Psilocybin is a rapid-acting antidepressant, but its mechanism of action in major depressive disorder remains unclear. In this secondary analysis of randomized, placebo-controlled trial with multimodal CSF and blood biomarker measurements, psilocybin selectively reduced CSF galanin and noradrenaline, implicating that normalization of these co-transmitters is a key pharmacodynamic signature.

Abstract Psychoactive and psychotoxic drugs are particularly harmful, if their use coincides with critical developmental windows of brain maturation. Methamphetamine is one such stimulant with developmental exposure increasing seizure susceptibility and long-term neuronal maladaptation in children. Nevertheless, the extent at which infant and adult vulnerability to methamphetamine could differ in time-course and severity remains incompletely understood. Here, we developed a method to monitor methamphetamine-induced hyperactivity in infant mice at high temporal resolution, differentiate it from a biphasic response in adults, and link it to activity changes in cortical areas executing goal-directed (escape) behaviors in infant subjects when using Fos expression as a molecular surrogate. Subsequently, we hypothesized that methamphetamine could alter the expression and cellular distribution of ‘inhibitory’ neuropeptides, which, when co-released with fast neurotransmitters, could protect circuit plasticity by counteracting methamphetamine-induced hyperexcitability. Methamphetamine differentially altered somatostatin, cholecystokinin, and galanin expression in corticolimbic areas. These data suggest that methamphetamine can evoke age-specific neurocircuit modifications, at least in mice.

Traumatic brain injury (TBI) is frequently followed by persistent affective symptoms. Dysregulation of monoaminergic and galanin signalling has been implicated but it is unclear whether such changes generalize across distinct biomechanical injury modes. Here we examined a rotational head-acceleration model of mild-moderate injury and directly compared radioactive in situ hybridization (rISH) with a non-radioactive method, alongside immunohistochemistry (IHC), in adult male rats. We quantified transcripts and proteins/peptides of tyrosine hydroxylase (TH), tryptophan hydroxylase-2 (TPH2), and galanin in locus coeruleus (LC) and dorsal raphe nucleus (DRN) and assessed the neuronal stress marker activating transcription factor-3 (ATF3). rISH revealed a rapid, bilateral rise of TH and galanin mRNA in LC at one day post-injury (dpi) and transient increases of TPH2 and galanin mRNA at 1 dpi in mid-DRN. Non-radioactive ISH confirmed these patterns, although modest temporal differences were observed. Peptide measurements showed a similar pattern of increase as their transcripts: TH- and galanin-immunoreactivity in LC increased at 3 dpi, and galanin also rose at 7 dpi in DRN, while TPH2 remained stable. Finally, ATF3 was robustly induced in LC neuronal nuclei at 1 dpi and remained elevated thereafter, indicating activation of a conserved stress response and possible axonal injury. These findings demonstrate that rotational head acceleration triggers selective, time-dependent modulation of monoaminergic and galanin signalling - paralleling prior blast models and confirm ATF3 as an informative marker of injury-activated neuronal states. The concordance across injury models highlights the monoamine and galanin systems as translatable targets for mitigating post-injury affective disturbances.

Introduction:Chronic pain is a major unmet medical need, with current treatments often providing limited relief. The neuropeptide galanin, acting through GalR1-3 receptors, has been implicated in pain modulation. Although galanin analogues are typically administered intrathecally, emerging evidence suggests that peptides can cross the blood-brain barrier. We hypothesized that systemic administration of the biologically active fragment galanin (1-16) could attenuate neuropathic pain. Objectives:To evaluate whether intravenous galanin (1-16) reduces pain-like behaviors in a rat model of neuropathic pain and to compare its effects when using a selective GalR1 agonist. Methods:Male Sprague-Dawley rats underwent spared nerve injury. Animals received intravenous galanin (1-16), M617 (selective GalR1), or vehicle. Mechanical and cold allodynia were assessed using von Frey filaments and acetone testing, respectively. Open-field tests evaluated locomotor activity to exclude more general behavioral effects. Data were analyzed using blinded protocols and appropriate statistical tests. Results:Galanin (1-16) and M617 significantly reversed mechanical allodynia compared with vehicle, with effects evident at 0.5 hours, peaking at 2 hours, still present after 4 hours, and absent by 6 hours (P < 0.0001). No significant differences were observed between galanin (1-16) and M617. By contrast, neither compound significantly affected cold allodynia. Locomotor activity, total distance travelled, or center time were not affected by galanin (1-16). Conclusion:Intravenous administration of galanin (1-16) produces robust but transient antiallodynic effects in neuropathic rats, likely mediated through GalR1 activation, without impairing locomotion. These findings highlight the therapeutic potential of systemically administered galanin or galanin analogues targeting GalR1 for neuropathic pain management.

