Characterization of Ultrasonic Vocalization-Modulated Neurons in Rat Motor Cortex Based on Their Activity Modulation and Axonal Projection to the Periaqueductal Gray.

Vocalization, a means of social communication, is prevalent among many species, including humans. Both rats and mice use ultrasonic vocalizations (USVs) in various social contexts and affective states. The motor cortex is hypothesized to be involved in precisely controlling USVs through connections with critical regions of the brain for vocalization, such as the periaqueductal gray matter (PAG). However, it is unclear how neurons in the motor cortex are modulated during USVs. Moreover, the relationship between USV modulation of neurons and anatomical connections from the motor cortex to PAG is also not clearly understood. In this study, we first characterized the activity patterns of neurons in the primary and secondary motor cortices during emission of USVs in rats using large-scale electrophysiological recordings. We also examined the axonal projection of the motor cortex to PAG using retrograde labeling and identified two clusters of PAG-projecting neurons in the anterior and posterior parts of the motor cortex. The neural activity patterns around the emission of USVs differed between the anterior and posterior regions, which were divided based on the distribution of PAG-projecting neurons in the motor cortex. Furthermore, using optogenetic tagging, we recorded the USV modulation of PAG-projecting neurons in the posterior part of the motor cortex and found that they showed predominantly sustained excitatory responses during USVs. These results contribute to our understanding of the involvement of the motor cortex in the generation of USV at the neuronal and circuit levels.

Electroencephalographic Effective Connectivity Analysis of the Neural Networks during Gesture and Speech Production Planning in Young Adults.

Gestures and speech, as linked communicative expressions, form an integrated system. Previous functional magnetic resonance imaging studies have suggested that neural networks for gesture and spoken word production share similar brain regions consisting of fronto-temporo-parietal brain regions. However, information flow within the neural network may dynamically change during the planning of two communicative expressions and also differ between them. To investigate dynamic information flow in the neural network during the planning of gesture and spoken word generation in this study, participants were presented with spatial images and were required to plan the generation of gestures or spoken words to represent the same spatial situations. The evoked potentials in response to spatial images were recorded to analyze the effective connectivity within the neural network. An independent component analysis of the evoked potentials indicated 12 clusters of independent components, the dipoles of which were located in the bilateral fronto-temporo-parietal brain regions and on the medial wall of the frontal and parietal lobes. Comparison of effective connectivity indicated that information flow from the right middle cingulate gyrus (MCG) to the left supplementary motor area (SMA) and from the left SMA to the left precentral area increased during gesture planning compared with that of word planning. Furthermore, information flow from the right MCG to the left superior frontal gyrus also increased during gesture planning compared with that of word planning. These results suggest that information flow to the brain regions for hand praxis is more strongly activated during gesture planning than during word planning.

Suppressive effects of ketamine on auditory steady-state responses in intact, awake macaques: A non-human primate model of schizophrenia.

Auditory steady-state responses (ASSRs) are recurrent neural activities entrained to regular cyclic auditory stimulation. ASSRs are altered in individuals with schizophrenia, and may be related to hypofunction of the N-methyl-D-aspartate (NMDA) glutamate receptor. Noncompetitive NMDA receptor antagonists, including ketamine, have been used in ASSR studies of rodent models of schizophrenia. Although animal studies using non-human primates are required to complement rodent studies, the effects of ketamine on ASSRs are unknown in intact awake non-human primates. In this study, after administration of vehicle or ketamine, click trains at 20-83.3 Hz were presented to elicit ASSRs during recording of electroencephalograms in intact, awake macaque monkeys. The results indicated that ASSRs quantified by event-related spectral perturbation and inter-trial coherence were maximal at 83.3 Hz after vehicle administration, and that ketamine reduced ASSRs at 58.8 and 83.3 Hz, but not at 20 and 40 Hz. The present results demonstrated a reduction of ASSRs by the NMDA receptor antagonist at optimal frequencies with maximal responses in intact, awake macaques, comparable to ASSR reduction in patients with schizophrenia. These findings suggest that ASSR can be used as a neurophysiological biomarker of the disturbance of gamma-oscillatory neural circuits in this ketamine model of schizophrenia using intact, awake macaques. Thus, this model with ASSRs would be useful in the investigation of human brain pathophysiology as well as in preclinical translational research.

