Graybiel

Approach-Avoidance conflict (AAC) arises from decisions with embedded positive and negative outcomes, such that approaching leads to reward and punishment and avoiding to neither. Despite its importance, the field lacks a mechanistic understanding of which regions are driving avoidance behavior during conflict. In the current task, we utilized transcranial magnetic stimulation (TMS) and drift-diffusion modeling to investigate the role of one of the most prominent regions relevant to AAC-the dorsolateral prefrontal cortex (dlPFC)...

CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntington's disease and levodopa-induced dyskinesia in Parkinson's disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation...

Clinical studies have shown that patients with anxiety disorders exhibited coactivation of limbic cortices and basal ganglia, which together form a large-scale brain network. The mechanisms by which such a large-scale network could induce or modulate anxiety-like states are largely unknown. This article reviews our experimental program in macaques demonstrating a causal involvement of local striatal and frontal cortical sites in inducing pessimistic decision-making that underlies anxiety. Where relevant, we related these findings to the wider literature...

Adaptive behavior requires balancing approach and avoidance based on the rewarding and aversive consequences of actions. Imbalances in this evaluation are thought to characterize mood disorders such as major depressive disorder (MDD). We present a novel application of the drift diffusion model (DDM) suited to quantify how offers of reward and aversiveness, and neural correlates thereof, are dynamically integrated to form decisions, and how such processes are altered in MDD. Hierarchical parameter estimation from the DDM demonstrated that the MDD group differed in three distinct reward-related parameters driving approach-based decision making...

BACKGROUND: Fatigue can be induced after acceleration exposure, however the mechanism of it is still unclear. The aim of the present study was to examine whether metabolites changes can decrease cognitive and physical function after acceleration. METHODS: Graybiel scale and Fatigue Self-rating scale were used to assess the seasickness and fatigue degrees of eighty-seven male seafarers respectively after sailing. To test the effect of pyruvate on cognitive and physical functions, five different doses of pyruvate were administrated into rats...

Disruptive or excessive repetitive motor patterns (stereotypies) are cardinal symptoms in numerous neuropsychiatric disorders. Stereotypies are also evoked by psychomotor stimulants such as amphetamine. The acquisition of motor sequences is paralleled by changes in activity patterns in the striatum, and stereotypies have been linked to abnormal plasticity in these reinforcement-related circuits. Here, we designed experiments in mice to identify transcriptomic changes that underlie striatal plasticity occurring alongside the development of drug-induced stereotypic behavior...

The striatum of humans and other mammals is divided into macroscopic compartments made up of a labyrinthine striosome compartment embedded in a much larger surrounding matrix compartment. Anatomical and snRNA-Seq studies of the Huntington's disease (HD) postmortem striatum suggest a preferential decline of some striosomal markers, and mRNAs studies of HD model mice concur. Here, by immunohistochemical methods, we examined the distribution of the canonical striosomal marker, mu-opioid receptor 1 (MOR1), in the striatum of the Q175 knock-in mouse model of HD in a postnatal time series extending from 3 to 19 months...

Prager et al. demonstrate an opposite regulation of activity in striosomes and matrix of the striatum. By a D1-receptor-linked L-VGCC-dependent mechanism, dopamine release can extend upstates in matrix D1-expressing direct pathway projection neurons (dSPNs) but shorten them in striosomal dSPNs.

BACKGROUND: The vestibular system is important in the pathogenesis of seasickness. Our objective is to investigate whether routine vestibular tests detect seasickness. METHODS: Included were 17 professional naval personnel (mean age of 29.76 4.73 yr) diagnosed as having seasickness and 29 healthy age- and gender-matched controls. Cervical (c) vestibular evoked myogenic potentials (VEMP) and ocular (o) VEMP and bithermal caloric tests were performed after ear, nose, and throat examination, pure tone audiometry, and magnetic resonance imaging...

Learning valence-based responses to favorable and unfavorable options requires judgments of the relative value of the options, a process necessary for species survival. We found, using engineered mice, that circuit connectivity and function of the striosome compartment of the striatum are critical for this type of learning. Calcium imaging during valence-based learning exhibited a selective correlation between learning and striosomal but not matrix signals. This striosomal activity encoded discrimination learning and was correlated with task engagement, which, in turn, could be regulated by chemogenetic excitation and inhibition...

On May 26, 2020, Dr. Oleh Hornykiewicz died at the age of 93 years. His twin discoveries in the early 1960s of dopamine deficiency in the brains of subjects with Parkinson's disease and the amelioration of patients' symptoms by levodopa therapy represent milestone events in the history of medicine. These breakthroughs enabled much-needed relief for millions of patients suffering from neurological disorders every year and have given rise to the field of dopamine signaling in the regulation of complex behaviors in primates...