Traditional views in cellular neurobiology stipulate that neuropeptides, biologically active peptides cleaved from precursor proteins with substantial expression in the nervous system, modulate bidirectional synaptic neurotransmission in the adult brain by engaging mostly, if not exclusively, G protein-coupled receptors. Recent evidence also places neuropeptides into developmental processes, with both transient and permanent expression foci in the fetal nervous system contributing to neuronal fate choices, notably axonal growth and directional guidance. Neuropeptide receptors are partitioned within navigating growth cones, with the bulk of neuropeptides inducing steering decisions, at least in vitro. Thus, any developmental process that disrupts growth cone motility and biases guidance decisions might render neuropeptide signaling inadequate for neuronal circuit formation. We recognize maternal drug abuse during pregnancy as a major liability for neuropeptide signaling, because the most common psychoactive drugs alter neuropeptide levels, their molecular targets coexist with neuropeptide receptors in growth cones, and symptomatically, neuropeptide signaling is altered in neurodevelopmental disorders in children with either prenatal or adolescent drug exposure. Mechanistically, the epigenetic deregulation of neuropeptide expression is suggested. Thus, we propose that neuropeptide-sensitive developmental programs, chiefly neurogenesis and synaptogenesis, are susceptible to psychoactive drugs. Thus, any means to rescue or reinstate neuropeptide signaling could attenuate nervous system pathobiology in offspring passively subjected to substance abuse during pregnancy.

BACKGROUND AND PURPOSE:Galanin receptor subtype 1 (GALR1) and subtype 2 (GALR2) are G protein-coupled receptors (GPCRs) that mediate galanin's diverse physiological roles, including neurotransmission and neuronal modulation. Although both receptors share functional similarities, they exhibit distinct differences in signalling pathways. Whilst previous studies have focussed on galanin binding and G-protein selectivity, the role of plasma membrane-specific mechanisms, particularly cholesterol depletion's influence, remains unclear. This study investigates cholesterol's role in regulating trafficking of GALR1 and GALR2 and their function in live cells. EXPERIMENTAL APPROACH:We employed real-time fluorescence techniques-Fluorescence Correlation Spectroscopy (FCS), Fluorescence Cross-Correlation Spectroscopy (FCCS), and Fluorescence Recovery After Photobleaching (FRAP)-to assess receptor-ligand interactions and lateral mobility in PC12 cells expressing EGFP-tagged GALR1 or GALR2. KEY RESULTS:Both receptors were co-localised, co-trafficked and internalised with galanin, with receptor-peptide complexes dissociating prior to lysosomal degradation. Cholesterol selectively restricted GALR1's lateral diffusion and enhanced galanin binding and complex formation, whereas GALR2 remained unaffected. Interestingly, galanin binding relieved GALR1 from cholesterol-mediated restriction, increasing receptor mobility and suggesting a dynamic, cholesterol-dependent regulatory mechanism. CONCLUSIONS AND IMPLICATIONS:Cholesterol selectively modulates GALR1 trafficking and ligand interactions, whereas GALR2 operates independently of cholesterol, revealing distinct regulatory mechanisms for each receptor subtype. These findings provide new insights into the interplay between membrane composition and receptor function, with potential implications for developing targeted therapies for galanin-related disorders.

New technologies enable single-cell transcriptome analysis, mapping genome-wide expression across the human body. Here, we present an extended analysis of protein-coding genes in all major human tissues and organs, combining single-cell and bulk transcriptomics. To enhance transcriptome depth, 31 tissues were analyzed using a pooling method, identifying 557 unique cell clusters, manually annotated by marker gene expression. Genes were classified by body-wide expression and validated through antibody-based profiling. All results are available in the updated open-access Single Cell Type section of the Human Protein Atlas for genome-wide exploration of genes, proteins, and their spatial distribution in cells.

