Pathways for Naturalistic Looking Behavior in Primate II. Superior Colliculus Integrates Parallel Top-down and Bottom-up Inputs.

Volitional signals for gaze control are provided by multiple parallel pathways converging on the midbrain superior colliculus (SC), whose deeper layers output to the brainstem gaze circuits. In the first of two papers (Takahashi and Veale, 2023), we described the properties of gaze behavior of several species under both laboratory and natural conditions, as well as the current understanding of the brainstem and spinal cord circuits implementing gaze control in primate. In this paper, we review the parallel pathways by which sensory and task information reaches SC and how these sensory and task signals interact within SC's multilayered structure. This includes both bottom-up (world statistics) signals mediated by sensory cortex, association cortex, and subcortical structures, as well as top-down (goal and task) influences which arrive via either direct excitatory pathways from cerebral cortex, or via indirect basal ganglia relays resulting in inhibition or dis-inhibition as appropriate for alternative behaviors. Models of attention such as saliency maps serve as convenient frameworks to organize our understanding of both the separate computations of each neural pathway, as well as the interaction between the multiple parallel pathways influencing gaze. While the spatial interactions between gaze's neural pathways are relatively well understood, the temporal interactions between and within pathways will be an important area of future study, requiring both improved technical methods for measurement and improvement of our understanding of how temporal dynamics results in the observed spatiotemporal allocation of gaze.

Majority rule can help solve difficult tasks even when confident members opt out to serve individual interests.

When sharing a common goal, confident and competent members are often motivated to contribute to the group, boosting its decision performance. However, it is unclear whether this process remains effective when members can opt in or out of group decisions and prioritize individual interests. Our laboratory experiment (n = 63) and cognitive modeling showed that at the individual level, confidence, competence, and a preference for risk motivated participants' opt-out decisions. We then analyzed the group-level accuracy of majority decisions by creating many virtual groups of 25 members resampled from the 63 participants in the experiment. Whereas the majority decisions by voters who preferred to participate in group decision making were inferior to individual decisions by loners who opted out in an easy task, this was reversed in a difficult task. Bootstrap-simulation analyses decomposed these outcomes into the effects of a decrease in group size and a decrease in voters' accuracy accruing from the opt-in/out mechanism, demonstrating how these effects interacted with task difficulty. Our results suggest that the majority rule still works to tackle challenging problems even when individual interests are emphasized over collective performance, playing a functional as well as a democratic role in consensus decision making under uncertainty.

Pathways for Naturalistic Looking Behavior in Primate I: Behavioral Characteristics and Brainstem Circuits.

Organisms control their visual worlds by moving their eyes, heads, and bodies. This control of "gaze" or "looking" is key to survival and intelligence, but our investigation of the underlying neural mechanisms in natural conditions is hindered by technical limitations. Recent advances have enabled measurement of both brain and behavior in freely moving animals in complex environments, expanding on historical head-fixed laboratory investigations. We juxtapose looking behavior as traditionally measured in the laboratory against looking behavior in naturalistic conditions, finding that behavior changes when animals are free to move or when stimuli have depth or sound. We specifically focus on the brainstem circuits driving gaze shifts and gaze stabilization. The overarching goal of this review is to reconcile historical understanding of the differential neural circuits for different "classes" of gaze shift with two inconvenient truths. (1) "classes" of gaze behavior are artificial. (2) The neural circuits historically identified to control each "class" of behavior do not operate in isolation during natural behavior. Instead, multiple pathways combine adaptively and non-linearly depending on individual experience. While the neural circuits for reflexive and voluntary gaze behaviors traverse somewhat independent brainstem and spinal cord circuits, both can be modulated by feedback, meaning that most gaze behaviors are learned rather than hardcoded. Despite this flexibility, there are broadly enumerable neural pathways commonly adopted among primate gaze systems. Parallel pathways which carry simultaneous evolutionary and homeostatic drives converge in superior colliculus, a layered midbrain structure which integrates and relays these volitional signals to brainstem gaze-control circuits.

Antiferroptotic Activities of Oxindole GIF-0726-r Derivatives: Involvement of Ferrous Iron Coordination and Free-Radical Scavenging Capacities.

