Abstract
Emotion-related states encompass a wide range of affective and behavioral dimensions, including anxiety, fear, pleasure, and aversion, whereas motivation refers to internal drives that energize goal-directed behaviors such as feeding, reward seeking, or avoidance. These states are thought to arise from the brain’s integration of exteroceptive inputs, interoceptive signals reflecting bodily states, and prior experiences. Recent studies have increasingly highlighted the critical role of gut-to-brain communication, particularly vagal and other interoceptive pathways, in shaping emotion-related and motivational behaviors. In parallel, advances in genetic manipulation techniques have enabled the identification of neuronal circuits innervating the gastrointestinal tract and have provided new insights into their links with affective-like behavior. A better understanding of these mechanisms will be essential for elucidating how gastrointestinal-derived signals contribute to emotion-related states and how they are represented and processed in the brain. In this review, we discuss recent advances in gut-to-brain neural pathways, with a particular focus on vagal afferent and interoceptive mechanisms, while also considering spinal afferent pathways and ENS-related mechanisms that may contribute to emotion-related behavioral regulation.
1 Introduction
Afferent signals from the gastrointestinal system to the brain are increasingly recognized as important contributors to emotion-related and motivational states. Consistent with this view, patients with gastrointestinal disorders such as inflammatory bowel disease show a markedly increased prevalence of depression and anxiety disorders, suggesting that afferent signals associated with mechanical and chemical stimuli, as well as immune responses, may influence affective symptoms (Barberio et al., 2021; Bisgaard et al., 2022). Moreover, accumulating evidence has linked alterations in the gut microbiota to emotion-related symptoms and psychiatric disorders (McGuinness et al., 2022; Wang T. T. et al., 2026), and the therapeutic efficacy of vagus nerve stimulation (VNS) has been demonstrated in both clinical and preclinical settings. Gastrointestinal signals reach the brain through multiple routes, including vagal and spinal afferent pathways, as well as indirect signaling involving the enteric nervous system (ENS), immune mediators, and humoral factors (Wang et al., 2025). Nevertheless, direct causal evidence linking these pathways to emotion-related behavioral regulation remains limited.
In this review, we summarize rodent studies conducted under both physiological and pathological conditions, with a primary focus on vagal afferent and interoceptive mechanisms linking gastrointestinal signals to emotion-related behaviors. We also discuss spinal afferent pathways and ENS-related mechanisms where direct evidence is available, while acknowledging that these non-vagal routes remain less extensively characterized in the context of affective-like behavior. Because rodent behavioral assays do not directly measure subjective emotional experience, we use the terms “emotion-related behavior,” “affective-like behavior,” and “motivational behavior” according to the behavioral domain being examined. We highlight studies that have directly examined the relationship between internal organ-derived signals, especially those originating from the gastrointestinal tract, and behavioral regulation using denervation approaches such as vagotomy, electrical stimulation, pharmacological interventions, and genetic manipulations.
1.1 Vagal pathway
Visceral afferent signals carried by the vagus nerve are transmitted to the brainstem via sensory neurons in the nodose ganglion (NG). Classical experimental approaches, including vagotomy and subdiaphragmatic vagotomy (SDV), have been used to investigate vagal function. However, these manipulations affect not only afferent fibers but also, to some extent, efferent fibers. Studies employing VNS have additional limitations. First, conventional VNS does not selectively target gut-derived signals from specific organs. Second, it can activate both afferent and efferent fibers, making it difficult to attribute behavioral effects to a defined ascending interoceptive pathway. In contrast, targeted delivery of cholecystokinin-saporin (CCK-SAP) to the NG enables selective ablation of gastrointestinal vagal afferent pathways by inhibiting protein synthesis and inducing cell death in CCK-responsive neurons (Diepenbroek et al., 2017). More recently, advances in genetic techniques, including the use of transgenic mouse lines combined with adeno-associated virus (AAV)-mediated approaches, and single-cell RNA sequencing of vagal ganglia, have enabled precise manipulation of neural activity and the identification of distinct neuronal subtypes (Kupari et al., 2019; Bai et al., 2019; Ichiki et al., 2022). Collectively, these approaches permit selective targeting of organ-specific NG neurons and offer new opportunities to elucidate how gastrointestinal signals influence emotion-related and motivational behaviors. Studies examining anxiety-like and depression-like behaviors, fear extinction, reward, and motivation are summarized in Table 1.
