Crosstalk Between Peripheral Innervation and Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy, characterized by late diagnosis, aggressive growth, and therapy resistance, leading to a poor overall prognosis. Emerging evidence shows that the peripheral nerve is an important non-tumor component in the tumor microenvironment that regulates tumor growth and immune escape. The crosstalk between the neuronal system and PDAC has become a hot research topic that may provide novel mechanisms underlying tumor progression and further uncover promising therapeutic targets. In this review, we highlight the mechanisms of perineural invasion and the role of various types of tumor innervation in the progression of PDAC, summarize the potential signaling pathways modulating the neuronal-cancer interaction, and discuss the current and future therapeutic possibilities for this condition.

The peripheral nervous system.

The peripheral nervous system (PNS) represents a highly heterogeneous entity with a broad range of functions, ranging from providing communication between the brain and the body to controlling development, stem cell niches and regenerative processes. According to the structure and function, the PNS can be subdivided into sensory, motor (i.e. the nerve fibers of motor neurons), autonomic and enteric domains. Different types of neurons correspond to these domains and recent progress in single-cell transcriptomics has enabled the discovery of new neuronal subtypes and improved the previous cell-type classifications. The developmental mechanisms generating the domains of the PNS reveal a range of embryonic strategies, including a variety of cell sources, such as migratory neural crest cells, placodal neurogenic cells and even recruited nerve-associated Schwann cell precursors. In this article, we discuss the diversity of roles played by the PNS in our body, as well as the origin, wiring and heterogeneity of every domain. We place a special focus on the most recent discoveries and concepts in PNS research, and provide an outlook of future perspectives and controversies in the field.

Crosstalk Between Peripheral Innervation and Pancreatic Ductal Adenocarcinoma / 神经科学通报·英文版

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive lethal malignancy, characterized by late diagnosis, aggressive growth, and therapy resistance, leading to a poor overall prognosis. Emerging evidence shows that the peripheral nerve is an important non-tumor component in the tumor microenvironment that regulates tumor growth and immune escape. The crosstalk between the neuronal system and PDAC has become a hot research topic that may provide novel mechanisms underlying tumor progression and further uncover promising therapeutic targets. In this review, we highlight the mechanisms of perineural invasion and the role of various types of tumor innervation in the progression of PDAC, summarize the potential signaling pathways modulating the neuronal-cancer interaction, and discuss the current and future therapeutic possibilities for this condition.

Modifying quantitative sensory testing to investigate behavioral reactivity in a pediatric global developmental delay sample: Relation to peripheral innervation and chronic pain outcomes.

Early tactile and nociceptive (pain) mechanisms in children with global developmental delay at risk for intellectual and developmental disability are not well understood. Sixteen children with global developmental delay (mean age = 5.1 years, SD = 1.4; 50% male) completed a modified quantitative sensory testing (mQST) protocol, an epidermal (skin) punch biopsy procedure, and parent-endorsed measures of pain. Children with reported chronic pain had significantly greater epidermal nerve fiber density (ENFd) compared to children without chronic pain. Based on the mQST trials, ENFd values were associated with increased vocal reactivity overall and specifically during the light touch and cool thermal stimulus trials. The findings support the feasibility of an integrative biobehavioral approach to test nociceptive and tactile peripheral innervation and behavioral reactivity during a standardized sensory test in a high-risk sample for which there is often sensory dysfunction and adaptive behavior impairments.

Peripheral nerves in the tibial subchondral bone : the role of pain and homeostasis in osteoarthritis.

Osteoarthritis (OA) is a highly prevalent degenerative joint disorder characterized by joint pain and physical disability. Aberrant subchondral bone induces pathological changes and is a major source of pain in OA. In the subchondral bone, which is highly innervated, nerves have dual roles in pain sensation and bone homeostasis regulation. The interaction between peripheral nerves and target cells in the subchondral bone, and the interplay between the sensory and sympathetic nervous systems, allow peripheral nerves to regulate subchondral bone homeostasis. Alterations in peripheral innervation and local transmitters are closely related to changes in nociception and subchondral bone homeostasis, and affect the progression of OA. Recent literature has substantially expanded our understanding of the physiological and pathological distribution and function of specific subtypes of neurones in bone. This review summarizes the types and distribution of nerves detected in the tibial subchondral bone, their cellular and molecular interactions with bone cells that regulate subchondral bone homeostasis, and their role in OA pain. A comprehensive understanding and further investigation of the functions of peripheral innervation in the subchondral bone will help to develop novel therapeutic approaches to effectively prevent OA, and alleviate OA pain. Cite this article: Bone Joint Res 2022;11(7):439-452.

