The micturition reflex relies on complex neural signaling to enable the coordination of the lower urinary tract. In neonates, this reflex is organized in the lumbosacral spinal cord and responds automatically to distension of the bladder or, in animals, to stimulation of the perigenital region by the mother. During development, competitive reorganization by supraspinal inputs places the reflex under conscious control and gives rise to the mature micturition reflex. Traumatic injury to the spinal cord that interrupts supraspinal inputs to the lumbosacral spinal cord can result in reversion to an automatic, spinal micturition reflex accompanied by lower urinary tract dysfunction such as neurogenic detrusor overactivity and detrusor–sphincter dyssynergia. This is accompanied by a number of changes in the anatomy and function of the lower urinary tract; various signaling pathways, including neurotrophins and neuropeptides; and reorganization of spinal circuitry. Evidence suggests that, following spinal cord injury, the bladder hypertrophies and urothelial and external urethral sphincter function are altered, giving rise to phasic spontaneous behavior and reduced bladder outlet bursting during voiding, respectively. Sensitization of Aδ-fiber afferents and “awakening” of C-fibers in the lumbosacral micturition pathway contribute to the emergence of a spinal micturition reflex and subsequent lower urinary tract dysfunction, with substantial evidence indicating a primary role for altered neurotrophin and neuropeptide signaling.
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Article
Plasticity in the Micturition Circuit During Development and Following Spinal Cord Injury
Harrison W. Hsiang and Margaret A. Vizzard
Article
Genetics of C. elegans Behavior
Denise S. Walker, Yee Lian Chew, and William R. Schafer
The nematode Caenorhabditis elegans is among the most intensely studied animals in modern experimental biology. Its amenability to classical and molecular genetics, compact nervous system, and transparency to optogenetic recording and manipulation have led to its being widely used to investigate how individual gene products act in the context of neuronal circuits to generate behavior. C. elegans was the first animal neuronal connectome to be characterized at the level of individual neurons and synapses, and the wiring organization shows significant parallels with the micro- and macro-level structures of more complex brains. It uses a wide array of sensory cues (mechanical, gustatory, olfactory, and thermal), with impressive precision, to determine an appropriate behavioral response, in the form of changes in locomotion and other motor outputs. The small number of neurons (302) and their highly stereotyped morphology have enabled the interrogation of the precise function of individual neurons, in terms of both the genes that they express and the behaviors in which they function. Approximately one third are sensory neurons, located around the mouth and in the tail, as well as along the length of the body. A complex network of interneurons connects these to the motor neurons, the majority of which output to the body wall muscles, arranged along the body, determining the changes in direction and speed of locomotion required for behaviors such as taxiing up gradients of food-related cues or avoiding noxious cues. The ability to combine information about the precise function of individual neurons with circuit knowledge, genetics, and optogenetic approaches has been critical in advancing the molecular and circuit-level understanding of the mechanisms underlying C. elegans’s behavior. In common with that of other animals, C. elegans’s behavior is subject to change in response to prior experience, and this same complement of experimental approaches has provided significant insight into how plasticity and changes in behavioral states are achieved.
Article
History of the Vermis Cerebelli: From Mechanical Function to Neuropsychological Circuits
Klaus F. Steinsiepe and Valentin K. Steinsiepe
The vermis cerebelli, the middle part of the cerebellum, has been anatomically known and named since Galen (around 200 ce). As part of his work in physiology, which was based on the distribution of pneuma, Galen attributed to the worm a mechanical valve function for the flow of psychic pneuma (spiritus animalis) in the brain. This function was adopted and expanded by Arab scholars who translated Galen. In Costa ben Luca (around 900 ce), for example, the worm regulates memory and thinking, whereas Avicenna (ca. 1000) sticks to Galen’s ideas. In 1316, Mondino assigned this function within the cerebral ventricles to the worm-like choroid plexus; the cerebellar vermis is forgotten. Vesalius corrected Galen on several points in 1543/1555 and clarified that the vermis cerebelli has no mechanical function; he ignored Mondino’s new, different worm. However, this vermis survived the Middle Ages and was depicted in numerous illustrations until the 17th century.
Since Thomas Willis (1621-1675), the vermis remained an anatomically conspicuous part of the cerebellum but generally does not play a special role within the general function of the cerebellum, even if there are individual speculative assumptions about its function (e.g., respiration or coenesthesia). Since Rolando in the early 19th century, the cerebellum has been increasingly associated with motor activity, but any localized functions of the cerebellum were denied by Pierre Flourens (1794-1867) and even later by Luigi Luciani (1840-1919).
