Characterization of cerebrospinal fluid biomarkers associated with neurodegenerative diseases in healthy cynomolgus and rhesus macaque monkeys.

Monkeys are becoming important translational models of neurodegenerative disease. To facilitate model development, we measured cerebrospinal fluid (CSF) concentrations of key biomarkers in healthy male and female cynomolgus and rhesus macaques. Amyloid beta (Aβ40, Aβ42), tau (total tau [t-tau], phosphorylated tau [pThr181]), and neurofilament light (NfL) concentrations were measured in CSF of 82 laboratory-housed, experimentally naïve cynomolgus (n = 33) and rhesus (n = 49) macaques.

The effect of lumbar puncture on the neurodegeneration biomarker neurofilament light in macaque monkeys.

Introduction: Neurofilament light (NFL) in cerebrospinal fluid (CSF) is elevated in neurodegenerative disease patients, and may track disease progression and treatment. Macaque monkeys are emerging as important translational models of neurodegeneration, and NFL may be a useful biomarker.

Methods: To determine the influence of a previous lumbar puncture (LP) on NFL, we collected CSF at multiple time points in macaque monkeys via LP or cisterna magna puncture.

Behavioral shaping of rhesus macaques using the Cambridge neuropsychological automated testing battery.

Background: The Cambridge neuropsychological test automated battery (CANTAB) is a set of computerized visuospatial tests used to probe cognition in humans. The non-human primate (NHP) version of the battery is a valuable translational research tool to quantify cognitive changes in NHP models of disease by allowing direct comparison with performance data from human patient populations. One limitation is the long training times required for NHPs to reach appropriate levels of task performance, which is prohibitive for high throughput experimental designs.

Understanding the link between insulin resistance and Alzheimer's disease: Insights from animal models.

Alzheimer's disease (AD) is a devastating neurodegenerative disease affecting millions of people worldwide. AD is characterized by a profound impairment of higher cognitive functions and still lacks any effective disease-modifying treatment. Defective insulin signaling has been implicated in AD pathophysiology, but the mechanisms underlying this process are not fully understood.

The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease-modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon-like peptide-1 (GLP-1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling.

Multisensory integration in orienting behavior: Pupil size, microsaccades, and saccades.

Signals from different sensory modalities are integrated in the brain to optimize behavior. Although multisensory integration has been demonstrated in saccadic eye movements, its influence on other orienting responses, including pupil size and microsaccades, is still poorly understood. We examined human gaze orienting responses following presentation of visual, auditory, or combined audiovisual stimuli.

Spatio-temporal response properties of local field potentials in the primate superior colliculus.

Local field potentials (LFPs) are becoming increasingly popular in neurophysiological studies. However, to date, most of the knowledge about LFPs has been obtained from cortical recordings. Here, we recorded single unit activity (SUA) and LFPs simultaneously from the superior colliculus (SC) of behaving rhesus monkeys.

Alzheimer's disease-like pathology induced by amyloid-β oligomers in nonhuman primates.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and a major medical problem. Here, we have investigated the impact of amyloid-β (Aβ) oligomers, AD-related neurotoxins, in the brains of rats and adult nonhuman primates (cynomolgus macaques). Soluble Aβ oligomers are known to accumulate in the brains of AD patients and correlate with disease-associated cognitive dysfunction.

Transient pupil response is modulated by contrast-based saliency.

The sudden appearance of a novel stimulus in the environment initiates a series of orienting responses that include coordinated shifts of gaze and attention, and also transient changes in pupil size. Although numerous studies have identified a significant effect of stimulus saliency on shifts of gaze and attention, saliency effects on pupil size are less understood. To examine salience-evoked pupil responses, we presented visual, auditory, or audiovisual stimuli while monkeys fixated a central visual spot.

Competitive integration of visual and goal-related signals on neuronal accumulation rate: a correlate of oculomotor capture in the superior colliculus.

The mechanisms that underlie the integration of visual and goal-related signals for the production of saccades remain poorly understood. Here, we examined how spatial proximity of competing stimuli shapes goal-directed responses in the superior colliculus (SC), a midbrain structure closely associated with the control of visual attention and eye movements. Monkeys were trained to perform an oculomotor-capture task [Theeuwes, J.

Microstimulation of the monkey superior colliculus induces pupil dilation without evoking saccades.

The orienting reflex is initiated by a salient stimulus and facilitates quick, appropriate action. It involves a rapid shift of the eyes, head, and attention and other physiological responses such as changes in heart rate and transient pupil dilation. The SC is a critical structure in the midbrain that selects incoming stimuli based on saliency and relevance to coordinate orienting behaviors, particularly gaze shifts, but its causal role in pupil dilation remains poorly understood in mammals.

Visual adaptation and novelty responses in the superior colliculus.