Etv4 regulates nociception by controlling peptidergic sensory neuron development and peripheral tissue innervation.

The perception of noxious environmental stimuli by nociceptive sensory neurons is an essential mechanism for the prevention of tissue damage. Etv4 is a transcriptional factor expressed in most nociceptors in dorsal root ganglia (DRG) during the embryonic development. However, its physiological role remains unclear. Here, we show that Etv4 ablation results in defects in the development of the peripheral peptidergic projections in vivo, and in deficits in axonal elongation and growth cone morphology in cultured sensory neurons in response to NGF. From a mechanistic point of view, our findings reveal that NGF regulates Etv4-dependent gene expression of molecules involved in extracellular matrix (ECM) remodeling. Etv4-null mice were less sensitive to noxious heat stimuli and chemical pain, and this behavioral phenotype correlates with a significant reduction in the expression of the pain-transducing ion channel TRPV1 in mutant mice. Together, our data demonstrate that Etv4 is required for the correct innervation and function of peptidergic sensory neurons, regulating a transcriptional program that involves molecules associated with axonal growth and pain transduction.

The importance of the neuro-immuno-cutaneous system on human skin equivalent design.

The skin is a highly complex organ, responsible for sensation, protection against the environment (pollutants, foreign proteins, infection) and thereby linked to the immune and sensory systems in the neuro-immuno-cutaneous (NIC) system. Cutaneous innervation is a key part of the peripheral nervous system; therefore, the skin should be considered a sensory organ and an important part of the central nervous system, an 'active interface' and the first connection of the body to the outside world. Peripheral nerves are a complex class of neurons within these systems, subsets of functions are conducted, including mechanoreception, nociception and thermoception. Epidermal and dermal cells produce signalling factors (such as cytokines or growth factors), neurites influence skin cells (such as via neuropeptides), and peripheral nerves have a role in both early and late stages of the inflammatory response. One way this is achieved, specifically in the cutaneous system, is through neuropeptide release and signalling, especially via substance P (SP), neuropeptide Y (NPY) and nerve growth factor (NGF). Cutaneous, neuronal and immune cells play a central role in many conditions, including psoriasis, atopic dermatitis, vitiligo, UV-induced immunosuppression, herpes and lymphomas. Therefore, it is critical to understand the connections and interplay between the peripheral nervous system and the skin and immune systems, the NIC system. Relevant in vitro tissue models based on human skin equivalents can be used to gain insight and to address impact across research and clinical needs.

Inervación del músculo extensor radial corto del carpo en individuos brasileños: biometría de su origen y distribución / Innervation of the extensor carpi radialis brevis muscle in Brazilian individuals: biometry of its origin and distribution

El ramo de inervación para el músculo extensor radial corto del carpo (MERCC) ha sido utilizado para restablecer funciones de la musculatura del miembro superior en pacientes con lesiones medulares, del plexo braquial o de sus ramos terminales. El origen del nervio para el MERCC es variable, pudiendo originarse desde el tronco del nervio radial (NR), del ramo profundo de este nervio (RPNR) o del ramo superficial del mismo (RSNR). Con el propósito de complementar la anatomía sobre el origen y distribución del ramo para el MERCC, se utilizaron 30 miembros superiores, formolizados, de cadáveres de individuos Brasileños, localizados en los laboratorios de Anatomía de la Universidad Estadual de Ciencias da Saude, Maceió, Brasil. A través de disección se localizó el músculo y su inervación, determinando su origen, así como su distribución. Para efectuar la biometría, se consideró como referencia una línea transversal que pasaba entre las partes más prominentes de los epicóndilos lateral y medial del húmero (LBE), registrando la distancia entre esta línea y el punto de origen de este ramo muscular, así como la distancia entre la LBE y los puntos motores. El nervio para el MERCC se originó del RPNR en 50 % de los casos; desde el tronco principal del NR en 26, 7 % y desde el RSNR en 23, 3 %. La distancia entre el origen del ramo en estudio y la LBE fue en promedio de 23 ± 12 mm; la distancia entre el 1º, 2º y 3º punto motor respecto a la LBE fue de 55 ± 17 mm, 66 ± 17 mm y 79 ± 11 mm, respectivamente. La distribución de la inervación fue clasificada en 4 tipos en relación a sus puntos motores. Los resultados obtenidos son un importante aporte al conocimiento anatómico, así como a la neurocirugía en las transferencias nerviosas con propósitos de restauración de las funciones de músculos lesionados en el miembro superior.

