Abstract:

Sporadic Alzheimer’s disease (AD) is associated with numerous risk factors, yet its precise cause remains unclear. Here, we describe a novel framework for AD pathogenesis, whereby diverse risk factors converge on neuromodulatory subcortical systems to confer AD risk or resilience. Neuromodulatory projection neurons are uniquely fragile due to their large size, sparse myelination, and high basal metabolic demands. We propose that the increased prevalence of AD in older adult populations likely reflects a universal weakness within these projection systems, which is increasingly exposed as cellular transport and maintenance mechanisms deteriorate with age. The key insight of this ‘neuromodulatory fragility framework’ is that neuromodulatory system dysfunction is sufficient to explain both tau hyperphosphorylation and b-amyloid (Ab) plaque formation, the two pathological hallmarks of AD. We therefore predict that strengthening or preserving the endogenous functions of these systems in midlife represents the most effective strategy for preventing AD.

Abstract:

In pathological conditions, elevated activity of connexin and pannexin hemichannels facilitates Adenosine triphosphate (ATP) efflux and Ca²⁺ influx, activating metabolic pathways of neuroinflammation. While a small insult could result in a protective inflammatory response, more intense and/or prolonged insults induce cell death, causing tissue dysfunction. In the brain, different stressors elevate glucocorticoid (GC) levels that are sensed by mast cells and microglia, and this response persists for a long time, causing continuous inflammasome activation and release of IL-1β and IL-18. These proinflammatory cytokines, together with those released by mast cells, activate astrocytes and oligodendrocytes, which in turn release glutamate and ATP, and altogether reduce neuronal functionality and survival. The extent of neuroinflammation also depends on host features that result in different degrees of alterations during brain ontogeny, consequently changing the brain cytoarchitecture and leading to spectrums of behavioral diseases. Selective hemichannel blockers have been recently discovered and shown to reduce neuroinflammation, as well as neuronal suffering and symptoms linked to adult models of depression and epilepsy. These blockers can serve as tools to dissect the role of neuroinflammation in behavioral diseases. Early treatment during brain ontogeny could reduce detrimental impacts on the brain cytoarchitecture, inducing behavioral alterations elicited in adulthood.

Abstract: Background: The three Synuclein family members (α-, β-, and γ-synuclein) are presynaptic proteins that regulate synaptic vesicle trafficking and thereby influence neurotransmitter release. Synucleins belong to a class of intrinsically disordered proteins and are prone to aggregation into pathological deposits, which may impair their physiological synaptic functions. Knockout (KO) mouse lines, commonly used to model synuclein depletion in the nervous system, reveal a range of phenotypes with different motor and behavioral deficits. However, given the high sequence homology and functional interplay among the three synucleins, the specific contribution of each family member to these phenotypes remains poorly understood. Objective: In this study, we conducted a comparative phenotypic analysis of γ-synuclein KO, α- and β-synuclein KO, and αβγ-synuclein KO mice. Methods: Mice were subjected to a battery of behavioral tests assessing motor activity and coordination, anxiety-like behavior, and spatial learning and memory. Synaptic vesicle proteins were analyzed in brain tissues using Western blotting. Results: We observed that knocking out γ-synuclein but not α- and β-synucleins reduces mouse lifespan and leads to sustained reduction in muscle strength implicating that γ-synuclein is essential for neuromuscular function. Another consequence of γ-synuclein deficiency is altered anxiety-like behavior manifested as a diminished aversive response, while exploratory behavior and memory remain intact. The triple KO mice mirror γ-synuclein KO mice in some behavioral changes, including shortened lifespan, reduced muscle strength, and decreased anxiety-like behavior. However, the triple KO mice additionally exhibit hyperactivity, which is not present in the other groups. No changes in synaptic vesicle marker levels were detected, indicating that the observed motor and behavioral abnormalities are not attributable to impaired synaptic connectivity. Conclusions: Taken together, these findings demonstrate nonredundant functions of individual synuclein family members and highlight a distinct role of γ-synuclein in regulating motor performance and behavioral responses.

