Adult visual deprivation engages associative, presynaptic plasticity of thalamic input to cortex.

Associative plasticity at thalamocortical synapses is thought to be constrained by age in the mammalian cortex. However, here we show for the first time that prolonged visual deprivation induces robust and reversible plasticity at synapses between first order visual thalamus and cortical layer 4 pyramidal neurons. The plasticity is associative and expressed by changes in presynaptic function, thereby amplifying and relaying the change in efferent drive to the visual cortex.

Chronic Monocular Deprivation Reveals MMP9-Dependent and -Independent Aspects of Murine Visual System Plasticity.

The deletion of matrix metalloproteinase MMP9 is combined here with chronic monocular deprivation (cMD) to identify the contributions of this proteinase to plasticity in the visual system. Calcium imaging of supragranular neurons of the binocular region of primary visual cortex (V1b) of wild-type mice revealed that cMD initiated at eye opening significantly decreased the strength of deprived-eye visual responses to all stimulus contrasts and spatial frequencies. cMD did not change the selectivity of V1b neurons for the spatial frequency, but orientation selectivity was higher in low spatial frequency-tuned neurons, and orientation and direction selectivity were lower in high spatial frequency-tuned neurons.

All-or-none disconnection of pyramidal inputs onto parvalbumin-positive interneurons gates ocular dominance plasticity.

Disinhibition is an obligatory initial step in the remodeling of cortical circuits by sensory experience. Our investigation on disinhibitory mechanisms in the classical model of ocular dominance plasticity uncovered an unexpected form of experience-dependent circuit plasticity. In the layer 2/3 of mouse visual cortex, monocular deprivation triggers a complete, "all-or-none," elimination of connections from pyramidal cells onto nearby parvalbumin-positive interneurons (Pyr→PV).

High-Frequency Visual Stimulation Primes Gamma Oscillations for Visually Evoked Phase Reset and Enhances Spatial Acuity.

The temporal frequency of sensory stimulation is a decisive factor in the plasticity of perceptual detection thresholds. However, surprisingly little is known about how distinct temporal parameters of sensory input differentially recruit activity of neuronal circuits in sensory cortices. Here we demonstrate that brief repetitive visual stimulation induces long-term plasticity of visual responses revealed 24 h after stimulation and that the location and generalization of visual response plasticity is determined by the temporal frequency of the visual stimulation.

Naturalistic Spike Trains Drive State-Dependent Homeostatic Plasticity in Superficial Layers of Visual Cortex.

The history of neural activity determines the synaptic plasticity mechanisms employed in the brain. Previous studies report a rapid reduction in the strength of excitatory synapses onto layer 2/3 (L2/3) pyramidal neurons of the primary visual cortex (V1) following two days of dark exposure and subsequent re-exposure to light. The abrupt increase in visually driven activity is predicted to drive homeostatic plasticity, however, the parameters of neural activity that trigger these changes are unknown.

Homeostatic regulation of perisynaptic matrix metalloproteinase 9 (MMP9) activity in the amblyopic visual cortex.

Dark exposure (DE) followed by light reintroduction (LRx) reactivates robust synaptic plasticity in adult mouse primary visual cortex (V1), which allows subsequent recovery from amblyopia. Previously we showed that perisynaptic proteolysis by MMP9 mediates the enhancement of plasticity by LRx in binocular adult mice (Murase et al., 2017).

17α Estradiol promotes plasticity of spared inputs in the adult amblyopic visual cortex.

The promotion of structural and functional plasticity by estrogens is a promising approach to enhance central nervous system function in the aged. However, how the sensitivity to estrogens is regulated across brain regions, age and experience is poorly understood. To ask if estradiol treatment impacts structural and functional plasticity in sensory cortices, we examined the acute effect of 17α-Estradiol in adult Long Evans rats following chronic monocular deprivation, a manipulation that reduces the strength and selectivity of deprived eye vision.

Acute forced exercise increases Bdnf IV mRNA and reduces exploratory behavior in C57BL/6J mice.

Acute exercise has been shown to improve memory in humans. Potential mechanisms include increased Bdnf expression, noradrenergic activity and modification of glutamate receptors. Because mice are commonly used to study exercise and brain plasticity, it is important to explore how acute exercise impacts behavior in this model.

Critical periods in amblyopia.

