Inhibition of Cdk5 in PV Neurons Reactivates Experience-Dependent Plasticity in Adult Visual Cortex

Cyclin-dependent kinase 5 (Cdk5) has been shown to play a critical role in brain development, learning, memory and neural processing in general. Cdk5 is widely distributed in many neuron types in the central nervous system, while its cell-specific role is largely unknown. Our previous study showed that Cdk5 inhibition restored ocular dominance (OD) plasticity in adulthood. In this study, we specifically knocked down Cdk5 in different types of neurons in the visual cortex and examined OD plasticity by optical imaging of intrinsic signals. Downregulation of Cdk5 in parvalbumin-expressing (PV) inhibitory neurons, but not other neurons, reactivated adult mouse visual cortical plasticity. Cdk5 knockdown in PV neurons reduced the evoked firing rate, which was accompanied by an increment in the threshold current for the generation of a single action potential (AP) and hyperpolarization of the resting membrane potential. Moreover, chemogenetic activation of PV neurons in the visual cortex can attenuate the restoration of OD plasticity by Cdk5 inhibition. Taken together, our results suggest that Cdk5 in PV interneurons may play a role in modulating the excitation and inhibition balance to control the plasticity of the visual cortex.

Heterosynaptic Plasticity and the Experience-Dependent Refinement of Developing Neuronal Circuits

Neurons remodel the structure and strength of their synapses during critical periods of development in order to optimize both perception and cognition. Many of these developmental synaptic changes are thought to occur through synapse-specific homosynaptic forms of experience-dependent plasticity. However, homosynaptic plasticity can also induce or contribute to the plasticity of neighboring synapses through heterosynaptic interactions. Decades of research in vitro have uncovered many of the molecular mechanisms of heterosynaptic plasticity that mediate local compensation for homosynaptic plasticity, facilitation of further bouts of plasticity in nearby synapses, and cooperative induction of plasticity by neighboring synapses acting in concert. These discoveries greatly benefited from new tools and technologies that permitted single synapse imaging and manipulation of structure, function, and protein dynamics in living neurons. With the recent advent and application of similar tools for in vivo research, it is now feasible to explore how heterosynaptic plasticity contribute to critical periods and the development of neuronal circuits. In this review, we will first define the forms heterosynaptic plasticity can take and describe our current understanding of their molecular mechanisms. Then, we will outline how heterosynaptic plasticity may lead to meaningful refinement of neuronal responses and observations that suggest such mechanisms are indeed at work in vivo. Finally, we will use a well-studied model of cortical plasticity—ocular dominance plasticity during a critical period of visual cortex development—to highlight the molecular overlap between heterosynaptic and developmental forms of plasticity, and suggest potential avenues of future research.

Symmetry of Peripapillary-Optical Coherence Tomography Angiography Parameters between Dominant and Non-dominant Eyes in Normal Eyes

Purpose: To assess whether optical coherence tomography (OCT) measurements and peripapillary microvascular parameters measured via optical coherence tomography angiography (OCTA) were similar between the dominant and non-dominant eyes of normal subjects.Methods: We retrospectively analyzed spectral domain OCT and OCTA data on healthy Koreans. The “hole-in-the-card” technique was used to determine ocular dominance. The perfusion density (PD) and flux index (FI) of the peripapillary 4.5 × 4.5-mm area were measured via OCTA. Central macular, peripapillary retinal nerve fiber layer, and macular ganglion cell-inner plexiform layer thicknesses were measured with the aid of spectral-domain OCT. The OCT and OCTA data of dominant and non-dominant eyes were compared.Results: A total of 84 eyes of 42 healthy subjects were analyzed. The average age was 27.3 ± 5.63 years. Twenty-eight subjects (66.7%) were right eye-dominant and 14 (33.3%) left eye-dominant. None of the central macular (260.00 ± 14.16 μm, 258.71 ± 15.18 μm, p = 0.183), macular ganglion cell-inner plexiform layer (82.02 ± 5.07 μm, 82.43 ± 5.60 μm, p = 0.460), or peripapillary retinal nerve fiber layer thickness (99.36 ± 9.27 μm, 97.90 ± 9.46 μm, p = 0.091) differed between the eyes; neither did any OCTA-assessed microvascular parameter.Conclusions: No OCT or OCTA parameter differed between dominant and non-dominant eyes. No parameter identified ocular dominance.

Short-term plasticity in the visual thalamus

While there is evidence that the visual cortex retains a potential for plasticity in adulthood, less is known about the subcortical stages of visual processing. Here we asked whether short-term ocular dominance plasticity affects the visual thalamus. We addressed this question in normally sighted adult humans, using ultra-high field (7T) magnetic resonance imaging combined with the paradigm of short-term monocular deprivation. With this approach, we previously demonstrated transient shifts of perceptual eye dominance and ocular dominance in visual cortex (Binda et al., 2018). Here we report evidence for short-term plasticity in the ventral division of the pulvinar (vPulv), where the deprived eye representation was enhanced over the non-deprived eye. This pulvinar plasticity effect was similar as previously seen in visual cortex and it was correlated with the ocular dominance shift measured behaviorally. In contrast, there was no short-term plasticity effect in Lateral Geniculate Nucleus (LGN), where results were reliably different from vPulv, despite their spatial proximity. We conclude that the visual thalamus retains potential for short-term plasticity in adulthood; the plasticity effect differs across thalamic subregions, possibly reflecting differences in their cortical connectivity.