Abstract:

Cell motility—the dynamic process encompassing migration, adhesion modulation, cytoskeletal remodeling, and extracellular matrix (ECM) interactions—is fundamental to ocular homeostasis. In glaucoma, disrupted motility of trabecular meshwork (TM) and Schlemm’s canal (SC) cells contributes to impaired aqueous humor outflow and elevated intraocular pressure (IOP), while reactive motility of optic nerve head (ONH) glial cells promotes fibrosis and neurodegeneration. Mechanistically, TM/SC motility is regulated by Rho GTPase and ROCK signaling, focal adhesion dynamics, and ECM interactions, while glial cells respond to mechanical stress and cytokines such as TGF-β2. Cytoskeletal alterations, ECM stiffening, and endothelial–mesenchymal transition (EndMT) contribute to glaucomatous damage by reducing normal cell motility and tissue remodeling capacity. Aberrant motility at the ONH, including heterogeneous astrocytic reactivity, leads to lamina cribrosa remodeling and retinal ganglion cell degeneration. Therapeutically, ROCK inhibitors improve TM/SC motility and outflow, suppress EndMT, and may confer neuroprotection. Stem cell–based strategies and modulation of TGF-β2 or mechanotransduction pathways represent emerging approaches to restore physiological motility and regenerative potential. Despite promising advances, challenges remain in ensuring targeted, durable, and safe modulation of cellular dynamics. Understanding and therapeutically harnessing cell motility offers a unifying framework to address both pressure-dependent and neurodegenerative mechanisms in glaucoma.

Abstract: This review examines convergent neurobiological mechanisms linking stress and drugs that drives stress-induced drug-related behaviors. It first outlines main theoretical frameworks explaining substance use disorders (SUDs), emphasizing vulnerability factors—particularly stressful life events—that increase addiction risk. The analysis integrates preclinical evidence demonstrating that chronic stress facilitates cross-sensitization to psychostimulants and accelerates drug self-administration, underscoring how stress and drugs converge on glutamatergic and dopaminergic transmission within the Nucleus Accumbens (NAc). Special attention is given to the glial cells, particularly microglia and astrocytes, in mediating stress-induced neuroimmune activation and glutamate dysregulation in the NAc. Three major themes related to microglia–astrocyte crosstalk are addressed: (i) the contribution of these glial cells to neuroimmune and glutamatergic alterations induced by stress; (ii) their role in synaptic and structural plasticity changes within the NAc; and (iii) the mechanisms by which stress and drug exposure reshape glial–neuronal communication, driving the comorbidity between stress and SUDs. A dedicated section focuses on key neuroimmune signaling pathways—particularly the TNF-α/NF-κB axis—and their involvement in stress-induced vulnerability to cocaine addiction. Finally, the review discusses preclinical evidence supporting the therapeutic potential of repurposed glutamate-modulating agents, as promising pharmacological candidates for treating comorbid stress and cocaine use disorder.

Abstract: Early life experiences and the process of exploration play a vital role in shaping brain development and lifelong learning. In March 2020, population-wide restrictions were imposed due to the COVID-19 pandemic. It remains to be determined whether having been raised under the global stress and restrictions of COVID-19 has influenced children’s development as they enter formal schooling. The aim of this study was to examine the extent to which having more than 50% of one’s first year of life and/or prenatal period in the COVID-19 era influences the developmental trajectory in preschool. The study compared 3-to 5-year-old children born before the pandemic (n = 63) with those who were five months or younger at its onset (n = 40). Variables assessed included executive function skills, vocabulary, and common developmental domains. Using the BRIEF-P as a standardized measure of executive function, the results demonstrate that, the pandem-ic-born cohort exhibit greater impairments than those born before the pandemic. There was also a significant increase in reports of speech and language therapy enrollment; frequent ear infections; diagnoses of hearing, speech, or language impairments; and delays in reaching developmental milestones. The pandemic-born cohort additionally reported delays in fine motor skills compared to the pre-pandemic cohort. The present study underscores the urgent need for additional resources to better support children in this cohort as they begin formal schooling.

