Search Results (123)

The pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1) plays a pivotal role in central nervous system development and homeostasis. Comparisons of PAC1 knockout (PAC1^−/−), heterozygous (PAC1^+/−) and wild-type (PAC1^+/+) mice demonstrate that PAC1 deficiency severely impairs pre-weaning survival and results in marked developmental deficits, including reduced postnatal weight and altered locomotor behavior. PAC1^−/− mice exhibited hyperlocomotion, reduced anxiety-like behavior, and transient deficits in motor coordination. Gene expression analyses revealed widespread dysregulation of oligodendrocyte-associated markers, with significant myelin reduction and decreased mature oligodendrocyte density in the corpus callosum. ER stress was evidenced in both white matter and motor cortex, as indicated by altered expression of UPR-related genes and increased phosphorylated (p)IRE1⁺ neurons. Retinal morphology was compromised in PAC1^−/− animals, with reduced overall retinal and ganglion cell layer thickness. Notably, no gross morphological or molecular abnormalities were detected in the spinal cord regarding myelin content or MBP expression; however, synaptic marker expression was selectively reduced in the ventral horn of PAC1-deficient mice. Together, these findings highlight a critical role for PAC1 in oligodendrocyte maturation, retinal development, and synaptogenesis, providing new insights with relevance in multiple sclerosis and other neurodevelopmental and neurodegenerative conditions. Full article

Intercellular communication in the central nervous system (CNS) is essential for maintaining neural function and coordinating responses to injury or disease. With recent advances in single-cell and spatial transcriptomics, a growing body of research has revealed that this communication is highly dynamic, shifting across states of health, aging, demyelination, and neurodegeneration. In this review, we synthesize the current findings on intercellular communication networks involving neurons, astrocytes, microglia, oligodendrocytes, and other glial populations in the CNS across four major states: healthy homeostasis, aging, demyelinating diseases, and Alzheimer’s disease (AD). We focus on how changes in intercellular communication contribute to the maintenance or disruption of CNS integrity and function. Mechanistic insights into these signaling networks have revealed new molecular targets and pathways that may be exploited for therapeutic intervention. By comparing the intercellular signaling mechanisms across different disease contexts, we underscore the importance of CNS crosstalk not only as a hallmark of disease progression, but also as a potential gateway for precision therapy. Full article

Spinal cord injury (SCI) is a major disability that, to this day, does not have a permanent cure. The spinal cord extends caudally through the body structure of the vertebral column and is part of the central nervous system (CNS). The spinal cord enables neural communication and motor coordination, so injuries can disrupt sensation, movement, and autonomic functions. Mechanical and traumatic damage to the spinal cord causes lesions to the nerves, resulting in the disruption of relayed messages to the extremities. Various forms of treatment for the spinal cord include functional electrical stimulation (FES), epidural electrical stimulation (EES), ‘SMART’ devices, exoskeleton and robotic systems, transcranial magnetic stimulation, and neuroprostheses using AI for the brain–computer interface. This research is going to analyse and review these current treatment methods for spinal cord injury and identify the current gaps and limitations in these, such as long-term biocompatibility, wireless adaptability, cost, regulatory barriers, and risk of surgery. Future advancements should work on implementing wireless data logging with AI algorithms to increase SCI device adaptability, as well as maintaining regulatory and health system integration. Full article

Background: Some neonates are assessed for the risk of atypical psychomotor development at birth and are referred for reflex locomotion therapy using the Vojta method. Aim: The aim of this study was to analyze the relationships between spontaneous motor activity (SMA), ideal movement patterns (IMPs), central coordination disorders (CCDs), vital signs at birth, involuntary reflexes, and postural asymmetry in infants. Methods: This study involved 90 female and 107 male subjects in the age interval of 1–16 months (4.15 ± 2.18). Their psychomotor development was assessed using the Vojta method. Age-appropriate involuntary reflexes were evaluated, and both parameters were correlated with perinatal risk factors. Results: Males scored significantly higher than females (difference of −0.7, p = 0.022) in the SMA test. In both genders, SMA (p < 0.001 in both genders) and IMP scores improved significantly with age. In male infants, higher CCD scores were associated with significantly lower SMA and IMP scores (p = 0.017 and p < 0.001, respectively). Significantly higher CCD scores were noted in female subjects with the Moro reflex and postural asymmetry (p = 0.003 and p = 0.002, respectively). In males, the Moro reflex was significantly correlated with the Vojta reaction (p = 0.012) and the Collis vertical suspension reflex (p < 0.001). Conclusions: Vital signs at birth, including birth weight, Apgar score, and type of delivery, can predict motor development disorders but do not clearly differentiate infants that require neurodevelopmental therapy. Full article

Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling—a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac), and cAMP-response element-binding protein (CREB). Among the various AC isoforms, calcium-sensitive AC1, AC8, and AC5, as well as bicarbonate-responsive soluble AC (sAC), have emerged as crucial mediators of neuroplasticity and axon regeneration. These isoforms coordinate diverse cellular responses—including gene transcription, cytoskeletal remodeling, and neurotransmitter release—to metabolic, synaptic, and injury-related signals. Dysregulation of AC activity has been implicated in the pathophysiology of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, as well as in chronic pain syndromes. Pharmacological modulation of cAMP levels through AC activation, phosphodiesterase (PDE) inhibition, or pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor signaling has shown therapeutic promise in preclinical models by enhancing neurogenesis, remyelination, and synaptic repair. Conversely, targeted inhibition of specific AC isoforms, particularly AC1, has demonstrated efficacy in reducing maladaptive plasticity and neuropathic pain. This review highlights the diverse roles of ACs in neuronal function and injury response and discusses emerging strategies for their therapeutic targeting. Full article

Glutamate is an excitatory neurotransmitter in the central nervous system (CNS) that mediates synaptic transmission. However, glutamate homeostasis among neural cells is broken in cerebral ischemia. Excessive glutamate triggers N-methyl-d-aspartate receptors (NMDARs) in postsynaptic neurons, leading to intracellular calcium (Ca²⁺) overload and excitoneurotoxicity. At this moment, L-lactate may affect NMDARs and play a protective role in cerebral ischemia. This work proposes that L-lactate regulates glutamate signaling among neural cells. But, dysregulation of L-lactate in glutamate signaling cascades contributes to glutamate excitotoxicity in cerebral ischemia. In detail, L-lactate regulates the glutamine(Gln)-glutamate cycle between astrocytes and presynaptic neurons, which triggers the astroglial L-lactate-sensitive receptor (LLR)-cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, coordinating astroglial glutamate uptake and neuronal glutamate transmission. L-lactate mediates glutamate signaling and synaptic transmission among neural cells. In addition, L-lactate promotes the function of mitochondrial calcium uniporter complex (MCUC), which quickly depletes intracellular Ca²⁺ in postsynaptic neurons. In addition, L-lactate can promote the conversion of microglia from the pro-inflammatory (M1) to anti-inflammatory (M2) phenotype. Therefore, regulation of L-lactate in glutamate signaling in the CNS might become a preventive target for cerebral ischemia. Full article

Microglia, the resident immune cells of the central nervous system (CNS), play essential roles in maintaining brain homeostasis. While transient activation is protective, chronic microglial reactivity contributes to neuroinflammatory damage and neurodegeneration. The mitochondrial mechanisms underlying this shift remain poorly understood. Here, we investigated whether lipopolysaccharide (LPS) induces coordinated mitochondrial and metabolic alterations in BV-2 microglial cells. LPS stimulation (100 ng/mL, 24 h) induced a reactive phenotype, with increased Iba1 (+82%), F4/80 (+132%), and Cd68 (+44%), alongside elevated hydrogen peroxide (~6-fold) and nitrite (~45-fold). Cytotoxicity increased by 40% (LDH assay), and cell viability dropped to ~80% of the control (MTT). Extracellular lactate increased, indicating glycolytic reprogramming. However, LPS-primed cells showed greater ATP depletion under antimycin A challenge, reflecting impaired metabolic flexibility. Hoechst staining revealed a ~4-fold increase in pyknotic nuclei, indicating apoptosis. Mitochondrial dysfunction was confirmed by a 30–40% reduction in membrane potential (TMRE, JC-1), a ~30% loss of Tomm20, and changes in dynamics: phospho-Drp1 increased (+23%), while Mfn1/2 decreased (33%). Despite a ~70% rise in Lamp2 signal, Tomm20–Lamp2 colocalization decreased, suggesting impaired mitophagy. High-resolution respirometry revealed decreased basal (−22%), ATP-linked (24%), and spare respiratory capacity (41%), with increased non-mitochondrial oxygen consumption. These findings demonstrate that LPS induces mitochondrial dysfunction, loss of metabolic adaptability, and increased apoptotic susceptibility in microglia. Mitochondrial quality control and energy flexibility emerge as relevant targets to better understand and potentially modulate microglial responses in neuroinflammatory and neurodegenerative conditions. Full article