The branch of the innervation for the extensor carpi radialis brevis muscle (ECRBm), has been used to reestablish muscle functions in the upper limbs of patients who have spinal cord injury, of the brachial plexus or its terminal branches. The origin of the ECRBm varies, and can originate from the trunk of the radial nerve (RN), from the deep branch of the radial nerve (DBRN), or from the superficial branch of the radial nerve (SBRN). In order to further complement the anatomy related to the origin and distribution of the ECRBm branch, 30 formolized upper limbs from Brazilian individuals, from the Universidad Estadual de Ciencias da Saude, Maiceió, Brazil were used. Through dissection, the muscle and its innervations was located, determining the origin of the branch as well as distribution. To determine biometry, a transversal reference line, which passed through the most prominent areas of the epicondyles of the humerus (BEL) was considered. The nerve for ECRBm originated from DBRN in 50 % of cases; from the main trunk of RN in 26.7 % and from SBRN in 23.3 %. The distance from the origin of the branch studied and the BEL was an average of 23 ± 12 mm; the distance from the first, second and third motor point to the BEL was 55 ± 17 mm, 66 ± 17 mm and 79±11 mm, respectively. The distribution of the innervation was classified in four types in relation to the motor points. The results are an important contribution to anatomical knowledge, as well as neurosurgery during nerve transfers to restore functions of damaged muscles in the upper limb.

Central Somatosensory Networks Respond to a De Novo Innervated Penis: A Proof of Concept in Three Spina Bifida Patients.

INTRODUCTION: Spina bifida (SB) causes low spinal lesions, and patients often have absent genital sensation and a highly impaired sex life. TOMAX (TO MAX-imize sensation, sexuality and quality of life) is a surgical procedure whereby the penis is newly innervated using a sensory nerve originally targeting the inguinal area. Most TOMAX-treated SB patients initially experience penile stimulation as inguinal sensation, but eventually, the perception shifts to penis sensation with erotic feelings. The brain mechanisms mediating this perceptual shift, which are completely unknown, could hold relevance for understanding the brain's role in sexual development. AIM: The aim of this study was to study how a newly perceived penis would be mapped onto the brain after a lifelong disconnection. METHODS: Three TOMAX-treated SB patients participated in a functional magnetic resonance imagery experiment while glans penis, inguinal area, and index finger were stimulated with a paint brush. MAIN OUTCOME MEASURE: Brush stimulation-induced activation of the primary somatosensory cortex (SI) and functional connectivity between SI and remote cerebral regions. RESULTS: Stimulation of the re-innervated side of the glans penis and the intact contralateral inguinal area activated a very similar location on SI. Yet, connectivity analysis identified distinct SI functional networks. In all three subjects, the middle cingulate cortex (MCC) and the parietal operculum-insular cortex (OIC) were functionally connected to SI activity during glans penis stimulation, but not to SI activity induced by inguinal stimulation. CONCLUSIONS: Investigating central somatosensory network activity to a de novo innervated penis in SB patients is feasible and informative. The consistent involvement of MCC and OIC above and beyond the brain network expected on the basis of inguinal stimulation suggests that these areas mediate the novel penis sensation in these patients. The potential role of MCC and OIC in this process is discussed, along with recommendations for further research.

Peripheral Innervation in Children With Global Developmental Delay: Biomarker for Risk for Self-Injurious Behavior?