The shift in ocular dominance (OD) of binocular neurons induced by monocular deprivation is the canonical model of synaptic plasticity confined to a postnatal critical period. Developmental constraints on this plasticity not only lend stability to the mature visual cortical circuitry but also impede the ability to recover from amblyopia beyond an early window. Advances with mouse models utilizing the power of molecular, genetic, and imaging tools are beginning to unravel the circuit, cellular, and molecular mechanisms controlling the onset and closure of the critical periods of plasticity in the primary visual cortex (V1).

Two distinct mechanisms for experience-dependent homeostasis.

Models of firing rate homeostasis such as synaptic scaling and the sliding synaptic plasticity modification threshold predict that decreasing neuronal activity (for example, by sensory deprivation) will enhance synaptic function. Manipulations of cortical activity during two forms of visual deprivation, dark exposure (DE) and binocular lid suture, revealed that, contrary to expectations, spontaneous firing in conjunction with loss of visual input is necessary to lower the threshold for Hebbian plasticity and increase miniature excitatory postsynaptic current (mEPSC) amplitude. Blocking activation of GluN2B receptors, which are upregulated by DE, also prevented the increase in mEPSC amplitude, suggesting that DE potentiates mEPSCs primarily through a Hebbian mechanism, not through synaptic scaling.

Light reintroduction after dark exposure reactivates plasticity in adults via perisynaptic activation of MMP-9.

The sensitivity of ocular dominance to regulation by monocular deprivation is the canonical model of plasticity confined to a critical period. However, we have previously shown that visual deprivation through dark exposure (DE) reactivates critical period plasticity in adults. Previous work assumed that the elimination of visual input was sufficient to enhance plasticity in the adult mouse visual cortex.

Neuregulin-Dependent Regulation of Fast-Spiking Interneuron Excitability Controls the Timing of the Critical Period.

Unlabelled: Maturation of excitatory drive onto fast-spiking interneurons (FS INs) in the visual cortex has been implicated in the control of the timing of the critical period for ocular dominance plasticity. However, the mechanisms that regulate the strength of these synapses over cortical development are not understood. Here we use a mouse model to show that neuregulin (NRG) and the receptor tyrosine kinase erbB4 regulate the timing of the critical period.

Optimization of visual training for full recovery from severe amblyopia in adults.

The severe amblyopia induced by chronic monocular deprivation is highly resistant to reversal in adulthood. Here we use a rodent model to show that recovery from deprivation amblyopia can be achieved in adults by a two-step sequence, involving enhancement of synaptic plasticity in the visual cortex by dark exposure followed immediately by visual training. The perceptual learning induced by visual training contributes to the recovery of vision and can be optimized to drive full recovery of visual acuity in severely amblyopic adults.

Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability.

In early postnatal development, naturally occurring cell death, dendritic outgrowth, and synaptogenesis sculpt neuronal ensembles into functional neuronal circuits. Here, we demonstrate that deletion of the extracellular proteinase matrix metalloproteinase-9 (MMP-9) affects each of these processes, resulting in maladapted neuronal circuitry. MMP-9 deletion increases the number of CA1 pyramidal neurons but decreases dendritic length and complexity.

Obligatory role for the immediate early gene NARP in critical period plasticity.

The immediate early gene neuronal activity-regulated pentraxin (NARP) is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) binding protein that is specifically enriched at excitatory synapses onto fast-spiking parvalbumin-positive interneurons (FS [PV] INs). Here, we show that transgenic deletion of NARP decreases the number of excitatory synaptic inputs onto FS (PV) INs and reduces net excitatory synaptic drive onto FS (PV) INs. Accordingly, the visual cortex of NARP(-/-) mice is hyperexcitable and unable to express ocular dominance plasticity, although many aspects of visual function are unimpaired.

Repetitive visual stimulation enhances recovery from severe amblyopia.

Severe amblyopia, characterized by a significant reduction in visual acuity through the affected eye, is highly resistant to reversal in adulthood. We have previously shown that synaptic plasticity can be reactivated in the adult rat visual cortex by dark exposure, and the reactivated plasticity can be harnessed to promote the recovery from severe amblyopia. Here we show that deprived-eye visually evoked responses are rapidly strengthened in dark-exposed amblyopes by passive viewing of repetitive visual stimuli.

Recovery from chronic monocular deprivation following reactivation of thalamocortical plasticity by dark exposure.

