When faced with a multi-step decision problem, humans and animals must balance flexible and accurate decision making with computational complexity. One prominent approach, the Successor Representation (SR), takes advantage of temporal abstraction of future states: by learning to predict long-run future trajectory independently of rewards, the brain can avoid the costs of iterative, multi-step model-based mental simulation, while retaining some ability to cheaply replan when goals change. Human behavior shows signatures of such temporal abstraction, but the characterization of the strategy of individuals, as well as whether people dynamically adapt their reliance on such abstractions in the face of environmental statistics, e.g. the predictability of long-run states, remains an open question. We developed a novel task to measure SR usage during dynamic, trial-by-trial learning. Using this approach, we find that participants exhibit a mix of SR and model-based learning strategies that varies across individuals. Further, by dynamically manipulating the task structure within-subject, we observe evidence of resource-rational reliance on the SR, which decreases when the ability to use prior experience to build valid temporal abstractions decreases. Our work adds to a growing body of research showing that the brain arbitrates between approximate decision strategies. The current study extends these ideas from simple habits into usage of more sophisticated approximate predictive models, and demonstrates that individuals dynamically adapt these in response to the predictibility of their environment. less

Processing pathways between sensory and default mode network (DMN) regions support recognition, navigation, and memory but their organisation is not well understood. We show that functional subdivisions of visual cortex and DMN sit at opposing ends of parallel streams of information processing that support visually-mediated semantic and spatial cognition, providing convergent evidence from univariate and multivariate task responses, intrinsic functional and structural connectivity. Participants learned virtual environments consisting of buildings populated with objects, drawn from either a single semantic category or multiple categories. Later, they made semantic and spatial context decisions about these objects and buildings during functional magnetic resonance imaging. A lateral ventral occipital to frontotemporal DMN pathway was primarily engaged by semantic judgements, while a medial visual to medial temporal DMN pathway supported spatial context judgements. These pathways had distinctive locations in functional connectivity space: the semantic pathway was both further from unimodal systems and more balanced between visual and auditory-motor regions compared with the spatial pathway. When semantic and spatial context information could be integrated (in buildings containing objects from a single category), regions at the intersection of these pathways responded, suggesting that parallel processing streams interact at multiple levels of the cortical hierarchy to produce coherent memory-guided cognition. less

Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1. Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occurs alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD. less

The brain can flexibly reorganize motor sequence, or program, execution to efficiently reach positive outcomes. These behavioral adaptations are primarily driven by reinforcement learning, leading to structural and kinematic modifications of consolidated motor programs. While previous studies established the critical contribution of cortical and basal ganglia circuits in controlling motor sequences or movement-by-movement kinematics, the neural mechanisms that adaptively shape efficient motor programs are not fully understood. Here, we found increased action-locked activity and network synchrony of somatostatin (SST) interneurons in the primary motor cortex (M1), compared to desynchronized pyramidal (PYR) neuron calcium activity, upon the acquisition of a single lever-press task in freely moving mice. After motor consolidation, cortical SST interneurons disengaged from action execution and then re-engaged when mice reorganized their motor programs upon changes in task complexity. Notably, the activity of M1 SST interneurons encoded structural and kinematic information of these more complex motor sequences. Finally, we showed that inhibition of SST interneurons interfered with the kinematics and disrupted the efficiency of motor program execution. These findings demonstrate a causal role for M1 SST interneuron re-engagement in regulating efficient motor sequence reorganization. less

Contextual associations are critical for survival but must be extinguished when new conditions render them nonproductive. By most accounts, extinction forms a new memory that competes with the original association for control over behavior, but the mechanisms underlying this competition remain largely enigmatic. Here we find the retrieval of contextual fear conditioning and extinction yield contrasting patterns of activity in prefrontal cortex and ventral hippocampus. Within ventral CA1, activation of somatostatin-expressing interneurons (SST-INs) occurs preferentially during extinction retrieval and correlates with differences in input synaptic transmission. Optogenetic manipulation of these cells but not parvalbumin interneurons (PV-INs) elicits bidirectional changes in fear expression following extinction, and the ability of SST-INs to gate fear is specific to the context in which extinction was acquired. A similar pattern of results was obtained following reward-based extinction. These data show that ventral hippocampal SST-INs are critical for extinguishing prior associations and thereby gate relapse of both aversive and appetitive responses. less

Humans use their voice concurrently with upper limb movements, known as hand gestures. Recently it has been shown that fluctuations in intensity and the tone of the human voice synchronizes with upper limb movement (including gesticulation). In this research direct evidence is provided that the voice changes with arm movements because it interacts with whole-body muscle activity (measured through surface EMG and postural measurements). We show that certain muscles (e.g., pectoralis major) that are associated with posture and upper limb movement are especially likely to interact with the voice. Adding wrist weights to increase the mass of the moving upper limb segment led to increased coupling between movement and voice. These results show that the voice co-patterns with whole-body kinetics relating to force, rather than kinematics, invoking several implications how the voice is biomechanically modeled, how it should be simulated, and importantly how the human voice must have evolved in relation to the whole-body motor system. We concluded that the human voice is animated by the kinetics of the whole body. less