Abstract: Since there is no cure for Parkinson's disease yet, pharmacobiotic drugs based on the gut microbiota capable of producing the necessary pharmacologically active compo-nents are being developed. The drug LfU21 based on the strain of Limosilactobacillus fermentum U-21 is proposed as a candidate for pharmacobiotics in this work. To char-acterize the effectiveness of the studied drug, a combined LPS and lactacystin (LAC) induced PD model in the Wistar rat line was used. The analysis was performed using behavioral, biochemical, immune, and transcriptomic biomarkers. LfU21 reduces the level of α-synuclein, changes motor activity in the “Rung ladder” test and the expres-sion of the bdnf gene in both hemispheres of the brain. When exposed to LPS, LfU21 prevents changes in the level of the immune response, GSH, expression of the drd2 and bdnf genes, and the number of goblet cells in the intestine. When exposed to LAC and LAC+LPS, LfU21 prevents an increase in α-synuclein, a decrease in bdnf expression, and indicators in the “Open Field” and “Rung ladder” tests, respectively. The effect of LfU21 in a combined model of Parkinson's disease confirms its multifunctionality. This allows us to determine the cohort of patients for future clinical trials of LfU21.

Abstract: Brain-derived growth factor, BDNF, has critical roles in a wide variety of neuronal aspects, including cell survival, differentiation, and synaptic function after their maturation. TrkB, a high affinity receptor for BDNF, is a major contributor in these neuronal aspects, and its functions are exerted via stimulating intracellular signaling pathways including the mitogen-activated protein kinase (MAPK) pathways. Especially, extracellular regulated kinase 1/2 (ERK 1/2), a major serine-threonine kinase and belonging to MAPK family, also works as a downstream molecule after activation of BDNF/TrkB system. Interestingly, growing evidence has demonstrated that ERK1/2 signaling exerts positive or negative influence on neurons in both healthy and pathological conditions in the central nervous system (CNS). Indeed, activation of ERK 1/2 stimulated by the BDNF/TrkB system is involved in regulation of synaptic plasticity. On the other hand, over-activation of ERK1/2 signaling under the pathological conditions is closely related to the neurodegeneration. In this review, we show how ERK1/2 signaling affects neuronal fate, including cell survival or cell death, in the CNS. Moreover, we discuss the involvement of overactivation of ERK signaling in the neurodegeneration observed in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington’s disease (HD).

Abstract:

Background: Predictive processing abnormalities offer a unifying account of perceptual and expressive disturbances in psychosis, yet classical predictive coding frameworks remain difficult to translate due to limited neurophysiological grounding. Emerging evidence positions beta-band oscillations and their transient burst dynamics as a biologically plausible mechanism for implementing top-down predictions that stabilize internal models. Study Design: This narrative review synthesizes evidence from electrophysiology, laminar physiology, computational modelling, language research, and clinical neuroimaging to evaluate beta oscillations as a mechanistic target for predictive processing deficits in psychosis. We integrate data from modified predictive routing frameworks and dendritic computation models to clarify how beta rhythms prepare cortical pathways for predicted inputs. Study Results: Across sensory, motor, cognitive, and language domains, schizophrenia features impaired generation, timing, and contextual deployment of beta activity. These include attenuated post-movement beta rebound, reduced or mistimed beta bursts during working memory and inhibition, abnormal beta-gamma interactions during perception, and weakened beta-mediated contextual guidance during language comprehension. Laminar and computational findings indicate that beta bursts arise from the integration of apical (contextual) and basal (sensory) dendritic inputs in layer 5 pyramidal neurons, providing a mechanistic substrate for top-down predictions. Beta disruptions, therefore, offer a parsimonious account of disorganization, psychomotor slowing, and failures of contextual maintenance. Early neuromodulation, pharmacologic, and neurofeedback studies suggest that beta dynamics are modifiable. Conclusions: Beta oscillations provide a tractable and mechanistically grounded target for predictive processing deficits in psychosis. Standardizing burst metrics and developing individualized, closed-loop approaches will be critical for advancing beta-based interventions.