Chronic monocular deprivation induces severe amblyopia that is resistant to spontaneous reversal. However, dark exposure initiated in adulthood reactivates synaptic plasticity in the visual cortex and promotes recovery from chronic monocular deprivation in Long Evans rats. Here we show that chronic monocular deprivation induces a significant decrease in the density of dendritic spines on principal neurons throughout the deprived visual cortex.

A refractory period for rejuvenating GABAergic synaptic transmission and ocular dominance plasticity with dark exposure.

Dark exposure initiated in adulthood reactivates robust ocular dominance plasticity in the visual cortex. Here, we show that a critical component of the response to dark exposure is the rejuvenation of inhibitory synaptic transmission, resulting in a decrease in functional inhibitory synaptic density, a decrease in paired-pulse depression, and a reexpression of endocannabinoid-dependent inhibitory long-term depression (iLTD). Importantly, pharmacological acceleration of the maturation of inhibition in dark-exposed adults inhibits the reexpression of iLTD and the reactivation of ocular dominance plasticity.

Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes.

Cortical GABAergic dysfunction may underlie the pathophysiology of psychiatric disorders, including schizophrenia. Here, we characterized a mouse strain in which the essential NR1 subunit of the NMDA receptor (NMDAR) was selectively eliminated in 40-50% of cortical and hippocampal interneurons in early postnatal development. Consistent with the NMDAR hypofunction theory of schizophrenia, distinct schizophrenia-related symptoms emerged after adolescence, including novelty-induced hyperlocomotion, mating and nest-building deficits, as well as anhedonia-like and anxiety-like behaviors.

Pharmacology of ionotropic and metabotropic glutamate receptors on neurons involved in feeding behavior in the pond snail, Helisoma trivolvis.

Glutamate is a key regulatory neurotransmitter in the triphasic central pattern generator controlling feeding behavior in the pond snail, Helisoma trivolvis. It excites phase two motor neurons while inhibiting those in phases one and three. However, the receptors that mediate this regulation are only partially characterized.

Experience-dependent recovery of vision following chronic deprivation amblyopia.

The shift in ocular dominance induced by brief monocular deprivation is greatest during a postnatal critical period and is thought to decline irreversibly thereafter. However, here we demonstrate that complete visual deprivation through dark exposure restores rapid ocular dominance plasticity in adult rats. In addition, the loss of visual acuity resulting from chronic monocular deprivation is reversed if dark exposure precedes removal of the occlusion in adulthood, suggesting a potential use for dark exposure in the treatment of adult amblyopia.

Learning in the absence of experience-dependent regulation of NMDAR composition.

Olfactory discrimination (OD) learning consists of two phases: an initial N-methyl-D-aspartate (NMDA) receptor-sensitive rule-learning phase, followed by an NMDA receptor (NMDAR)-insensitive pair-learning phase. The rule-learning phase is accompanied by changes in the composition and function of NMDARs at synapses in the piriform cortex, resulting in a high level of the NR2a subunit relative to NR2b. Here we show that the learning-induced changes in NMDAR composition in the adult piriform cortex are due to a decrease in the level of the NR2b subunit protein, rather than an increase in the level of NR2a.

Visual deprivation reactivates rapid ocular dominance plasticity in adult visual cortex.

Brief monocular deprivation (< or =3 d) induces a rapid shift in the ocular dominance of binocular neurons in the juvenile rodent visual cortex but is ineffective in adults. Here, we report that persistent, rapid, juvenile-like ocular dominance plasticity can be reactivated in adult rodent visual cortex when monocular deprivation is preceded by visual deprivation. Ocular dominance shifts in visually deprived adults are caused by a rapid depression of the response to stimulation of the deprived eye, previously only reported in juveniles, and a simultaneous potentiation of the response to stimulation of the nondeprived eye.

A model of bidirectional synaptic plasticity: from signaling network to channel conductance.

In many regions of the brain, including the mammalian cortex, the strength of synaptic transmission can be bidirectionally regulated by cortical activity (synaptic plasticity). One line of evidence indicates that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD), correlate with the phosphorylation/dephosphorylation of sites on the alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit protein GluR1. Bidirectional synaptic plasticity can be induced by different frequencies of presynaptic stimulation, but there is considerable evidence indicating that the key variable is calcium influx through postsynaptic N-methyl-d-aspartate (NMDA) receptors.