Annual Review of Neuroscience - Early Publication

Because organisms are able to sense its passage, it is perhaps tempting to treat time as a sensory modality, akin to vision or audition. Indeed, certain features of sensory estimation, such as Weber's law, apply to timing and sensation alike. However, from an organismal perspective, time is a derived feature of other signals, not a stimulus that can be readily transduced by sensory receptors. Its importance for biology lies in the fact that the physical world comprises a complex dynamical system. The multiscale spatiotemporal structure of sensory and internally generated signals within an organism is the informational fabric underlying its ability to control behavior. Viewed this way, temporal computations assume a more fundamental role than is implied by treating time as just another element of the experienced world. Thus, in this review we focus on temporal processing as a means of approaching the more general problem of how the nervous system produces adaptive behavior.

We review recent developments of the use of topology in neuroscience. From grid cells and head direction cells to the geometry of olfactory space, modern applied topology methods such as persistent homology are increasingly being used to study neural circuits and perception. In addition to outlining the big picture and reviewing various applications of topological data analysis (TDA) to neuroscience, we take a deep dive into the basic homology computation to make the underlying mathematics more accessible to neuroscientists. A discussion of practical considerations and pointers to TDA software are also included.

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.

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.

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.

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.

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.

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.

Updated on April 9, 2025.

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.

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.