Neuronal structures controlling locomotor behavior during active and inactive motor states.

Animal behaviors can be divided into two states according to their motor activity: the active motor state, which involves significant body movements, and the inactive motor state, which refers to when the animal is stationary. The timing and duration of these states are determined by the activity of the neuronal circuits involved in motor control. Among these motor circuits, those that generate locomotion are some of the most studied neuronal networks and are widely distributed from the spinal cord to the cerebral cortex. In this review, we discuss recent discoveries, mainly in rodents using state-of-the-art experimental approaches, of the neuronal mechanisms underlying the initiation and termination of locomotion in the brainstem, basal ganglia, and prefrontal cortex. These findings is discussed with reference to studies on the neuronal mechanism of motor control during sleep and the modulation of cortical states in these structures. Accumulating evidence has unraveled the complex yet highly structured network that controls the transition between motor states.

Neural basis of topographical disorientation in the primate posterior cingulate gyrus based on a labeled graph.

Patients with lesions in the posterior cingulate gyrus (PCG), including the retrosplenial cortex (RSC) and posterior cingulate cortex (PCC), cannot navigate in familiar environments, nor draw routes on a 2D map of the familiar environments. This suggests that the topographical knowledge of the environments (i.e., cognitive map) to find the right route to a goal is represented in the PCG, and the patients lack such knowledge. However, theoretical backgrounds in neuronal levels for these symptoms in primates are unclear. Recent behavioral studies suggest that human spatial knowledge is constructed based on a labeled graph that consists of topological connections (edges) between places (nodes), where local metric information, such as distances between nodes (edge weights) and angles between edges (node labels), are incorporated. We hypothesize that the population neural activity in the PCG may represent such knowledge based on a labeled graph to encode routes in both 3D environments and 2D maps. Since no previous data are available to test the hypothesis, we recorded PCG neuronal activity from a monkey during performance of virtual navigation and map drawing-like tasks. The results indicated that most PCG neurons responded differentially to spatial parameters of the environments, including the place, head direction, and reward delivery at specific reward areas. The labeled graph-based analyses of the data suggest that the population activity of the PCG neurons represents the distance traveled, locations, movement direction, and navigation routes in the 3D and 2D virtual environments. These results support the hypothesis and provide a neuronal basis for the labeled graph-based representation of a familiar environment, consistent with PCG functions inferred from the human clinicopathological studies.

Young female participants show blunted placebo effects associated with blunted responses to a cue predicting a safe stimulus in the right dorsolateral prefrontal cortex.

Discrimination of cues predicting non-nociceptive/nociceptive stimuli is essential for predicting whether a non-painful or painful stimulus will be administered and for eliciting placebo/nocebo (pain reduction/pain enhancement) effects. Dysfunction of the neural system involved in placebo effects has been implicated in the pathology of chronic pain, while female sex is one of the important risk factors for development of chronic pain in young adults. The dorsolateral prefrontal cortex (dl-PFC) is suggested to be involved in placebo effects and is sensitive to sex and age. In this study, to examine the neural mechanisms by which sex and age alter placebo and nocebo effects, we analyzed cerebral hemodynamic activities in the dl-PFC in different sex and age groups during a differential conditioning task. During the training session, two different sounds were followed by low- and high-intensity electrical shocks. In the following recording session, electrical shocks, the intensity of which was mismatched to the sounds, were occasionally administered to elicit placebo and nocebo effects. In young female participants, both placebo effects and hemodynamic responses to the conditioned sounds in the right dl-PFC were significantly lower than those in elderly female participants, while there were no age differences in male participants. The hemodynamic responses to the sound paired with the safe stimulus in the right dl-PFC were significantly correlated with placebo effects, except in the young female group. These results suggest that blunted placebo effects in the young female participants are ascribed to blunted responses to the sound associated with the safe stimulus in the right dl-PFC, and that sex- and age-related factors may alter the responsiveness of the right dl-PFC to associative cues predicting a safe stimulus.

