing use of the contralateral, impaired limb, for the month after M1 inactivation (PW8-PW13; "restraint alone"). A second group wore the restraint during PW8-PW13 and was also trained for 1 h/d in a reaching task with the contralateral forelimb ("early training"). To test the efficacy of intervention during adolescence, a third group wore the restraint and received reach training during PW20-PW24 ("delayed training"). Early training restored CST connections and the M1 motor map, increased cholinergic spinal interneurons numbers on the contralateral, relative to ipsilateral, side, and abrogated limb control impairments. Delayed training restored CST connectivity and the M1 motor map but not contralateral spinal cholinergic cell counts or motor performance. Restraint alone only restored CST connectivity. Our findings stress the need to reestablish the integrated functions of the CS system at multiple hierarchical levels in restoring skilled motor function after developmental injury.

The Battle over Inhibitory Synaptic Plasticity in Satiety Brain Circuits

The synaptic basis underlying food intake is poorly understood. New research shows that an animal's satiety state dictates the polarity of long-term inhibitory synaptic plasticity in the hypothalamus, which is mediated by an activity-dependent competition between endocannabinoid and nitric oxide signaling.

Pathway-Specific Genetic Attenuation of Glutamate Release Alters Select Features of Competition-Based Visual Circuit Refinement

A hallmark of mammalian neural circuit development is the refinement of initially imprecise connections by competitive activity-dependent processes. In the developing visual system retinal ganglion cell (RGC) axons from the two eyes undergo activity-dependent competition for territory in the dorsal lateral geniculate nucleus (dLGN). The direct contributions of synaptic transmission to this process, however, remain unclear. We used a genetic approach to reduce glutamate release selectively from ipsilateral-projecting RGCs and found that their release-deficient axons failed to exclude competing axons from the ipsilateral eye territory in the dLGN. Nevertheless, the release-deficient axons consolidated and maintained their normal amount of dLGN territory, even in the face of fully active competing axons. These results show that during visual circuit refinement glutamatergic transmission plays a direct role in excluding competing axons from inappropriate target regions, but they argue that consolidation and maintenance of axonal territory are largely insensitive to alterations in synaptic activity levels.

Multiple Forms of Activity-Dependent Competition Refine Hippocampal Circuits In Vivo

Efficient memory formation relies on the establishment of functional hippocampal circuits. It has been proposed that synaptic connections are refined by neural activity to form functional brain circuitry. However, it is not known whether and how hippocampal connections are refined by neural activity in vivo. Using a mouse genetic system in which restricted populations of neurons in the hippocampal circuit are inactivated, we show that inactive axons are eliminated after they develop through a competition with active axons. Remarkably, in the dentate gyrus, which undergoes neurogenesis throughout life, axon refinement is achieved by a competition between mature and young neurons. These results demonstrate that activity-dependent competition plays multiple roles in the establishment of functional memory circuits in vivo.

Synaptic Activity and Activity-Dependent Competition Regulates Axon Arbor Maturation, Growth Arrest, and Territory in the Retinotectal Projection

In the retinotectal projection, synapses guide retinal ganglion cell (RGC) axon arbor growth by promoting branch formation and by selectively stabilizing branches. To ask whether presynaptic function is required for this dual role of synapses, we have suppressed presynaptic function in single RGCs using targeted expression of tetanus toxin light-chain fused to enhanced green fluorescent protein (TeNT-Lc:EGFP). Time-lapse imaging of singly silenced axons as they arborize in the tectum of zebrafish larvae shows that presynaptic function is not required for stabilizing branches or for generating an arbor of appropriate complexity. However, synaptic activity does regulate two distinct aspects of arbor development. First, single silenced axons fail to arrest formation of highly dynamic but short-lived filopodia that are a feature of immature axons. Second, single silenced axons fail to arrest growth of established branches and so occupy significantly larger territories in the tectum than active axons. However, if activity-suppressed axons had neighbors that were also silent, axonal arbors appeared normal in size. A similar reversal in phenotype was observed when single TeNT-Lc:EGFP axons are grown in the presence of the NMDA receptor antagonist MK801 [(+)-5-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate]. Although expansion of arbor territory is prevented when neighbors are silent, formation of transient filopodia is not. These results suggest that synaptic activity by itself regulates filopodia formation regardless of activity in neighboring cells but that the ability to arrest growth and focusing of axonal arbors in the target is an activity-dependent, competitive process.