Abstract: Background: Visualization (motor imagery) is used in sports to enhance performance. Fencing relies on point control and lunge distance, yet little is known about how visualization affects these skills across experience levels. Objective: To examine the effects of brief visualization on point control and lunge distance in fencers of different experience levels. Methods: Nineteen fencers (age 10–56) completed pre- and post-tests of point control (10 hits) and lunge distance (maximum reach). Between tests, the experimental group performed a 1-minute guided visualization, while the control group (n = 20) repeated the tests without visualization. Results: Visualization significantly improved point control (+1.4 hits, 25.5%; p = 0.0078). Lunge distance increased (+15.6 cm, 11.1%) but was not significant (p = 0.0830). Less experienced fencers improved more in point control (39.0% vs. 14.8%), while experienced fencers improved more in lunge distance (12.8% vs. 7.2%). Control participants showed no meaningful gains, and between-group comparisons confirmed significant advantages for visualization in both skills (p < 0.01). Conclusion: Even a short visualization exercise improved fencing performance, with novices benefiting most in accuracy and experienced fencers in explosive reach. Visualization offers a low-cost, adaptable supplement to fencing training.

Abstract: Synaptic plasticity is a fundamental mechanism underlying learning and memory, through which neuronal networks in the brain exhibit rhythmic activity at distinct frequencies (e.g., θ and γ oscillations) to enable efficient information processing and maintain network stability. However, the plasticity rules of in vitro neuronal networks under different stimulation frequencies, as well as their regulatory responses to rhythmic driving, remain insufficiently characterized. To investigate how in vitro neuronal networks achieve learning and memory processes, we cultured mice hippocampal networks on multielectrode arrays (MEAs) and conducted two related experiments. (1) Electrical stimulation patterns at distinct frequencies, combined with network connectivity analysis, demonstrated clear frequency-dependent plasticity, reflecting core properties of learning and memory. (2) Physiologically relevant rhythmic stimulation (θ: 7.8 Hz, γ: 40 Hz) with varying intensities was then applied. Although both rhythms induced distinct frequency-specific modulation, increasing stimulation intensity led to a pronounced suppression of frequency-dependent plasticity, revealing an intrinsic homeostatic regulatory mechanism. Together, out findings characterize frequency-dependent plasticity of in vitro hippocampal networks and uncover their adaptive homeostatic regulation under rhythmic modulation. These results advance our understanding of learning and memory mechanisms and provide a foundation for leveraging in vitro neural systems to perform complex learning and memory tasks.

Abstract:

Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition driven by rare de novo variants, copy number variations, and polygenic risk. SFARI-curated genes show high mutational constraint and enriched expression in cortical neurons and glia. This review highlights recent advances in CRISPR-based functional genomics using human pluripotent stem cells and induced pluripotent stem cells differentiated into neural progenitors, excitatory and inhibitory neurons, astrocytes, microglia, and brain organoids. CRISPR modalities including knockouts, CRISPRi and CRISPRa, base and prime editing, and Cas13 enable pooled and arrayed screens with high coverage at low multiplicity of infection. Integration of multimodal readouts such as Perturb-seq, single-cell and spatial transcriptomics, proximity labeling proteomics, and functional assays including microelectrode arrays and calcium imaging provides system-level insights into ASD gene function. Computational frameworks like MIMOSCA and SCEPTRE facilitate network reconstruction and pseudo-time inference. Case studies reveal Wnt and BAF complex dysregulation, microglial pruning deficits, and non-cell autonomous effects. Translational approaches target haplo-insufficient genes such as CHD8 and SCN2A using AAV or antisense oligonucleotides supported by isogenic iPSC models. Remaining challenges include model immaturity and scalability, while future directions focus on spatial perturb-omics, AI-driven causal inference, and standardized biobanks for precision ASD therapeutics.

Abstract: HIV neuroinvasion results in neuronal dysregulation and compromised neurocognition. Neuroplasticity measures, such as HIV cognitive rehabilitation, have shown potential in partially reversing cognitive deficits sequent HIV invasion. Previous functional NIRS (fNIRS) studies demonstrate that customised attention brain training (ABT), has the potential to alter brain activity in adolescent HIV. Nonetheless, the effects of ABT on brain functional connectivity in adolescent HIV remains unclear. The study investigated behavioural and functional connectivity changes in adolescent HIV amongst participants (N=26) receiving 12 weeks of ABT compared to Treatment as Usual (TAU) controls. Twenty-six adolescents living with HIV were recruited, and randomly assigned to either the ABT treatment group (N = 13) or TAU group (N = 13). Participants completed NEPSY-II and fNIRS measures, before and after the training. Functional connectivity (FC) measures were evaluated using seed-based correlation analysis, located in the central executive network (CEN) and across the hemispheres. No significant behavioural differences were noted on the NEPSY-II and BRIEF scores, however, functional connectivity measures indicated that the ABT group exhibited significantly increased FCs in the left hemisphere (p < 0.05) following brain training. Significantly, thresholding analysis indicated the dorsolateral prefrontal cortex as a potential marker for brain training in adolescent neuroHIV.