Characteristics of auditory steady-state responses to different click frequencies in awake intact macaques.

BACKGROUND: Auditory steady-state responses (ASSRs) are periodic evoked responses to constant periodic auditory stimuli, such as click trains, and are suggested to be associated with higher cognitive functions in humans. Since ASSRs are disturbed in human psychiatric disorders, recording ASSRs from awake intact macaques would be beneficial to translational research as well as an understanding of human brain function and its pathology. However, ASSR has not been reported in awake macaques. RESULTS: Electroencephalograms (EEGs) were recorded from awake intact macaques, while click trains at 20-83.3 Hz were binaurally presented. EEGs were quantified based on event-related spectral perturbation (ERSP) and inter-trial coherence (ITC), and ASSRs were significantly demonstrated in terms of ERSP and ITC in awake intact macaques. A comparison of ASSRs among different click train frequencies indicated that ASSRs were maximal at 83.3 Hz. Furthermore, analyses of laterality indices of ASSRs showed that no laterality dominance of ASSRs was observed. CONCLUSIONS: The present results demonstrated ASSRs, comparable to those in humans, in awake intact macaques. However, there were some differences in ASSRs between macaques and humans: macaques showed maximal ASSR responses to click frequencies higher than 40 Hz that has been reported to elicit maximal responses in humans, and showed no dominant laterality of ASSRs under the electrode montage in this study compared with humans with right hemisphere dominance. The future ASSR studies using awake intact macaques should be aware of these differences, and possible factors, to which these differences were ascribed, are discussed.

Acoustic camera system for measuring ultrasound communication in mice.

To investigate biological mechanisms underlying social behaviors and their deficits, social communication via ultrasonic vocalizations (USVs) in mice has received considerable attention as a powerful experimental model. The advances in sound localization technology have facilitated the analysis of vocal interactions between multiple mice. However, existing sound localization systems are built around distributed-microphone arrays, which require a special recording arena and long processing time. Here, we report a novel acoustic camera system, USVCAM, which enables simpler and faster USV localization and assignment. The system comprises recently developed USV segmentation algorithms with a modification for overlapping vocalizations that results in high accuracy. Using USVCAM, we analyzed USV communications in a conventional home cage, and demonstrated novel vocal interactions in female ICR mice under a resident-intruder paradigm. The extended applicability and usability of USVCAM may facilitate future studies investigating typical and atypical vocal communication and social behaviors, as well as the underlying mechanisms.

Fast Detection of Snakes and Emotional Faces in the Macaque Amygdala.

Primate vision is reported to detect snakes and emotional faces faster than many other tested stimuli. Because the amygdala has been implicated in avoidance and emotional behaviors to biologically relevant stimuli and has neural connections with subcortical nuclei involved with vision, amygdalar neurons would be sensitive to snakes and emotional faces. In this study, neuronal activity in the amygdala was recorded from Japanese macaques (Macaca fuscata) during discrimination of eight categories of visual stimuli including snakes, monkey faces, human faces, carnivores, raptors, non-predators, monkey hands, and simple figures. Of 527 amygdalar neurons, 95 responded to one or more stimuli. Response characteristics of the amygdalar neurons indicated that they were more sensitive to the snakes and emotional faces than other stimuli. Response magnitudes and latencies of amygdalar neurons to snakes and monkey faces were stronger and faster than those to the other categories of stimuli, respectively. Furthermore, response magnitudes to the low pass-filtered snake images were larger than those to scrambled snake images. Finally, analyses of population activity of amygdalar neurons suggest that snakes and emotional faces were represented separately from the other stimuli during the 50-100 ms period from stimulus onset, and neutral faces during the 100-150 ms period. These response characteristics indicate that the amygdala processes fast and coarse visual information from emotional faces and snakes (but not other predators of primates) among the eight categories of the visual stimuli, and suggest that, like anthropoid primate visual systems, the amygdala has been shaped over evolutionary time to detect appearance of potentially threatening stimuli including both emotional faces and snakes, the first of the modern predators of primates.

