Primates use perceptual and mnemonic visuospatial representations to perform everyday functions. Neurons in the lateral prefrontal cortex (LPFC) have been shown to encode both of these representations during tasks where eye movements are strictly controlled and visual stimuli are reduced in complexity. This raises the question of whether perceptual and mnemonic representations encoded by LPFC neurons remain robust during naturalistic vision—in the presence of a rich visual scenery and during eye movements. Here we investigate this issue by training macaque monkeys to perform working memory and perception tasks in a visually complex virtual environment that requires navigation using a joystick and allows for free visual exploration of the scene. We recorded the activity of 3950 neurons in the LPFC (areas 8a and 9/46) of two male rhesus macaques using multielectrode arrays, and measured eye movements using video tracking. We found that navigation trajectories to target locations and eye movement behavior dif...

Although recent studies have revealed an involvement of hippocampal interneurons in learning the association among time-separated events, its underlying cellular mechanisms remained not fully clarified. Here, we combined multichannel recording and optogenetics to elucidate how the hippocampal parvalbumin-expressing interneurons (PV-INs) support associative learning. To address this issue, we trained the mice (both sexes) to learn hippocampus-dependent trace eyeblink conditioning (tEBC) in which they associated a light flash conditioned stimulus (CS) with a corneal air puff unconditioned stimuli (US) separated by a 250 ms time interval. We found that the hippocampal PV-INs exhibited learning-associated sustained activity at the early stage of tEBC acquisition. Moreover, the PV-IN sustained activity was positively correlated with the occurrence of conditioned eyeblink responses at the early learning stage. Suppression of the PV-IN sustained activity impaired the acquisition of tEBC, whereas the PV-IN activit...

The outer hair cells in the mammalian cochlea are cellular actuators essential for sensitive hearing. The geometry and stiffness of the structural scaffold surrounding the outer hair cells will determine how the active cells shape mammalian hearing by modulating the organ of Corti (OoC) vibrations. Specifically, the tectorial membrane and the Deiters cell are mechanically in series with the hair bundle and soma, respectively, of the outer hair cell. Their mechanical properties and anatomic arrangement must determine the relative motion among different OoC structures. We measured the OoC mechanics in the cochleas acutely excised from young gerbils of both sexes at a resolution fine enough to distinguish the displacement of individual cells. A three-dimensional finite element model of fully deformable OoC was exploited to analyze the measured data in detail. As a means to verify the computer model, the basilar membrane deformations because of static and dynamic stimulations were measured and simulated. Two s...

The chromatin remodeler CHD8 represents a high-confidence risk factor in autism, a multistage progressive neurologic disorder, however the underlying stage-specific functions remain elusive. In this study, by analyzing Chd8 conditional knock-out mice (male and female), we find that CHD8 controls cortical neural stem/progenitor cell (NSC) proliferation and survival in a stage-dependent manner. Strikingly, inducible genetic deletion reveals that CHD8 is required for the production and fitness of transit-amplifying intermediate progenitors (IPCs) essential for upper-layer neuron expansion in the embryonic cortex. p53 loss of function partially rescues apoptosis and neurogenesis defects in the Chd8 -deficient brain. Further, transcriptomic and epigenomic profiling indicates that CHD8 regulates the chromatin accessibility landscape to activate neurogenesis-promoting factors including TBR2, a key regulator of IPC neurogenesis, while repressing DNA damage- and p53-induced apoptotic programs. In the adult brain, C...

Epilepsies are characterized by paroxysmal electrophysiological events and seizures, which can propagate across the brain. One of the main unsolved questions in epilepsy is how epileptic activity can invade normal tissue and thus propagate across the brain. To investigate this question, we consider three computational models at the neural network scale to study the underlying dynamics of seizure propagation, understand which specific features play a role, and relate them to clinical or experimental observations. We consider both the internal connectivity structure between neurons and the input properties in our characterization. We show that a paroxysmal input is sometimes controlled by the network while in other instances, it can lead the network activity to itself produce paroxysmal activity, and thus will further propagate to efferent networks. We further show how the details of the network architecture are essential to determine this switch to a seizure-like regime. We investigated the nature of the in...

