Retrograde Optogenetics Reveals Functional Convergence within a Corticotectal Pathway of Non-Human Primates.

Understanding how cerebral cortex communicates with subcortical areas to drive behavior remains a central question in system neuroscience. One key unresolved issue is whether prefrontal cortical outputs to motor-related subcortical regions carry predominantly motor commands or mixed sensory - motor signals. Retrograde optogenetics offers a powerful way to interrogate such projection-defined circuits, but its use in non-human primates has been limited.

Position paper: leveraging non-human primate (NHP) specificities to accelerate Parkinson's disease and ageing research.

The PD-AGE international task force underscores the pivotal role that non-human primate (NHP) models play in advancing our understanding of Parkinson's disease (PD) and ageing. Due to their close genetic, anatomical, and behavioural similarity to humans, NHPs uniquely enable translational research to bridge basic science towards clinical application. They are indispensable for modelling the complex motor and non-motor symptoms of PD, as well as age-related neurodegeneration.

Distinct roles of two thalamostriatal systems in visually triggered decision-making in common marmosets.

The cortico-basal ganglia circuitry plays important roles in the control of various higher-order functions, such as motor control, cognition, and emotion. The thalamostriatal system is involved in learning and switching of behaviors and recovery from cognitive and motor deficits in rodents. Here, we applied selective neural pathway targeting to investigate roles of two representative thalamostriatal pathways arising from the parafascicular nucleus (Pf) and centre médian nucleus (CM) in common marmosets.

Three-dimensional markerless motion capture of multiple freely behaving monkeys toward automated characterization of social behavior.

Given their high sociality and close evolutionary distance to humans, monkeys are an essential animal model for unraveling the biological mechanisms underlying human social behavior and elucidating the pathogenesis of diseases exhibiting abnormal social behavior. However, behavioral analysis of naturally behaving monkeys requires manual counting of various behaviors, which has been a bottleneck due to problems in throughput and objectivity. Here, we developed a three-dimensional markerless motion capture system that used multi-view data for robust tracking of individual monkeys and accurate reconstruction of the three-dimensional poses of multiple monkeys living in groups.

Bidirectional optogenetic modulation of peripheral sensory nerve activity: Induction vs. suppression through channelrhodopsin and halorhodopsin.

In this study, we investigated the potential of optogenetics for modulating activity of peripheral sensory nerves, particularly tactile and proprioceptive afferents. Using adeno-associated virus serotype 9 vector, we selectively transduced channelrhodopsin (ChR2(H134R)) and halorhodopsin (eNpHR3.0) into large-diameter sciatic nerve afferents of rats.

Evaluation of the loading capacity and patterns of packaged DNA in AAV genomes of different sizes using long-read sequencing.

The loading capacity of adeno-associated virus (AAV) vectors is reportedly 4.7-5.0 kb, which limits the size of genes that can be treated with gene therapy.

Functional Heterogeneity within the Primate Ventral Striatum for Motivational Regulation.

The ventral striatum (VS) is a key brain region for reward processing and motivation, and its dysfunctions have been implicated in psychiatric disorders such as apathy and obsessive-compulsive disorder. Although functional heterogeneity within the VS has been well established in rodents, its relevance and mechanisms in primates remain unclear. To address this issue, we performed bilateral pharmacological inactivation of the VS in two male macaque monkeys using muscimol, a GABA receptor agonist.

Fluorescence detection of dopamine signaling to the primate striatum in relation to stimulus-reward associations.

Dopamine (DA) signals to the striatum play critical roles in shaping and sustaining stimulus-reward associations. In primates, however, the dynamics of the DA signals remain unknown since conventional methods are not necessarily appropriate in terms of the spatiotemporal resolution or chemical specificity sufficient for detecting the DA signals. In our study, fiber photometry with a fluorescent DA sensor was employed to identify reward-related DA transients in the monkey striatum.

Temporal dynamics of neurovascular unit changes following blood-brain barrier opening in the putamen of non-human primates.

Low-intensity focused ultrasound (LIFU) combined with intravenously circulating microbubbles has recently emerged as a novel approach for increasing delivery through the blood-brain barrier (BBB). This technique safely and transiently enables therapeutic agents to overcome the BBB, which typically poses a significant obstacle for treatment of brain disorders. However, the full impact of LIFU on the entire neurovascular unit (NVU), as well as the mechanisms and factors involved in restoring BBB integrity still require further elucidation.

Distinct roles of monkey OFC-subcortical pathways in adaptive behavior.

Primates must adapt to changing environments by optimizing their behavior to make beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities.