Neuronal Representation of Locomotion During Motivated Behavior in the Mouse Anterior Cingulate Cortex.

The anterior cingulate cortex (ACC) is located within the dorsomedial prefrontal cortex (PFC), and processes and facilitates goal-directed behaviors relating to emotion, reward, and motor control. However, it is unclear how ACC neurons dynamically encode motivated behavior during locomotion. In this study, we examined how information for locomotion and behavioral outcomes is temporally represented by individual and ensembles of ACC neurons in mice during a self-paced locomotor reward-based task. By recording and analyzing the activity of ACC neurons with a microdrive tetrode array while the mouse performed the locomotor task, we found that more than two-fifths of the neurons showed phasic activity relating to locomotion or the reward behavior. Some of these neurons showed significant differences in their firing rate depending on the behavioral outcome. Furthermore, by applying a demixed principal component analysis, the ACC population activity was decomposed into components representing locomotion and the previous/future outcome. These results indicated that ACC neurons dynamically integrate motor and behavioral inputs during goal-directed behaviors.

Preferential Neuronal Responses to Snakes in the Monkey Medial Prefrontal Cortex Support an Evolutionary Origin for Ophidiophobia.

Ophidiophobia (snake phobia) is one of the most common specific phobias. It has been proposed that specific phobia may have an evolutionary origin, and that attentional bias to specific items may promote the onset of phobia. Noninvasive imaging studies of patients with specific phobia reported that the medial prefrontal cortex (mPFC), especially the rostral part of the anterior cingulate cortex (rACC), and amygdala are activated during the presentation of phobogenic stimuli. We propose that the mPFC-amygdala circuit may be involved in the pathogenesis of phobia. The mPFC receives inputs from the phylogenically old subcortical visual pathway including the superior colliculus, pulvinar, and amygdala, while mPFC neurons are highly sensitive to snakes that are the first modern predator of primates, and discriminate snakes with striking postures from those with non-striking postures. Furthermore, the mPFC has been implicated in the attentional allocation and promotes amygdala-dependent aversive conditioning. These findings suggest that the rACC focuses attention on snakes, and promotes aversive conditioning to snakes, which may lead to anxiety and ophidiophobia.

Nutritional Intervention with Dried Bonito Broth for the Amelioration of Aggressive Behaviors in Children with Prenatal Exposure to Dioxins in Vietnam: A Pilot Study.

Dioxins have been suggested to induce inflammation in the intestine and brain and to induce neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), partly due to deficits in parvalbumin-positive neurons in the brain that are sensitive to inflammatory stress. Previously, we reported ADHD traits with increased aggressiveness in children with prenatal exposure to dioxins in Vietnam, whereas dried bonito broth (DBB) has been reported to suppress inflammation and inhibit aggressive behavior in animal and human studies. In the present study, we investigated the association between dioxin exposure and the prevalence of children with highly aggressive behaviors (Study 1), as well as the effects of DBB on the prevalence of children with highly aggressive behaviors (Study 2). METHODS: In Study 1, we investigated the effects of dioxin exposure on the prevalence of children with high aggression scores, which were assessed using the Children's Scale of Hostility and Aggression: Reactive/Proactive (C-SHARP) in dioxin-contaminated areas. The data were analyzed using a logistic regression model after adjusting for confounding factors. In Study 2, we performed nutritional intervention by administering DBB for 60 days to ameliorate the aggressiveness of children with high scores on the C-SHARP aggression scale. The effects of DBB were assessed by comparing the prevalence of children with high C-SHARP scores between the pre- and post-intervention examinations. RESULTS: In Study 1, only the prevalence of children with high covert aggression was significantly increased with an increase in dioxin exposure. In Study 2, in the full ingestion (>80% of goal ingestion volume) group, the prevalence of children with high covert aggression associated with dioxin exposure was significantly lower in the post-ingestion examination compared with in the pre-ingestion examination. However, in other ingestion (<20% and 20-79%) groups and a reference (no intervention) group, no difference in the prevalence of children with high covert aggression was found between the examinations before and after the same experimental period. CONCLUSIONS: The findings suggest that DBB ingestion may ameliorate children's aggressive behavior, which is associated with perinatal dioxin exposure.

