The review, published in Frontiers in Psychiatry, synthesized studies published from 2005 through 2026 that were identified in Medline/PubMed and Google Scholar. It focused particularly on cerebrospinal fluid (CSF) concentrations of 5-HIAA and HVA in relation to suicidal ideation, suicide attempts, attempt lethality and subsequent suicide-related outcomes. Studies in other biological matrices, along with clinical, genetic, inflammatory and metabolic research, were included only as context. The authors did not pool effect estimates, and their qualitative synthesis was complicated by small samples, differing diagnoses, inconsistent CSF collection procedures and multiple observational designs.

Across the evidence base, reduced CSF 5-HIAA was the more consistent neurochemical finding. In depressed patients with comorbid alcohol dependence, people whose attempts were classified as high lethality had about 23.5% lower 5-HIAA concentrations than those making low-lethality attempts. The difference remained after adjustment for age and sex, even though the groups did not differ in depression severity, suicidal ideation or impulsivity. HVA and 3-methoxy-4-hydroxyphenylglycol, a norepinephrine metabolite, did not differ between the two groups. This pattern suggests that low 5-HIAA may be more closely related to the medical severity of a suicidal act than to the presence of suicidal thoughts or depressive symptoms alone.

Prospective evidence adds an important qualification. In people with bipolar depression followed for up to two years, baseline CSF concentrations of 5-HIAA, HVA and MHPG did not distinguish patients who later attempted suicide from those who did not. Lower baseline concentrations of all three metabolites were instead associated with greater lethality of attempts occurring during follow-up. The authors interpret this as evidence that monoaminergic activity may relate more closely to the severity of suicidal behavior than to whether an attempt occurs. The distinction matters because suicidal ideation, attempts, non-suicidal self-injury and suicide death are not interchangeable outcomes, and attempts themselves vary greatly in intent, reversibility and medical severity.

Findings also depend on psychiatric diagnosis. Evidence for lower 5-HIAA was comparatively coherent in mood disorders, including depression with alcohol dependence and bipolar depression, but inconclusive in schizophrenia spectrum disorders. In a cohort of people with schizophrenia followed for approximately 25 years, absolute CSF 5-HIAA and HVA concentrations did not differ significantly between those who died by suicide and survivors. A lower HVA-to-5-HIAA ratio was associated with suicide, however, indicating a relative monoaminergic imbalance rather than a deficit in either metabolite alone. A separate long-term study found no significant relationship between CSF 5-HIAA and early mortality or suicidal history after adjustment for confounders. These findings argue against treating low 5-HIAA as a universal marker operating independently of psychiatric context.

The review also emphasizes that suicidal behavior probably reflects interacting systems rather than a single neurochemical defect. A principal-component analysis of 20 CSF biomarkers identified one profile combining higher 5-HIAA, HVA and interleukin-6 with lower orexin that was associated with violent attempts and greater suicide mortality during follow-up. This does not fit a simple model in which every suicidal state produces uniformly low monoamine concentrations. Other studies linked persistent kynurenine-pathway dysregulation, including higher quinolinic acid and lower kynurenic acid, to suicidal symptoms and depression severity, while elevated cortisol in attempters pointed to activity in the hypothalamic-pituitary-adrenal stress system. Genetic research in the contextual evidence also suggested that suicide-related traits share a highly polygenic architecture involving synaptic function, cellular stress and DNA repair, among other pathways.

Early-life adversity and sex may modify these neurochemical associations. In one study of people who had attempted suicide, greater childhood exposure to violence was associated with lower CSF 5-HIAA in women but not men; among trauma-exposed participants, lower 5-HIAA was also linked with greater adult expression of violent behavior. In another sample, lower CSF HVA was associated with more severe anxiety among female attempters, but HVA was not associated with depression, overall psychopathology or suicidal ideation. A long-term schizophrenia cohort found more childhood bullying among those who died by suicide, while the separate finding of a lower HVA-to-5-HIAA ratio connected this exposure with a relative neurochemical imbalance. These observational associations cannot establish whether early stress causes the measured changes or whether both reflect other vulnerabilities.

Postmortem findings further complicate a simple “low serotonin” interpretation. In brain tissue from suicide cases, serotonin and 5-HIAA concentrations were higher in the brainstem, but the 5-HIAA-to-serotonin ratio was lower, indicating reduced serotonergic turnover rather than uniformly low metabolite concentrations. No significant difference was detected in the prefrontal cortex. Such regional patterns are compatible with altered release, receptor regulation or compensatory changes, but they do not establish causality. Nor do they prove that increasing serotonergic transmission would prevent suicide. Clinical responses to selective serotonin reuptake inhibitors vary by diagnosis, age and treatment context, so the observational biomarker findings cannot be used to infer preventive or therapeutic effects.

Even if the associations were stronger, CSF testing is poorly suited to routine suicide-risk screening. Lumbar puncture is invasive, most commonly causes post-lumbar-puncture headache and requires trained personnel, specialized facilities, sample storage and chromatographic analysis. CSF metabolites also reflect cumulative neurotransmitter turnover rather than an acute state, limiting their value for identifying imminent risk. Peripheral alternatives have also performed inconsistently. A single plasma 5-HIAA measurement did not reliably infer an individual’s absolute CSF concentration, despite correlations in within-person changes over time. Salivary 5-HIAA showed no overall difference between drug-naive patients with first-episode major depression and controls, and platelet serotonin findings remain limited to particular populations. Broader biomarker panels may eventually prove more informative, but no threshold or assay has been validated for individual clinical decisions.

The review therefore treats CSF 5-HIAA and, to a lesser extent, HVA as research-level correlates of suicidal behavior rather than actionable biomarkers. Lower 5-HIAA has the strongest support as an association with high-lethality attempts in selected clinical groups, but prospective studies have not consistently shown that it forecasts future attempts or suicide. The evidence remains limited by small samples, heterogeneous diagnoses, residual confounding, differences in medication and substance use, and variation in CSF collection and assay methods. Larger longitudinal studies would need standardized protocols, diagnostic stratification, independent validation and assessment of false-positive and false-negative classifications before these measures could contribute to objective risk models. Even then, any future use would have to complement rather than replace clinical assessment of psychiatric history, previous attempts, intent, social circumstances and access to lethal means.

Subject of Research: Review of cerebrospinal fluid serotonin and dopamine metabolites as correlates of suicidal behavior and attempt lethality

Article Title: Neurobiological basis of suicidal behavior: a narrative review of cerebrospinal fluid monoamine metabolites

Article References: Stefani, L., Marsella, L. T., & Tittarelli, R. (2026). Neurobiological basis of suicidal behavior: a narrative review of cerebrospinal fluid monoamine metabolites. Frontiers in Psychiatry, 17, Article 1968256. https://doi.org/10.3389/fpsyt.2026.1968256

Image Credits: AI Generated

DOI: 10.3389/fpsyt.2026.1968256

Keywords: suicide risk, suicidal behavior, cerebrospinal fluid, 5-HIAA, serotonin, HVA, dopamine, attempt lethality, biomarkers, neurobiology, Neurobiological, basis

Water deficit reduced flower weight, stigma dry weight, leaf dry weight, relative water content and total chlorophyll content in the experiment. It also increased hydrogen peroxide, malondialdehyde and electrolyte leakage. SER and EBL, particularly when applied together, were associated with improved physiological and biochemical measures under deficit conditions. The combined treatment was associated with higher catalase activity, phenol and flavonoid contents, compatible solute accumulation and nitric oxide, as well as lower levels of the measured oxidative-damage indicators. These results concern the specific compounds, concentrations, irrigation treatments and two-season field scope evaluated in the study.

The combined treatment also corresponded to higher saffron quality-compound measurements under deficit irrigation than in untreated stressed plants: crocin content was 9.2% higher, picrocrocin content was 24% higher and safranal content was 55% higher. Multivariate analysis identified distinct physiological and defense-related dimensions. Principal component analysis explained 88.4% of the variation, with the first component accounting for 66% and being primarily associated with physiological traits, while the second accounted for 22.4% and was linked to antioxidant defense and secondary metabolism. Positive correlations between stigma yield and photosynthetic pigments indicated an association between pigment status and saffron productivity, rather than establishing a separate causal effect.

The abstract concludes that simultaneous SER and EBL application produced greater improvements across the measured traits under water deficit than either individual treatment and describes the combination as a potential biostimulant strategy for saffron grown under water-limited conditions. Its scope remains bounded by the two field seasons and the conditions tested. The authors state that validation across multiple locations is necessary to determine whether the findings generalize beyond the experimental setting. This report is based on the supplied abstract of the open-access, early-publication version, which notes that the text is subject to further editorial changes before replacement by the final Version of Record.