Acute pain is an unpleasant experience caused by noxious stimuli. How the spinal neural circuits attribute differences in quality of noxious information remains unknown. By means of genetic capturing, activity manipulation and single-cell RNA sequencing, we identified distinct neural ensembles in the adult mouse spinal cord encoding mechanical and heat pain. Reactivation or silencing of these ensembles potentiated or stopped, respectively, paw shaking, lifting and licking within but not across the stimuli modalities. Within ensembles, polymodal Gal+ inhibitory neurons with monosynaptic contacts to A-fiber sensory neurons gated pain transmission independent of modality. Peripheral nerve injury led to inferred microglia-driven inflammation and an ensemble transition with decreased recruitment of Gal+ inhibitory neurons and increased excitatory drive. Forced activation of Gal+ neurons reversed hypersensitivity associated with neuropathy. Our results reveal the existence of a spinal representation that forms the neural basis of the discriminative and defensive qualities of acute pain, and these neurons are under the control of a shared feed-forward inhibition.

The significance of transient neuropeptide expression during postnatal brain development is unknown. Here, we show that galanin expression in the ventrobasal thalamus of infant mice coincides with whisker map development and modulates subcortical circuit wiring. Time-resolved neuroanatomy and single-nucleus RNA-seq identified complementary galanin (Gal) and galanin receptor 1 (Galr1) expression in the ventrobasal thalamus and the principal sensory nucleus of the trigeminal nerve (Pr5), respectively. Somatodendritic galanin release from the ventrobasal thalamus was time-locked to the first postnatal week, when Gal1R+ Pr5 afferents form glutamatergic (Slc17a6 +) synapses for the topographical whisker map to emerge. RNAi-mediated silencing of galanin expression disrupted glutamatergic synaptogenesis, which manifested as impaired whisker-dependent exploratory behaviors in infant mice, with behavioral abnormalities enduring into adulthood. Pharmacological probing of receptor selectivity in vivo corroborated that target recognition and synaptogenesis in the thalamus, at least in part, are reliant on agonist-induced Gal1R activation in inbound excitatory axons. Overall, we suggest a neuropeptide-dependent developmental mechanism to contribute to the topographical specification of a fundamental sensory neurocircuit in mice. The function of transient neuropeptides in developmental roles in the nervous system remains elusive. Here, authors demonstrate that galanin shapes synaptic wiring in the whisker pathway, a fundamental sensory modality for infant rodents before eye opening.

Neuropeptides are key modulators of adult neurocircuits, balancing their sensitivity to both excitation and inhibition, and fine-tuning fast neurotransmitter action under physiological conditions. Here, we reason that transient increases in neuropeptide availability and action exist during brain development for synapse maturation, selection, and maintenance. We discuss fundamental concepts of neuropeptide signaling at G protein-coupled receptors (GPCRs), with a particular focus on how signaling at neuropeptide GPCRs could underpin neuronal morphogenesis. We use galanin, a 29/30 amino acid-long neuropeptide, as an example for its retrograde release from the dendrites of thalamic neurons to impact the selection and wiring of sensory afferents originating at the trigeminal nucleus through galanin receptor 1 (GalR1) engagement. Thus, we suggest novel roles for neuropeptides, expressed transiently or permanently during both pre- and postnatal neuronal circuit development, with potentially life-long effects on circuit layout and ensuing behavioral operations.

Acquisition of specialized cellular features is controlled by the ordered expression of transcription factors (TFs) along differentiation trajectories. Here, we find a member of the Onecut TF family, ONECUT3, expressed in postmitotic neurons that leave their Ascl1(+)/Onecut1/2(+) proliferative domain in the vertebrate hypothalamus to instruct neuronal differentiation. We combined single-cell RNA-seq and gain-of-function experiments for gene network reconstruction to show that ONECUT3 affects the polarization and morphogenesis of both hypothalamic GABA-derived dopamine and thyrotropin-releasing hormone (TRH)(+) glutamate neurons through neuron navigator-2 (NAV2). In vivo, siRNA-mediated knockdown of ONECUT3 in neonatal mice reduced NAV2 mRNA, as well as neurite complexity in Onecut3-containing neurons, while genetic deletion of Onecut3/ceh-48 in C. elegans impaired neurocircuit wiring, and sensory discrimination-based behaviors. Thus, ONECUT3, conserved across neuronal subtypes and many species, underpins the polarization and morphological plasticity of phenotypically distinct neurons that descend from a common pool of Ascl1(+) progenitors in the hypothalamus.