Activity-dependent synaptic competition by STDP and its role in critical period plasticity

Activity-dependent synaptic competition by STDP and its role in critical period plasticity

Metaplasticity Governs Natural Experience-Driven Plasticity of Nascent Embryonic Brain Circuits

During embryogenesis, brain neurons receiving the same sensory input may undergo potentiation or depression. While the origin of variable plasticity in vivo is unknown, it plays a key role in shaping dynamic neural circuit refinement. Here, we investigate effects of natural visual stimuli on neuronal firing within the intact, awake, developing brain using calcium imaging of 100 s of central neurons in the Xenopus retinotectal system. We find that specific patterns of visual stimuli shift population responses toward either potentiation or depression in an N-methyl-D-aspartate receptor (NMDA-R)-dependent manner. In agreement with Bienenstock-Cooper-Munro metaplasticity, our results show that functional potentiation or depression can be predicted by individual neurons' specific receptive field properties and historic firing rates. Interestingly, this activity-dependent metaplasticity is itself NMDA-R dependent. Furthermore, network analysis reveals increased correlated firing of neurons that undergo potentiation. These findings implicate metaplasticity as a natural property regulating experience-dependent refinement of nascent embryonic brain circuits.

It's Lonely at the Top: Winning Climbing Fibers Ascend Dendrites Solo

In mammals, climbing fiber axons compete for sole innervation at each Purkinje cell. At the same time, synapses disappear from Purkinje somata and appear in great numbers on the dendrites. In this issue of Neuron, Hashimoto et al. show that, by the time climbing fibers ascend the dendrites, the winner and losers are already decided.

On the mechanism of action of muscle fibre activity in synapse competition and elimination at the mammalian neuromuscular junction

Activity-dependent competition plays a crucial role in the refinement of synaptic connections in the peripheral and central nervous system. The reduction in number of axons innervating each neuromuscular junction during development, i.e. synapse elimination, appears to be one such competitive activity-driven event. Recently, we showed that asynchronous firing of competing presynaptic terminals is a key player in synapse elimination. Although some previous studies suggested that activity of the postsynaptic cell may be an intermediary in the disposal of redundant presynaptic inputs, the mechanism involved remains unknown. In the present study, in order to assess the role of evoked muscle activity in this process, we inhibited the generation of postsynaptic action potentials in muscle fibers in vivo, through the overexpression of inwardly rectifying Kir2.1 and Kir2.2 channels, via electroporation of the soleus muscle in the mouse hindlimb. Electrophysiological and morphological data show that overexpression of potassium channels in the endplate region of neonatal muscle fibres induces membrane hyperpolarization and an increase in conductance, inhibition of the action potential mechanism and prolonged persistence of polyneuronal innervation. These changes are not seen in muscle fibres with overexpression of a non-conducting Kir2.1 mutant. Our results are compatible with the interpretation that the block of action potential generation, even in single endplates, can inhibit synapse elimination through local signalling.

Molecular development of the lateral geniculate nucleus in the absence of retinal waves during the time of retinal axon eye-specific segregation

When retinal waves are inhibited binocularly, eye-specific segregation of retinal axons is disrupted, and retinal axons from the two eyes remain intermingled in the lateral geniculate nucleus (LGN). This effect of binocular retinal wave inhibition is mediated by the lack of activity-dependent competition between retinal axons from the two eyes, but it is unknown whether this effect is also mediated by the developmental arrest of the LGN in an immature state. Here we find developmental markers of the LGN during eye-specific segregation. The expression levels of Purkinje cell protein 4 ( PCP4/PEP19), transcription factor 7- like 2 ( TCF7L2/TCF4) and LIM homeobox protein 9 ( Lhx9) in the LGN change significantly during eye-specific segregation. Using PCP4, TCF7L2 and Lhx9 as developmental markers of the LGN, we examine whether LGN development is affected by binocular disruption of retinal waves during eye-specific segregation. Binocular injection of epibatidine strongly inhibits eye-specific segregation, whereas it does not affect the expression of PCP4, TCF7L2 and Lhx9. Furthermore, the expression of PCP4, TCF7L2 and Lhx9 is normal in binocularly enucleated animals and in mice treated with the monoamine oxidase A (MAOA) inhibitor, clorgyline. In addition, our experiments using LGN slice cultures show that the expression of PCP4 and TCF7L2 in LGN slices changes as in vivo. Our results suggest that LGN development proceeds, at least in part, even in the absence of retinal inputs. PCP4, TCF7L2 and Lhx9 should be useful to examine LGN development during eye-specific segregation in mice and in ferrets.