Subject of Research: Two-year field testing of combined serotonin and 24-epibrassinolide treatments in saffron under water deficit

Article Title: Serotonin and 24-epibrassinolide enhance physiological performance and saffron quality under water deficit: evidence from two-year field and multivariate analyses

Article References: Makarian, H., Ebrahimi, A., Sahabi, H., & Feizi, H. (2026). Serotonin and 24-epibrassinolide enhance physiological performance and saffron quality under water deficit: evidence from two-year field and multivariate analyses. BMC Plant Biology. https://doi.org/10.1186/s12870-026-10018-6

Image Credits: AI Generated

DOI: 10.1186/s12870-026-10018-6

Keywords: saffron, water deficit, serotonin, 24-epibrassinolide, field experiment, plant physiology, multivariate analysis, crop quality, epibrassinolide, enhance, physiological, performance

The experiment involved 72 clean-grade ICR mice divided equally among six groups. Except for an unstressed control, each animal was housed alone and exposed to one of 13 unpredictable challenges on a rotating schedule. These included food and water deprivation, wet bedding, cold-water swimming, restraint, tail pinching, disrupted light-dark cycles, heat exposure, noise, shaking and cohabitation with another mouse. The protocol was intended to reproduce several features of chronic stress, including anhedonia, impaired weight gain and behavioral withdrawal. Weekly sucrose-preference and open-field tests tracked motivation, locomotion, exploration and anxiety-like behavior, while fluoxetine at 0.01 gram per kilogram served as the pharmacological positive control.

Stress markedly changed the mice’s behavior, but the deficits were attenuated by CCTE in a broadly dose-dependent manner. At the end of modeling, sucrose preference fell to 30.9% in stressed mice receiving water, compared with 70.6% in controls, indicating loss of interest in a rewarding solution. The extract increased this measure to 45.3%, 48.3% and 52.0% at doses of 0.25, 0.5 and 1 gram per kilogram, respectively; fluoxetine produced a value of 48.1%. High-dose CCTE also restored aspects of open-field behavior, including rearing, crossings of the central area and time spent in that region. No experimental deaths occurred, and the extract also counteracted the stress-related suppression of weight gain.

Molecular measurements showed that CCTE affected both serotonin metabolism and the stress-hormone system. Relative to controls, CUMS lowered serotonin, or 5-HT, in serum by 36.7% and in brain tissue by 27.6%, while increasing its major metabolite, 5-hydroxyindoleacetic acid, by 44.8% in serum and 24.6% in brain tissue. High-dose CCTE substantially restored the brain measures, reducing the deficit in 5-HT to about 15.6% and the excess in its metabolite to about 10.5%. The same dose lowered serum corticotropin-releasing hormone, adrenocorticotropic hormone and corticosterone, indicating reduced hyperactivity of the hypothalamic-pituitary-adrenal axis. These hormonal changes were comparable in magnitude to those caused by fluoxetine.

The extract also shifted biomarkers associated with inflammation and oxidative stress. Chronic stress raised circulating interleukin-1β, interleukin-6, tumor necrosis factor-α and nuclear factor kappa-B, while high-dose CCTE lowered all four relative to stressed controls. In brain tissue, stress reduced superoxide dismutase activity, increased malondialdehyde, a marker of lipid peroxidation, and altered catalase and glutathione levels. High-dose CCTE increased superoxide dismutase by roughly 80% relative to the stressed group, reduced malondialdehyde by about 34%, and normalized the other two indicators. The authors interpret the elevated catalase in stressed animals as a compensatory response to oxidative burden rather than evidence of greater protection, because treatment brought it back toward the control level while strengthening other antioxidant measures.

Protection extended to the hippocampus, a brain region closely linked to learning, memory and stress responses. Histological examination revealed disorganized neurons, shrunken cell bodies, pale cytoplasm, condensed nuclei and neuronal loss in the CA1, CA3 and dentate gyrus regions of stressed mice. Counts of intact neurons in those areas had fallen by approximately 47%, 61% and 67%, respectively. High-dose CCTE increased intact-neuron counts by about 78%, 138% and 172% relative to stressed controls, bringing the values to roughly 90–93% of unstressed levels. Nissl staining, which visualizes structures associated with neuronal health, showed a parallel recovery in staining intensity, cellular alignment and the number of Nissl-positive neurons.

At the molecular level, the treatment appeared to restrain two linked inflammatory systems in hippocampal tissue. CUMS increased expression of the NLRP3 inflammasome components NLRP3, apoptosis-associated speck-like protein containing a CARD, caspase-1 and interleukin-1β. High-dose CCTE reduced their immunoreactivity by approximately 31% to 57% compared with stressed animals, with an overall effect similar to fluoxetine. It also suppressed phosphorylated nuclear factor kappa-B p65, phosphorylated inhibitor kappa-B-alpha and cleaved caspase-3, a marker of apoptosis. The combined pattern is consistent with a coordinated interruption of NF-κB-driven inflammatory priming, NLRP3 inflammasome activation and neuronal cell-death signaling, although the experiments did not directly manipulate these targets to prove that each was necessary for the behavioral effect.

LC-MS/MS analysis offered a more specific explanation for how CCTE might influence the brain. After oral administration, only three of the extract’s 11 major polyphenols were detected in brain tissue: the flavonoid aglycones okanin, isookanin and taxifolin. Five flavonoid glycosides and three phenolic acids were not detected, a pattern consistent with their greater polarity and molecular weight restricting passage across the blood-brain barrier. Okanin and isookanin reached peak brain concentrations after about 45 minutes, while taxifolin peaked after 20 minutes. Enzymatic treatment revealed that the compounds were present largely as glucuronide or sulfate conjugates, and measurable levels of okanin and isookanin remained at 240 minutes. The aglycones may also be generated when intestinal enzymes remove sugar groups from larger glycosides before absorption.

All three brain-accessible compounds inhibited monoamine oxidase A, the enzyme responsible for oxidative deamination of serotonin, in laboratory assays. Their half-maximal inhibitory concentrations were 38.66 micromolar for okanin, 48.23 micromolar for isookanin and 47.28 micromolar for taxifolin. An equimolar mixture was more potent than any compound alone, with a half-maximal inhibitory concentration of 18.79 micromolar, indicating a supra-additive interaction in the test system. The mechanism-specific reference inhibitor pargyline was more potent, at 8.71 micromolar. Because whole-brain concentrations were below the individual assay thresholds, the researchers cautioned that local accumulation in mitochondria-rich presynaptic terminals, along with synergy and the extract’s anti-inflammatory and antioxidant effects, may be important in vivo. The study therefore supports a multi-target model, but it does not establish CCTE as a treatment for human depression or establish a safe and effective dietary dose.

Several limitations constrain translation. The CUMS model reproduces selected features of stress-related mood disturbance but cannot capture the full heterogeneity of human depression. Most mechanistic analysis focused on the hippocampus, and the findings were largely correlational rather than based on genetic or cell-specific tests of causality. The extract is also a complex mixture whose other components may act through peripheral routes or contribute indirectly to central effects. Before CCTE could be positioned as a functional food ingredient, researchers would need to assess raw-material safety, digestion and bioavailability, determine an appropriate human dietary equivalent, and conduct clinical studies. The immediate advance is mechanistic rather than clinical: the study connects a chemically defined plant extract to measurable improvements in stress-exposed mice and identifies brain-penetrant compounds whose combined effects may help explain those improvements.

Subject of Research: Effects of Coreopsis tinctoria polyphenols on stress-related mood and hippocampal injury in mice

Article Title: Coreopsis tinctoria Nutt. Polyphenols Ameliorate CUMS‐Induced Depressive Behaviors and Hippocampal Neuronal Damage in Mice

Article References: Han, H., Feng, Y., Wang, Z., Ma, R., Sun, J., Yang, X., Cui, Y., Wang, J., & Jia, M. (2026). Coreopsis tinctoria Nutt. Polyphenols Ameliorate CUMS ‐Induced Depressive Behaviors and Hippocampal Neuronal Damage in Mice. Food Science & Nutrition, 14(10), Article e72480. https://doi.org/10.1002/fsn3.72480

Image Credits: AI Generated

DOI: 10.1002/fsn3.72480

Keywords: Coreopsis tinctoria, polyphenols, depression, chronic stress, hippocampus, serotonin, MAO-A, neuroinflammation, oxidative stress, mouse model, Coreopsis, tinctoria

The glutamatergic and GABAergic evidence tells a complementary story about excitation-inhibition balance. Enrichment consistently upregulates components of glutamatergic signaling, including AMPA and NMDA receptor subunit expression, alongside enhanced synaptic protein levels and dendritic spine density. Rather than producing runaway excitation, these changes are paired with coordinated adjustments in inhibitory tone, including modifications in GABA synthesis enzymes, vesicular transporters, and the maturation state of interneurons. This paired recalibration is precisely what theories of homeostatic plasticity would predict: when a brain receives sustained increases in afferent stimulation, it does not simply amplify all signals but instead adjusts the gain of excitatory and inhibitory circuits to preserve information processing within functional ranges. The practical consequence is a network that is more responsive to novel input yet less prone to the excitotoxic cascades that follow injury or chronic stress, a combination highly relevant to conditions ranging from epilepsy to stroke recovery.