Neuropeptides represent the most diverse family of neurotransmitters counting numerous members and even more G protein-coupled receptors, all of which are potential targets for drug development. Here, we focus on galanin and its three receptors by describing their possible involvement in pain and regeneration. Although animal experiments indicate that galanin, together with other molecules, may act as an endogenous system protecting against pain and improving nerve growth, these results have so far not been translated into patient treatments.

Vesicular release of neurotransmitters and hormones relies on the dynamic assembly of the exocytosis/trans-SNARE complex through sequential interactions of synaptobrevins, syntaxins, and SNAP-25. Despite SNARE-mediated release being fundamental for intercellular communication in all excitable tissues, the role of auxiliary proteins modulating the import of reserve vesicles to the active zone, and thus, scaling repetitive exocytosis remains less explored. Secretagogin is a Ca 2+ -sensor protein with SNAP-25 being its only known interacting partner. SNAP-25 anchors readily releasable vesicles within the active zone, thus being instrumental for 1st phase release. However, genetic deletion of secretagogin impedes 2nd phase release instead, calling for the existence of alternative protein–protein interactions. Here, we screened the secretagogin interactome in the brain and pancreas, and found syntaxin-4 grossly overrepresented. Ca 2+ -loaded secretagogin interacted with syntaxin-4 at nanomolar affinity and 1:1 stoichiometry. Crystal structures of the protein complexes revealed a hydrophobic groove in secretagogin for the binding of syntaxin-4. This groove was also used to bind SNAP-25. In mixtures of equimolar recombinant proteins, SNAP-25 was sequestered by secretagogin in competition with syntaxin-4. K d differences suggested that secretagogin could shape unidirectional vesicle movement by sequential interactions, a hypothesis supported by in vitro biological data. This mechanism could facilitate the movement of transport vesicles toward release sites, particularly in the endocrine pancreas where secretagogin, SNAP-25, and syntaxin-4 coexist in both α- and β-cells. Thus, secretagogin could modulate the pace and fidelity of vesicular hormone release by differential protein interactions.

The aim of the article is to describe our work on peptides discovered in Dr. Mutt's laboratory, particularly galanin. Some personal recollections of meetings with Viktor Mutt and a brief overview of early neuropeptide research at Karolinska Institutet are provided. General aspects on neuropeptide signalling and neuropeptide-neurotransmitter coexistence are followed by the presentation of a possible involvement of the galanin system in pain and depression. Special emphasis is on the role of galanin in the rat and human locus coeruleus. Additional analyses of the human postmortem brains have given results on galanin and other peptides both in the normal prefrontal cortex as well as in different brain regions of depressed patients who have committed suicide and in control subjects. Possible options for developing treatment strategies for pain and depression based on galaninergic mechanisms are discussed. Finally, some recent drugs approved by the FDA for the treatment of conditions such as migraine, which target the signalling of other peptides, are highlighted. In conclusion, the aim of the article is to highlight the potential of the large group of neuropeptides as targets for the development of drugs that may further help patients with illnesses afflicting the nervous system.

The entorhinal cortex is involved in establishing enduring visuo-auditory associative memory in the neocortex. Here we explored the mechanisms underlying this synaptic plasticity related to projections from the visual and entorhinal cortices to the auditory cortex in mice using optogenetics of dual pathways. High-frequency laser stimulation (HFS laser) of the visuo-auditory projection did not induce long-term potentiation. However, after pairing with sound stimulus, the visuo-auditory inputs were potentiated following either infusion of cholecystokinin (CCK) or HFS laser of the entorhino-auditory CCK-expressing projection. Combining retrograde tracing and RNAscope in situ hybridization, we show that Cck expression is higher in entorhinal cortex neurons projecting to the auditory cortex than in those originating from the visual cortex. In the presence of CCK, potentiation in the neocortex occurred when the presynaptic input arrived 200 ms before postsynaptic firing, even after just five trials of pairing. Behaviorally, inactivation of the CCK+ projection from the entorhinal cortex to the auditory cortex blocked the formation of visuo-auditory associative memory. Our results indicate that neocortical visuo-auditory association is formed through heterosynaptic plasticity, which depends on release of CCK in the neocortex mostly from entorhinal afferents.

Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of 'normal' postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on 'normal' noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.