The Expression Patterns of Cytochrome Oxidase and Immediate-Early Genes Show Absence of Ocular Dominance Columns in the Striate Cortex of Squirrel Monkeys Following Monocular Inactivation

Because at least some squirrel monkeys lack ocular dominance columns (ODCs) in the striate cortex (V1) that are detectable by cytochrome oxidase (CO) histochemistry, the functional importance of ODCs on stereoscopic 3-D vision has been questioned. However, conventional CO histochemistry or trans-synaptic tracer study has limited capacity to reveal cortical functional architecture, whereas the expression of immediate-early genes (IEGs), c-FOS and ZIF268, is more directly responsive to neuronal activity of cortical neurons to demonstrate ocular dominance (OD)-related domains in V1 following monocular inactivation. Thus, we wondered whether IEG expression would reveal ODCs in the squirrel monkey V1. In this study, we first examined CO histochemistry in V1 of five squirrel monkeys that were subjected to monocular enucleation or tetrodotoxin (TTX) treatment to address whether there is substantial cross-individual variation as reported previously. Then, we examined the IEG expression of the same V1 tissue to address whether OD-related domains are revealed. As a result, staining patterns of CO histochemistry were relatively homogeneous throughout layer 4 of V1. IEG expression was also moderate and homogeneous throughout layer 4 of V1 in all cases. On the other hand, the IEG expression was patchy in accordance with CO blobs outside layer 4, particularly in infragranular layers, although they may not directly represent OD clusters. Squirrel monkeys remain an exceptional species among anthropoid primates with regard to OD organization, and thus are potentially good subjects to study the development and function of ODCs.

Ocular Asymmetry in Electrooculographic Responses

Between the cornea and the posterior pole of the eye, there is a transepithelial potential capable of being registered through an electrooculogram (EOG). It is questionable whether electrooculographic responses are similar in both eyes despite ocular dominance in human beings. We studied the effect of different electrooculographic stimulation parameters, in terms of directionality, linear and angular velocity, contrast, and state of adaptation to light/dark, that may induce possible interocular differences in visual function. The study was carried out with electroencephalography-type surface electrodes placed in the medial, lateral, superior, and inferior positions of both human eyes to record the eye movements. We found a greater amplitude of the EOG response in the left eye than to the right eye for light bars moving from right to left (p < 0.01; t-test). The EOG response amplitude was similar in both eyes for light bars moving in vertical directions, but greater than horizontal or rotational stimuli. We conclude that vertical stimuli should be used for EOG functional evaluation of eye movements, since horizontal stimuli generate significant interocular differences.

Critical Period Plasticity as a Framework for Psychedelic-Assisted Psychotherapy

As psychedelic compounds gain traction in psychiatry, there is a need to consider the active mechanism to explain the effect observed in randomized clinical trials. Traditionally, biological psychiatry has asked how compounds affect the causal pathways of illness to reduce symptoms and therefore focus on analysis of the pharmacologic properties. In psychedelic-assisted psychotherapy (PAP), there is debate about whether ingestion of the psychedelic alone is thought to be responsible for the clinical outcome. A question arises how the medication and psychotherapeutic intervention together might lead to neurobiological changes that underlie recovery from illness such as post-traumatic stress disorder (PTSD). This paper offers a framework for investigating the neurobiological basis of PAP by extrapolating from models used to explain how a pharmacologic intervention might create an optimal brain state during which environmental input has enduring effects. Specifically, there are developmental “critical” periods (CP) with exquisite sensitivity to environmental input; the biological characteristics are largely unknown. We discuss a hypothesis that psychedelics may remove the brakes on adult neuroplasticity, inducing a state similar to that of neurodevelopment. In the visual system, progress has been made both in identifying the biological conditions which distinguishes the CP and in manipulating the active ingredients with the idea that we might pharmacologically reopen a critical period in adulthood. We highlight ocular dominance plasticity (ODP) in the visual system as a model for characterizing CP in limbic systems relevant to psychiatry. A CP framework may help to integrate the neuroscientific inquiry with the influence of the environment both in development and in PAP.

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). This binary form of circuit plasticity is unique, as it is transient, local, and discrete. It lasts only 1 d, and it does not manifest as widespread changes in synaptic strength; rather, only about half of local connections are lost, and the remaining ones are not affected in strength. Mechanistically, the deprivation-induced loss of Pyr→PV is contingent on a reduction of the protein neuropentraxin2. Functionally, the loss of Pyr→PV is absolutely necessary for ocular dominance plasticity, a canonical model of deprivation-induced model of cortical remodeling. We surmise, therefore, that this all-or-none loss of local Pyr→PV circuitry gates experience-dependent cortical plasticity.