Abstract: Rett syndrome (RTT), an X-linked neurodevelopmental disorder predominantly arising from de novo MECP2 mutations, manifests with psychomotor regression, stereotypic hand movements, gait apraxia, and expressive aphasia, driven by dosage-sensitive epigenetic dysregulation via MeCP2's methyl-CpG-binding domain (MBD) and transcriptional repression domain (TRD). Isoform-specific expression (MeCP2-E1 neuronal predominance) and X-chromosome inactivation mosaicism underpin phenotypic variability, with missense (R133C, T158M) and nonsense (R168X, R255X) variants correlating to severity gradients. Multisystem pathophysiology encompasses brainstem-mediated respiratory dysrhythmias, QTc prolongation via ion channel perturbations, enteric hypomotility, osteopenic fractures, and mitochondrial bioenergetic deficits, exacerbated by glial-neuronal crosstalk and oxidative stress. Preclinical platforms, including Mecp2-null rodents, patient-derived iPSCs, and cerebral organoids, elucidate synaptic hyperexcitability, dendritic arborization deficits, and reversibility upon Mecp2 reactivation. Therapeutic modalities span supportive multidisciplinary interventions, FDA-approved trofinetide (IGF-1 analog modulating neurotrophic cascades), AAV-mediated gene replacement (NGN-401, TSHA-102 with miRARE autoregulation), ASOs for dosage normalization, and emerging PPAR-γ agonists targeting metabolic homeostasis. Prioritized research agendas emphasize validated biomarkers (BDNF/IGF-1 axes, miRNA signatures), combinatorial regimens, and equitable global access to mitigate caregiver burden and phenotypic heterogeneity.

Abstract: Background/Objectives: Traumatic spinal cord (SC) injury (SCI) is a debilitating neurological condition. Minimally invasive approaches to monitor in real-time the functional state of the neuromotor apparatus in animal models of SCI (at rest and movement) to assess effectiveness of therapy are needed in preclinical studies. We aimed to develop such a bioethically acceptable platform for SCI studies on non-human primates (Rhesus macaques) Methods: Epidural and myographic electrode implantation (EI) (wireless and wired, connected via a head-plug) was performed. After EI, motor responses caused by electrical stimulation of the SC at the level of the cervical and lumbar thickening were recorded; electromyography of the limb muscles was recorded during quadrupedal movement of the animal on a treadmill with simultaneous assessment of movements’ kinematic parameters. Five weeks after EI, three animals underwent lateral hemisection of the SC in the C4-5 segment under the control of a surgical microscope and intraoperative recording of motor and sensory evoked potentials. Results: Within 30 days after SCI, during treadmill testing, a decrease in electromyographic activity of the limb muscles and the volume of angular movement in the joints on the side of the injury was detected. Electrical stimulation at the L2-S1 segments of the SC at a frequency of 30 Hz led to the appearance of a locomotor pattern in the muscles of the hind limbs and an increase in the range of motion. Conclusions: Our platform can be used for pathophysiological studies of various neuromodulation modes and as a basis for the development of control neurointerfaces.