AIM:This study mapped the spatiotemporal positions and connectivity of Onecut3+ neuronal populations in the developing and adult mouse brain. METHODS:We generated fluorescent reporter mice to chart Onecut3+ neurons for brain-wide analysis. Moreover, we crossed Onecut3-iCre and Mapt-mGFP (Tau-mGFP) mice to visualize axonal projections. A dual Cre/Flp-dependent AAV construct in Onecut3-iCre cross-bred with Slc17a6-FLPo mice was used in an intersectional strategy to map the connectivity of glutamatergic lateral hypothalamic neurons in the adult mouse. RESULTS:We first found that Onecut3 marks a hitherto undescribed Slc17a6+ /Vglut2+ neuronal cohort in the lateral hypothalamus, with the majority expressing thyrotropin-releasing hormone. In the adult, Onecut3+ /Vglut2+ neurons of the lateral hypothalamus had both intra- and extrahypothalamic efferents, particularly to the septal complex and habenula, where they targeted other cohorts of Onecut3+ neurons and additionally to the neocortex and hippocampus. This arrangement suggests that intrinsic reinforcement loops could exist for Onecut3+ neurons to coordinate their activity along the brain's midline axis. CONCLUSION:We present both a toolbox to manipulate novel subtypes of hypothalamic neurons and an anatomical arrangement by which extrahypothalamic targets can be simultaneously entrained.

The locus coeruleus (LC) is a small nucleus in the pons from which ascending and descending projections innervate major parts of the central nervous system. Its major transmitter is norepinephrine (NE). This system is evolutionarily conserved, including in humans, and its functions are associated with wakefulness and related to disorders, such as depression. Here, we performed single-cell ribonucleic acid-sequencing (RNA-seq) to subdivide neurons in the LC (24 clusters in total) into 3 NE, 17 glutamate, and 5 γ-aminobutyric acid (GABA) subtypes, and to chart their neuropeptide, cotransmitter, and receptor profiles. We found that NE neurons expressed at least 19 neuropeptide transcripts, notably galanin (Gal) but not Npy, and >30 neuropeptide receptors. Among the galanin receptors, Galr1 was expressed in ~19% of NE neurons, as was also confirmed by in situ hybridization. Unexpectedly, Galr1 was highly expressed in GABA neurons surrounding the NE ensemble. Patch-clamp electrophysiology and cell-type-specific Ca2+-imaging using GCaMP6s revealed that a GalR1 agonist inhibits up to ~35% of NE neurons. This effect is direct and does not rely on feed-forward GABA inhibition. Our results define a role for the galanin system in NE functions, and a conceptual framework for the action of many other peptides and their receptors.