The cholinergic findings occupy an intermediate position in the evidence hierarchy, with meaningful but less extensive support. Enrichment has been shown to influence acetylcholine release and muscarinic and nicotinic receptor density in hippocampus and cortex, changes that plausibly mediate the attentional and learning enhancements enrichment produces. Given the central role of basal forebrain cholinergic neurons in Alzheimer’s disease pathology, even modest environmental modulation of cholinergic tone carries translational weight. The adrenergic and histaminergic systems, by contrast, have received far less direct investigation in enrichment studies. What evidence exists suggests enrichment alters noradrenergic signaling in ways that interact with stress physiology, since the locus coeruleus-noradrenergic system is a primary conduit between environmental challenge and arousal state. But these findings are often secondary observations rather than the focus of dedicated experiments, which explains their characterization as indirect in the review’s synthesis.

The mechanistic convergence on CREB-dependent transcription and epigenetic remodeling merits particular attention because it suggests a common final pathway through which diverse environmental inputs produce lasting neural change. CREB, the cAMP response element-binding protein, functions as a molecular switch whose phosphorylation state determines whether activity patterns are translated into durable gene expression changes. Enrichment reliably increases CREB phosphorylation in hippocampal neurons, and this activation cascades into the expression of genes governing synaptic structural proteins, neurotrophic factors, and receptor subunits. Epigenetic mechanisms, including histone acetylation and DNA methylation changes at promoters of plasticity-related genes, provide the substrate for these transcriptional shifts to persist. This layered architecture, from receptor-level changes through intracellular signaling to genome regulation, explains why enrichment effects are not merely transient fluctuations in neurotransmitter release but durable reorganizations of circuit function that can outlast the enriched experience itself.

Brain-derived neurotrophic factor deserves specific mention as perhaps the most consistently replicated molecular mediator of enrichment effects. Enrichment robustly increases BDNF expression across hippocampus, cortex, and other regions, and BDNF signaling through its receptor TrkB activates intracellular cascades that intersect directly with both glutamatergic synaptic plasticity and monoaminergic function. The interplay is bidirectional: serotonergic and dopaminergic signaling can themselves regulate BDNF expression, creating feedback loops in which neurotransmitter changes and trophic factor changes reinforce one another. This mutual reinforcement may underlie the observation that enrichment produces effects across multiple domains simultaneously, improving mood, cognition, and stress resilience in parallel rather than sequentially. It also suggests that BDNF could serve as a useful biomarker in future human studies, since peripheral BDNF levels are measurable and correlate with central changes in some contexts, though this correlation remains imperfect and requires careful validation.

The methodological heterogeneity that the review identifies as a limiting factor warrants elaboration, because it shapes how confidently any single finding can be interpreted. Enrichment paradigms vary enormously across laboratories: cage size, the number and identity of enrichment objects, the frequency of object rotation, group housing density, the presence and complexity of running wheels, and the duration of exposure all differ between studies. Some paradigms emphasize sensory novelty, others social complexity, others physical activity, and many combine all three without disentangling their relative contributions. This variability means that when two studies report divergent effects on a given neurotransmitter system, it is often impossible to determine whether the discrepancy reflects true biological differences or simply different operational definitions of enrichment. Standardized reporting of enrichment parameters, analogous to the rigor now expected in reporting genetic constructs or behavioral protocols, would substantially improve the field’s ability to synthesize findings across studies.

The predominance of animal data raises translation questions that deserve honest treatment. Rodent enrichment paradigms, even elaborate ones, cannot fully capture the richness of human environmental experience, and the neural systems they engage may differ in important respects from their human homologs. Nevertheless, several convergent lines of evidence support the relevance of enrichment principles to human health. Epidemiological studies consistently associate educational attainment, occupational complexity, social engagement, and physical activity with reduced dementia risk and better cognitive aging outcomes. Clinical interventions incorporating structured cognitive stimulation, physical exercise, and social interaction have shown measurable benefits in populations ranging from children with neurodevelopmental conditions to older adults with mild cognitive impairment. While these human findings cannot isolate neurotransmitter mechanisms with the precision available in animal work, their consistency with the preclinical literature provides reasonable grounds for cautious optimism about translational potential.

The question of timing, which the review flags as a priority for future research, has particular significance given what is known about developmental sensitive periods. Enrichment during adolescence produces effects on prefrontal cortical development and stress responsiveness that differ qualitatively from enrichment initiated in adulthood, and enrichment in early life can program long-term trajectories of HPA axis function that persist into later stages. Conversely, enrichment initiated in aged animals still produces measurable benefits on neurogenesis and cognition, demonstrating that plasticity is not extinguished with age but rather modified in its magnitude and mechanisms. This lifespan perspective suggests that enrichment is not a single intervention but a family of interventions whose optimal composition depends on the developmental window and the clinical target. A protocol designed to enhance resilience in a healthy adolescent may differ substantially from one intended to slow cognitive decline in an elderly patient with early neurodegeneration.

The therapeutic implications for specific disease categories merit individual consideration. In stroke models, enrichment accelerates functional recovery and promotes peri-infarct plasticity, effects that appear to depend on glutamatergic and BDNF-mediated mechanisms and that have informed rehabilitation approaches emphasizing enriched, task-specific environments over conventional single-skill training. In addiction models, enrichment reduces drug-seeking and relapse-like behavior, likely through normalization of dopaminergic reward circuitry that has been pathologically sensitized by repeated drug exposure. In neurodegenerative disease models, enrichment delays onset and slows progression of pathology in transgenic animals, though whether these effects reflect neurotransmitter modulation, reduced neuroinflammation, enhanced clearance mechanisms, or some combination remains actively investigated. Each of these applications carries distinct translational challenges, but they share the common feature of engaging endogenous plasticity mechanisms rather than introducing exogenous pharmacological agents, which may offer favorable safety profiles if the interventions can be adequately specified and controlled.

The relationship between enrichment and stress physiology provides an additional integrative framework. Enrichment is not simply pleasant stimulation; it involves novelty, complexity, and challenge, elements that activate stress-responsive systems in controlled doses. This controlled activation appears to produce stress inoculation, a phenomenon in which prior manageable challenge enhances subsequent resilience to more severe stressors. The neurochemical signature of this inoculation includes altered glucocorticoid receptor expression, modified serotonergic tone in limbic regions, and enhanced inhibitory control over stress-responsive circuits. Understanding enrichment through this lens reframes it not as the absence of stress but as the presence of optimally calibrated challenge, a distinction with practical implications for designing interventions. Environments that are stimulating but unpredictable in threatening ways may produce different, potentially harmful, outcomes compared to environments that are complex but controllable.

Looking forward, the most productive research directions likely involve combining enrichment paradigms with modern neuroscientific tools that allow cell-type-specific and circuit-level resolution. Single-cell transcriptomics applied to enriched versus standard-housed animals could identify which neuronal populations undergo which transcriptional changes, moving beyond regional averages that obscure cellular heterogeneity. Chemogenetic and optogenetic approaches could test causality by selectively disrupting candidate circuits during enrichment exposure. Longitudinal imaging in animal models could track how enrichment-induced changes unfold over time and whether they persist after enrichment is withdrawn. On the human side, wearable sensing and ecological momentary assessment could quantify real-world environmental complexity in ways that laboratory proxies cannot, enabling more precise characterization of the dose-response relationship between environmental richness and neural outcomes. Advances in non-invasive neurochemistry, including magnetic resonance spectroscopy and emerging PET tracers for specific receptor systems, may eventually allow direct testing of whether the neurotransmitter mechanisms identified in rodents operate similarly in enriched human environments.

The synthesis offered by this review ultimately positions environmental enrichment as more than a laboratory convenience or a welfare improvement for laboratory animals. It represents a naturally occurring, multi-component intervention that engages the brain’s own plasticity machinery across multiple neurotransmitter systems simultaneously, producing coordinated changes that pharmacological approaches targeting single receptors have struggled to achieve. The convergence of evidence across serotonergic, dopaminergic, glutamatergic, and GABAergic systems, unified by common mechanisms of neurotrophic signaling and transcriptional regulation, provides a coherent framework for understanding how environment shapes brain function. Translating this framework into clinical practice will require the methodological standardization, mechanistic dissection, and human validation that the review rightly identifies as priorities, but the foundational evidence now assembled makes this translation a realistic goal rather than a speculative aspiration.

Subject of Research: Environmental enrichment as a multisystem modulator of neurotransmitter function: mechanisms, plasticity, and therapeutic implications

Article Title: Environmental enrichment as a multisystem modulator of neurotransmitter function: mechanisms, plasticity, and therapeutic implications

Article References: Singhal, G., & Baune, B. T. (2026). Environmental enrichment as a multisystem modulator of neurotransmitter function: mechanisms, plasticity, and therapeutic implications. Frontiers in Molecular Neuroscience, 19, Article 1927924. https://doi.org/10.3389/fnmol.2026.1927924

Image Credits: AI Generated

DOI: 10.3389/fnmol.2026.1927924

Keywords: environmental enrichment, neurotransmitters, serotonin, dopamine, glutamate, GABA, neuroplasticity, neurogenesis, CREB signaling, mood disorders, neurodegeneration, preclinical research

IPANs function as the gut’s local sentinels. Morphologically, they correspond to what anatomists call Dogiel type II neurons, cells with smooth, multipolar bodies and long processes that wrap circumferentially around the intestinal wall. Electrophysiologically, they are characterized as AH-type neurons, distinguished by a prominent slow afterhyperpolarization, a prolonged electrical reset that limits repetitive firing and gives these cells their distinctive excitability profile. Unlike extrinsic sensory neurons housed in the dorsal root and nodose ganglia, which relay gut information to the central nervous system, IPANs detect mechanical deformation, chemical cues, nutrients, microbial metabolites, and immune-derived signals, then pass this information to interneurons, motor neurons, and secretomotor pathways entirely within the enteric network. This architecture allows the intestine to mount rapid, localized reflexes, peristalsis, secretion, and vasodilation, without waiting for central approval.