Ferroptosis and oxytosis are iron- and oxidative stress-dependent cell death pathways strongly implicated in neurodegenerative diseases, cancers, and metabolic disorders. Therefore, specific inhibitors may have broad clinical applications. We previously reported that 3-[4-(dimethylamino)benzyl]-2-oxindole (GIF-0726-r) and derivatives protected the mouse hippocampal cell line HT22 against oxytosis/ferroptosis by suppressing reactive oxygen species (ROS) accumulation. In this study, we evaluated the biological activities of GIF-0726-r derivatives with modifications at the oxindole skeleton and other positions. The addition of a methyl, nitro, or bromo group to C-5 of the oxindole skeleton enhanced antiferroptotic efficacy on HT22 cells during membrane cystine-glutamate antiporter inhibition and ensued intracellular glutathione depletion. In contrast, the substitution of the dimethylamino group on the side chain phenyl ring with a methyl, nitro, or amine group dramatically suppressed antiferroptotic activity regardless of other modifications. Compounds with antiferroptotic activity also directly scavenged ROS and decreased free ferrous ions in both HT22 cells and cell-free reactions while those compounds without antiferroptotic activity had little effect on either ROS or ferrous-ion concentration. Unlike oxindole compounds, which we have previously reported, the antiferroptotic compounds had little effect on the nuclear factor erythroid-2-related factor 2-antioxidant response element pathway. Oxindole GIF-0726-r derivatives with a 4-(dimethylamino)benzyl moiety at C-3 and some types of bulky group at C-5 (whether electron-donating or electron-withdrawing) can suppress ferroptosis, warranting safety and efficacy evaluations in animal models of disease.

Quercetin and resveratrol inhibit ferroptosis independently of Nrf2-ARE activation in mouse hippocampal HT22 cells.

Oxidative stress is the central pathomechanism in multiple cell death pathways, including ferroptosis, a form of iron-dependent programmed cell death. Various phytochemicals, which include the inducers of the nuclear factor erythroid-2-related factor 2-antioxidant response element (Nrf2-ARE) transcription pathway, prevent ferroptosis. We recently reported that several compounds, such as the potent Nrf2-ARE inducer curcumin, protect mouse hippocampus-derived HT22 cells against ferroptosis independently of Nrf2-ARE activity. The present study characterized the anti-ferroptotic mechanisms of two additional Nrf2-ARE inducers, quercetin and resveratrol. Both compounds prevented erastin- and RSL3-induced ferroptosis of wild-type HT22 cells, and also blocked the exacerbated erastin- and RSL3-induced ferroptosis of Nrf2-knockdown HT22 cells. In both HT22 cells, quercetin and resveratrol blocked erastin- and RSL3-induced elevation in reactive oxygen species. These results suggest that the Nrf2-ARE pathway does protect against ferroptosis, but quercetin and resveratrol act by reducing oxidative stress independently of Nrf2-ARE induction. Quercetin and resveratrol also reduced Fe2+ concentrations in HT22 cells and in cell-free reactions. Thus, quercetin and resveratrol likely protect against erastin- and RSL3-induced ferroptosis by inhibiting the iron-catalyzed generation of hydroxyl radicals. Unlike quercetin, resveratrol cannot form a chelate structure with Fe2+ but the density functional theory computation demonstrates that resveratrol can form stable monodentate complexes with the alkene moiety and the electron-rich A ring.

Brainstem Circuits Triggering Saccades and Fixation.

Omnipause neurons (OPNs) in the nucleus raphe interpositus have tonic activity while the eyes are stationary ("fixation") but stop firing immediately before and during saccades. To locate the source of suppression, we analyzed synaptic inputs from the rostral and caudal superior colliculi (SCs) to OPNs by using intracellular recording and staining, and investigated pathways transmitting the inputs in anesthetized cats of both sexes. Electrophysiologically or morphologically identified OPNs received monosynaptic excitation from the rostral SCs with contralateral dominance, and received disynaptic inhibition from the caudal SCs with ipsilateral dominance. Cutting the tectoreticular tract transversely between the contralateral OPN and inhibitory burst neuron (IBN) regions eliminated inhibition from the caudal SCs, but not excitation from the rostral SCs in OPNs. In contrast, a midline section between IBN regions eliminated disynaptic inhibition in OPNs from the caudal SCs but did not affect the monosynaptic excitation from the rostral SCs. Stimulation of the contralateral IBN region evoked monosynaptic inhibition in OPNs, which was facilitated by preconditioning SC stimulation. Three-dimensional reconstruction of HRP-stained cells revealed that individual OPNs have axons that terminate in the opposite IBN area, while individual IBNs have axon collaterals to the opposite OPN area. These results show that there are differences in the neural circuit from the rostral and caudal SCs to the brainstem premotor circuitry and that IBNs suppress OPNs immediately before and during saccades. Thus, the IBNs, which are activated by caudal SC saccade neurons, shut down OPN firing and help to trigger saccades and suppress ("latch") OPN activity during saccades.SIGNIFICANCE STATEMENT Saccades are the fastest eye movements to redirect gaze to an object of interest and bring its image on the fovea for fixation. Burst neurons (BNs) and omnipause neurons (OPNs) which behave reciprocally in the brainstem, are important for saccade generation and fixation. This study investigated unsolved important questions about where these neurons receive command signals and how they interact for initiating saccades from visual fixation. The results show that the rostral superior colliculi (SCs) excite OPNs monosynaptically for fixation, whereas the caudal SCs monosynaptically excite inhibitory BNs, which then directly inhibit OPNs for the initiation of saccades. This inhibition from the caudal SCs may account for the omnipause behavior of OPNs for initiation and maintenance of saccades in all directions.