Examination of the Prefrontal Cortex Hemodynamic Responses to the Fist-Edge-Palm Task in Naïve Subjects Using Functional Near-Infrared Spectroscopy.

The Fist-Edge-Palm (FEP) task, a manual hand task, has been used to detect frontal dysfunctions in clinical situations: its performance failures are observed in various prefrontal cortex (PFC)-related disorders, including schizophrenia. However, previous imaging studies reported that the performance of the FEP task activated motor-related areas, but not the PFC. Here, we aimed to investigate the relationships between the performance of the FEP task and PFC functions. Hemodynamic activity in the PFC, including the dorsolateral PFC (area 46) and frontal pole (area 10), was recorded. Healthy young subjects performed the FEP task as well as a palm tapping (PT) task (control task) three times. The subjects also completed a Wisconsin Card Sorting Test (WCST) and Schizotypal Personality Scale (STA) questionnaire. We found that hemodynamic activity (Oxy-Hb) in the PFC increased in the first trial of the FEP task but decreased considerably in the second and third trials compared to the PT task. The number of performance errors in the FEP task also decreased in the second and third trials. Error reduction (i.e., learning) in the FEP task between the first and second trials was negatively correlated with schizotypal trait and the number of perseveration errors in the WCST. Furthermore, changes in the PFC hemodynamic activity between the first and second trials were positively correlated with error reduction in the FEP task between the first and second trials, and negatively correlated with the number of perseveration errors in the WCST. These results suggest that learning in the FEP task requires PFC activation, which is negatively associated with perseveration errors in the WCST. The results further suggest that the FEP task, in conjunction with near-infrared spectroscopy, may be useful as a diagnostic method for various disorders with PFC dysfunction.

Performance in a gaze-cueing task is associated with autistic traits.

Individuals with autism spectrum disorder (ASD) show impairments in processing social cues such as facial expressions and gaze direction. Several researchers have proposed that autistic traits form a continuum that may be distributed within the general, typically developed, population. Accordingly, several studies have indicated that typically developed individuals with high levels of self-reported autistic traits have autistic-like performance in a variety of paradigms. Here, we designed a gaze-cueing task to examine whether gaze-triggered orienting is related to the extent of typically developed (TD) individuals' autistic traits (determined by their AQ test scores) and whether it is modulated by previous eye contact and different facial expressions. At each trial, TD subjects observed faces with or without eye contact. This facial stimulus then gazed toward the left or right side. Finally, a target appeared on the left or right side of the display and reaction time (RT) to the target was measured. RTs were modulated by congruency between gazing directions and target locations, and by prior eye contact in the congruent trials. In addition, individuals with higher AQ scores were slower at detecting the target when the cue was a happy face. Furthermore, faster RTs in congruent trials were associated with one specific autistic trait (attention switching deficits). Together, these results indicate that autistic traits may influence performance in a gaze cueing task.

Configural Cues Associated with Reward Elicit Theta Oscillations of Rat Retrosplenial Cortical Neurons Phase-Locked to LFP Theta Cycles.

Previous behavioral studies implicated the retrosplenial cortex (RSC) in stimulus-stimulus associations, and also in the retrieval of remote associative memory based on EEG theta oscillations. However, neural mechanisms involved in the retrieval of stored information of such associations and memory in the RSC remain unclear. To investigate the neural mechanisms underlying these processes, RSC neurons and local field potentials (LFPs) were simultaneously recorded from well-trained rats performing a cue-reward association task. In the task, simultaneous presentation of two multimodal conditioned stimuli (configural CSs) predicted a reward outcome opposite to that associated with the individual presentation of each elemental CS. Here, we show neurophysiological evidence that the RSC is involved in stimulus-stimulus association where configural CSs are discriminated from each elementary CS that is a constituent of the configural CSs, and that memory retrieval of rewarding CSs is associated with theta oscillation of RSC neurons during CS presentation, which is phase-locked to LFP theta cycles. The results suggest that cue (elementary and configural CSs)-reinforcement associations are stored in the RSC neural circuits, and are retrieved in synchronization with LFP theta rhythm.