The review emphasizes that IPAN excitability is remarkably plastic. Inflammation, serotonergic signaling, cytokines, neurotrophins, and microbial products can all alter firing thresholds, modify the slow afterhyperpolarization, and reshape synaptic transmission. In experimental models, repetitive stimulation or exposure to inflammatory mediators produces lasting sensitization of these neurons, a form of neural memory that may persist long after the initial insult has resolved. The authors propose that such maladaptive plasticity could shift IPANs from adaptive sensory encoders into persistently hyperexcitable states, lowering reflex thresholds and amplifying enteric responses in ways that promote urgency, diarrhea, and visceral hypersensitivity. Conversely, suppressed sensory gain could impair the initiation of peristaltic and secretory reflexes, contributing to stasis, constipation, and defective mucosal clearance.

One of the most striking recent advances comes from molecular profiling. Single-cell and single-nucleus transcriptomic analyses have identified neuromedin U, or NMU, as a conserved marker of putative myenteric IPANs in both mice and humans, though its expression is strongly region dependent, marking roughly 50 to 75 percent of putative IPANs in the human small intestine but only 5 to 10 percent in the colon. In the mouse colon, researchers identified cadherins Cdh6 and Cdh8 as selective markers of Dogiel type II/AH sensory neurons, enabling cell-type-specific manipulation for the first time. Optogenetic activation of Cdh6-positive IPANs was shown to evoke retrograde colonic motor complexes, while pharmacological blockade of their hyperpolarization-activated current disrupted spontaneous generation of these motor patterns. This established that a molecularly defined IPAN population is both sufficient and necessary for a specific motor program under physiological conditions, a milestone in enteric neurobiology.

Perhaps the most conceptually transformative finding involves neuroimmunity. IPANs express a broad repertoire of cytokine, chemokine, and pattern-recognition receptors, including receptors for the type 2 cytokines IL-4 and IL-13, Toll-like receptors, and receptors for TNF, IL-1β, IL-6, and IL-17. Work by Wang and colleagues, using genetic and viral approaches combined with single-nucleus RNA sequencing, identified a population of IL-13 receptor-expressing IPANs as a functional node in gut neuroimmune signaling during helminth infection. In this circuit, group 2 innate lymphoid cells release IL-13, which activates IPANs through the IL-13 receptor, inducing the release of beta-calcitonin gene-related peptide. That neuropeptide then suppresses ILC2 activity, establishing a reciprocal feedback loop. When the researchers deleted the neuronal IL-13 receptor alpha 1 subunit, host defense against the parasite Heligmosomoides polygyrus was impaired, and combined administration of NMU and beta-CGRP restored parasite clearance, supporting a causal role for this neuronal pathway in protective immunity.

The microbiome adds another layer of complexity. Studies in germ-free rodents revealed that jejunal myenteric AH/Dogiel type II neurons exhibit impaired excitability, with elevated firing thresholds, reduced input resistance, and prolonged calcium-dependent slow afterhyperpolarization. Remarkably, conventionalizing adult germ-free animals with a normal microbiota normalized these electrophysiological properties. Subsequent work showed that pharmacological excitation of IPANs increased mesenteric nerve discharge by 21 percent in specific pathogen-free mice and 41 percent in conventionalized mice, but by only 2 percent in germ-free animals, suggesting that microbial input is required for normal signal transmission from IPANs to extrinsic afferent pathways. Pattern-recognition receptors such as TLR2 and TLR4 on enteric neurons and glia mediate some of these effects, and commensal-derived N-formyl peptides can directly activate IPANs through FPR1-dependent reactive oxygen species generation.

Serotonergic signaling provides some of the strongest pharmacological evidence for IPAN involvement in gut function, though the picture is far from simple. Enterochromaffin cell-derived serotonin activates 5-HT1P receptors on primary afferent neurons to initiate secretory reflexes, while 5-HT3 receptors on interneurons and secretomotor neurons participate in peristaltic signaling. Clinically, 5-HT4 receptor agonists such as prucalopride accelerate gastrointestinal transit, whereas 5-HT3 antagonists like alosetron delay transit and increase colonic compliance. Yet the review notes that mucosal removal can abolish cyclical serotonin release without preventing peristalsis, and Tph1 deletion does not necessarily impair transit, challenging a strictly mucosal serotonin-dependent reflex model and pointing instead to direct enteric mechanotransduction as a critical mechanism.

Despite this wealth of convergent evidence, the authors are candid about the field’s central limitation: no study has yet completed the canonical experimental sequence of selectively disrupting IPANs, inducing a gastrointestinal phenotype, and then reversing it through targeted rescue, particularly in human tissue. Pharmacological approaches often lack anatomical specificity because their targets are expressed by multiple cell types. Transcriptomic atlases predominantly define neuronal identity under healthy conditions rather than in disease. Germ-free models establish that microbial input is required for normal IPAN function but do not prove that dysbiosis directly corrupts afferent coding. Whether maladaptive IPAN sensory coding is a primary driver of disease, an amplifier of existing pathology, or merely a consequence of broader enteric dysfunction remains unresolved.

The therapeutic implications, however, are tantalizing. The antibiotic rifaximin, which modulates the gut microbiota, has been shown to reduce visceral hypersensitivity in both patients with diarrhea-predominant IBS and murine models, implicating microbial regulation of afferent signaling in human disease. If future studies can establish IPAN-specific causal links using conditional genetics, gnotobiotic reconstitution with defined microbial consortia, and validation in human enteric preparations, the review suggests that therapeutic recalibration of sensory gain and neuroimmune signaling could offer a rational strategy for restoring gut homeostasis in chronic inflammatory and functional gastrointestinal disorders. Such an approach would represent a fundamental shift from treating symptoms to correcting the underlying neural code that governs how the gut perceives and responds to its internal world.

For the millions of people worldwide living with IBS, IBD, chronic constipation, and unexplained visceral pain, the message from this synthesis is one of cautious optimism. The enteric nervous system is not merely a passive conduit for central commands but an autonomous integrative hub whose sensory neurons sit at the intersection of mechanical, chemical, microbial, and immunological signaling. Understanding how IPANs encode these signals in health, and how that encoding goes wrong in disease, may finally provide the mechanistic foundation needed to develop targeted therapies that restore, rather than merely suppress, the gut’s intrinsic intelligence.

Subject of Research: The role of maladaptive sensory coding by enteric nervous system neurons in gastrointestinal disorders

Article Title: Maladaptive sensory coding in the enteric nervous system playing a role in gastrointestinal disorders

Article References: Yu, L. C.-H., Huang, C.-Y., Lin, C.-Y., Tsai, Y.-S., Chang, Y.-C., Huang, C.-W., Chao, Z.-L., & Kuo, W.-T. (2026). Maladaptive sensory coding in the enteric nervous system playing a role in gastrointestinal disorders. Frontiers in Cellular Neuroscience, 20, Article 1903390. https://doi.org/10.3389/fncel.2026.1903390

Image Credits: AI Generated

DOI: 10.3389/fncel.2026.1903390

Keywords: enteric nervous system, intrinsic primary afferent neurons, irritable bowel syndrome, inflammatory bowel disease, visceral hypersensitivity, neuroimmune communication, gut microbiota, serotonin, IPANs, gastrointestinal motility, neural plasticity, Dogiel type II neurons

Researchers at the Affiliated Hospital of Jiangnan University in Wuxi enrolled 204 patients with chronic nonspecific low back pain in a single-arm, before-and-after exploratory study, publishing their results in Frontiers in Integrative Neuroscience. Each participant received twenty sessions of heat-sensitive moxibustion, or HSM, over four consecutive weeks, five sessions per week. Unlike conventional moxibustion, which applies burning moxa at fixed acupoints, HSM begins with a scanning procedure: a lit moxa stick is hovered about three centimeters above the lumbosacral skin while the practitioner searches for so-called heat-sensitized points, where patients report striking non-local sensations such as penetrating heat, spreading warmth, or warmth traveling to distant body regions. The single most strongly sensitized point, most often Shenshu (BL23), Dachangshu (BL25), Weizhong (BL40), or an Ashi point, was then treated for 30 to 45 minutes per session, continuing until the propagated heat sensation faded.

