Wave-like dopamine dynamics as a mechanism for spatiotemporal credit assignment.

Significant evidence supports the view that dopamine shapes learning by encoding reward prediction errors. However, it is unknown whether striatal targets receive tailored dopamine dynamics based on regional functional specialization. Here, we report wave-like spatiotemporal activity patterns in dopamine axons and release across the dorsal striatum. These waves switch between activational motifs and organize dopamine transients into localized clusters within functionally related striatal subregions. Notably, wave trajectories were tailored to task demands, propagating from dorsomedial to dorsolateral striatum when rewards are contingent on animal behavior and in the opponent direction when rewards are independent of behavioral responses. We propose a computational architecture in which striatal dopamine waves are sculpted by inference about agency and provide a mechanism to direct credit assignment to specialized striatal subregions. Supporting model predictions, dorsomedial dopamine activity during reward-pursuit signaled the extent of instrumental control and interacted with reward waves to predict future behavioral adjustments.

Tracing the genetic footprints of vertebrate landing in non-teleost ray-finned fishes.

Rich fossil evidence suggests that many traits and functions related to terrestrial evolution were present long before the ancestor of lobe- and ray-finned fishes. Here, we present genome sequences of the bichir, paddlefish, bowfin, and alligator gar, covering all major early divergent lineages of ray-finned fishes. Our analyses show that these species exhibit many mosaic genomic features of lobe- and ray-finned fishes. In particular, many regulatory elements for limb development are present in these fishes, supporting the hypothesis that the relevant ancestral regulation networks emerged before the origin of tetrapods. Transcriptome analyses confirm the homology between the lung and swim bladder and reveal the presence of functional lung-related genes in early ray-finned fishes. Furthermore, we functionally validate the essential role of a jawed vertebrate highly conserved element for cardiovascular development. Our results imply the ancestors of jawed vertebrates already had the potential gene networks for cardio-respiratory systems supporting air breathing.

Functional diversity for body actions in the mesencephalic locomotor region.

The mesencephalic locomotor region (MLR) is a key midbrain center with roles in locomotion. Despite extensive studies and clinical trials aimed at therapy-resistant Parkinson's disease (PD), debate on its function remains. Here, we reveal the existence of functionally diverse neuronal populations with distinct roles in control of body movements. We identify two spatially intermingled glutamatergic populations separable by axonal projections, mouse genetics, neuronal activity profiles, and motor functions. Most spinally projecting MLR neurons encoded the full-body behavior rearing. Loss- and gain-of-function optogenetic perturbation experiments establish a function for these neurons in controlling body extension. In contrast, Rbp4-transgene-positive MLR neurons project in an ascending direction to basal ganglia, preferentially encode the forelimb behaviors handling and grooming, and exhibit a role in modulating movement. Thus, the MLR contains glutamatergic neuronal subpopulations stratified by projection target exhibiting roles in action control not restricted to locomotion.

The genomic history of the Middle East.

The Middle East region is important to understand human evolution and migrations but is underrepresented in genomic studies. Here, we generated 137 high-coverage physically phased genome sequences from eight Middle Eastern populations using linked-read sequencing. We found no genetic traces of early expansions out-of-Africa in present-day populations but found Arabians have elevated Basal Eurasian ancestry that dilutes their Neanderthal ancestry. Population sizes within the region started diverging 15-20 kya, when Levantines expanded while Arabians maintained smaller populations that derived ancestry from local hunter-gatherers. Arabians suffered a population bottleneck around the aridification of Arabia 6 kya, while Levantines had a distinct bottleneck overlapping the 4.2 kya aridification event. We found an association between movement and admixture of populations in the region and the spread of Semitic languages. Finally, we identify variants that show evidence of selection, including polygenic selection. Our results provide detailed insights into the genomic and selective histories of the Middle East.

Regulation of Collective Metastasis by Nanolumenal Signaling.

