Neuroscience

How is language organized in the human brain? The Neuroscience of Language, published in 2003, puts forth a systematic model of language to bridge the gap between linguistics and neuroscience. Neuronal models of word and serial order processing are presented in the form of a computational, connectionist neural network. The linguistic emphasis is on words and elementary syntactic rules. Introductory chapters focus on neuronal structure and function, cognitive brain processes, the basics of classical aphasia research and modern neuroimaging of language, neural network approaches to language, and the basics of syntactic theories. The essence of the work is contained in chapters on neural algorithms and networks, basic syntax, serial order mechanisms, and neuronal grammar. Throughout, excursuses illustrate the functioning of brain models of language, some of which are accessible as animations on the book's accompanying web site. It will appeal to graduate students and researchers in neuroscience, psychology, linguistics, and computational modeling.

Neuroscience is at a crossroads. Great effort is being invested into deciphering specific neural interactions and circuits. At the same time, there exist few general theories or principles that explain brain function. We attribute this disparity, in part, to limitations in current methodologies. Traditional neurophysiological approaches record the activities of one neuron or a few neurons at a time. Neurochemical approaches focus on single neurotransmitters. Yet, there is an increasing realization that neural circuits operate at emergent levels, where the interactions between hundreds or thousands of neurons, utilizing multiple chemical transmitters, generate functional states. Brains function at the nanoscale, so tools to study brains must ultimately operate at this scale, as well. Nanoscience and nanotechnology are poised to provide a rich toolkit of novel methods to explore brain function by enabling simultaneous measurement and manipulation of activity of thousands or even millions of neurons. We and others refer to this goal as the Brain Activity Mapping Project. In this Nano Focus, we discuss how recent developments in nanoscale analysis tools and in the design and synthesis of nanomaterials have generated optical, electrical, and chemical methods that can readily be adapted for use in neuroscience. These approaches represent exciting areas of technical development and research. Moreover, unique opportunities exist for nanoscientists, nanotechnologists, and other physical scientists and engineers to contribute to tackling the challenging problems involved in understanding the fundamentals of brain function.

There have been two recent revolutionary advances in neuroscience: First, genetically encoded activity sensors have brought the goal of optical detection of single action potentials in vivo within reach. Second, optogenetic actuators now allow the activity of neurons to be controlled with millisecond precision. These revolutions have now been combined, together with advanced microscopies, to allow "all-optical" readout and manipulation of activity in neural circuits with single-spike and single-neuron precision. This is a transformational advance that will open new frontiers in neuroscience research. Harnessing the power of light in the all-optical approach requires coexpression of genetically encoded activity sensors and optogenetic probes in the same neurons, as well as the ability to simultaneously target and record the light from the selected neurons. It has recently become possible to combine sensors and optical strategies that are sufficiently sensitive and cross talk free to enable single-action-potential sensitivity and precision for both readout and manipulation in the intact brain. The combination of simultaneous readout and manipulation from the same genetically defined cells will enable a wide range of new experiments as well as inspire new technologies for interacting with the brain. The advances described in this review herald a future where the traditional tools used for generations by physiologists to study and interact with the brain-stimulation and recording electrodes-can largely be replaced by light. We outline potential future developments in this field and discuss how the all-optical strategy can be applied to solve fundamental problems in neuroscience. SIGNIFICANCE STATEMENT: This review describes the nexus of dramatic recent developments in optogenetic probes, genetically encoded activity sensors, and novel microscopies, which together allow the activity of neural circuits to be recorded and manipulated entirely using light. The optical and protein engineering strategies that form the basis of this "all-optical" approach are now sufficiently advanced to enable single-neuron and single-action potential precision for simultaneous readout and manipulation from the same functionally defined neurons in the intact brain. These advances promise to illuminate many fundamental challenges in neuroscience, including transforming our search for the neural code and the links between neural circuit activity and behavior.

Understanding how different kinds of neuron in the brain work together to implement sensations, feelings, thoughts, and movements, and how deficits in specific kinds of neuron result in brain diseases, has long been a priority in basic and clinical neuroscience. "Optogenetic" tools are genetically encoded molecules that, when targeted to specific neurons in the brain, enable their activity to be driven or silenced by light. These molecules are microbial opsins, seven-transmembrane proteins adapted from organisms found throughout the world, which react to light by transporting ions across the lipid membranes of cells in which they are genetically expressed. These tools are enabling the causal assessment of the roles that different sets of neurons play within neural circuits, and are accordingly being used to reveal how different sets of neurons contribute to the emergent computational and behavioral functions of the brain. These tools are also being explored as components of prototype neural control prosthetics capable of correcting neural circuit computations that have gone awry in brain disorders. This review gives an account of the birth of optogenetics and discusses the technology and its applications.