Ipsilateral Eye Cortical Maps Are Uniquely Sensitive to Binocular Plasticity

In the cerebral cortex, neuronal circuits are first laid down by intrinsic mechanisms and then refined by experience. In the canonical model, this refinement is driven by activity-dependent competition between inputs for some limited cortical resource. Here we examine this idea in the mouse visual cortex at the peak of the critical period for experience-dependent plasticity. By imaging intrinsic optical responses, we mapped the strength and size of each eye's cortical representation in normal mice, mice that had been deprived of patterned vision uni- or bilaterally, and in mice in which the contralateral eye had been removed. We find that for both eyes, a period of visual deprivation results in a loss of cortical responsiveness to stimulation through the deprived eye. In addition, the ipsilateral eye pathway is affected by the quality of vision through the opposite eye. Our findings indicate that although both contra- and ipsilateral eye pathways require visual experience for their maintenance, ipsilateral eye projections bear an additional, unique sensitivity to binocular interactions.

Electrical stimulation of spared corticospinal axons augments connections with ipsilateral spinal motor circuits after injury.

Activity-dependent competition shapes corticospinal (CS) axon outgrowth in the spinal cord during development. An important question in neural repair is whether activity can be used to promote outgrowth of CS axons in maturity. After injury, spared CS axons sprout and make new connections, but often not enough to restore function. We propose that electrically stimulating spared axons after injury will enhance sprouting and strengthen connections with spinal motor circuits. To study the effects of activity, we electrically stimulated CS tract axons in the medullary pyramid. To study the effects of injury, one pyramid was lesioned. We studied sparse ipsilateral CS projections of the intact pyramid as a model of the sparse connections preserved after CNS injury. We determined the capacity of CS axons to activate ipsilateral spinal motor circuits and traced their spinal projections. To understand the separate and combined contributions of injury and activity, we examined animals receiving stimulation only, injury only, and injury plus stimulation. Both stimulation and injury alone strengthened CS connectivity and increased outgrowth into the ipsilateral gray matter. Stimulation of spared axons after injury promoted outgrowth that reflected the sum of effects attributable to activity and injury alone. CS terminations were densest within the ventral motor territories of the cord, and connections in these animals were significantly stronger than after injury alone, indicating that activity augments injury-induced plasticity. We demonstrate that activity promotes plasticity in the mature CS system and that the interplay between activity and injury preferentially promotes connections with ventral spinal motor circuits.

Bilateral Activity-Dependent Interactions in the Developing Corticospinal System

Activity-dependent competition between the corticospinal (CS) systems in each hemisphere drives postnatal development of motor skills and stable CS tract connections with contralateral spinal motor circuits. Unilateral restriction of motor cortex (M1) activity during an early postnatal critical period impairs contralateral visually guided movements later in development and in maturity. Silenced M1 develops aberrant connections with the contralateral spinal cord whereas the initially active M1, in the other hemisphere, develops bilateral connections. In this study, we determined whether the aberrant pattern of CS tract terminations and motor impairments produced by early postnatal M1 activity restriction could be abrogated by reducing activity-dependent synaptic competition from the initially active M1 later in development. We first inactivated M1 unilaterally between postnatal weeks 5-7. We next inactivated M1 on the other side from weeks 7-11 (alternate inactivation), to reduce the competitive advantage that this side may have over the initially inactivated side. Alternate inactivation redirected aberrant contralateral CS tract terminations from the initially silenced M1 to their normal spinal territories and reduced the density of aberrant ipsilateral terminations from the initially active side. Normal movement endpoint control during visually guided locomotion was fully restored. This reorganization of CS terminals reveals an unsuspected late plasticity after the critical period for establishing the pattern of CS terminations in the spinal cord. Our findings show that robust bilateral interactions between the developing CS systems on each side are important for achieving balance between contralateral and ipsilateral CS tract connections and visuomotor control.