The clinical results were dramatic. Average pain on the 10-point Visual Analog Scale fell from 5.87 at baseline to 2.21 after treatment, a mean reduction of 3.66 points with a Cohen’s d effect size of 2.71, far exceeding the 1.5-to-2.0-point threshold conventionally considered clinically important in chronic pain research. The Oswestry Disability Index, which quantifies how much back pain limits daily life, dropped from 33.86 to 18.42, and standardized depression and anxiety scores also fell significantly. Using the benchmark of at least a 50 percent pain reduction recommended by the IMMPACT initiative, 117 of the 186 completers, or 62.9 percent, qualified as treatment responders, a rate that matches or exceeds the 40-to-60 percent response rates typically reported in acupuncture trials for the same condition. Attrition was modest at 8.8 percent, and safety was reassuring: the 28 adverse events recorded in 24 patients, mostly mild redness, small blisters, transient dizziness, or itching, were all self-limiting and resolved within one to three days without intervention.

What elevates this study beyond a simple efficacy report is its simultaneous tracking of nine serum biomarkers spanning four dimensions of the brain-gut-immune axis, the bidirectional communication network linking the central nervous system, the intestinal barrier, and the immune system through neural, endocrine, and immune signaling. After false-discovery-rate correction, eight of the nine markers changed significantly. In the neuroendocrine dimension, beta-endorphin, the body’s principal endogenous opioid and the main ligand at mu-opioid receptors, rose substantially, while cortisol, the hormonal output of the stress-responsive hypothalamic-pituitary-adrenal axis, fell. In the intestinal barrier dimension, both lipopolysaccharide, the gram-negative bacterial endotoxin used as a surrogate for gut leakiness, and D-lactate, a bacterial fermentation product reflecting mucosal damage, declined markedly.

The immune-inflammatory dimension told a coherent story as well. Pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha decreased, high-sensitivity C-reactive protein dropped from 4.72 to 2.53 milligrams per liter, and the anti-inflammatory cytokine interleukin-10 rose. The authors propose that this rebalancing may be driven partly by vagally mediated activation of the cholinergic anti-inflammatory pathway, in which thermal afferent input from heat-sensitized acupoints engages vagal reflexes that release acetylcholine onto alpha-7 nicotinic receptors on macrophages, suppressing NF-kappa-B-dependent cytokine production. Because IL-6 and TNF-alpha sensitize peripheral nociceptors and promote spinal glial activation that sustains central sensitization, damping them down could translate directly into less pain. Consistent with that idea, changes in IL-6 correlated significantly with changes in both pain intensity and disability scores.

The neuroendocrine findings tie into classical pain neuroscience. Beta-endorphin released from the hypothalamic arcuate nucleus drives descending pain inhibition through projections to the periaqueductal gray and rostral ventromedial medulla, and landmark experiments since the 1970s have shown that acupuncture analgesia can be partially reversed by the opioid antagonist naloxone, though the authors caution that direct naloxone evidence specific to moxibustion remains limited. In this cohort, the greater a patient’s rise in beta-endorphin, the greater their pain reduction, with a correlation of r = -0.45. Meanwhile, the parallel fall in cortisol may matter beyond stress physiology: chronic glucocorticoid exposure potentiates spinal nociceptive transmission, impairs hippocampal neurogenesis involved in pain memory, and, crucially, disrupts intestinal tight-junction proteins, increasing gut permeability. Cortisol normalization may therefore act as an upstream hinge connecting the neuroendocrine, intestinal, and immune arms of the axis.

That gut connection is where the study becomes particularly provocative. A proposed gut-disc axis holds that LPS leaking across a damaged intestinal barrier enters the circulation, binds Toll-like receptor 4 on innate immune cells, and triggers low-grade inflammation that may even accelerate intervertebral disc degeneration. Supporting evidence for gut-driven pain outside the viscera is accumulating rapidly: recent work showed that transplanting fecal microbiota from fibromyalgia patients into germ-free mice produces mechanical allodynia and thermal hyperalgesia, and Mendelian randomization analyses of tens of thousands of participants have linked specific gut microbial taxa and metabolites, including serotonin, to low back pain risk. In the present study, changes in LPS correlated positively with changes in IL-6, TNF-alpha, and pain scores, and exploratory mediation analysis suggested that shifts in beta-endorphin, IL-6, hs-CRP, LPS, and cortisol partially mediated the link between treatment dose and pain improvement, with beta-endorphin accounting for the largest mediated share at 44.9 percent.

Not every biomarker behaved as predicted. Serum serotonin, or 5-hydroxytryptamine, showed only a numerical increase that failed to reach significance after correction for multiple comparisons. The authors acknowledge that serum 5-HT largely reflects platelet serotonin stores rather than free gut-derived signaling, since platelets sequester roughly 95 percent of circulating serotonin, making it a noisy surrogate. Interestingly, serotonin changes correlated weakly with improvements in depression scores but not with pain intensity, hinting that serotonergic modulation, when it occurs, may engage the affective-motivational side of pain rather than its sensory-discriminative dimension. Individual variability was also striking: 79.6 percent of patients showed beta-endorphin increases, but only 58.1 percent showed serotonin increases, suggesting subgroup-dependent effects that larger studies may disentangle.

Perhaps the most clinically actionable finding came from the prediction modeling. A multivariable logistic regression retained three independent predictors of treatment response: the mean heat-sensitization intensity score across sessions, baseline pain severity, and baseline serum LPS. The model achieved an area under the curve of 0.828, with a bootstrap-corrected value of 0.806, and sensitivity and specificity both near 77 to 78 percent. Heat-sensitization intensity, graded on a four-point scale from no sensitization to strong distant heat transmission, was the strongest predictor, echoing prior EEG evidence that heat-sensitization responses have distinct cortical signatures and parallels with temporal summation measures used to predict acupuncture response. The LPS finding is especially novel: patients with more baseline barrier disruption had more room for the gut-restoration pathway to work, and if replicated, baseline LPS could serve as a stratification biomarker for enrichment designs in future trials and for personalized treatment selection in the clinic.

The authors are careful, appropriately, about what this study cannot show. Because there was no control group, no sham moxibustion, and no blinding, the findings establish association and biological plausibility rather than causal efficacy, and expectation effects on subjective outcomes cannot be excluded, although non-responders still showed significant changes in several objective biomarkers. There was no follow-up assessment to gauge durability, no fecal microbiome sequencing to characterize microbial mediation, and serum LPS and D-lactate remain indirect measures of intestinal permeability validated mainly in surgical and gastroenterological cohorts. Still, the image that emerges is compelling: a four-week course of targeted heat therapy was accompanied by a coordinated, four-dimensional recalibration of the brain-gut-immune axis, spanning endogenous opioid activation, intestinal barrier restoration, serotonergic regulation, and immune rebalancing, in patients whose pain had resisted explanation and often resisted treatment. Whether that coordination reflects a true causal chain or an accompanying epiphenomenon will be the question for the randomized, sham-controlled trial the authors say must come next. If the answer holds, one of humanity’s oldest therapies may find its mechanism written in the language of modern systems biology, and the humble gut may take its place alongside the spine in the story of chronic back pain.

Subject of Research: Heat-sensitive moxibustion for chronic nonspecific low back pain and its putative analgesic mechanism via the brain-gut-immune axis

Article Title: Clinical efficacy and putative analgesic mechanism of heat-sensitive moxibustion for chronic nonspecific low back pain: a single-arm before-after study based on the brain-gut-immune axis

Article References: Xie, Y., & Li, C. (2026). Clinical efficacy and putative analgesic mechanism of heat-sensitive moxibustion for chronic nonspecific low back pain: a single-arm before-after study based on the brain-gut-immune axis. Frontiers in Integrative Neuroscience, 20, Article 1894020. https://doi.org/10.3389/fnint.2026.1894020

Image Credits: AI Generated

DOI: 10.3389/fnint.2026.1894020

Keywords: chronic low back pain, heat-sensitive moxibustion, brain-gut-immune axis, beta-endorphin, cortisol, lipopolysaccharide, intestinal permeability, interleukin-6, serotonin, inflammation, acupoint heat sensitization, pain biomarkers

The article, written by Erika Bistran, M. Evelyn Carpenter and Daniel J. Sprague of the Medical University of South Carolina, focuses on bioaminergic signaling, the system of neurotransmitters that includes serotonin, dopamine, histamine, tyramine and octopamine. These molecules have been implicated in flatworm neuromuscular control for decades, but the authors contend that the field has been stuck cataloging which amines are present and which compounds make worms twitch. What is needed, they say, is mechanistic depth: knowing exactly which receptor detects the signal, which second messenger carries it inside the cell, which tissue hosts the signaling, and which parasite behavior changes when the pathway is disrupted.

To organize that effort, the researchers propose a pathway-to-phenotype framework built on six interconnected areas of investigation. These are the bioamine ligand itself, the receptor or transporter that detects or clears it, the downstream signaling pathway it engages, the cell type or tissue where signaling occurs, the experimental perturbation used to test function, and the resulting parasite phenotype. No single experiment needs to cover all six domains, the authors stress, but each experimentally supported connection between them raises the resolution of the pathway model, moving the field from association toward mechanism.