The relation between somatosensory mechanisms and self-injury among children with neurologic impairments associated with developmental delay is not well understood. We evaluated the feasibility of procuring skin biopsies to examine epidermal nerve fiber density and reported self-injury. Following informed parental consent, epidermal skin biopsies were obtained from a distal leg site with no pre-existing skin damage from 11 children with global developmental delay (55% male; mean age = 36.8 months, 17-63 months). Visual microscopic examination and quantitative analyses showed extremely high epidermal nerve fiber density values for some children. Children with reported self-injury (5/11) had significantly (P < .02) greater density values (138.8, standard deviation = 45.5) than children without self-injury (80.5, standard deviation = 17.5). Results from this novel immunohistologic analysis of skin in very young children with neurodevelopmental delays suggest it may be a useful tool to study peripheral innervation as a possible sensory risk factor for self-injury.

Adaptación de la técnica de impregnación argéntica de Llombart para la demostración de fibras nerviosas, en cualquier tejido en cortes por parafina / Adaptation of Llombart's silver impregnation technique for demonstration of nerve fibers in any tissue in paraffin sections

En la investigación biológica sigue siendo necesaria la demostración de la inervación periférica en numerosos tejidos y órganos. El objetivo de este trabajo fue rescatar y modernizar uno de los métodos más constantes que hemos probado para demostrar la inervación periférica. La técnica de Llombart para fibras nerviosas se adaptó en cortes por parafina de 7 µm en diferentes tejidos animales. La impregnación argéntica se hizo por goteo en cámara húmeda. Se demostraron en forma constante, precisa y seriada terminaciones nerviosas y corpúsculos sensoriales, neuronas y fibras nerviosas periféricas. A pesar de la alta especificidad para fibras nerviosas, la técnica no compromete el panorama tisular por lo que da bellas imágenes de conjunto. Sin ser una técnica para argentafinidad, demuestra claramente dos tipos de células argentafines en las glándulas adrenales. La adición de los reactivos metálicos en gotas y en cámara húmeda, ofrece una variante sumamente económica.

In Biological research is still necessary for the demonstration of the peripheral innervation in numerous tissues and organs. The aim of this study was to rescue and modernize one of the most consistent methods that we have tried to demonstrate peripheral innervation. Llombart's technique for nerve fibers was adapted by paraffin cuts of 7 µm in different animal tissue. The silver impregnation was done by dripping in a moist chamber. It was demonstrated in a constant, precise and serial form, nerve terminations, and sensorial corpuscles, neurons, and peripheral nerve fibers. Despite being highly specific to nerve fibers, the technique does not sacrifice tissue panorama so it gives beautiful images set. Without being a technique to argentaffin structures, it clearly shows two types of argentaffin cells in the adrenal glands. The addition of the metal reactive in droplets and in a humid chamber provides a very economical variant.

Lack of nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2): consequences for mouse bladder development and function.

AIMS: To describe the morphological and functional consequences for bladder development and function when nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) is lacking or reduced. METHODS: The Bloated Bladder (Blad) mouse, lacking Nmnat2, and heterozygotes were utilized for this investigation. Morphology and development of the bladder were studied using immunohistochemistry against urothelial, smooth muscle, and nerve markers. Functional effects were assessed by organ bath experiments and cystometry. RESULTS: Homozygote mutants were malformed and died at birth, whereas heterozygotes survived and morphologically did not differ from wild-type controls. Morphological bladder changes appeared in the Blad mutants as early as embryonic day 15.5 (E15.5) with an extremely distended bladder at E18.5. Staining revealed that all the bladder layers were present and expressed mature markers in all three genotypes. No nerves could be demonstrated by immunohistochemistry in the Blad mutant bladder at E18.5. Organ bath analysis showed that bladders from Blad mutant showed signs of denervation supersensitivity in response to carbachol, and no response to electrical stimulation of nerves at E18.5. Adult heterozygotes, which have a reduced expression of Nmnat2 at E18.5, showed decreased responses to carbachol and electrical stimulation compared to wild-type controls. The latter also retained their ability to empty their bladders, but showed increased micturition pressures compared to controls. CONCLUSIONS: Complete loss of Nmnat2 leads to a mature but distended bladder in utero and is not compatible with survival. Moderate loss of Nmnat2 has no effect on bladder development, survival, and has only modest effects on bladder function later in life.