General anesthesia is characterized by loss of consciousness, amnesia, analgesia, and immobility. Important molecular targets of general anesthetics have been identified, but the neural circuits underlying the discrete end points of general anesthesia remain incompletely understood. General anesthesia and natural sleep share the common feature of reversible unconsciousness, and recent developments in neuroscience have enabled elegant studies that investigate the brain nuclei and neural circuits underlying this important end point. A common approach to measure cortical activity across the brain is electroencephalogram (EEG), which can reflect local neuronal activity as well as connectivity among brain regions. The EEG oscillations observed during general anesthesia depend greatly on the anesthetic agent as well as dosing, and only some resemble those observed during sleep. For example, the EEG oscillations during dexmedetomidine sedation are similar to those of stage 2 nonrapid eye movement (NREM) sleep, but high doses of propofol and ether anesthetics produce burst suppression, a pattern that is never observed during natural sleep. Sleep is primarily driven by withdrawal of subcortical excitation to the cortex, but anesthetics can directly act at both subcortical and cortical targets. While some anesthetics appear to activate specific sleep-active regions to induce unconsciousness, not all sleep-active regions play a significant role in anesthesia. Anesthetics also inhibit cortical neurons, and it is likely that each class of anesthetic drugs produces a distinct combination of subcortical and cortical effects that lead to unconsciousness. Conversely, arousal circuits that promote wakefulness are involved in anesthetic emergence and activating them can induce emergence and accelerate recovery of consciousness. Modern neuroscience techniques that enable the manipulation of specific neural circuits have led to new insights into the neural circuitry underlying general anesthesia and sleep. In the coming years, we will continue to better understand the mechanisms that generate these distinct states of reversible unconsciousness.

The neural circuits of the central nervous system are the regulatory pathways for feeling, motion control, learning, and memory, and their dysfunction is closely related to various neurodegenerative diseases. Despite the growing demand for the unraveling of the physiology and functional connectivity of the neural circuits, their fundamental investigation is hampered because of the inability to access the components of neural circuits and the complex microenvironment. As an alternative approach, in vitro human neural circuits show principles of in vivo human neuronal circuit function. They allow access to the cellular compartment and permit real-time monitoring of neural circuits. In this review, we summarize recent advances in reconstituted in vitro neural circuits using engineering techniques. To this end, we provide an overview of the fabrication techniques and methods for stimulation and measurement of in vitro neural circuits. Subsequently, representative examples of in vitro neural circuits are reviewed with a particular focus on the recapitulation of structures and functions observed in vivo, and we summarize their application in the study of various brain diseases. We believe that the in vitro neural circuits can help neuroscience and the neuropharmacology. STATEMENT OF SIGNIFICANCE: Despite the growing demand to unravel the physiology and functional connectivity of the neural circuits, the studies on the in vivo neural circuits are frequently limited due to the poor accessibility. Furthermore, single neuron-based analysis has an inherent limitation in that it does not reflect the full spectrum of the neural circuit physiology. As an alternative approach, in vitro engineered neural circuit models have arisen because they can recapitulate the structural and functional characteristics of in vivo neural circuits. These in vitro neural circuits allow the mimicking of dysregulation of the neural circuits, including neurodegenerative diseases and traumatic brain injury. Emerging in vitro engineered neural circuits will provide a better understanding of the (patho-)physiology of neural circuits.

New neurotechnologies fueled by the BRAIN Initiative now allow investigators to map, monitor and modulate complex neural circuits, enabling the pursuit of research questions previously considered unapproachable. Yet it is the convergence of molecular neuroscience with the new systems neuroscience that promises the greatest future advances. This is particularly true for our understanding of nervous system disorders, some of which have known molecular drivers or pathology but result in unknown perturbations in circuit function. NIH-supported research on "BRAIN Circuits" programs integrate experimental, analytic, and theoretical capabilities for analysis of specific neural circuits and their contributions to perceptions, motivations, and actions. In this review, we describe the BRAIN priority areas, review our strategy for balancing early feasibility with mature projects, and the balance of individual with team science for this 'BRAIN Circuits' program. We also highlight the diverse portfolio of techniques, species, and neural systems represented in these projects.

Anxiety, depression, and schizophrenia are complex psychiatric disorders characterized by disruptions in neural circuits, neurotransmitter systems, and brain connectivity, resulting in impairments in emotional regulation and cognitive functioning. This review examines the genetic, environmental, and neurobiological factors influencing these conditions, empha sizing the critical roles of neurotransmitters such as serotonin, dopamine, and norepinephrine in mood regulation, stress response, and neuroplasticity. These findings underscore the need for personalized treatment approaches. The review also explores integrative strategies that combine pharmacological interventions with non-pharmacological modalities, including acupuncture, herbal medicine, and mindfulness, which show promise for individualized care. Advances in neuro imaging and neurostimulation techniques, such as eigenvector centrality mapping and machine learning-driven analyses, provide deeper insights into brain connectivity and enable more targeted interventions. This is particularly significant for schizophrenia, where dopamine-mediated disruptions in striatal-prefrontal connectivity contribute to cognitive deficits and clinical symptoms. However, current limitations, such as an inadequate understanding of the neural circuits underlying these disorders and the limited effectiveness of conventional treatments for certain subgroups, highlight critical gaps in existing research and therapeutic approaches. Furthermore, the article discusses how integrating computational models with traditional medicine enhances our understanding of neurotransmitter interactions and neural pathways. This integration fosters innovative therapies that address both immediate symptoms and long-term resilience. This interdisciplinary approach bridges basic neuroscience and clinical practice, paving the way for effective, personalized treatments and offering renewed hope for individuals with psychiatric disorders.