Objectives: This article describes the neurobiology of psychological injuries—chronic pain, concussion/mild traumatic brain injury (MTBI), and fear/posttraumatic stress disorder (PTSD)—toward elucidating common mechanisms in central and peripheral sensitization that contribute to their onset, exacerbation, and maintenance. Central sensitization refers to central nervous system (CNS) and related processes, while peripheral sensitization is typically referred to as receptor field expansion. The three psychological injury diagnoses/conditions are accompanied by impairments in function after negligent events (such as motor vehicle accidents (MVAs)) that lead to tort court action. Methods: The conducted literature review involved an extensive scoping review of recent neurobiological literature on chronic pain, PTSD, and MTBI. The literature review sought biological markers that distinguish them. Results: For chronic pain, concussion/MTBI, and fear/PTSD, this article reviewed definitions and critical neurobiological research. The literature review did not find evidence of biological markers, but the role of sensitization emerged as important. Conclusions: Common therapeutic processes, such as focusing on sensitization, might be helpful for these conditions. As for causal mechanisms related to sensitization in the causality of psychological injuries, the major ones hypothesized relate to the biopsychosocial model, psychological control, and activation–inhibition coordination. Full article

The diverse methylation modifications of DNA, histones and RNA have emerged as pivotal regulatory mechanisms of gene expression in multiple biological processes at the epigenetic level. They function by coordinating gene expression through impacting gene transcription, mRNA processing and maturation, protein translation and metabolism. Changes in methylation profiles of nucleic acids and histones have been observed in many different types neural injuries in both the central nervous system and the peripheral nervous system, such as 5-methylcytosine in DNA, N6-methyladenosine in RNA and methylation of lysine residues in various histones. Importantly, altering these modifications plays key roles in regulation of neural injury and repair. In this review, we highlight recent research advances of the methylation-related epigenetic modifications in multiple aspects of neural injury and regeneration, including neural protection, axon regeneration, microenvironment modulation and neural functional recovery. We also discuss the current unsolved problems in the field and propose potential future research directions. Full article

Folk medicine in Thailand has long made use of Pterocarpus indicus Willd. for treating inflammation-related disorders. However, scientific exploration of isolated compounds from P. indicus for improving inflammation-associated sickness conditions and their impact on central nervous system (CNS) safety remain unexplored. The present study initially screened the anti-neuroinflammatory effects of angolensin, a compound isolated from P. indicus heartwood in vitro. Following substantial findings, the efficacy of angolensin was further evaluated in a mouse model of lipopolysaccharide (LPS)-induced sickness behaviors, alongside an assessment of its CNS safety profiles. The anti-neuroinflammatory effects of angolensin were evaluated in LPS-induced BV-2 microglial cells. The effects of angolensin on sickness behaviors were examined in LPS-induced mice using the Laboratory Animal Behaviors Observation, Registration and Analysis System (LABORAS). Proinflammatory cytokine expression in plasma samples of mice was also determined. LABORAS and rotarod tests were conducted to investigate its impact on the CNS. In vitro assessment of the anti-inflammatory activity of angolensin on BV-2 microglial cells revealed a concentration-dependent reduction in the release of LPS-induced nitric oxide (NO) and proinflammatory cytokines (TNF-α and IL-6). At a concentration of 20 µM, angolensin showed comparable results to the positive control, 20 µM minocycline. In mice, angolensin significantly improved LPS-induced sickness behaviors, as indicated by improved home-cage behaviors. Consistent with the in vitro findings, angolensin attenuated the release of proinflammatory cytokines in the plasma of LPS-induced mice. Importantly, angolensin did not induce any adverse effects on locomotion, motor coordination, or general well-being, indicating a favorable CNS safety profile. Overall, these results highlight the anti-inflammatory potential of angolensin in mitigating sickness behaviors in mice, while demonstrating its CNS safety. Full article

Multiple sclerosis (MS) is a chronic and incurable neurological disease of the central nervous system. Three main forms of the disease have been distinguished: relapsing–remitting form (RRMS), secondary progressive form (SPMS), and primary progressive form (PPMS). Currently, in patients with MS, in addition to pharmacotherapy, neurorehabilitation is indicated to improve the motor function of the body and action in the most physiological movement patterns possible. In this therapy, work on lost or incorrect functions is used to provide the patient with self-sufficiency in everyday life. Kinesiotherapy is used as part of neurorehabilitation. This therapy for MS includes coordination exercises aimed at facilitating movement, strengthening exercises and resistance training, balance exercises, improving stability during everyday activities stretching and relaxation exercises, improving tissue elasticity, reducing tension, and breathing exercises. In this article, we present various possibilities for using kinesiotherapy in patients with MS at various stages of disease development. Moreover, we would like to draw attention to the benefits of physical activity leading to a significant improvement in the quality of life in MS patients. We believe that a regular exercise program should be part of the neurorehabilitation program in these patients in the future. Full article

