Enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits.

We present an enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits. Best-in-class vectors were curated for accessing major striatal neuron populations including medium spiny neurons (MSNs), direct and indirect pathway MSNs, as well as Sst-Chodl, Pvalb-Pthlh, and cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, three different routes of virus delivery, and with diverse transgene cargos.

Comparison of adaptation characteristics between visually and memory-guided saccades.

Saccade adaptation plays a crucial role in maintaining saccade accuracy. The behavioral characteristics and neural mechanisms of saccade adaptation for an externally cued movement, such as visually guided saccades (VGS), are well studied in nonhuman primates. In contrast, little is known about the saccade adaptation of an internally driven movement, such as memory-guided saccades (MGS), which are guided by visuospatial working memory.

Cognition and saccadic eye movement performance are impaired in chronic rhinosinusitis.

Background: Patients with chronic rhinosinusitis (CRS) can experience cognitive dysfunction. The literature on this topic mostly reflects patient-reported measurements. Our goal was to assess cognitive function in patients with CRS using objective measures, including saccadic eye movements-a behavioral response reflecting cognitive and sensory information integration that is often compromised in conditions with impaired cognition.

The superior colliculus projection upon the macaque inferior olive.

Saccade accommodation is a productive model for exploring the role of the cerebellum in behavioral plasticity. In this model, the target is moved during the saccade, gradually inducing a change in the saccade vector as the animal adapts. The climbing fiber pathway from the inferior olive provides a visual error signal generated by the superior colliculus that is believed to be crucial for cerebellar adaptation.

Compensatory saccade in the vestibular impaired monkey.

Introduction: Loss of the vestibulo-ocular reflex (VOR) affects visual acuity during head movements. Patients with unilateral and bilateral vestibular deficits often use saccadic eye movements to compensate for an inadequate VOR. Two types of compensatory saccades have been distinguished, covert saccades and overt saccades.

Activity of the Substantia Nigra Pars Reticulata during Saccade Adaptation.

When movements become inaccurate, the resultant error induces motor adaptation to improve accuracy. This error-based motor learning is regarded as a cerebellar function. However, the influence of the other brain areas on adaptation is poorly understood.

The Superior Colliculus Projection Upon the Macaque Inferior Olive.

Saccade accommodation is a productive model for exploring the role of the cerebellum in behavioral plasticity. In this model, the target is moved during the saccade, gradually inducing a change in the saccade vector as the animal adapts. The climbing fiber pathway from the inferior olive provides a visual error signal generated by the superior colliculus that is believed to be crucial for cerebellar adaptation.

P-sort: an open-source software for cerebellar neurophysiology.

Analysis of electrophysiological data from Purkinje cells (P-cells) of the cerebellum presents unique challenges to spike sorting. Complex spikes have waveforms that vary significantly from one event to the next, raising the problem of misidentification. Even when complex spikes are detected correctly, the simple spikes may belong to a different P-cell, raising the danger of misattribution.

Injections of AAV Vectors for Optogenetics in Anesthetized and Awake Behaving Non-Human Primate Brain.

Optogenetic techniques have revolutionized neuroscience research and are poised to do the same for neurological gene therapy. The clinical use of optogenetics, however, requires that safety and efficacy be demonstrated in animal models, ideally in non-human primates (NHPs), because of their neurological similarity to humans. The number of candidate vectors that are potentially useful for neuroscience and medicine is vast, and no high-throughput means to test these vectors yet exists.

Functional enhancer elements drive subclass-selective expression from mouse to primate neocortex.

Viral genetic tools that target specific brain cell types could transform basic neuroscience and targeted gene therapy. Here, we use comparative open chromatin analysis to identify thousands of human-neocortical-subclass-specific putative enhancers from across the genome to control gene expression in adeno-associated virus (AAV) vectors. The cellular specificity of reporter expression from enhancer-AAVs is established by molecular profiling after systemic AAV delivery in mouse.

The Substantia Nigra Pars Reticulata Modulates Error-Based Saccadic Learning in Monkeys.

The basal ganglia have long been considered crucial for associative learning, but whether they also are involved in another type of learning, error-based motor learning, is not clear. Error-based learning has been considered the province of the cerebellum. However, learning to use a robotic arm and saccade adaptation, which use error-based learning, are facilitated by motivation, which is a function of the basal ganglia.

A neuronal process for adaptive control of primate saccadic system.

In 1980, Dr. Optican established the existence of an adaptive plasticity of saccades and its dependence on the cerebellum with Dr. Robinson.

How cerebellar motor learning keeps saccades accurate.

The neuronal substrate underlying the learning of a sophisticated task has been difficult to study. However, the advent of a behavioral paradigm that deceives the saccadic system into thinking it is making an error has allowed the mechanisms of the adaptation that corrects this error to be revealed in a primate. The neural elements that fashion the command signal for the generation of accurate saccades involve subcortical structures in the brain stem and cerebellum.