The clearest proof that this approach works is the serotonin receptor Sm5HTR in Schistosoma mansoni, the blood fluke responsible for schistosomiasis, a disease that afflicts hundreds of millions of people. Serotonin has long been known to excite schistosome movement and potentiate body wall muscle contraction. The characterization of Sm5HTR turned that observation into a complete molecular story. The receptor is a serotonin-responsive G protein-coupled receptor distantly related to human 5-HT7 receptors. When expressed in heterologous systems, it responds to serotonin by raising intracellular cAMP, consistent with a Gαs-coupled mechanism. Immunolocalization places it throughout the parasite nervous system, including the cerebral ganglia, the longitudinal nerve cords and the peripheral innervation of body wall muscle. Crucially, knocking the receptor down with RNA interference in larvae and adults causes marked hypoactivity and blunted responses to exogenous serotonin.

Sm5HTR has also proven pharmaceutically fruitful. Screening campaigns have identified novel agonists and antagonists, including parasite-selective inhibitor classes, and efforts have been made to distinguish schistosome-specific from human-specific ligands. For the authors, this makes Sm5HTR the benchmark against which every other aminergic system in flatworms should be judged: ligand, receptor, second messenger, anatomy, perturbation and phenotype all connected in one system.

Other aminergic pathways in schistosomes are promising but incomplete. Two dopamine-responsive GPCRs, SmD2 and SmGPR-3, are associated with the parasite neuromusculature, yet the full chain from receptor activation to parasite phenotype has not been closed. The dopamine system also delivers a cautionary lesson about assuming that parasite receptors behave like their mammalian counterparts. SmGPR-3 shows a mixed pharmacological profile in which a mammalian dopamine receptor antagonist acts as an agonist. SmD2, meanwhile, resembles human D2 receptors by sequence, but while the mammalian D2 family couples to inhibitory Gαi/o proteins, SmD2 appears to couple to Gαs instead. Such divergences are exactly what the authors argue could create parasite-selective drug targets.

Histamine adds a further twist: not all flatworm aminergic receptors converge on cAMP. A histamine-responsive receptor called SmGPR-1, expressed mainly in body wall muscles, is linked to intracellular calcium mobilization rather than cAMP accumulation, suggesting a Gαq-like pathway. This matters practically, because receptor screens built solely on cAMP readouts will miss or misclassify calcium-linked receptors. A second histamine receptor, SmGPR-2, is upregulated in schistosomula and expressed in the subtegumental nerve plexus, and it carries a striking molecular anomaly. The conserved aspartate residue at position 3.32 in transmembrane helix 3, a linchpin of ligand activation in most Class A GPCRs, is replaced by an asparagine, and many mammalian histamine antagonists are ineffective against it. Histamine is also conceptually intriguing because parasites may encounter it both as their own signal and as a host-derived inflammatory cue, raising the possibility that some aminergic pathways serve in host sensing rather than classical neurotransmission.

Octopamine and tyramine may offer the largest selectivity window of all, because these tyrosine-derived amines are prominent in invertebrate neuromodulation but peripheral to mammalian neurobiology. Anatomical, phenotypic and pharmacological evidence supports octopamine signaling in S. mansoni, and octopamine-related compounds alter schistosomulum motility and length. But no octopamine or tyramine receptor has yet been functionally profiled, leaving the field unable to say whether these signals travel through cAMP, calcium, inhibitory G proteins or biased pathways. Until the receptors are deorphanized and compared with host targets, the authors note, parasite selectivity remains a hypothesis rather than a fact.

The perspective also warns against a schistosome-centric view. Serotonin-responsive GPCRs have been cloned and characterized from tapeworms such as Echinococcus and Mesocestoides, including a set of 5-HT7-like receptors that stimulate cAMP production and a novel class of 5-HT1-like receptors deorphanized through a promiscuous Gα15 effector and calcium-flux assays. Serotonin boosts larval motility in cestodes, and receptor localization near the suckers of Echinococcus granulosus larvae hints that the same signaling may influence attachment as well as movement. In liver flukes, recent work in Fasciola hepatica has localized serotonin receptors and transporters and used RNAi to probe their function, while dopaminergic antagonists disrupt bile chemotaxis and egg production in the carcinogenic fluke Clonorchis sinensis, even though no aminergic receptor from that parasite has been cloned. Comparing these lineages, the authors argue, will reveal which signaling features are broadly conserved targets and which are lineage-specific opportunities.

Transporters form the underdeveloped half of the story. By clearing serotonin, dopamine and other amines from the extracellular space, transporters control signal duration and receptor desensitization, and inhibiting them could disrupt multiple receptor pathways at once. Candidate and characterized transporters exist in schistosomes, F. hepatica and C. sinensis, but their substrate specificity, inhibitor sensitivity, expression patterns and whole-parasite consequences remain poorly mapped. Any transporter-directed strategy will demand careful selectivity profiling, since host monoamine transporters are the pharmacologically sensitive targets of drugs such as antidepressants. Looking forward, the authors highlight three unresolved questions: what intracellular signaling machinery parasite receptors actually use outside heterologous systems, whether the worms are sensing their own neurotransmitters or host-derived chemical cues, and how aminergic pathways crosstalk with neuropeptidergic and cholinergic networks. The most promising future drug targets, they conclude, will combine functional importance, parasite-selective pharmacology and measurable whole-parasite consequences, and the Sm5HTR story provides the template for finding them.

Subject of Research: Bioaminergic GPCR signaling pathways and drug discovery in parasitic flatworms

Article Title: Bioaminergic signaling in parasitic flatworms: a perspective for linking GPCRs to behavior and drug discovery

Article References: Bistran, E., Carpenter, M. E., & Sprague, D. J. (2026). Bioaminergic signaling in parasitic flatworms: a perspective for linking GPCRs to behavior and drug discovery. Frontiers in Parasitology, 5, Article 1933406. https://doi.org/10.3389/fpara.2026.1933406

Image Credits: AI Generated

DOI: 10.3389/fpara.2026.1933406

Keywords: parasitic flatworms, schistosomiasis, G protein-coupled receptors, serotonin, dopamine, histamine, octopamine, neurotransmitter transporters, anthelmintics, drug discovery, Schistosoma mansoni, trematodes

The research team, led by Samir Haj-Dahmane, with Renee Rouleau as first author, combined whole-cell patch-clamp recordings, light-based uncaging of serotonin, and precise receptor pharmacology in brain slices from adult rats. This technical arsenal allowed them to measure the electrical behavior of individual claustrum neurons with millivolt precision while systematically blocking or activating specific serotonin receptor subtypes. What they found was a level of cellular specialization that few would have predicted for a structure this small.

The first surprise came from the neurons themselves. Rather than behaving as a uniform population, claustrum neurons split into four electrophysiologically distinct groups. Regular-spiking type I neurons, which made up nearly half of the sampled cells, fire steadily with little fatigue and show a characteristic sag in their membrane voltage when hyperpolarized. Regular-spiking type II neurons fire at similar rates but display a fast afterdepolarization that can trigger bursts of doublets. Strongly adapting neurons, as their name suggests, rapidly dampen their own firing under sustained stimulation. A rare fourth group fires fast and hard, reaching frequencies around 60 hertz. When the researchers filled recorded cells with biocytin and reconstructed their shapes, the regular-spiking type I neurons turned out to have pyramid-like cell bodies with an apical dendrite, while the type II and strongly adapting neurons were triangular with multiple radiating dendrites, all bearing spines.

When serotonin was applied to these cells, the responses diverged along cell-type lines in a striking way. In regular-spiking type I and type II neurons, serotonin could push the membrane potential in either direction, producing depolarization in most recorded cells but hyperpolarization in a subset. In strongly adapting neurons, however, the response was unambiguous: every single one was hyperpolarized by serotonin. Using caged serotonin released by a flash of blue light, the team confirmed that these bidirectional effects could be evoked by brief, physiologically plausible surges of the transmitter, with depolarizations averaging about 4 millivolts and hyperpolarizations close behind at roughly 3.9 millivolts.

The molecular logic behind this push-pull system came into focus through receptor pharmacology. The depolarizing responses vanished when the researchers blocked 5-HT2A receptors with the antagonist MDL 100907, while the hyperpolarizing responses were abolished by WAY 100635, a 5-HT1A receptor antagonist. In other words, the same neurotransmitter carries two opposing messages to the same cells, and the net effect on any given claustrum neuron depends on the balance of receptor subtypes it happens to express. This arrangement mirrors what has been described in the prefrontal cortex, where 5-HT1A and 5-HT2A receptors likewise mediate opposing effects on membrane excitability, but the study is among the first to work out the details in the claustrum.

Serotonin’s influence did not stop at the neuronal membrane. The team next examined the glutamatergic synapses that deliver excitatory input to claustrum neurons, and here they found a second, independent layer of control. Bath application of serotonin cut the amplitude of evoked excitatory postsynaptic currents to roughly half of baseline. Three classic pieces of evidence pointed to a presynaptic site of action: the paired-pulse ratio increased, the coefficient of variation rose, and the frequency of miniature excitatory postsynaptic currents, which reflect single vesicles of glutamate released independently of action potentials, dropped significantly while their amplitudes stayed constant. Together, these results indicate that serotonin reduces the probability of glutamate release from the nerve terminals that feed the claustrum.