Abstract: Objective To propose a revised neurobiological framework for traumatic memory that explains the phenomenology of flashbacks not as mere reactivations of fear circuits, but as the hippocampal complex’s ongoing attempt to integrate unprocessed sensory–emotional fragments encoded without temporal context during extreme stress. Background Classical models—the fear-network theory (Foa & Kozak, 1986) and the dual-representation theory (Brewin et al., 1996, 2010)—conceptualize flashbacks as intrusive replays of amygdala-driven sensory representations that fail to link with hippocampal–prefrontal systems. These frameworks accurately describe fragmentation but overlook the hippocampus’s potential active role in later integration. Neurobiological and computational findings across the last two decades show that traumatic stress disrupts prefrontal inhibition, amygdala dominance, and hippocampal contextual encoding, resulting in memories stripped of temporal and narrative structure. The persistence of flashbacks despite safety suggests a dynamic process rather than a static lesion. Methods / Theoretical Approach This chapter synthesizes evidence from functional neuroimaging, neuroendocrinology, and predictive-coding theory to construct a tri-systemic model of trauma involving the medial prefrontal cortex, amygdala, and hippocampus. The analysis follows the chronological breakdown of this system under threat—prefrontal disinhibition, amygdala hyper-encoding, HPA-axis discontrol, and hippocampal silencing—and explores subsequent re-engagement mechanisms. Results / Proposed Mechanism Flashbacks are conceptualized as failed integration events: partial hippocampal reactivation of unbound sensory–emotional traces in the absence of temporal coding. This re-engagement triggers amygdala-mediated affective flooding, creating the illusion of present-tense re-living. Conclusions / Implications Re-experiencing may represent a neural system striving for coherence, not solely pathology. Understanding flashbacks as integration attempts clarifies why they can emerge during calm, why therapies restoring safety and context diminish them, and how hippocampal–prefrontal synchronization transforms traumatic immediacy into autobiographical memory. This model reframes trauma as a process of disrupted, yet potentially recoverable, neurobiological integration.

Abstract: Background/Objectives: Obesity and insulin resistance (IR) increase the risk for mood disorders, which often manifest during young adulthood. However, neuroelectrophysiological investigations of whether adiposity and/or IR modify electrocortical activity and emotional processing outcomes remain underexplored, particularly in younger adults. Therefore, this study used electroencephalography (EEG) to investigate whether obesity and/or IR moderated the relationships between brain potentials and affective processing in younger adults. Methods: Thirty younger adults completed a passive picture-viewing task utilizing the International Affective Picture System while real-time electroencephalography was recorded. Two event-related potentials—early posterior negativity (EPN) and late positive potential (LPP)—were quantified. Affective processing parameters included mean valence ratings and stimulus-to-response-onset reaction times in response to unpleasant, pleasant, and neutral images. Body fat percentage and Homeostatic Model Assessment for Insulin Resistance values were measured. Hierarchical moderated regression analysis was utilized to test the interrelationships between brain potentials, adiposity, IR, and affective processing. Results: In the Negative–Neutral condition, lean and insulin-sensitive participants gave less negative valence ratings to unpleasant versus neutral images when late-window LPP amplitudes were larger, whereas respective counterparts showed no such relationship. Contrariwise, neither obesity nor IR moderated LPP responses to affective processing parameters in the Positive–Neutral or Negative–Positive conditions. Conclusions: Lean, insulin-sensitive young adults showed attenuated affective processing of unpleasant stimuli through stronger neural responses, whereas neural responses to pleasant stimuli did not vary across levels of body fat or IR. These preliminary findings suggest that both obesity and IR increase the vulnerability to mood disorders in young adulthood.

Abstract: Rosemary (Salvia rosmarinus) has been linked to improvements in psychological wellbeing through cholinergic mechanisms. However, this study investigated whether individual differences in eye blink rate (EBR) and blink variability (EBV), which are proxies of dopaminergic activity and attentional control, influence the cognitive and mood-enhancing properties of a rosemary-containing drink. Forty-eight healthy adults completed a 3-stimulus odd-ball cognitive task under rosemary or control conditions, while vertical electrooculograms were recorded. Event-related brain potentials (ERPs) were also measured using the P3a component at the Cz scalp electrode as an additional index of dopaminergic activity. Subjective mood and arousal (alert, contented, calm) were collected pre- and post-task using Bond–Lader visual analogue scales. Reaction times during the task were modelled with ex-Gaussian parameters (μ, σ, τ). Rosemary ingestion led to increased alertness and contentedness following the task. Cognitive effects were moderated by blink metrics, with significant interactions between rosemary and blink metrics for mean reaction time μ and response variability σ. Rosemary also increased P3a amplitudes, indicative of dopaminergic contribution. The effects of rosemary on cognition and mood were moderated by individual blink profiles, indicating that baseline neurocognitive state plays a role. Although cholinergic accounts are well established, this study highlights the use of proxies of dopamine to investigate broader neurotransmitter involvement in rosemary's enhancing properties.