Collective metastasis is defined as the cohesive migration and metastasis of multicellular tumor cell clusters. Disrupting various cell adhesion genes markedly reduces cluster formation and colonization efficiency, yet the downstream signals transmitted by clustering remain largely unknown. Here, we use mouse and human breast cancer models to identify a collective signal generated by tumor cell clusters supporting metastatic colonization. We show that tumor cell clusters produce the growth factor epigen and concentrate it within nanolumina-intercellular compartments sealed by cell-cell junctions and lined with microvilli-like protrusions. Epigen knockdown profoundly reduces metastatic outgrowth and switches clusters from a proliferative to a collective migratory state. Tumor cell clusters from basal-like 2, but not mesenchymal-like, triple-negative breast cancer cell lines have increased epigen expression, sealed nanolumina, and impaired outgrowth upon nanolumenal junction disruption. We propose that nanolumenal signaling could offer a therapeutic target for aggressive metastatic breast cancers.

LAP2 Proteins Chaperone GLI1 Movement between the Lamina and Chromatin to Regulate Transcription.

Understanding transcription factor navigation through the nucleus remains critical for developing targeted therapeutics. The GLI1 transcription factor must maintain maximal Hedgehog pathway output in basal cell carcinomas (BCCs), and we have previously shown that resistant BCCs increase GLI1 deacetylation through atypical protein kinase Cι/λ (aPKC) and HDAC1. Here we identify a lamina-associated polypeptide 2 (LAP2) isoform-dependent nuclear chaperoning system that regulates GLI1 movement between the nuclear lamina and nucleoplasm to achieve maximal activation. LAP2ß forms a two-site interaction with the GLI1 zinc-finger domain and acetylation site, stabilizing an acetylation-dependent reserve on the inner nuclear membrane (INM). By contrast, the nucleoplasmic LAP2α competes with LAP2ß for GLI1 while scaffolding HDAC1 to deacetylate the secondary binding site. aPKC functions to promote GLI1 association with LAP2α, promoting egress off the INM. GLI1 intranuclear trafficking by LAP2 isoforms represents a powerful signal amplifier in BCCs with implications for zinc finger-based signal transduction and therapeutics.

Molecular Diversity and Specializations among the Cells of the Adult Mouse Brain.

The mammalian brain is composed of diverse, specialized cell populations. To systematically ascertain and learn from these cellular specializations, we used Drop-seq to profile RNA expression in 690,000 individual cells sampled from 9 regions of the adult mouse brain. We identified 565 transcriptionally distinct groups of cells using computational approaches developed to distinguish biological from technical signals. Cross-region analysis of these 565 cell populations revealed features of brain organization, including a gene-expression module for synthesizing axonal and presynaptic components, patterns in the co-deployment of voltage-gated ion channels, functional distinctions among the cells of the vasculature and specialization of glutamatergic neurons across cortical regions. Systematic neuronal classifications for two complex basal ganglia nuclei and the striatum revealed a rare population of spiny projection neurons. This adult mouse brain cell atlas, accessible through interactive online software (DropViz), serves as a reference for development, disease, and evolution.

Optogenetic Editing Reveals the Hierarchical Organization of Learned Action Sequences.

The organization of action into sequences underlies complex behaviors that are essential for organismal survival and reproduction. Despite extensive studies of innate sequences in relation to central pattern generators, how learned action sequences are controlled and whether they are organized as a chain or a hierarchy remain largely unknown. By training mice to perform heterogeneous action sequences, we demonstrate that striatal direct and indirect pathways preferentially encode different behavioral levels of sequence structure. State-dependent closed-loop optogenetic stimulation of the striatal direct pathway can selectively insert a single action element into the sequence without disrupting the overall sequence length. Optogenetic manipulation of the striatal indirect pathway completely removes the ongoing subsequence while leaving the following subsequence to be executed with the appropriate timing and length. These results suggest that learned action sequences are not organized in a serial but rather a hierarchical structure that is distinctly controlled by basal ganglia pathways.

A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity.

Breast cancer (BC) comprises multiple distinct subtypes that differ genetically, pathologically, and clinically. Here, we describe a robust protocol for long-term culturing of human mammary epithelial organoids. Using this protocol, >100 primary and metastatic BC organoid lines were generated, broadly recapitulating the diversity of the disease. BC organoid morphologies typically matched the histopathology, hormone receptor status, and HER2 status of the original tumor. DNA copy number variations as well as sequence changes were consistent within tumor-organoid pairs and largely retained even after extended passaging. BC organoids furthermore populated all major gene-expression-based classification groups and allowed in vitro drug screens that were consistent with in vivo xeno-transplantations and patient response. This study describes a representative collection of well-characterized BC organoids available for cancer research and drug development, as well as a strategy to assess in vitro drug response in a personalized fashion.