Elimination of the error signal in the superior colliculus impairs saccade motor learning.

When movements become dysmetric, the resultant motor error induces a plastic change in the cerebellum to correct the movement, i.e., motor adaptation.

Encoding of error and learning to correct that error by the Purkinje cells of the cerebellum.

The primary output cells of the cerebellar cortex, Purkinje cells, make kinematic predictions about ongoing movements via high-frequency simple spikes, but receive sensory error information about that movement via low-frequency complex spikes (CS). How is the vector space of sensory errors encoded by this low-frequency signal? Here we measured Purkinje cell activity in the oculomotor vermis of animals during saccades, then followed the chain of events from experience of visual error, generation of CS, modulation of simple spikes, and ultimately change in motor output. We found that while error direction affected the probability of CS, error magnitude altered its temporal distribution.

Change in sensitivity to visual error in superior colliculus during saccade adaptation.

Saccadic eye movements provide a valuable model to study the brain mechanisms underlying motor learning. If a target is displaced surreptitiously while a saccade is underway, the saccade appears to be in error. If the error persists gradual neuronal adjustments cause the eye movement again to land near the target.

Selective Optogenetic Control of Purkinje Cells in Monkey Cerebellum.

Purkinje cells of the primate cerebellum play critical but poorly understood roles in the execution of coordinated, accurate movements. Elucidating these roles has been hampered by a lack of techniques for manipulating spiking activity in these cells selectively-a problem common to most cell types in non-transgenic animals. To overcome this obstacle, we constructed AAV vectors carrying the channelrhodopsin-2 (ChR2) gene under the control of a 1 kb L7/Pcp2 promoter.

Selective reward affects the rate of saccade adaptation.

In this study we tested whether a selective reward could affect the adaptation of saccadic eye movements in monkeys. We induced the adaptation of saccades by displacing the target of a horizontal saccade vertically as the eye moved toward it, thereby creating an apparent vertical dysmetria. The repeated upward target displacement caused the originally horizontal saccade to gradually deviate upward over the course of several hundred trials.

Encoding of action by the Purkinje cells of the cerebellum.

Execution of accurate eye movements depends critically on the cerebellum, suggesting that the major output neurons of the cerebellum, Purkinje cells, may predict motion of the eye. However, this encoding of action for rapid eye movements (saccades) has remained unclear: Purkinje cells show little consistent modulation with respect to saccade amplitude or direction, and critically, their discharge lasts longer than the duration of a saccade. Here we analysed Purkinje-cell discharge in the oculomotor vermis of behaving rhesus monkeys (Macaca mulatta) and found neurons that increased or decreased their activity during saccades.

Adaptation and adaptation transfer characteristics of five different saccade types in the monkey.

Shifts in the direction of gaze are accomplished by different kinds of saccades, which are elicited under different circumstances. Saccade types include targeting saccades to simple jumping targets, delayed saccades to visible targets after a waiting period, memory-guided (MG) saccades to remembered target locations, scanning saccades to stationary target arrays, and express saccades after very short latencies. Studies of human cases and neurophysiological experiments in monkeys suggest that separate pathways, which converge on a common locus that provides the motor command, generate these different types of saccade.

Cerebellar fastigial nucleus influence on ipsilateral abducens activity during saccades.

To characterize the cerebellar influence on neurons in the abducens (ABD) nucleus, we recorded ABD neurons before and after we inactivated the caudal part of the ipsilateral cerebellar fastigial nucleus (cFN) with muscimol injection. cFN activity influences the horizontal component of saccades. cFN inactivation increased the activity of most ipsilateral ABD neurons (19/22 in 2 monkeys) during ipsiversive (hypermetric) saccades, primarily by increasing burst duration.

A case of streptococcal toxic shock syndrome due to Group G streptococci identified as Streptococcus dysgalactiae subsp. equisimilis.

A 79-year-old man with a 3-month history of lymphedema of the lower limbs, and diabetes mellitus, was admitted to our hospital for suspected deep venous thrombosis. Several hours after admission, leg pain and purpura-like skin color appeared. On the 2nd hospital day, he was referred to our department for possible acute occlusive peripheral artery disease (PAD) and skin necrosis with blisters; however, computed tomography with contrast showed no occlusive lesions.

Effect of inactivation and disinhibition of the oculomotor vermis on saccade adaptation.

The ability to adapt a variety of motor acts to compensate for persistent natural or artificially induced errors in movement accuracy requires the cerebellum. For adaptation of the rapid shifts in the direction of gaze called saccades, the oculomotor vermis (OMV) of the cerebellum must be intact. We disrupted the neural circuitry of the OMV by manipulating gamma aminobutyric acid (GABA), the transmitter used by many neurons in the vermis.