Annual Review of Neuroscience - Current Issue

The twenty-first century has brought forth a deluge of theories and data shedding light on the neural mechanisms of motivated behavior. Much of this progress has focused on dopaminergic dynamics, including their signaling properties (how do they vary with expectations and outcomes?) and their downstream impacts in target regions (how do they affect learning and behavior?). In parallel, the basal ganglia have been elevated from their original implication in motoric function to a canonical circuit facilitating the initiation, invigoration, and selection of actions across levels of abstraction, from motor to cognitive operations. This review considers how striatal D1 and D2 opponency allows animals to perform cost-benefit calculations across multiple scales: locally, whether to select a given action, and globally, whether to engage a particular corticostriatal circuit for guiding behavior. An emerging understanding of such functions reconciles seemingly conflicting data and has implications for neuroscience, psychology, behavioral economics, and artificial intelligence.

Locomotion, like all behaviors, possesses an inherent flexibility that allows for the scaling of movement kinematic features, such as speed and vigor, in response to an ever-changing external world and internal drives. This flexibility is embedded in the organization of the spinal locomotor circuits, which encode and decode commands from the brainstem and proprioceptive feedback. This review highlights our current understanding of the modular organization of these locomotor circuits and how this modularity endows them with intrinsic mechanisms to adjust speed and vigor, thereby contributing to the flexibility of locomotor movements.

Cognition unfolds dynamically over flexible timescales. A major goal of the field is to understand the computational and neurobiological principles that enable this flexibility. Here, we argue that the neurobiology of timing provides a platform for tackling these questions. We begin with an overview of proposed coding schemes for the representation of elapsed time, highlighting their computational properties. We then leverage the one-dimensional and unidirectional nature of time to highlight common principles across these coding schemes. These principles facilitate a precise formulation of questions related to the flexible control, variability, and calibration of neural dynamics. We review recent work that demonstrates how dynamical systems analysis of thalamocortical population activity in timing tasks has provided fundamental insights into how the brain calibrates and flexibly controls neural dynamics. We conclude with speculations about the architectural biases and neural substrates that support the control and calibration of neural dynamics more generally.

During rest and sleep, the brain processes information through replay, reactivating neural patterns linked to past events and facilitating the exploration of potential future scenarios. This review summarizes recent advances in understanding human replay and its biomarker, sharp-wave ripples (SPW-Rs). We explore detection methods and connect insights from rodent studies. The review highlights unique aspects of human replay in internal cognition such as prioritizing past experiences for offline learning, generating hypothesized solutions to current problems, and factorizing structural representations for future generalization. We also examine the characteristics of SPW-Rs in humans, including their distribution along the hippocampal longitudinal axis, their widespread brain activations, and their influence on internal cognitive processes. Finally, we emphasize the need for improved methodologies and technologies to advance our understanding of cognitive processes during rest and sleep.

Medulloblastoma is the most common malignant pediatric brain cancer and is broadly categorized into four molecular subgroups. Understanding the cell origins of medulloblastoma is crucial for preventing tumor formation and relapse. Recent single-cell transcriptomics studies have identified the potential cell lineage vulnerabilities and mechanisms underpinning malignant transformation in medulloblastoma. Emerging evidence suggests that genetic-epigenetic alterations specific to each subgroup lead to a lineage-specific stall in the neural developmental program and subsequent tumorigenesis. We discuss the putative cells of origin, plasticity, and heterogeneity within medulloblastoma subgroups and delve into the genetic and epigenetic changes that predispose cells to transformation. Additionally, we review the current insights into how cerebellar stem/progenitor cells and lineage plasticity impact medulloblastoma pathogenesis and highlight recent therapeutic advances targeting specific oncogenic vulnerabilities in this malignancy.

Major depressive disorder and treatment-resistant depression are significant worldwide health problems that need new therapies. The success of the anesthetic ketamine as an antidepressant is well known. It is less widely known that several other anesthetic agents have also shown antidepressant effects. These include nitrous oxide, propofol, isoflurane, sevoflurane, dexmedetomidine, and xenon. We review clinical and basic science investigations that have studied the therapeutic value of these anesthetics for treating depression. We propose potential neurophysiological mechanisms underlying the antidepressant effects of anesthetics by combining our understanding of how anesthetics modulate brain dynamics to alter arousal states, current theories of depression pathophysiology, and findings from other depression treatment modalities.

Social behaviors, including parental care, mating, and fighting, all depend on the hormonal milieu of an organism. Decades of work highlighted estrogen as a key hormonal controller of social behaviors, exerting its influence primarily through binding to estrogen receptor alpha (ERα). Recent technological advances in chemogenetics, optogenetics, gene editing, and transgenic model organisms have allowed for a detailed understanding of the neuronal subpopulations and circuits for estrogen action across Esr1-expressing interconnected brain regions. Focusing on rodent studies, in this review we examine classical and contemporary research demonstrating the multifaceted role of estrogen and ERα in regulating social behaviors in a sex-specific and context-dependent manner. We highlight gaps in knowledge, particularly a missing link in the molecular cascade that allows estrogen to exert such a diverse behavioral repertoire through the coordination of gene expression changes. Understanding the molecular and cellular basis of ERα’s action in social behaviors provides insights into the broader mechanisms of hormone-driven behavior modulation across the lifespan.