The brain's ability to ignore repeating, often redundant, information while enhancing novel information processing is paramount to survival. When stimuli are repeatedly presented, the response of visually sensitive neurons decreases in magnitude, that is, neurons adapt or habituate, although the mechanism is not yet known. We monitored the activity of visual neurons in the superior colliculus (SC) of rhesus monkeys who actively fixated while repeated visual events were presented.

The eccentricity effect for auditory saccadic reaction times is independent of target frequency.

Although much is understood about the stimulus properties affecting the latency of saccadic eye movements to visual targets, relatively little is known about the properties affecting saccades to auditory targets. This study examined the effect of three primary acoustic features-frequency, intensity, and spatial location-on auditory saccade characteristics in humans, and compared them to visual saccades. Saccade targets were presented from an azimuthal array of speakers and LEDs spanning +/-36 degrees.

Color-related signals in the primate superior colliculus.

Color is important for segmenting objects from backgrounds, which can in turn facilitate visual search in complex scenes. However, brain areas involved in orienting the eyes toward colored stimuli in our environment are not believed to have access to color information. Here, we show that neurons in the intermediate layers of the monkey superior colliculus (SC), a critical structure for the production of saccadic eye movements, can respond to isoluminant color stimuli with the same magnitude as a maximum contrast luminance stimulus.

Free viewing of dynamic stimuli by humans and monkeys.

Due to extensive homologies, monkeys provide a sophisticated animal model of human visual attention. However, for electrophysiological recording in behaving animals simplified stimuli and controlled eye position are traditionally used. To validate monkeys as a model for human attention during realistic free viewing, we contrasted human (n = 5) and monkey (n = 5) gaze behavior using 115 natural and artificial video clips.

On the importance of the transient visual response in the superior colliculus.

A salient event in the environment can initiate a complex orienting response that includes a shift in gaze. The midbrain superior colliculus (SC) contains the appropriate circuitry to generate and distribute a signal of the priority of this event, and co-ordinate the orienting response. The magnitude and timing of the short-latency transient visual response in the SC, when combined with cortical inputs signaling stimulus relevance and expectation, influences the type and latency of the orienting response.

Cue repetition increases inhibition of return.

Inhibition of return (IOR) refers to slowed responses to targets presented at the same location as a preceding stimulus. We explored whether the IOR effect would increase with the number of cues preceding the target (a 'cue'). Subjects performed a Posner cueing task with 1-5 cue presentations prior to the target, to which they made either a manual localization (Experiment 1) or target discrimination response (Experiment 2).

Physiological evidence that pyramidal neurons lack functional water channels.

The physiological conditions that swell mammalian neurons are clinically important but contentious. Distinguishing the neuronal component of brain swelling requires viewing intact neuronal cell bodies, dendrites, and axons and measuring their changing volume in real time. Cultured or dissociated neuronal somata swell within minutes under acutely overhydrated conditions and shrink when strongly dehydrated.

The relation between auditory temporal interval processing and sequential stream segregation examined with stimulus laterality differences.

In this study, we examine the effects of laterality differences between noise bursts on two objective measures of temporal interval processing (gap detection and temporal asymmetry detection) and one subjective measure of temporal organization (stream segregation). Noise bursts were lateralized by presentation to different ears or dichotic presentation with oppositely signed interaural level (ILD) or time (ITD) differences. Objective thresholds were strongly affected by ear-of-entry differences, were moderately affected by ILD differences, but were unaffected by ITD differences.

Auditory saltation in the vertical midsagittal plane.

Auditory saltation is an illusion in which a train of clicks, the first half of which is presented at one location and the other half of which is presented from a second location, is perceived as originating not only from the anchor points, but also from locations between them. That is, intermediate members of the series of clicks have their spatial locations systematically misperceived. In the present study, auditory saltation was examined for the first time in the vertical midsagittal plane.

Detection of static and dynamic changes in interaural correlation.

This study examines the relation between a static and a dynamic measure of interaural correlation discrimination: (1) the just noticeable difference (JND) in interaural correlation and (2) the minimum detectable duration of a fixed interaural correlation change embedded within a single noise-burst of a given reference correlation. For the first task, JNDs were obtained from reference interaural correlations of + 1, -1, and from 0 interaural correlation in either the positive or negative direction. For the dynamic task, duration thresholds were obtained for a brief target noise of +1, -1, and 0 interaural correlation embedded in reference marker noise of +1, -1, and 0 interaural correlation.

Spatial stimulus cue information supplying auditory saltation.

Auditory saltation is a misperception of the spatial location of repetitive, transient stimuli. It arises when clicks at one location are followed in perfect temporal cadence by identical clicks at a second location. This report describes two psychophysical experiments designed to examine the sensitivity of auditory saltation to different stimulus cues for auditory spatial perception.