Redox dysregulation has been proposed as a convergent point of childhood trauma and the emergence of psychiatric disorders, such as schizophrenia (SCZ). However, the impact of severe stressors during adolescence on the ventral hippocampus (vHip) redox states and their functional consequences, including behavioral and electrophysiological changes related to SCZ, are not entirely understood. After exposing adolescent animals to physical stress (postnatal day, PND31 - 40), we explored social and cognitive behaviors (PND47 - 49) and the activity of pyramidal glutamate neurons, the number of parvalbumin (PV) interneurons, and the transcriptomic signature of the vHip (PND51). We also evaluated the impact of stress on the redox system one and ten days after stress, while glutathione levels were measured in the vHip and serum following the behavioral test. Adolescent-stressed animals exhibited loss of sociability, cognitive impairment, and vHip excitatory/inhibitory (E/I) imbalance. Genome-wide transcriptional profiling unveiled the impact of stress on synaptic and redox system-related genes. Stress impacted mitochondrial respiratory function, leading to changes in reactive oxygen species levels in the vHip. Glutathione (GSH) and glutathione disulfide (GSSG) levels were elevated in the serum of stressed animals, while GSSG was also increased in the vHip and negatively correlated with sociability. Additionally, PV interneuron deficits in the vHip caused by adolescent stress were associated with oxidative stress. Our results highlight the negative impact of adolescent stress on vHip redox regulation and mitochondrial function, which are partially associated with E/I imbalance and behavioral abnormalities related to SCZ. less

A major question in attention research is how the brain identifies task-relevant stimuli in the absence of exogenous instructions or cues. Recent studies propose that endogenous attention control expected information gains (EIG) or, equivalently, minimizes decision uncertainty, but the mechanisms of this process are not understood. We show that, in a task in which participants covertly attended to decision-relevant stimuli, their perceptual sensitivity (d\') for discriminating the stimuli depended on the diagnosticity of the stimuli and the participants\' prior decision uncertainty, consistent with Bayesian EIG. The fronto-parietal network, in particular left areas V3A/B and IPS1/2, integrated uncertainty with diagnosticity in a manner correlating with behavioral effects on d\', and uncertainty signals relied on interactions between this network and the medial prefrontal cortex (mPFC). The findings show that covert attention can be deployed based on EIG and reveal the neural mechanisms of this process. less

The neural communication process heavily relies on vesicular release of neurotransmitters and/or neuromodulators primarily from synaptic vesicles (SVs) or dense-core vesicles (DCVs), within neurons and neuroendocrine cells. SVs (~40 nm) are responsible for releasing classical neurotransmitters, while DCVs (100-500 nm in diameter) release both classic neurotransmitters and neuropeptides. DCVs contain a variety of neuropeptides, hormones, and neurotransmitters, playing crucial roles in diverse physiological processes, such as brain development, neurogenesis, and synaptic plasticity. However, the biogenesis of DCVs and the sorting mechanism of different neuropeptides into DCVs remained largely unknown. Recent studies have revealed that liquid-liquid phase separation (LLPS) of matrix protein-chromogranins plays pivotal roles in the formation of DCVs and the sorting process of neurotransmitters/neuromodulators in endocrine cells. Here we highlight recent advancements in mechanisms of LLPS\'s regulation of DCVs [1, 2], which selectively affect release of some co-transmitters (catecholamines) but not others (i.e. ATP) [3]. We term this phenomenon \"1-2-2\": 1 vesicle, 2 transmitters (catecholamine and ATP), 2 release modes (quanta and sub-quanta). less

Tau forms toxic fibrillar aggregates in a family of neurodegenerative diseases known as tauopathies. The faithful replication of tauopathy-specific fibril structures is a critical gap for developing diagnostic and therapeutic tools. This study debuts a strategy of identifying a critical segment of tau that forms a folding motif that is characteristic of a family of tauopathies and isolating it as a standalone peptide that form seeding-competent fibrils. The 19-residue jR2R3 peptide (295-313) spanning the R2/R3 splice junction of tau, in the presence of P301L, forms seeding-competent amyloid fibrils. This tau fragment contains the hydrophobic VQIVYK hexapeptide that is part of the core of every pathological tau fibril structure solved to-date and an intramolecular counter-strand that stabilizes the strand-loop-strand (SLS) motif observed in 4R tauopathy fibrils. This study shows that P301L exhibits a duality of effects: it lowers the barrier for the peptide to adopt aggregation-prone conformations and enhances the local structuring of water around the mutation site that facilitates site-specific dewetting and in-register stacking of tau to form cross {beta}-sheets. We solve a 3 [A] cryo-EM structure of jR2R3-P301L fibrils with a pseudo 21 screw symmetry in which each half of the fibril\'s cross-section contains two jR2R3-P301L peptides. One chain adopts a SLS fold found in 4R tauopathies that is stabilized by a second chain wrapping around the SLS fold, reminiscent of the 3-fold and 4-fold structures observed in 4R tauopathies. These jR2R3-P301L fibrils are able to template full-length tau in a prion-like fashion. less