The synapse is polarized and highly compartmentalized on both its pre- and postsynaptic sides. The compartmentalization of synaptic vesicles, as well as vesicle releasing and recycling machineries, allows neurotransmitters to be released with precisely controlled timing, speed, and amplitude. The compartmentalized and clustered organization of neurotransmitter receptors and their downstream signaling enzymes allows neuronal signals to be properly received and amplified. Synaptic adhesion molecules also form clustered assemblies to align pre- and postsynaptic subcompartments for synaptic formation, stability, and transmission. Recent studies indicate that such synaptic and subsynaptic compartmentalized organizations are formed via phase separation. This review discusses how such condensed subsynaptic compartments may form and function in the context of synapse formation and plasticity. We discuss how phase separation allows for the formation of multiple distinct condensates on both sides of a synapse and how such condensates communicate with each other. We also highlight how proteins display unique properties in condensed phases compared to the same proteins in dilute solutions.

The formation of new synapses, the connections between neurons, is the critical step for neural circuit assembly. Newly formed glutamatergic synapses are initially silent and require activity-dependent plasticity to become fully functional connections. While these synapses have long been considered a vital part of the developmental program for neural networks, recent findings now indicate that silent synapses are a key source of neural circuit plasticity in the adult brain. Here, we review current evidence for silent synapses in the adult brain and explore the potential roles of these highly plastic structures. We argue that silent synapses may be instrumental in adult neural circuit remodeling and can serve as a latent reservoir of plasticity that enhances information processing and storage. This previously underappreciated aspect of adult plasticity underscores the need for innovative approaches and further investigation into the dynamic contribution of silent synapses to learning and memory in the adult brain.

Sexually dimorphic instinctual behaviors that set females and males apart are found across animal clades. Recent studies in a variety of animal systems have provided deep insights into the neural circuits that guide sexually dimorphic behaviors, such as mating practices and social responses, and how sex differences in these circuits develop. Here, we discuss the neural circuits of several sexually dimorphic instinctual behaviors in rodents, flies, and worms—from mate attraction and aggression to pain perception and empathy. We highlight several salient similarities and differences between these circuits and reveal general principles that underlie the function and development of neural circuits for dimorphic behaviors.

Life on this planet is heavily influenced by light, the most critical external environmental factor. Mammals perceive environmental light mainly through three types of photoreceptors in the retina—rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs). The latest discovered ipRGCs are particularly sensitive to short-wavelength light and have a unique phototransduction mechanism, compared with rods and cones. Piles of evidence suggest that ipRGCs mediate a series of light-regulated physiological functions such as circadian rhythms, sleep, metabolic homeostasis, mood, development, and higher cognitions, collectively known as non-image-forming vision. Recent advances in systems neuroscience, driven by modern neural circuit tools, have illuminated the structure and function of the neural pathways connecting the retina to subcortical regions, highlighting their involvement in an array of non-image-forming functions. Here we review key discoveries and recent progress regarding the neural circuit mechanisms employed by ipRGCs to regulate diverse biological functions and provide insights into unresolved scientific questions in this area.

Astrocytes, the bushy, star-shaped glial cells of the brain and spinal cord, support the proper development and function of many cells in the central nervous system. In response to disease or injury they transform, adopting varied morphologies, molecular signatures, and functions—this state of transformation is known as reactivity. For over a century, the reactivity of astrocytes has been recognized, but it is the recent surge in technological innovation that has shed light on the diverse nature of this reactivity. It is this developing understanding of the heterogeneity of reactive astrocytes across disease-specific contexts and a spatiotemporal gradient that now excites the astrocyte field. In this review, we discuss the current understanding of reactive astrocyte heterogeneity, highlight the biological implications of this heterogeneity, and propose future approaches to aid in fully understanding the heterogeneity of reactive astrocytes.

Astrocytes, traditionally viewed as supportive cells within the central nervous system (CNS), are now recognized as dynamic regulators of neural signaling and homeostasis. They actively engage in synaptic transmission and brain health by releasing gliotransmitters such as glutamate, GABA, ATP, adenosine, lactate, and d-serine. Astrocytes also play a critical role in ion homeostasis and immune response through cytokine modulation and reactive oxygen species regulation. In pathological states, astrocytes can become reactive, contributing to neurodegeneration through dysregulated gliotransmitter release and metabolic dysfunction. Recently developed molecular and pharmacological tools allow the exploration of astrocytic response to injury and its influence on neuronal function. This review explores the multifaceted roles of astrocytes in health and disease, emphasizing sensory and motor functions as well as various neurological and psychiatric disorders. Understanding astrocyte-neuron signaling in health and disease provides crucial insights into their dual roles, offering novel avenues for therapeutic interventions in CNS disorders.