Among living organisms, higher animals primarily use a combination of vocal and non-verbal cues for communication. In other species, however, chemical signaling holds a central role. The chemical and biological activity of the molecules produced by the organisms themselves and the existence of receptors/targeting sites that allow recognition of such molecules leads to various forms of responses by the producer and recipient organisms and is a fundamental principle of such communication. Chemical language can be used to coordinate processes within one species or between species. Chemical signals are thus information for other organisms, potentially inducing modification of their behavior. Additionally, this conversation is influenced by the external environment in which organisms are found. This review presents examples of chemical communication among microorganisms, between microorganisms and plants, and between microorganisms and animals. The mechanisms and physiological importance of this communication are described. Chemical interactions can be both cooperative and antagonistic. Microbial chemical signals usually ensure the formation of the most advantageous population phenotype or the disadvantage of a competitive species in the environment. Between microorganisms and plants, we find symbiotic (e.g., in the root system) and parasitic relationships. Similarly, mutually beneficial relationships are established between microorganisms and animals (e.g., gastrointestinal tract), but microorganisms also invade and disrupt the immune and nervous systems of animals. Full article

Background: Reactive astrogliosis and microgliosis are coordinated responses to CNS insults and are pathological hallmarks of traumatic brain injury (TBI). In these conditions, persistent reactive gliosis can impede tissue repopulation and limit neurogenesis. Thus, modulating this phenomenon has been increasingly recognized as potential therapeutic approach. Methods: In this study, we investigated the potential of the flavonoid agathisflavone to modulate astroglial and microglial injury responses and promote neurogenesis in the subventricular zone (SVZ) neurogenic niche. Agathisflavone, or the vehicle in controls, was administered directly into the lateral ventricles in postnatal day (P)8-10 mice by twice daily intracerebroventricular (ICV) injections for 3 days, and brains were examined at P11. Results: In the controls, ICV injection caused glial reactivity along the needle track, characterised immunohistochemically by increased astrocyte expression of glial fibrillary protein (GFAP) and the number of Iba-1+ microglia at the lesion site. Treatment with agathisflavone decreased GFAP expression, reduced both astrocyte reactivity and the number of Iba-1⁺ microglia at the core of the lesion site and the penumbra, and induced a 2-fold increase on the ratio of anti-inflammatory CD206+ to pro-inflammatory CD16/32+ microglia. Notably, agathisflavone increased the population of neuroblasts (GFAP+ type B cells) in all SVZ microdomains by up to double, without significantly increasing the number of neuronal progenitors (DCX+). Conclusions: Although future studies should investigate the underlying molecular mechanisms driving agathisflavone effects on microglial polarization and neurogenesis at different timepoints, these data indicate that agathisflavone could be a potential adjuvant treatment for TBI or central nervous system disorders that have reactive gliosis as a common feature. Full article

Lung cancer, both non-small cell and small cell, harbors a high propensity for spreading to the central nervous system. Radiation therapy remains the backbone of the management of brain metastases. Recent advances in stereotactic radiosurgery have expanded its indications and ongoing studies seek to elucidate optimal fractionation and coordination with systemic therapies, especially targeted inhibitors with intracranial efficacy. Efforts in whole-brain radiotherapy aim to preserve neurocognition and to investigate the need for prophylactic cranial irradiation. As novel combinatorial strategies are tested and prognostic/predictive biomarkers are identified and tested, the management of brain metastases in lung cancer will become increasingly personalized to optimally balance intracranial efficacy with preserving neurocognitive function and patient values. Full article

Corticotropin-releasing hormone (CRH) neurons within the paraventricular hypothalamic nucleus (PVH) play a crucial role in initiating the neuroendocrine response to stress and are also pivotal in coordination of autonomic, metabolic, and behavioral stress reactions. Although the role of parvocellular CRH^PVH neurons in activation of the hypothalamic–pituitary–adrenal (HPA) axis is well established, the distribution and function of CRH-expressing neurons across the whole central nervous system are less understood. Stress responses activate complex neural networks, which differ depending on the type of stressor and on the sex of the individual. Because of the technical difficulties of localizing CRH neurons throughout the rodent brain, several CRH reporter mouse lines have recently been developed. In this study, we used Crh-IRES-Cre;Ai9 reporter mice to examine whether CRH neurons are recruited in a stressor- or sex-specific manner, both within and outside the hypothalamus. In contrast to the clear sexual dimorphism of CRH-mRNA-expressing neurons, quantification of CRH-reporting, tdTomato-positive neurons in different stress-related brain areas revealed only subtle differences between male and female subjects. These results strongly imply that sex differences in CRH mRNA expression occur later in development under the influence of sex steroids and reflects the limitations of using genetic reporter constructs to reveal the current physiological/transcriptional status of a specific neuron population. Next, we compared the recruitment of stress-related, tdTomato-expressing (putative CRH) neurons in male and female Crh-IRES-Cre;Ai9 reporter mice that had been exposed to predator odor. In male mice, fox odor triggered more c-Fos in the CRH neurons of the paraventricular hypothalamic nucleus, central amygdala, and anterolateral bed nucleus of the stria terminalis compared to females. These results indicate that male mice are more sensitive to predator exposure due to a combination of hormonal, environmental, and behavioral factors. Full article