Involvement of Parvalbumin-Positive Neurons in the Development of Hyperalgesia in a Mouse Model of Fibromyalgia.

Fibromyalgia (FM) presents as chronic systemic pain, which might be ascribed to central sensitization, in which pain information processing is amplified in the central nervous system. Since patients with FM display elevated gamma oscillations in the pain matrix and parvalbumin (PV)-positive neurons play a critical role in induction of gamma oscillations, we hypothesized that changes in PV-positive neurons are involved in hyperalgesia in fibromyalgia. In the present study, to investigate a role of PV-positive neurons in neuropathic pain, mice received reserpine administration for 3 consecutive days as an animal model of FM (RES group), while control mice received vehicle injections in the same way (VEH group). The mice were subjected to hot-plate and forced swim tests, and immuno-stained PV-positive neurons were counted in the pain matrix. We investigated relationships between PV-positive neuron density in the pain matrix and pain avoidance behaviors. The results indicated that the mice in the RES group showed transient bodyweight loss and longer immobility time in the forced swim test than the mice in the VEH group. In the hot-plate test, the RES group showed shorter response latencies and a larger number of jumps in response to nociceptive thermal stimulus than the VEH group. Histological examination indicated an increase in the density of PV-positive neurons in the primary somatosensory cortex (S1) in the RES group. Furthermore, response latencies to the hot-plate were significantly and negatively correlated with the density of PV-positive neurons in the S1. These results suggest a critical role for PV-positive neurons in the S1 to develop hyperalgesia in FM.

Rat Paraventricular Neurons Encode Predictive and Incentive Information of Reward Cues.

The paraventricular nucleus of the thalamus (PVT) has been implicated in cue-induced motivated behaviors. Although reward-associated cues (conditioned stimuli, CSs) contain different types of information including predictive information of future reward delivery and incentive (motivational) value of the reward, it remains unknown whether PVT neurons represent predictive and incentive information of CSs. It is suggested that neural activity just after the onset of CSs (early activity) and that just before reward delivery (late activity) might more strongly represent predictive and incentive information, respectively. In this study, rats were trained to lick a tube, which was protruded close to their mouth just after a CS, to obtain a reward (sucrose or water) (cue-induced licking task). Auditory and visual CSs were used: each elemental cue (CS) predicted reward or non-reward outcome, while simultaneous presentation of the two elemental cues (configural cues) predicted the opposite reward outcome. We recorded PVT neurons in the cue-induced licking task, and report that half of the CS-responsive PVT neurons responded selectively to the CSs predicting reward outcome regardless of physical property of the cues (CS+-selective). In addition, the early activity of the CS+-selective neurons discriminated reward/non-reward association (predictive information) and was less sensitive to reward value and motivation reflected by lick latency (incentive information), while the late activity of the CS+-selective neurons was correlated with reward value and motivation rather than reward/non-reward association. Early and late population activity of the CS+-selective neurons also represented predictive and incentive information of the CSs, respectively. On the other hand, activity of more than half of the PVT neurons was correlated with individual licking during licking to acquire reward. Taken together, the results suggest that the PVT neurons engage in different neural processes involved in cue-induced motivated behaviors: CS encoding to determine reward availability and form motivation for reward-seeking behavior, and hedonic mouth movements during reward consumption.

Non-invasive electroencephalographical (EEG) recording system in awake monkeys.