Decades of research into human neurodegenerative diseases have revealed important similarities as well as dissimilarities between diseases. While investigations of specific mechanistic aspects of diseases have been aided by cell and animal models, true advances in the understanding of neurodegeneration require that we deal with the daunting complexities of the human brain. In this review, we discuss novel molecular profiling methods that have been applied to human postmortem brain tissue during the last decade and highlight insights into cell type–specific molecular characteristics and disease-associated changes in both vulnerable and resilient cell types in Huntington's disease, Parkinson's disease, and Alzheimer's disease. We also illustrate how these approaches can complement human genetic analyses and studies of animal models to advance our understanding of human neurodegeneration.

The mechanisms underlying synaptic vesicle endocytosis remain controversial. In the 1970s, Heuser and Reese put forward a hypothesis that clathrin-mediated endocytosis is the predominant vesicle retrieval mechanism. In their seminal papers, another pathway was also described: uncoated large vesicles or cisternae emanating from the plasma membrane 1 s after a single stimulus. This pathway likely represents a recently described ultrafast endocytic pathway that recovers synaptic vesicles during physiological stimuli. Had we known of the existence of ultrafast endocytosis or paid more attention to the cisternae-based uptake pathway, would the experimental results over subsequent years have been interpreted differently? Here, I retrospectively review the literature on synaptic vesicle recycling through the lens of ultrafast endocytosis.

The evolutionary success of animals can, at least in part, be attributed to the presence of neurons that allow long-distance communication between tissues, coordination of movements, and the capacity for learning. However, the evolutionary origin and relationship of neurons to other cell types are fundamental questions that remain unsolved. The first neurons probably evolved shortly after the rise of the first animals over 600 million years ago. Studies on early-diverging animal lineages have provided key insights into the mechanisms underlying the origin of neurons. Recent discoveries in morphology, molecular signatures, and function of neurons in cnidarians and comb jellies, as well as neuron-like cells in nerveless placozoans, sponges, and other eukaryotes, may prompt a redefinition of what constitutes a neuron. Here we review the latest insights into the origin of neurons and nervous systems, while also highlighting exciting technological advancements that not only are accelerating our understanding of nervous system evolution, morphology, and function but also hold the potential to revolutionize the field.

During navigation to a goal, a portion of the hippocampal place cells exhibit directional preferences, firing more in some directions than in others. These directional preferences create vector fields oriented toward locations scattered around the environment called ConSinks. The population vector field averaged across all of the cells recorded in each animal flows toward an average ConSink located close to the goal, providing a means for navigation in unobstructed environments. Closer examination of the ConSink place cell directional firing reveals a fantail representation in which alternative paths to the goal are evaluated, providing the basis for flexible navigation. Additional assumptions about how obstructions might be represented suggest a solution for navigation in more complicated environments. Implications for the phenomena of directionality on linear tracks and splitter cells are discussed.

Many epidemiological studies have indicated that prenatal immune stress, frequently elicited by maternal immune activation, underlies a major risk for neuropsychiatric disorders of neurodevelopmental origin, such as schizophrenia and autism spectrum disorders. Animal models have been utilized to understand the biological processes of how immune stress influences brain development and resultant behavioral changes. Through such studies, the impacts of orchestrated immune-inflammatory mechanisms led by interleukin-6 (IL-6) on several developing cells, such as neural progenitors, neurons, and microglia, have been deciphered. In addition to prenatal immune stress from adverse maternal environments, mechanisms regulated by intrinsic factors directly associated with the offspring also exist. This review also introduces human stem cell models for addressing this topic and refers to potential modifiers of prenatal immune stress that could influence the eventual behavioral outcomes. Altogether, a mechanistic understanding of the impact of prenatal immune stress on brain development provides a fundamental addition in translational and clinical neurology and psychiatry.

To understand the pathophysiology of and develop effective therapeutics for brain disorders, some of which may involve uniquely human features of the nervous system, scalable human models of neural cell diversity and circuit formation are essential. The discovery of cell reprogramming and the development of approaches for generating stem cell–derived neurons and glial cells in 3D preparations known as neural organoids and assembloids, both in vitro and following transplantation in vivo, provide new opportunities to tackle these challenges. Here, we outline strengths and limitations of currently available human experimental models as applied to neurological and psychiatric disorders for both environmental and genetic risk factors, and we discuss how these new tools hold promise for accelerating the development of therapeutics.

Thirst and hunger drives are fundamental survival mechanisms that transform physiological need into motivated behavior. In the brain, discrete types of circumventricular and hypothalamic neurons serve as neural circuit elements underlying thirst and hunger drives. These neurons receive signals of dehydration and starvation arising from outside the brain and communicate these homeostatic needs to downstream neural circuit elements. Recent advances in neural circuit activity recording and control in behaving mammals have elucidated how direct and indirect targets of these cells encode goal-relevant, affective, autonomic, and behavioral components of the drives, resulting in a finely tuned, robust, and flexible set of survival-appropriate behaviors.