Given the claustrum’s famously high expression of 5-HT2A receptors, which are the principal molecular target of serotonergic psychedelics such as LSD and psilocybin, the team suspected these receptors were responsible for the synaptic inhibition. The evidence was decisive. Blocking 5-HT2A receptors with MDL 100907 eliminated the serotonin-induced suppression of synaptic currents, and blocking 5-HT2 receptors more broadly with mesulergine not only abolished the inhibition but unmasked a potentiation, suggesting that other serotonin receptor subtypes exert a weaker, opposing influence. Conversely, TCB-2, a potent and selective 5-HT2A agonist with psychedelic-like properties, reproduced the inhibition on its own, reducing evoked synaptic currents and miniature EPSC frequency in a manner fully reversed by the antagonist.

Perhaps the most intriguing finding concerns where these receptors sit and how they signal. Immunohistochemistry confirmed dense 5-HT2A receptor labeling around claustrum neuron cell bodies and along their processes. Yet when the researchers dialyzed recorded neurons with GDP-beta-S, a reagent that jams G-protein signaling inside the recorded cell, the synaptic inhibition persisted undiminished even though the postsynaptic receptor response was abolished. The canonical downstream pathway of 5-HT2A receptors runs through Gq/11 proteins and phospholipase C, but blocking PLC with U73122 failed to touch the inhibition, and blocking CB1 cannabinoid receptors with AM251, which would have disrupted a retrograde endocannabinoid mechanism, was equally ineffective. The conclusion is that presynaptic 5-HT2A receptors on the glutamate terminals themselves suppress release through a signaling route that departs from the textbook PLC cascade, and the authors acknowledge that identifying that route is a task for future work.

Why does this matter beyond the slice chamber? The claustrum has been implicated in attention, decision-making, multimodal sensory integration, and the coordination of cortical slow-wave activity during sleep. Recent in vivo studies have shown that claustrum neurons projecting to cortex fire most vigorously during the synchronized brain state of non-REM sleep and quiet down during waking and REM sleep, a pattern that mirrors, in inverse fashion, the firing of the dorsal raphe serotonin neurons that innervate the claustrum so densely. The new findings suggest a plausible cellular mechanism: when serotonin tone is low, as it is during deep sleep, the brakes come off both the intrinsic excitability of claustrum output neurons and the strength of their excitatory inputs, potentially allowing the claustrum to drive the synchronized slow waves that sweep the sleeping cortex. When serotonin neurons fire briskly during wakefulness, the same receptors would dampen claustrum activity and gate its excitatory drive.

The psychedelic connection adds another layer of fascination. Psilocybin has been shown to acutely alter the functional connectivity between the claustrum and the brain networks supporting perception, memory, and attention, and psychedelic effects on consciousness are thought to involve the claustrum at least in part. By demonstrating that 5-HT2A receptors simultaneously depolarize major claustrum output neurons and suppress their glutamatergic inputs through a noncanonical presynaptic mechanism, the Buffalo team has provided a cellular blueprint for how a single psychedelic-sensitive receptor could reshape information flow through one of the brain’s great integration centers. As the authors note, the multifaceted and sometimes contradictory effects of 5-HT2A receptors across brain regions likely reflect differences in their subcellular distribution and downstream signaling partners. In the claustrum, at least, serotonin turns out to be less a simple dial than a conductor, coaxing different sections of the neural ensemble into different responses at the same moment.

Subject of Research: Serotonergic modulation of neuronal excitability and glutamatergic synaptic transmission in the rat claustrum

Article Title: Serotonergic regulation of neuronal excitability and glutamatergic synaptic transmission in rat claustrum

Article References: Rouleau, R., Oubraim, S., Cirone, L., Shen, R.-Y., & Haj-Dahmane, S. (2026). Serotonergic regulation of neuronal excitability and glutamatergic synaptic transmission in rat claustrum. Frontiers in Cellular Neuroscience, 20, Article 1951375. https://doi.org/10.3389/fncel.2026.1951375

Image Credits: AI Generated

DOI: 10.3389/fncel.2026.1951375

Keywords: claustrum, serotonin, 5-HT2A receptor, 5-HT1A receptor, patch-clamp, glutamate release, dorsal raphe nucleus, psychedelics, sleep, consciousness, electrophysiology, presynaptic inhibition

The experiment centered on what researchers call a subjective minute production task. Participants were asked to indicate when they believed sixty seconds had elapsed, first with their eyes open and then with their eyes closed. Crucially, they were instructed not to count, because counting converts the task from a felt sense of duration into a deliberate cognitive calculation. The production paradigm is one of the cleanest windows into interval timing: if a person signals that a minute has passed only after ninety real seconds, their subjective minute is stretched, meaning their internal accumulator is filling more slowly than the external clock. If they signal at forty-five seconds, their inner clock is running fast. Three groups took part: patients with remitted depressive disorder, patients with obsessive-compulsive disorder, and neurotypical controls.

The headline finding was a statistically significant main effect of diagnostic group on the length of the produced minute. Descriptively, the pattern was striking in its ordering: the OCD group produced the longest subjective minutes, the neurotypical group the shortest, and the depression group fell numerically in between. The statistical effect was driven specifically by a pronounced overproduction in the OCD group relative to the controls. In other words, people with OCD needed more real time to experience a minute as complete, a sign that their internal timing mechanism accumulates temporal information at a slower rate. Notably, this distortion held steady across both sensory conditions, whether participants sat with eyes open taking in the room or eyes closed in darkness, indicating that the effect is not an artifact of visual attention or environmental distraction but reflects something more fundamental in the timing system itself.

Perhaps the most intriguing result was what did not reach significance. The depressed group did not differ significantly from controls, nor from the OCD group. This is a nuanced outcome, because depression has long been associated with altered time experience. A well-known 2015 meta-analysis by Thönes and Oberfeld found that depression distorts time perception in specific ways, and earlier work by the same Russian team, published in 2023 in the Journal of Psychiatric Research, reported a lower loss rate in a serotonergically modulated neuronal accumulator for time in patients with major depressive disorder. The authors of the new study are careful to caution that these null findings should be interpreted with restraint, because the study had limited statistical power to detect small effects. A real but subtle difference between the depression and control groups could easily have escaped detection at this sample size, a reminder that absence of evidence in psychophysics is rarely evidence of absence.

Why would OCD stretch the subjective minute? The leading hypothesis points to the neurochemistry and circuitry of the disorder. OCD is characterized by dysfunction in cortico-striatal loops, the recurrent pathways linking the prefrontal cortex with the basal ganglia that are implicated in habit formation, error monitoring, and the sense of when to stop a behavior. Interval timing in the seconds-to-minutes range is itself thought to depend on striatal circuits, in which dopamine signals act as a gating mechanism that lets pulses from a pacemaker-like process accumulate. Serotonin also modulates timing, as a 2024 systematic review of the serotonergic system’s role in time perception documented. Given that both dopamine and serotonin systems are implicated in OCD, and that glutamate, described in one review as a forgotten target for interval timing, is increasingly central to OCD research, a slowed internal accumulator in OCD fits a coherent neurophysiological picture rather than standing as an isolated curiosity.

The study also probed what predicts individual differences within each diagnostic group, and here the results diverged sharply by condition. In the depression group, maladaptive stress coping predicted time overestimation, meaning that patients who coped poorly with stress tended to stretch their subjective minutes further. Pharmacotherapy showed no effect, so the distortions were not simply a byproduct of medication. Autonomic dysfunction and a history of psychological trauma likewise showed no measurable influence. This dissociation is theoretically important: it suggests that in depression, the experience of time is modulated less by the core illness biology or its treatment and more by psychological resources for handling stress, whereas in OCD, the timing distortion appears tied to the disorder’s neurophysiology itself. Emotion is known to color time perception, as Droit-Volet and Meck argued in their influential 2007 review, and stress coping may represent one channel through which emotional regulation shapes the felt flow of duration.

The eyes-open and eyes-closed manipulation deserves attention in its own right. Recent EEG source analysis work by Proshina, Mitiureva, and Sysoeva, published in 2024 in Frontiers in Neuroscience, showed that distinct brain systems are engaged when people estimate a subjective minute with eyes open versus closed, with visual input recruiting different cortical networks than introspective darkness. The fact that the OCD-related overproduction appeared in both conditions strengthens the case that the effect reflects a core timing deficit rather than condition-specific attentional strategies. It also demonstrates the robustness of the subjective minute as a behavioral measure: whatever the sensory context, the internal accumulator in OCD runs slow, and the consistency across conditions makes the finding harder to dismiss as a testing artifact.

The theoretical framing of the study draws on models of internal time representation such as the dual klepsydra model proposed by Wackermann and Ehm, which treats timing as the flow and accumulation of a biophysical resource rather than the ticking of a literal pacemaker. In such frameworks, psychiatric conditions that alter arousal, neurochemistry, or the gain of cortical networks would be expected to alter the rate of accumulation, and therefore the mapping between subjective and physical duration. Matthews and Meck’s broader account of temporal cognition connects subjective time to perception, attention, and memory, and the present findings add clinical psychiatry to that list of connective tissue. A behavioral signature like minute overproduction is valuable precisely because it is cheap to measure, requires no imaging equipment, and could in principle complement existing diagnostic assessments.