BACKGROUND: Human clinical studies reported that several electroencephalographical (EEG) parameters can be used as biomarkers of psychiatric disorders. EEGs recorded from non-human primates (monkeys) is useful for understanding of human pathologies of psychiatric disorders and development of new therapeutic agents. NEW METHODS: In this study, we expand a previous non-invasive head holding system with face masks for awake monkeys to be applied to scalp EEG recording. The new design of a head holding system allows to attach scalp EEG electrodes on the positions comparable to human electrode placement and to present auditory stimuli. RESULTS: With this system, we could record auditory evoked potentials (AEPs) in auditory sensory gating and oddball paradigms, which are often used as biomarkers of psychiatric disorders in animal models and human patients. The recorded AEPs were comparable to previous human clinical data. COMPARISON WITH EXISTING METHODS: Compared with previous non-invasive head holding systems, top, side (cheek and ears), and rear of the head can be open for attachment of EEG electrodes and auditory stimulation in the present system. CONCLUSIONS: The results suggest that the present system is useful in EEG recording from awake monkeys. Furthermore, this system can be applied to eye-tracking and chronic intra-cerebral recording experiments.

A Prototypical Template for Rapid Face Detection Is Embedded in the Monkey Superior Colliculus.

Human babies respond preferentially to faces or face-like images. It has been proposed that an innate and rapid face detection system is present at birth before the cortical visual pathway is developed in many species, including primates. However, in primates, the visual area responsible for this process is yet to be unraveled. We hypothesized that the superior colliculus (SC) that receives direct and indirect retinal visual inputs may serve as an innate rapid face-detection system in primates. To test this hypothesis, we examined the responsiveness of monkey SC neurons to first-order information of faces required for face detection (basic spatial layout of facial features including eyes, nose, and mouth), by analyzing neuronal responses to line drawing images of: (1) face-like patterns with contours and properly placed facial features; (2) non-face patterns including face contours only; and (3) nonface random patterns with contours and randomly placed face features. Here, we show that SC neurons respond stronger and faster to upright and inverted face-like patterns compared to the responses to nonface patterns, regardless of contrast polarity and contour shapes. Furthermore, SC neurons with central receptive fields (RFs) were more selective to face-like patterns. In addition, the population activity of SC neurons with central RFs can discriminate face-like patterns from nonface patterns as early as 50 ms after the stimulus onset. Our results provide strong neurophysiological evidence for the involvement of the primate SC in face detection and suggest the existence of a broadly tuned template for face detection in the subcortical visual pathway.

Astaxanthin Ameliorated Parvalbumin-Positive Neuron Deficits and Alzheimer's Disease-Related Pathological Progression in the Hippocampus of AppNL-G-F/NL-G-F Mice.

Growing evidence suggests that oxidative stress due to amyloid ß (Aß) accumulation is involved in Alzheimer's disease (AD) through the formation of amyloid plaque, which leads to hyperphosphorylation of tau, microglial activation, and cognitive deficits. The dysfunction or phenotypic loss of parvalbumin (PV)-positive neurons has been implicated in cognitive deficits. Astaxanthin is one of carotenoids and known as a highly potent antioxidant. We hypothesized that astaxanthin's antioxidant effects may prevent the onset of cognitive deficits in AD by preventing AD pathological processes associated with oxidative stress. In the present study, we investigated the effects of astaxanthin intake on the cognitive and pathological progression of AD in a mouse model of AD. The AppNL-G-F/NL-G-F mice were fed with or without astaxanthin from 5-to-6 weeks old, and cognitive functions were evaluated using a Barnes maze test at 6 months old. PV-positive neurons were investigated in the hippocampus. Aß42 deposits, accumulation of microglia, and phosphorylated tau (pTau) were immunohistochemically analyzed in the hippocampus. The hippocampal anti-oxidant status was also investigated. The Barnes maze test indicated that astaxanthin significantly ameliorated memory deficits. Astaxanthin reduced Aß42 deposition and pTau-positive areal fraction, while it increased PV-positive neuron density and microglial accumulation per unit fraction of Aß42 deposition in the hippocampus. Furthermore, astaxanthin increased total glutathione (GSH) levels, although 4-hydroxy-2,3-trans-nonenal (4-HNE) protein adduct levels (oxidative stress marker) remained high in the astaxanthin supplemented mice. The results indicated that astaxanthin ameliorated memory deficits and significantly reversed AD pathological processes (Aß42 deposition, pTau formation, GSH decrease, and PV-positive neuronal deficits). The elevated GSH levels and resultant recovery of PV-positive neuron density, as well as microglial activation, may prevent these pathological processes.