“Glial cells are in the brain to support neurons” is one of the commonplaces taught at regular lectures by neuroscientists to future generations of neurobiologists. Never mind that detailed insights into glial physiology and pathobiology are usually neglected in thematic neuroscience curricula. Indeed, the classic bias in the field of neuroscience comes from the term “neuro” itself. General thinking dictates that when one can manipulate specific subtypes of neurons distinguished by a signature of probably a handful of molecules at millisecond precision chemically or by light, and receive a behavioral response from the experimental organism, be this invertebrate or vertebrate, then neurons alone shall be sufficient to organize the brain's output. We could not be more wrong and on an arduous journey to fundamentally misinterpret brain operations if holding onto these views. It is time to acknowledge the contribution of other cell types, cumulatively termed “neuroglia,” with astroglia, oligodendroglia, and microglia being present in the central nervous system alone. Adding Schwann cells, satellite glia, enteric glia, and glial cells of sensory organs to this list is a thrilling reminder that an amazing variety of glial cell types not only exists at around 1:1 ratio but works in unison in the human nervous systems to allow it to reach its computational, intellectual, and emotional power that makes us unique. “Would you know a renown ‘glioscientist’ as if a neuroscientist?” For many, this could be an unexpectedly challenging question still. Here, we introduce Alexei Verkhratsky and Arthur M. Butt as two of the most eminent glia biologists of our time whose new book, titled “Neuroglia: Function and Pathology” is a wonderfully illustrated, comprehensive, thematic, and insightful account of the vast knowledge that has accumulated on glial cells of both the central and peripheral nervous systems over the past ~150 years. This book, the newest in a series of compendia on glial cells,1-4 is educational for it systematically summarizing the origins, development, anatomy, molecular make-up, membrane biophysics, cellular interactions, and functions in relation to nerve cells and the broader brain homeostasis of each major glial cell type. Yet, it is an enticing read that also answers many unexpected questions ranging from the history of neuroscience (e.g., “do you know who coined the word astrocyte?”) to debunking some of the most pressing dogmas, like the number of neurons versus other cells in the brain. To this point, and using even evolutionary biology, a ~ 1:1 neuron: astrocyte ratio is formulated, which could work well if one considers that each neuron could have its “personal” caretaker, which supports, interacts, facilitates, removes waste, and even protects against disease and demise. Neuroglia: Function and Pathology starts with a historical account of discoveries that shaped this field, continues with the in-depth narration of neuroglia physiology, and seamlessly flows to the detailed description of the defining roles of neuroglia in brain diseases. Its part on physiology embraces all types of glia, be these either central or peripheral, and provides an exciting picture of these highly heterogeneous cells in form and function: It goes on to highlight that the ability of constant change amongst glia provides the basis of lifelong adaptation of the nervous system. On astrocytes, we learn that learning, memory, or neural plasticity, phenomena that are commonly assigned to neurons, simply cannot take place without them. Likewise, it is sobering to realize that neurons are incapable of producing their acting tools, the two major amino acid neurotransmitters (whether glutamate or GABA) without astrocytes supplying them with glutamine, the obligatory precursor of both chemical messengers. Similarly, astrocytes support synaptogenesis and synapse integrity. When this function fails, synaptic plasticity is eliminated. On microglia, the concept of synapse turnover is exemplified, which is the dynamic cycle of synapses being born, maintained if used, and then removed. If synaptic pruning by microglia is affected, then the neurocircuits neither develop nor function properly. Instead, the brain consumes massive amounts of excess energy, the production of which is inevitably associated with oxidative stress. And astrocytes are the foremost cell type to protect against oxidative stress by producing the bulk of glutathione, its scavenger. Glutamate, however powerful as an excitatory neurotransmitter, is even more powerful as a natural poison that kills by producing a state of excitotoxicity for neurons. It is therefore not entirely unexpected that silencing glutamate clearance by astrocytes effectively tarnishes the brain. This and many similar fundamental homeostatic actions make neuroglia central to neuropathology: every disease is a homeostatic challenge. When homeostatic cells of the nervous system cannot meet a challenge, then the nervous system cannot survive. Despite the “neurocentric” views of modern-day neurology, this book reinforces the observation that neuroglia defines neuronal survival, neuronal protection, postlesion regeneration, and tissue rehabilitation. In other words, Verkratsky and Butt make it plain obvious that neuroglia defines the resilience of the nervous system. Accordingly, the decline of neuroglia accompanies aging, thus opening the gate for neurodegeneration, which limits cognitive longevity. It is commendable, therefore, that the second part of Neuroglia: Function and Pathology provides breathtaking insights into brain diseases, be these sporadic or inherited in origin, and includes pathological aging/neurodegeneration, mental illnesses, neurodevelopmental disorders, toxic encephalopathies, pain, viral infections, and cancer, to contextualize all that is said about the anatomy and function of glial cells populating the brain, as well as the peripheral nervous system. This new book shall undoubtedly find its way onto the bookshelves of the researchers working on glia biology because of its attention to detail, and depth of insight. But it shall equally be sought after by students of all ages because of it being an entertaining read and an educational summary of digestible bouts of information for anyone who needs to look up a specific feature of a certain glial cell type. In the age of Google, this book will still stand firm because of its completeness, conceptualization, and being exceptionally well-referenced for all its facts and figures. Therefore, and regardless of using its paper print or online document version, we will certainly be among those relying on its vast content for our own work until the next iteration1-3 will come about. Tibor Harkany and Tomas Hökfelt co-wrote this editorial. This work was supported by the Swedish Research Council (2020-01688, T.Hö.; 2018-02838; T.Ha.); The Arvid Carlsson Foundation (T.Hö.), the Swedish Brain Foundation (Hjärnfonden, FO2020-0178, T.Ha.), the Novo Nordisk Foundation (NNF20OC0053667, T.Ha.), and the European Research Council (FOODFORLIFE, ERC-2020-AdG-101021016; T.Ha.). There is no conflict of interest.