Genetic Modulation of BDNF Signaling Affects the Outcome of Axonal Competition In Vivo

Activity-dependent competition that operates on branch stability or formation plays a critical role in shaping the pattern and complexity of axonal terminal arbors. In the mammalian central nervous system (CNS), the effect of activity-dependent competition on axon arborization and on the assembly of sensory maps is well established. However, the molecular pathways that modulate axonal-branch stability or formation in competitive environments remain unknown. We establish an in vivo axonal-competition paradigm in the mouse olfactory system by employing a genetic strategy that permits suppression of neurosecretory activity in random subsets of olfactory sensory neurons (OSNs). Long-term follow up confirmed that this genetic manipulation triggers competition by revealing a bias toward selective stabilization of active arbors and local degeneration of synaptically silent ones. By using a battery of genetically modified mouse models, we demonstrate that a decrease either in the total levels or the levels of activity-dependent secreted BDNF (due to a val66met substitution), rescues silent arbors from withering. We show that this effect may be mediated, at least in part, by p75(NTR). We establish and experimentally validate a genetic in vivo axonal-competition paradigm in the mammalian CNS. By using this paradigm, we provide evidence for a specific effect of BDNF signaling on terminal-arbor pruning under competition in vivo. Our results have implications for the formation and refinement of the olfactory and other sensory maps, as well as for neuropsychiatric diseases and traits modulated by the BDNF val66met variant.

The Emergence of Contrast-Invariant Orientation Tuning in Simple Cells of Cat Visual Cortex

Simple cells in primary visual cortex exhibit contrast-invariant orientation tuning, in seeming contradiction to feed-forward models that rely on lateral geniculate nucleus (LGN) input alone. Contrast invariance has therefore been thought to depend on the presence of intracortical lateral inhibition. In vivo intracellular recordings instead suggest that contrast invariance can be explained by three properties of the excitatory pathway. (1) Depolarizations evoked by orthogonal stimuli are determined by the amount of excitation a cell receives from the LGN, relative to the excitation it receives from other cortical cells. (2) Depolarizations evoked by preferred stimuli saturate at lower contrasts than the spike output of LGN relay cells. (3) Visual stimuli evoke contrast-dependent changes in trial-to-trial variability, which lead to contrast-dependent changes in the relationship between membrane potential and spike rate. Thus, high-contrast, orthogonally oriented stimuli that evoke significant depolarizations evoke few spikes. Together these mechanisms, without lateral inhibition, can account for contrast-invariant stimulus selectivity.

Developmental homeostasis of mouse retinocollicular synapses.

Spontaneous retinal waves during development are thought to provide an instructive signal for precise retinotopic mapping by correlating the activity of neighboring retinal ganglion cells. In mutant mice (beta2-/-) that lack correlated waves, retinocollicular map refinement is impaired. In vivo recordings reveal that neurons in the superior colliculus of beta2-/- mice have large receptive fields and low peak visual responses, resulting in a conservation of total integrated response. We find that this "response homeostasis" is maintained on a cell-by-cell basis, and argue that it does not depend on regulation from the visual cortex during adulthood. Instead, in vitro recordings show that homeostasis arises from the conservation of total synaptic input from the retina, and that it is maintained via different mechanisms over development. In the absence of correlated retinal waves, beta2-/- neurons sample a larger number of weaker retinal inputs relative to controls after the first postnatal week. Once retinal waves are restored, developmental learning rules and homeostasis drive refinement so that fewer, stronger synapses are retained, as in wild-type mice, but from a larger retinal area. Homeostasis in neurons has been shown previously to regulate the gain of synaptic transmission in response to perturbations of activity. Our results suggest that during the development of sensory maps, a unique consequence of homeostatic mechanisms is the precise shaping of neuronal receptive fields in conjunction with activity-dependent competition.

A higher power for insulin

Glucose output from the liver is tightly regulated by insulin. But insulin holds sway over more than the liver — an unappreciated circuit in glucose control involves the opening of ion channels in the brain. The wiring of neural circuits is modulated by early neural activity in the developing network of axons, and an understanding of the mechanism involved is one of the central questions in neurobiology. Past research addressing this question has focused on the patterning of axon bundles, but now combined genetic and state-of-the-art imaging tools make it possible to follow axon growth of individual neurons in live animals. The observations show that activity-dependent competition between axons regulates axon growth even before any connection has been made. So axon competition acts upon axon branch formation, not just on branch stability as is commonly believed, a finding that broadens the range of potential signalling pathways contributing to neural development.