Abstract: The search for thought’s representational format has traditionally focused on Mentalese, neural codes, predictive processing, embodied sensorimotor models. Here we examine another hypothesis: human cognition may operate by default through a structurally poetic mode characterized by metaphorical mapping, rhythmic/repetitive patterning, imagistic compression, controlled ambiguity, acoustic structuring and affective resonance. These features correspond to identifiable computational and neurobiological mechanisms. Metaphor and analogy recruit fronto-parietal networks for cross-domain alignment, enabling dimensionality reduction and transfer across abstract spaces. Rhythmic and metrical structure entrain delta–theta–gamma hierarchies, improving prediction and memory via phase-aligned hippocampo-cortical loops. Imagery activates hippocampal–visual circuits and default-mode subsystems, supporting high-level generative simulation. Ambiguity/polysemy sustains parallel semantic states in frontal networks, enabling probabilistic inference under uncertainty. Sound patterning exploits phonological memory and auditory statistical learning, enhancing signal-to-noise resilience. Emotional resonance engages limbic and reward pathways, modulating salience and long-term retention. Comparative evidence indicates that structurally homologous “proto-poetic” systems exist across species. Birdsong and whale song show hierarchical, rhythmic sequence generation with cultural drift; honeybee dances encode spatial data cross-modally; primate calls display affix-like combinatoriality and contextual ambiguity; frog and insect chorusing reflects large-scale oscillator coupling; and ritual displays compress identity and fitness cues into symbolic form. These convergent data support the view that poetic structuring constitutes an evolutionarily conserved cognitive technology optimized for memory efficiency, predictive precision, adaptive flexibility and social synchrony. Reframing poetry as a computational architecture of thought motivates new empirical programs integrating neuroimaging, comparative biology and formal models of information compression, oscillatory coordination and cross-domain mapping.

Abstract: The dominant narrative of autonomic nervous function remains essentially that proposed by Walter B. Cannon over a hundred years ago. It emphasizes sympathetic mediation of “fight-or-flight” responses and catabolism and associates the parasympathetic system with “rest-and-digest” functions and anabolism. Dual innervation of tissues and an antagonistic relationship between the divisions is presented as the rule, with minor exceptions. Extensive evidence accumulated over the past century renders these generalizations untenable, as autonomic neuroscientists have been pointing out for decades. Yet such critiques have not changed how the system is taught or understood. To remedy this situation, it is proposed that an alternative framework is needed that aptly summarizes sympathetic and parasympathetic functions, respectively. Here, following a systematic critique of the traditional approach, such an alternative is proposed based on a consideration, first, of functions in tissues innervated by only one branch, such as the kidneys, and then, of specific functions in tissues receiving dual innervation where distinct regulatory responsibilities of one or the other branch is clear, e.g. respiratory sinus arrhythmia and the pupillary light reflex. The proposed schema describes the sympathetic division as the body’s “quartermaster,” responsible for regulating physico-chemical conditions and distributing metabolic resources to meet, and where necessary adjust, current and anticipated demand, under all circumstances. In contrast, the parasympathetic division is described as the body’s “coordinator,” regulating secretory and smooth muscle activity involved in interactions and exchanges with the outside world—eating, breathing, speaking, voiding, looking, mating, moving, etc—often closely articulated with associated somatic motor activity. The schema emphasizes that in each tissue, the activity of the respective branches relates to their respective regulatory responsibilities, and not to a generically counterbalancing relationship to the other. The proposed alternative leads to novel hypotheses regarding the function of autonomic innervation in cases where its physiological importance remains obscure, such as the parasympathetic supplies to pulmonary and cerebral vasculature and to airway smooth muscle. It is offered to stimulate debate directed toward the creation of a consensus alternative narrative that can displace the misleading traditional narrative and advance a more realistic view of autonomic function.