This attitude changed completely in the 20th century. Through the fundamental work of Bolk, Comolli, Edinger, Larsell, Jansen, and Brodal, the cerebellum and vermis were structured anatomically, phylogenetically, and functionally. At the same time, electrophysiological research led to the discovery of somatotopic representations in the cerebellar cortex. The second half of the 20th century was characterized by an expansion of functions. The vermis was recognized as a dynamic learning structure and as an important center of emotional control—the “limbic vermis.”
Research since the beginning of the 21st century relies much on functional neuroimaging and genetic expression patterns and may lead to a more integrated understanding of the cerebellum.
Article
Astrocytes
Alexei Verkhratsky
Astrocytes belong to an extended class of astroglia, a class of neural cells of ectodermal, neuroepithelial origin that sustain homeostasis and provide for defense of the brain and the spinal cord. Astroglial cells support homeostasis of the central nervous system at all levels of organization from molecular to organ-wide. Astrocytes cannot generate action potentials, being thus electrically nonexcitable cells. Astrocytic excitability is intracellular, being mediated by associations with spatiotemporal fluctuations of cytoplasmic ions and second messengers in response to chemical or mechanical stimulation. Astrocytes express an extended complement of receptors to neurotransmitters and neurohormones that allow them to coordinate their homeostatic function with neuronal activity. Astrocytic homeostatic responses are primarily mediated by plasmalemmal transporters, which in turn are regulated by cytoplasmic concentration of Na+ ions. Peripheral astrocytic processes, known as leaflets, establish intimate contacts with synapses forming an astroglial synaptic cradle. Astrocytes regulate synaptogenesis, synaptic isolation, synaptic maintenance, and synaptic extinction, thus being fundamental for neuronal plasticity. Loss of astrocytic homeostatic function leads to neuronal damage and is a universal part of pathogenesis of many neurological diseases.
Article
Camillo Golgi
Paolo Mazzarello
Camillo Golgi (1843–1926), a physician and researcher from Lombardy, was a leading figure in Italian science in the second half of the 19th century. His name is linked to several fundamental contributions: the invention of the “black reaction,” a method that made it possible to highlight, for the first time in history, the fine structure of the central nervous system; the discovery of the Golgi apparatus or complex, one of the fundamental components of the cell; the discovery of the perineural net (an extracellular matrix meshwork that wrap around some neurons with important physiological functions); the identification of the Golgi tendon organ (a proprioceptor that senses tension from the muscle); and the description of the malaria plasmodium cycle in the “tertian” and “quartan” forms of the disease with the identification of the correspondence between the multiplication of the parasite and febrile access (Golgi law). These are major scientific contributions that have profoundly changed basic areas of biology and medicine. To these must be added many other minor contributions that alone could have qualified the reputation of any researcher.
Article
The Medieval Cell Doctrine
Douglas J. Lanska
The medieval cell doctrine was a series of speculative psychological models derived from ancient Greco-Roman ideas in which cognitive faculties were assigned to “cells,” typically but not exclusively corresponding to the cerebral ventricles. During Late Antiquity and continuing during the Early Middle Ages, Christian philosophers reinterpreted Aristotle’s De Anima, along with later modifications by Herophilos and Galen, in a manner consistent with Christian doctrine. The resulting medieval cell doctrine was formulated by the fathers of the early Christian Church in the 4th and 5th centuries. Illustrations of the medieval cell doctrine were included in manuscripts since at least the 11th century. Printed images of the doctrine appeared in medical, philosophical, and religious works beginning with “graphic incunabula” at the end of the 15th century. Some of these early psychological models assigned various cognitive faculties to different nonoverlapping “cells” within the brain, while others specifically promoted or implied a linear sequence of events. By the 16th century, printed images of the doctrine were usually linear three-cell versions, with few exceptions having four or five cells. These psychological models were based on philosophical speculations rather than clinicopathologic evidence or experimentation. Despite increasingly realistic representations of the cerebral ventricles from the end of the 15th century until the middle of the 16th century, and direct challenges by Massa and Vesalius in the early 16th century and Willis in the 17th century, the doctrine saw its most elaborate formulations in the late 16th and early 17th centuries with illustrations by the Paracelsian physicians Bacci and Fludd. In addition, Descartes reinvigorated the ventricular localization of cerebral faculties in the 17th century beginning with his La Dioptrique (1637) and later with the Latin and French editions of his posthumously published Treatise of Man (1662-1667). Overthrow of the doctrine had to await the development of alternative models of brain function in the 17th and 18th centuries.