The clinical implications are tentative but real. OCD is a condition in which patients constantly struggle with the feeling that something is not yet finished, that a check must be repeated, that a ritual must run its course. A slowed internal accumulator offers a speculative but testable bridge between that phenomenology and its neural substrate: if the brain’s sense of completion in time arrives late, behaviors oriented toward closure might be correspondingly prolonged. The authors position subjective minute overproduction as a candidate behavioral signature of OCD-related neurophysiological dysfunction, a phrase that signals their intent for the measure to be validated in future work rather than treated as a finished diagnostic tool. For depression, the finding that stress coping, not medication or trauma, modulates temporal experience suggests that therapeutic work on coping strategies might have downstream effects on how depressed patients experience the passage of their days.

What makes this study resonate beyond the clinic is the reminder it offers about the constructed nature of time. Every reader who has watched a minute crawl during anxiety or vanish during absorption is already familiar with the plasticity of subjective duration. What this research adds is specificity: the plasticity is not random, it differs systematically across psychiatric conditions, it survives changes in sensory context, and it correlates with measurable psychological traits like coping style. With 179 participants, two sensory conditions, and three carefully defined groups, the study provides one of the more direct comparisons to date of interval timing across depression and OCD. The caveats about statistical power for the depression findings are honest and appropriate, and they define the next experiment almost by themselves: larger samples, and ideally longitudinal designs that track whether the subjective minute normalizes as symptoms remit. Until then, the study stands as evidence that the inner clock is not merely a metaphor, but a measurable physiological system that mental illness can visibly bend.

Subject of Research: Subjective time perception and minute production in depressive disorder and obsessive-compulsive disorder

Article Title: Subjective time perception in depressive disorder and obsessive-compulsive disorder

Article References: Safronov, P., Portnova, G., Khayrullina, G., Sysoeva, O., & Martynova, O. (2026). Subjective time perception in depressive disorder and obsessive-compulsive disorder. Current Psychology, 45(17), Article 1472. https://doi.org/10.1007/s12144-026-10039-2

Image Credits: AI Generated

DOI: 10.1007/s12144-026-10039-2

Keywords: time perception, subjective minute, obsessive-compulsive disorder, depressive disorder, interval timing, cortico-striatal circuits, serotonin, dopamine, stress coping, psychiatry, neurophysiology, Current Psychology

The research, led by Yufei Chen, Haoran Li, and Fenghua Long of West China Hospital of Sichuan University, together with Robert K. McNamara of the University of Cincinnati and senior author Fei Li, set out to resolve a stubborn inconsistency in the OCD literature. For years, structural MRI studies comparing cortical thickness, the width of the brain’s outer gray matter ribbon, between OCD patients and healthy controls have produced a patchwork of findings: some reported thinning in frontal regions, others in cingulate areas, and still others found no differences at all. Because cortical thickness is a sensitive marker of the health of neurons, synapses, and supporting glial cells within each cortical column, such inconsistency has made it difficult to build a coherent biological story about what the disorder does to the cortex.

To cut through the noise, the team performed a coordinate-based meta-analysis pooling cortical thickness comparisons across many independent studies of OCD patients and matched healthy controls. The approach treats each published brain map as a data point, allowing researchers to detect regions where structural differences reliably replicate across cohorts rather than appearing in only one or two samples. The results pointed to three regions where people with OCD consistently showed thinner cortex: the left posterior cingulate cortex, the left anterior cingulate cortex, and the right pars opercularis, a portion of the inferior frontal gyrus on the right side of the brain that plays a central role in response inhibition, the ability to stop an action already in progress.

The anatomical pattern is telling. The anterior and posterior cingulate cortices are core nodes of the default mode network, the set of regions most active when the mind wanders inward, ruminates, and generates self-referential thought, while the pars opercularis belongs to the cingulo-opercular network, which supports cognitive control and the suppression of inappropriate responses. Both networks have been repeatedly implicated in the characteristic symptoms of OCD, from persistent unwanted thoughts to compulsive behaviors that resist inhibition. The finding that cortical thinning concentrates precisely at the junction of these networks suggests that the structural substrate of the disorder may lie in the brain’s machinery for regulating internally directed thought and behavioral control.

Crucially, the researchers did not stop at the group-level map. They ran subgroup analyses and meta-regressions to ask whether clinical and methodological variables, factors that often differ between studies, were quietly shaping the results. Two stood out. In samples of medicated patients, and in samples with comorbid psychiatric conditions, additional cortical thinning emerged in the left inferior parietal lobule and the right posterior cingulate cortex. This is an important caveat for the field: medication status and comorbidity are not merely statistical nuisances but appear to leave their own signatures on cortical structure, meaning that studies enrolling different kinds of patient populations may legitimately reach different conclusions about where and how severely the cortex is affected in OCD.

The authors also flagged a note of scientific caution that adds credibility to the work. One of the three main findings, the thinning in the left anterior cingulate cortex, showed significant evidence of publication bias, the tendency of journals to publish positive results more readily than null ones. By transparently reporting this, the team signals that the left ACC finding should be interpreted with more caution than the others, while the posterior cingulate and pars opercularis results survived the standard robustness checks. In a literature notorious for small samples and inconsistent replication, this kind of self-scrutiny is exactly what meta-analytic science is supposed to provide.

The most ambitious part of the study, however, went beyond anatomy into molecular territory. Using spatial correlation methods, the researchers asked whether the brain regions showing cortical thinning in OCD are also the regions where particular genes are most highly expressed, drawing on transcriptomic atlases that map gene activity across the human cortex. The logic is straightforward: if a structural abnormality clusters in areas enriched for a specific set of genes, those genes become candidate molecular players in the disorder. The analysis revealed that the cortical thickness alterations in OCD were spatially associated with genes enriched in synaptic signaling and synaptic organization, the processes by which neurons form, maintain, and tune their connections with one another.

Zooming in further at the cellular level, the implicated genes were found to be highly expressed in excitatory neurons, inhibitory neurons, and glial cells, the three major cell classes that together build and support cortical circuits. This cellular profile points toward a disruption of excitatory-inhibitory balance, the delicate equilibrium between neurons that speed signals up and neurons that damp them down, as well as toward changes in signaling transmission efficiency, how effectively information moves through cortical microcircuits. Excitatory-inhibitory imbalance has emerged in recent years as a leading hypothesis for several psychiatric conditions, and this study provides structural and transcriptomic evidence that the same principle may apply to OCD, linking the macroscopic thinning seen on MRI to the microscopic choreography of synapses and cell types.

The molecular story extended to neurochemistry as well. When the team overlaid the cortical thinning map with atlases of neurotransmitter receptor and transporter density, they found associations with multiple neurotransmitter systems, principally glutamate, serotonin, dopamine, and gamma-aminobutyric acid, or GABA. The prominence of glutamate is particularly striking, because glutamate is the brain’s primary excitatory transmitter and has been repeatedly implicated in OCD by genetic, pharmacological, and imaging studies, including reports that glutamate-modulating agents can help some patients. The convergence of structural, transcriptomic, and receptor-level evidence on glutamatergic and synaptic pathways suggests that these systems may represent the most promising molecular targets for understanding, and eventually treating, the cortical abnormalities associated with the disorder.

The authors are careful to frame their molecular findings as hypothesis-generating rather than definitive. Spatial correlations between imaging maps and gene expression do not prove causation, and the cortical thickness differences observed in OCD could be causes, consequences, or compensatory responses related to the illness. Still, the study delivers something the field has lacked: a unified framework in which the inconsistent structural imaging literature is distilled into a small set of reliably affected regions, those regions are shown to be modulated by clinically meaningful factors like medication and comorbidity, and the whole pattern is anchored to a plausible molecular substrate centered on synaptic function and excitatory-inhibitory signaling. For a disorder that affects millions of people worldwide and often resists standard treatments, that framework offers a roadmap for the next generation of research, from cell-type-specific investigations of cingulate and frontal cortex to clinical trials aimed at the glutamate system. The work was supported by the Sichuan Science and Technology Program and conducted entirely on previously published, publicly available data, an approach that demonstrates how secondary analyses, done rigorously, can extract new biological insight from decades of accumulated brain imaging.

Subject of Research: Cortical thickness alterations and their molecular correlates in obsessive-compulsive disorder

Article Title: Reduced cortical thickness in obsessive-compulsive disorder and candidate molecular correlates

Article References: Chen, Y., Li, H., Long, F., Zhao, Y., McNamara, R. K., & Li, F. (2026). Reduced cortical thickness in obsessive-compulsive disorder and candidate molecular correlates. Translational Psychiatry. https://doi.org/10.1038/s41398-026-04510-8

Image Credits: AI Generated

DOI: 10.1038/s41398-026-04510-8

Keywords: obsessive-compulsive disorder, cortical thickness, meta-analysis, posterior cingulate cortex, anterior cingulate cortex, pars opercularis, synaptic signaling, excitatory-inhibitory balance, glutamate, serotonin, dopamine, GABA