The Striatum Organizes 3D Behavior via Moment-to-Moment Action Selection.

Many naturalistic behaviors are built from modular components that are expressed sequentially. Although striatal circuits have been implicated in action selection and implementation, the neural mechanisms that compose behavior in unrestrained animals are not well understood. Here, we record bulk and cellular neural activity in the direct and indirect pathways of dorsolateral striatum (DLS) as mice spontaneously express action sequences. These experiments reveal that DLS neurons systematically encode information about the identity and ordering of sub-second 3D behavioral motifs; this encoding is facilitated by fast-timescale decorrelations between the direct and indirect pathways. Furthermore, lesioning the DLS prevents appropriate sequence assembly during exploratory or odor-evoked behaviors. By characterizing naturalistic behavior at neural timescales, these experiments identify a code for elemental 3D pose dynamics built from complementary pathway dynamics, support a role for DLS in constructing meaningful behavioral sequences, and suggest models for how actions are sculpted over time.

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.

We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.

Chronic Stress Alters Striosome-Circuit Dynamics, Leading to Aberrant Decision-Making.

Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, "rational" decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Concomitantly, alterations in the task-related spike activity of medial prefrontal neurons correspond with increased activity of their striosome-predominant striatal projection neuron targets and with decreased and delayed striatal fast-firing interneuron activity. These effects of chronic stress on prefronto-striatal circuit dynamics could be blocked or be mimicked by selective optogenetic manipulation of these circuits. We suggest that altered excitation-inhibition dynamics of striosome-based circuit function could be an underlying mechanism by which chronic stress contributes to disorders characterized by aberrant decision-making under conflict. VIDEO ABSTRACT.

Striosomes and Matrisomes: Scaffolds for Dynamic Coupling of Volition and Action.

Striosomes form neurochemically specialized compartments of the striatum embedded in a large matrix made up of modules called matrisomes. Striosome-matrix architecture is multiplexed with the canonical direct-indirect organization of the striatum. Striosomal functions remain to be fully clarified, but key information is emerging. First, striosomes powerfully innervate nigral dopamine-containing neurons and can completely shut down their activity, with a following rebound excitation. Second, striosomes receive limbic and cognition-related corticostriatal afferents and are dynamically modulated in relation to value-based actions. Third, striosomes are spatially interspersed among matrisomes and interneurons and are influenced by local and global neuromodulatory and oscillatory activities. Fourth, striosomes tune engagement and the motivation to perform reinforcement learning, to manifest stereotypical behaviors, and to navigate valence conflicts and valence discriminations. We suggest that, at an algorithmic level, striosomes could serve as distributed scaffolds to provide formats of the striatal computations generated through development and refined through learning. We propose that striosomes affect subjective states. By transforming corticothalamic and other inputs to the functional formats of the striatum, they could implement state transitions in nigro-striato-nigral circuits to affect bodily and cognitive actions according to internal motives whose functions are compromised in neuropsychiatric conditions.

Distinct Hippocampal Pathways Mediate Dissociable Roles of Context in Memory Retrieval.

Memories about sensory experiences are tightly linked to the context in which they were formed. Memory contextualization is fundamental for the selection of appropriate behavioral reactions needed for survival, yet the underlying neuronal circuits are poorly understood. By combining trans-synaptic viral tracing and optogenetic manipulation, we found that the ventral hippocampus (vHC) and the amygdala, two key brain structures encoding context and emotional experiences, interact via multiple parallel pathways. A projection from the vHC to the basal amygdala mediates fear behavior elicited by a conditioned context, whereas a parallel projection from a distinct subset of vHC neurons onto midbrain-projecting neurons in the central amygdala is necessary for context-dependent retrieval of cued fear memories. Our findings demonstrate that two fundamentally distinct roles of context in fear memory retrieval are processed by distinct vHC output pathways, thereby allowing for the formation of robust contextual fear memories while preserving context-dependent behavioral flexibility.

Brainstem Circuits for Locomotion.