Neurochemical dysregulation underlies many pathologies and can be monitored by measuring the composition of brain interstitial fluid (ISF). Existing in vivo tools for sampling ISF do not enable measuring large rare molecules, such as proteins and neuropeptides, and thus cannot generate a complete picture of the neurochemical connectome. Our micro-invasive platform, composed of a nanofluidic pump coupled to a membrane-free probe, enables sampling multiple neural biomarkers in parallel. This platform outperforms the state of the art in low-flow pumps by offering low volume control (single stroke volumes, <3 nl) and bidirectional fluid flow (<100 nl/min) with negligible dead volume (<30 nl) and has been validated in vitro, ex vivo, and in vivo in rodents...

Parkinson's disease is characterized by decreased dopamine and increased beta-band oscillatory activity accompanying debilitating motor and mood impairments. Coordinate dopamine-beta opposition is considered a normative rule for basal ganglia function. We report a breakdown of this rule. We developed multimodal systems allowing the first simultaneous, chronic recordings of dopamine release and beta-band activity in the striatum of nonhuman primates during behavioral performance. Dopamine and beta signals were anticorrelated over seconds-long time frames, in agreement with the posited rule, but at finer time scales, we identified conditions in which these signals were modulated with the same polarity...

INTRODUCTION: One route to advancing psychological treatments is to harness mental health science, a multidisciplinary approach including individuals with lived experience and end users (e.g., Holmes, E. A., Craske, M. G., & Graybiel, A. M. (2014). Psychological treatments: A call for mental-health science. Nature , 511 (7509), 287-289. doi:10.1038/511287a). While early days, we here illustrate a line of research explored by our group-intrusive imagery-based memories after trauma...

OBJECTIVE: Motion sickness (MS) is a familiar condition to scuba divers. The purpose of this study was to compare otolith organ function of scuba divers who have MS to those without MS. METHOD: Video-oculography (VOG) goggles were used to measure video ocular counter-roll (vOCR) in 50 healthy scuba divers with no vestibular pathology. Divers with MS (n = 30) had Graybiel motion sickness (GMS) scores of ≥1 point, and divers without MS (n = 20) had GMS scores of 0...

The vast majority of techniques to study the physiology of the nervous system involve inserting probes into the brain for stimulation, recording, or sampling. Research is increasingly uncovering the fine microstructure of the brain, each of its regions with dedicated functions. Accurate knowledge of the placement and final positions of probes interrogating these regions is critical. We have developed a customizable concentric marking electrode (CME) consisting of an iron core within a 125 μm-stainless steel (SS) sheath for co-localization of targeted regions in the brain...

Cortical pyramidal cells are generated locally, from pre-programmed progenitors, to form functionally distinct areas. By contrast, striatal projection neurons (SPNs) are generated remotely from a common source, undergo migration to form mosaics of striosomes and matrix, and become incorporated into functionally distinct sectors. Striatal circuits might thus have a unique logic of developmental organization, distinct from those of the neocortex. We explore this possibility in mice by mapping one set of SPNs, those in striosomes, with striatonigral projections to the dopamine-containing substantia nigra pars compacta (SNpc)...

Treatments for neurologic diseases are often limited in efficacy due to poor spatial and temporal control over their delivery. Intracerebral delivery partially overcomes this by directly infusing therapeutics to the brain. Brain structures, however, are nonuniform and irregularly shaped, precluding complete target coverage by a single bolus without significant off-target effects and possible toxicity. Nearly complete coverage is crucial for effective modulation of these structures. We present a framework with computational mapping algorithms for neural drug delivery (COMMAND) to guide multi-bolus targeting of brain structures that maximizes coverage and minimizes off-target leakage...

BACKGROUND: Aerobatic flight is a challenge for the vestibular system, which is likely to lead to adaptive changes in the vestibular responses of pilots. We investigated whether aerobatic pilots, as individuals who experience intense vestibular stimulation, present modifications of the vestibular-ocular reflex, motion sickness susceptibility and intensity, visual vertical estimation, and visual dependence as compared to normal volunteers. METHODS: To evaluate vestibulo-ocular reflexes, eye movements were recorded with videonystagmography while subjects were rotated on a rotatory chair with the axis of rotation being vertical (canal-ocular reflex) or inclined to 17° (otolith-ocular reflex)...

An approach-avoidance (Ap-Av) conflict arises when an individual has to decide whether to accept or reject a compound offer that has features indicating both reward and punishment. During value judgments of likes and dislikes, arousal responses simultaneously emerge and influence reaction times and the frequency of behavioral errors. In Ap-Av decision-making, reward and punishment differentially influence valence and arousal, allowing us to dissociate their neural processing. The primate caudate nucleus (CN) has been implicated in affective judgment, but it is still unclear how neural responses in the CN represent decision-related variables underlying choice...