Deciphering social traits and pathophysiological conditions from natural behaviors in common marmosets.

Nonhuman primates (NHPs) are indispensable animal models by virtue of the continuity of behavioral repertoires across primates, including humans. However, behavioral assessment at the laboratory level has so far been limited. Employing the application of three-dimensional (3D) pose estimation and the optimal integration of subsequent analytic methodologies, we demonstrate that our artificial intelligence (AI)-based approach has successfully deciphered the ethological, cognitive, and pathological traits of common marmosets from their natural behaviors.

Distinct roles of monkey OFC-subcortical pathways in adaptive behavior.

To be the most successful, primates must adapt to changing environments and optimize their behavior by making the most beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities.

Reward expectation enhances action-related activity of nigral dopaminergic and two striatal output pathways.

Neurons comprising nigrostriatal system play important roles in action selection. However, it remains unclear how this system integrates recent outcome information with current action (movement) and outcome (reward or no reward) information to achieve appropriate subsequent action. We examined how neuronal activity of substantia nigra pars compacta (SNc) and dorsal striatum reflects the level of reward expectation from recent outcomes in rats performing a reward-based choice task.

Multimodal Imaging for Validation and Optimization of Ion Channel-Based Chemogenetics in Nonhuman Primates.

Chemogenetic tools provide an opportunity to manipulate neuronal activity and behavior selectively and repeatedly in nonhuman primates (NHPs) with minimal invasiveness. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are one example that is based on mutated muscarinic acetylcholine receptors. Another channel-based chemogenetic system available for neuronal modulation in NHPs uses pharmacologically selective actuator modules (PSAMs), which are selectively activated by pharmacologically selective effector molecules (PSEMs).

A mosaic adeno-associated virus vector as a versatile tool that exhibits high levels of transgene expression and neuron specificity in primate brain.

Recent emphasis has been placed on gene transduction mediated through recombinant adeno-associated virus (AAV) vector to manipulate activity of neurons and their circuitry in the primate brain. In the present study, we created a novel vector of which capsid was composed of capsid proteins derived from both of the AAV serotypes 1 and 2 (AAV1 and AAV2). Following the injection into the frontal cortex of macaque monkeys, this mosaic vector, termed AAV2.

Reorganization of Corticospinal Projections after Prominent Recovery of Finger Dexterity from Partial Spinal Cord Injury in Macaque Monkeys.

We investigated morphologic changes in the corticospinal tract (CST) to understand the mechanism underlying recovery of hand function after lesion of the CST at the C4/C5 border in seven macaque monkeys. All monkeys exhibited prominent recovery of precision grip success ratio within a few months. The trajectories and terminals of CST from the contralesional ( = 4) and ipsilesional ( = 3) hand area of primary motor cortex (M1) were investigated at 5-29 months after the injury using an anterograde neural tracer, biotinylated dextran amine (BDA).

Environmental context-dependent activation of dopamine neurons via putative amygdala-nigra pathway in macaques.

Seeking out good and avoiding bad objects is critical for survival. In practice, objects are rarely good every time or everywhere, but only at the right time or place. Whereas the basal ganglia (BG) are known to mediate goal-directed behavior, for example, saccades to rewarding objects, it remains unclear how such simple behaviors are rendered contingent on higher-order factors, including environmental context.

BBB opening with focused ultrasound in nonhuman primates and Parkinson's disease patients: Targeted AAV vector delivery and PET imaging.

Intracerebral vector delivery in nonhuman primates has been a major challenge. We report successful blood-brain barrier opening and focal delivery of adeno-associated virus serotype 9 vectors into brain regions involved in Parkinson's disease using low-intensity focus ultrasound in adult macaque monkeys. Openings were well tolerated with generally no associated abnormal magnetic resonance imaging signals.

Diurnal variation in declarative memory and the involvement of SCOP in cognitive functions in nonhuman primates.

Cognitive functions depend on the time of day in various organisms. Previously, we found that 24-h recognition memory performance of nocturnal mice changes diurnally through SCOP protein-dependent regulation. It remains unknown whether diurnal change and SCOP-dependent regulation of memory performance are conserved across species with diurnal/nocturnal habits.

Chemogenetic attenuation of cortical seizures in nonhuman primates.

Epilepsy is a disorder in which abnormal neuronal hyperexcitation causes several types of seizures. Because pharmacological and surgical treatments occasionally interfere with normal brain function, a more focused and on-demand approach is desirable. Here we examined the efficacy of a chemogenetic tool-designer receptors exclusively activated by designer drugs (DREADDs)-for treating focal seizure in a nonhuman primate model.