Article
Behavioral, Cognitive, and Neural Mechanisms of Human Social Interaction
Antonia F. de C. Hamilton
Social interaction is a fundamental part of what makes humans human and draws on a wide range of neural and cognitive mechanisms. This review summarizes research in terms of four suggested brain networks. First, the social perception network responds selectively to viewing and interpreting other people’s faces and bodies. Second, the theory of mind network is engaged when people think about other people’s beliefs and knowledge states. Third, the mirror neuron network has a role in understanding and imitating actions. Fourth, the emotion network shows some selective responses to emotional facial expressions and when people empathize with other’s pain. The role of these four networks in dynamic social interactions and real-world communication is also considered.
Article
Jean-René Cruchet (1875–1959)
Olivier Walusinski
Jean-René Cruchet (1875–1959) was a French physician from Bordeaux, where he practiced for the entirety of his career. His notoriety resulted from his publication of the first cases of the encephalitis lethargica epidemic in World War I soldiers in 1917, a few days before Constantin von Economo reported his cases. Cruchet developed an interest in abnormal movements, notably tics and dystonia, for which he primarily saw a psychological cause, to be treated rigorously with good habits and repressive precepts. He wrote prolifically about his areas of interest, also focusing on parkinsonian syndromes and the treatment of hysterics, notably soldiers with camptocormia. One of the first physicians to also be an aviator, Cruchet was a pioneer in the study of autonomic modifications caused by flying and pressure variations, which he referred to as aviator’s disease. As a personality with an outsized ego, he imagined that he would remain as famous after his death as Jean-Martin Charcot or Louis Pasteur.
Article
Transcriptional Regulation Underlying Long-Term Sensitization in Aplysia
Robert J. Calin-Jageman, Theresa Wilsterman, and Irina E. Calin-Jageman
The induction of a long-term memory requires both transcriptional change and neural plasticity. Many of the links between transcription and memory have been revealed through the study of long-term sensitization in the Aplysia genus of marine mollusks. Sensitization is a conserved, non-associative form of pain memory in which a painful stimulus produces an increase in arousal and defensive behavior. The neural circuits that help encode sensitization memory are well characterized, and sensitization can be simulated in neuronal cell cultures.
One feature of sensitization in Aplysia is that only some training protocols initiate transcription and produce long-term memory; others produce only short-term memories. This occurs because the induction of long-term sensitization requires the activation of two signal-transduction pathways that regulate transcription: (a) a fast but transient activation of the cAMP/PKA pathway that activates the transcription factor CREB1 and (b) a delayed activation of the ERK isoform of MAPK that deactivates the transcriptional repressor CREB2. The effectiveness of different training protocols is based on the synchronization of these pathways. The cAMP/PKA and MAPK pathways are complex, involving extracellular and trans-synaptic signaling, feedback loops, and crosstalk. It has proven possible to model transcriptional activation with enough fidelity to generate in silico predictions for optimized learning, which has been validated in cell cultures and intact animals.
Training protocols that successfully activate CREB1 while deactivating CREB2 produce a complex transcriptional cascade that helps encode long-term sensitization memory. The transcriptional cascade involves a focused wave of immediate-early transcriptional activations. This includes the activation of additional transcription factors, such as C/EBP, as well as effectors such as uch, sensorin, and tolloid/BMP-1. These early transcriptional changes close feedback loops that help extend and stabilize the early wave of transcriptional changes, triggering a broader late wave of transcriptional changes likely to alter neural signaling, increase protein production, transport mRNAs, and induce meta-plasticity. A small set of transcripts participate in both the early and late waves, and several of these (CREB1, synataxin, eIF4) play essential roles in completing the induction of long-term sensitization. Most transcriptional changes fade as sensitization memory is forgotten, but some changes persist beyond forgetting, including a long-lasting up-regulation of an inhibitory peptide transmitter that could foster forgetting.
The maintenance of long-term sensitization may involve self-sustaining transcriptional feedback loops. In particular, CREB1 binds to its own promoter, producing a long-lasting increase in CREB1 mRNA, protein, and gene activation that is essential for sustaining cellular correlates of sensitization for at least 1 day after induction.
Many aspects of the induction, stabilization, and maintenance of sensitization memory in Aplysia are conserved, suggesting that it will continue to be a fruitful, simpler system for understanding the physical basis of lasting memory.
Article
Crossmodal Plasticity, Sensory Experience, and Cognition
Valeria Vinogradova and Velia Cardin
Crossmodal plasticity occurs when sensory regions of the brain adapt to process sensory inputs from different modalities. This is seen in cases of congenital and early deafness and blindness, where, in the absence of their typical inputs, auditory and visual cortices respond to other sensory information. Crossmodal plasticity in deaf and blind individuals impacts several cognitive processes, including working memory, attention, switching, numerical cognition, and language. Crossmodal plasticity in cognitive domains demonstrates that brain function and cognition are shaped by the interplay between structural connectivity, computational capacities, and early sensory experience.