Role of sensory‐motor cortex activity in postnatal development of corticospinal axon terminals in the cat

The initial pattern of corticospinal (CS) terminations, as axons grow into the spinal gray matter, bears little resemblance to the pattern later in development and in maturity. This is because of extensive axon pruning and local axon terminal growth during early postnatal development. Pruning is driven by activity-dependent competition between the CS systems on each side during postnatal weeks (PW) 3-7. It is not known whether CS axon terminal growth and final topography are activity dependent. We examined the activity dependence of CS axon terminal growth and topography at different postnatal times. We inactivated sensory-motor cortex by infusion of the gamma-aminobutyric acid type A (GABA(A)) agonist muscimol and traced CS axons from the inactivated side. Inactivation between PW5 and PW7 produced permanent changes in projection topography, reduced local axon branching, and prevented development of dense clusters of presynaptic sites, which are normally characteristic of CS terminals. Inactivation at younger (PW3-5) and older (PW8-12) ages did not affect projection topography but impeded development of local axon branching and presynaptic site clusters. These effects were not due to increased cortical cell death during inactivation. Neural activity plays an important role in determining the morphology of CS terminals during the entire period of development, but, for the projection topography, the role of activity is exercised during a very brief period. This points to a complex, and possibly independent, regulation of termination topography and terminal morphology. Surprisingly, when a CS neuron's activity is blocked during early development, it does not recover lost connections later in development once activity resumes.

Spinal cord plasticity in response to unilateral inhibition of the rat motor cortex during development: changes to gene expression, muscle afferents and the ipsilateral corticospinal projection

In developing Wistar albino rats, ventral horn muscle afferent boutons are lost following corticospinal innervation. Motor cortex lesions rescue a proportion of these boutons and perturb activity dependent expression of cJun and parvalbumin (PV) in the spinal cord. Therefore, we tested whether activity-dependent competition between corticospinal and proprioreceptive afferents determines the balance of these inputs to motor output pathways by delivering the inhibitory GABA agonist muscimol unilaterally to the forelimb motor cortex using slow release polymer implants from postnatal day 7 (P7) coincident with corticospinal synaptogenesis. Controls received saline. Inhibition of immature cortical neurons by muscimol was confirmed with separate in vitro electrophysiological recordings. After P28, spinal cord sections were immunostained for PV, cJun and muscle afferents transganglionically labelled with cholera toxin-B (CTB). Unilateral inhibition reduced contralaterally the number of PV positive spinal cord neurons and muscle afferent boutons in the dorsolateral ventral horn, compared to controls, and significantly altered the distribution of motoneuronal cJun expression. Separately, descending tracts were retrogradely traced with CTB from the cervical hemicord contralateral to implants. Forelimb sensorimotor cortex sections were immunostained for either CTB or PV. In muscimol treated animals, significantly fewer neurons expressed PV in the inhibited hemicortex, but as many CTB labelled corticospinal neurons were present as in controls, along with an equally large corticospinal projection from contralateral to the implant, significantly greater than in controls. Unexpectedly, unilateral inhibition of the motor cortical input did not lead to an expanded muscle afferent input. Instead, this was reduced coincident with development of a bilateral corticospinal innervation.

Developing a robot visual system using a biologically inspired model of neuronal development

Animal, especially vertebrate, visual systems exhibit extraordinary levels of plasticity in response to manipulations of the visual environment in both the developing and mature states. This plasticity is thought to reflect an underlying activity-dependent competition between afferent neurons at the anatomical and physiological levels. Such plasticity allows an animal to tune its visual system in a manner conditioned by the animal’s individual morphology and its particular environment. We implement a well-characterised, biologically inspired model of developmental synaptic plasticity on a Koala robot equipped with a binocular visual system. We use this system to simulate the development of certain, well-studied anatomical characteristics of the vertebrate visual system. We find that our results are exquisitely sensitive to the statistical structure of the visual environment. This structure also has a bearing on the success or otherwise of models proposed to deal with plasticity.