Visuospatial attention is a prerequisite for the performance of visually guided movements: perceptual discrimination is regularly enhanced at target locations before movement initiation. It is known that this attentional prioritization evolves over the time of movement preparation; however, it is not clear whether this build-up simply reflects a time requirement of attention formation or whether, instead, attention build-up reflects the emergence of the movement decision. To address this question, we combined behavioral experiments, psychophysics, and computational decision-making models to characterize the time course of attention build-up during motor preparation. Participants ( n  = 46, 29 female) executed center-out reaches to one of two potential target locations and reported the identity of a visual discrimination target (DT) that occurred concurrently at one of various time-points during movement preparation and execution. Visual discrimination increased simultaneously at the two potential target lo...

Neurons express overlapping homeostatic mechanisms to regulate synaptic function and network properties in response to perturbations of neuronal activity. Endocannabinoids (eCBs) are bioactive lipids synthesized in the postsynaptic compartments to regulate synaptic transmission, plasticity, and neuronal excitability primarily through retrograde activation of presynaptic cannabinoid receptor type 1 (CB1). The eCB system is well situated to regulate neuronal network properties and coordinate presynaptic and postsynaptic activity. However, the role of the eCB system in homeostatic adaptations to neuronal hyperactivity is unknown. To address this issue, we used Western blotting and targeted lipidomics to measure adaptations in eCB system to bicuculline (BCC)-induced chronic hyperexcitation in mature cultured rat cortical neurons, and used multielectrode array (MEA) recording and live-cell imaging of glutamate dynamics to test the effects of pharmacological manipulations of eCB on network activities. We show th...

While the brain has evolved robust mechanisms to counter spatial disorientation, their neural underpinnings remain unknown. To explore these underpinnings, we monitored the activity of anterodorsal thalamic head direction (HD) cells in rats while they underwent unidirectional or bidirectional rotation at different speeds and under different conditions (light vs dark, freely-moving vs head-fixed). Under conditions that promoted disorientation, HD cells did not become quiescent but continued to fire, although their firing was no longer direction specific. Peak firing rates, burst frequency, and directionality all decreased linearly with rotation speed, consistent with previous experiments where rats were inverted or climbed walls/ceilings in zero gravity. However, access to visual landmarks spared the stability of preferred firing directions (PFDs), indicating that visual landmarks provide a stabilizing signal to the HD system while vestibular input likely maintains direction-specific firing. In addition, we...

Training of autobiographical memory has been proposed as an intervention to improve cognitive function. The neural substrates for such improvements are poorly understood. Several brain areas have been previously linked to autobiographical recollection, including structures in the default mode network (DMN) and the sensorimotor network. Here, we tested the hypothesis that changes in connectivity within different neural networks support distinct aspects of memory improvement in response to training on a group of 59 human subjects. We found that memory training using olfactory cues increases resting-state intranetwork DMN connectivity, and this associates with improved recollection of cue-specific memories. On the contrary, training decreased resting-state connectivity within the sensorimotor network, a decrease that correlated with improved ability for voluntary recall. Moreover, preliminary data indicate that only the decrease in sensorimotor connectivity associated with the training-induced decrease in the...

Respiration is strongly linked to internal states such as arousal, emotion, and even cognitive processes and provides objective biological information to estimate these states in humans and animals. However, the measurement of respiration has not been established in macaque monkeys, which have been widely used as model animals for understanding various higher brain functions. In the present study, we developed a method to monitor the respiration of behaving monkeys. We first measured the temperature of their nasal breathing, which changes between inspiration and expiration phases, in an anesthetized condition and estimated the respiration pattern. We compared the estimated pattern with that obtained by a conventional chest band method that has been used in humans and applied to anesthetized, but not behaving, monkeys. These respiration patterns matched well, suggesting that the measurement of nasal air temperature can be used to monitor the respiration of monkeys. Furthermore, we confirmed that the respira...