Locomotion is a universal motor behavior that is expressed as the output of many integrated brain functions. Locomotion is organized at several levels of the nervous system, with brainstem circuits acting as the gate between brain areas regulating innate, emotional, or motivational locomotion and executive spinal circuits. Here we review recent advances on brainstem circuits involved in controlling locomotion. We describe how delineated command circuits govern the start, speed, stop, and steering of locomotion. We also discuss how these pathways interface between executive circuits in the spinal cord and diverse brain areas important for context-specific selection of locomotion. A recurrent theme is the need to establish a functional connectome to and from brainstem command circuits. Finally, we point to unresolved issues concerning the integrated function of locomotor control.

Tissue and Organ Initiation in the Plant Embryo: A First Time for Everything.

Land plants can grow to tremendous body sizes, yet even the most complex architectures are the result of iterations of the same developmental processes: organ initiation, growth, and pattern formation. A central question in plant biology is how these processes are regulated and coordinated to allow for the formation of ordered, 3D structures. All these elementary processes first occur in early embryogenesis, during which, from a fertilized egg cell, precursors for all major tissues and stem cells are initiated, followed by tissue growth and patterning. Here we discuss recent progress in our understanding of this phase of plant life. We consider the cellular basis for multicellular development in 3D and focus on the genetic regulatory mechanisms that direct specific steps during early embryogenesis.

Basal Ganglia Circuits for Action Specification.

Behavior is readily classified into patterns of movements with inferred common goals-actions. Goals may be discrete; movements are continuous. Through the careful study of isolated movements in laboratory settings, or via introspection, it has become clear that animals can exhibit exquisite graded specification to their movements. Moreover, graded control can be as fundamental to success as the selection of which action to perform under many naturalistic scenarios: a predator adjusting its speed to intercept moving prey, or a tool-user exerting the perfect amount of force to complete a delicate task. The basal ganglia are a collection of nuclei in vertebrates that extend from the forebrain (telencephalon) to the midbrain (mesencephalon), constituting a major descending extrapyramidal pathway for control over midbrain and brainstem premotor structures. Here we discuss how this pathway contributes to the continuous specification of movements that endows our voluntary actions with vigor and grace.

The cell biology of neurogenesis: toward an understanding of the development and evolution of the neocortex.

Neural stem and progenitor cells have a central role in the development and evolution of the mammalian neocortex. In this review, we first provide a set of criteria to classify the various types of cortical stem and progenitor cells. We then discuss the issue of cell polarity, as well as specific subcellular features of these cells that are relevant for their modes of division and daughter cell fate. In addition, cortical stem and progenitor cell behavior is placed into a tissue context, with consideration of extracellular signals and cell-cell interactions. Finally, the differences across species regarding cortical stem and progenitor cells are dissected to gain insight into key developmental and evolutionary mechanisms underlying neocortex expansion.

DNA segregation in mitochondria and beyond: insights from the trypanosomal tripartite attachment complex.

The tripartite attachment complex (TAC) of the single mitochondrion of trypanosomes allows precise segregation of its single nucleoid mitochondrial genome during cytokinesis. It couples the segregation of the duplicated mitochondrial genome to the segregation of the basal bodies of the flagella. Here, we provide a model of the molecular architecture of the TAC that explains how its eight essential subunits connect the basal body, across the mitochondrial membranes, with the mitochondrial genome. We also discuss how the TAC subunits are imported into the mitochondrion and how they assemble to form a new TAC. Finally, we present a comparative analysis of the trypanosomal TAC with open and closed mitotic spindles, which reveals conserved concepts between these diverse DNA segregation systems.

Current Principles of Motor Control, with Special Reference to Vertebrate Locomotion.

The vertebrate control of locomotion involves all levels of the nervous system from cortex to the spinal cord. Here, we aim to cover all main aspects of this complex behavior, from the operation of the microcircuits in the spinal cord to the systems and behavioral levels and extend from mammalian locomotion to the basic undulatory movements of lamprey and fish. The cellular basis of propulsion represents the core of the control system, and it involves the spinal central pattern generator networks (CPGs) controlling the timing of different muscles, the sensory compensation for perturbations, and the brain stem command systems controlling the level of activity of the CPGs and the speed of locomotion. The forebrain and in particular the basal ganglia are involved in determining which motor programs should be recruited at a given point of time and can both initiate and stop locomotor activity. The propulsive control system needs to be integrated with the postural control system to maintain body orientation. Moreover, the locomotor movements need to be steered so that the subject approaches the goal of the locomotor episode, or avoids colliding with elements in the environment or simply escapes at high speed. These different aspects will all be covered in the review.