The Japan Society for Neuro-Oncology guideline on the diagnosis and treatment of central nervous system germ cell tumors.

Primary CNS germ cell tumors (GCTs) are rare neoplasms predominantly observed in the pediatric and young adult populations. In line with the hypothesis that the primordial germ cell is the cell-of-origin, histopathological examinations for this pathology involve a diverse range of components mirroring the embryogenic developmental dimensions. Chemotherapy and radiotherapy are the mainstays of treatment, with surgery having a limited role for diagnosis and debulking of residual tissue after treatment. While better management has been achieved over recent decades by modifying radiation coverage and selecting appropriate chemotherapy, standardization of treatment remains challenging, partly due to the low volume of cases encountered in each institution. As the incidence is higher in East Asia, including Japan, the Japan Society for Neuro-Oncology established a multidisciplinary task force to create an evidence-based guideline for CNS GCTs. This guideline provides recommendations for multiple dimensions of clinical management for CNS GCTs, with particular focus on diagnostic measures including serum markers, treatment algorithms including surgery, radiotherapy, and chemotherapy, and under-investigated but important areas such as treatment for recurrent cases, long-term follow-up protocols, and long-term sequelae. This guideline serves the purpose of helping healthcare professionals keep up to date with current knowledge and standards of management for patients with this rare disease in daily clinical practice, as well as driving future translational and clinical research by recognizing unmet needs concerning this tumor.

Identification of novel neuroprotective N,N-dimethylaniline derivatives that prevent oxytosis/ferroptosis and localize to late endosomes and lysosomes.

Oxidative stress has been implicated in the aging process and the progression of many neurodegenerative disorders. We previously reported that a novel oxindole compound, GIF-0726-r, effectively prevents endogenous oxidative stress, such as oxytosis/ferroptosis, an iron-dependent form of non-apoptotic cell death, in mouse hippocampal cells. In this study, using two hundred compounds that were developed based on the structure-activity relationship of GIF-0726-r, we screened for the most potent compounds that prevent glutamate- and erastin-induced oxytosis and ferroptosis. Using submicromolar concentrations, we identified nine neuroprotective compounds that have N,N-dimethylaniline as a common structure but no longer contain an oxindole ring. The most potent derivatives, GIF-2114 and GIF-2197-r (the racemate of GIF-2115 and GIF-2196), did not affect glutathione levels, had no antioxidant activity in vitro, or ability to activate the Nrf2 pathway, but prevented oxytosis/ferroptosis via reducing reactive oxygen production and decreasing ferrous ions. Furthermore, we developed fluorescent probes of GIF-2114 and GIF-2197-r to image their distribution in live cells and found that they preferentially accumulated in late endosomes/lysosomes, which play a central role in iron metabolism. These results suggest that GIF-2114 and GIF-2197-r protect hippocampal cells from oxytosis/ferroptosis by targeting late endosomes and lysosomes, as well as decreasing ferrous ions.

Neural Circuits of Inputs and Outputs of the Cerebellar Cortex and Nuclei.

This article is dedicated to the memory of Masao Ito. Masao Ito made numerous important contributions revealing the function of the cerebellum in motor control. His pioneering contributions to cerebellar physiology began with his discovery of inhibition and disinhibition of target neurons by cerebellar Purkinje cells, and his discovery of the presence of long-term depression in parallel fiber-Purkinje cell synapses. Purkinje cells formed the nodal point of Masao Ito's landmark model of motor control by the cerebellum. These discoveries became the basis for his ideas regarding the flocculus hypothesis, the adaptive motor control system, and motor learning by the cerebellum, inspiring many new experiments to test his hypotheses. This article will trace the achievements of Ito and colleagues in analyzing the neural circuits of the input-output organization of the cerebellar cortex and nuclei, particularly with respect to motor control. The article will discuss some of the important issues that have been solved and also those that remain to be solved for our understanding of motor control by the cerebellum.

Functional analysis of a novel lytic polysaccharide monooxygenase from Streptomyces griseus on cellulose and chitin.

Lytic polysaccharide monooxygenases (LPMOs) are enzymes that degrade polysaccharides with an oxidative mechanism and contributed to the efficiency in biomass degradation by glycoside hydrolases (GHs). In this study, the substrate and reaction specificity of SgLPMO10A that was an auxiliary activity family 10 (AA10) enzyme with a carbohydrate binding module family 2 (CBM2) domain from Streptomyces griseus, was analyzed. This enzyme produced oxidized cello-oligosaccharides from cellulose and boosted cellulose degradation by cellulases. Detailed study of the AA10 and CBM2 domains revealed that the binding ability of SgLPMO10A depended on CBM2 and that only the AA10 domain functions more effectively in the presence of a certain amount of substrates.