Table 1
| Anxiety-like behaviors | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| A. Normal conditions | B. Pathological conditions | |||||||||
| Methods | Gain/Loss | Phenotype | Behavioral tests | Ref. | Models | Methods | Gain/Loss | Phenotype | Behavioral tests | Ref. |
| VNS | Gain (+) | Anxiety-like behavior ↓ | EPM | Noble et al. (2019) | Social defeat stress | VNS | Gain (+) | Anxiety-like behavior ↓ | EPM | Okonogi et al. (2024) |
| Gq-DREADDs (gastro-duodenal NG) | Gain (+) | Anxiety-like behavior ↑ | OFT, EPM, and food neophobia test | Krieger et al. (2022) | PTSD model | VNS | Gain (+) | Anxiety-like behavior ↓ | OFT, EPM, and NSF | Souza et al. (2020) |
| Gq-DREADDs (Oxtr+ NG) | Gain (+) | Vigilance-related behavior ↑ | Indirect calorimetry/behavioral analysis | Scott et al. (2025) | DSS-induced colitis | SDV, CCK-SAP | Loss (−) | Anxiety-like behavior ↓ | OFT, EPM, LDB and NSF | Chen et al. (2023) |
| SDA | Loss (−) | Anxiety-like behavior ↓ | OFT, EPM, and food neophobia test | Klarer et al. (2014) | B. longum-treated colitis | SDV | Loss (−) | Anxiolytic effect abolished | Step-down test | Bercik et al. (2011) |
| CCK-SAP (NG) | Loss (−) | Anxiety-like behavior ↓ | OFT, acoustic startle reflex test, and food neophobia test | Krieger et al. (2022) | 0.1% iodoacetamide-induced FD | SDV | Loss (−) | Anxiety-like behavior ↓ | OFT | Cordner et al. (2021) |
| Cervical vagotomy | Loss (−) | Anxiety-like behavior ↑ | EPM | Okonogi et al. (2024) | L. rhamnosus-treated mice | SDV | Loss (−) | Anxiolytic effect abolished | EPM | Bravo et al. (2011) |
| Transfer of gut microbiota from chronically stressed mice | SDV | Loss (−) | Anxiety-like behavior ↓ | NSF | Siopi et al. (2023) | |||||
| High-fat diet-induced obesity | Caspase ablation (liver-innervating Avil+ NG neurons) | Loss (−) | Anxiety-like behavior ↓ | OFT, EPM, and LDB | Hwang et al. (2025) | |||||
| Depression-like behaviors | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| C. Normal conditions | D. Pathological conditions | |||||||||
| Methods | Gain/Loss | Phenotype | Behavioral tests | Ref. | Models | Methods | Gain/Loss | Phenotype | Behavioral tests | Ref. |
| VNS | Gain (+) | Depression-like behavior ↓ | FST | Krahl et al. (2004) | PTSD model | VNS | Gain (+) | Fear extinction ↑ | Auditory fear conditioning | Souza et al. (2020) |
| VNS | Gain (+) | Depression-like behavior → | FST | Biggio et al. (2009) | PTSD model | VNS | Gain (+) | Fear extinction ↑ | Auditory fear conditioning | Noble et al. (2017) |
| VNS | Gain (+) | Fear extinction ↑ | Auditory fear conditioning | Noble et al. (2019) | PTSD model | VNS | Gain (+) | Fear extinction ↑ | Auditory fear conditioning | Souza et al. (2021) |
| VNS | Gain (+) | Fear extinction ↑ | Auditory fear conditioning | Peña et al. (2013) | 0.1% iodoacetamide-induced FD | SDV | Loss (−) | Depression-like behavior ↓ | FST | Cordner et al. (2021) |
| VNS | Gain (+) | Fear extinction ↑ | Auditory fear conditioning | Peña et al. (2014) | L. rhamnosus-treated mice | SDV | Loss (−) | Antidepressant-like effect abolished | FST | Bravo et al. (2011) |
| VNS | Gain (+) | Fear extinction ↑ | Auditory fear conditioning | Alvarez-Dieppa et al. (2016) | Transfer of gut microbiota from chronically stressed mice | SDV | Loss (−) | Depression-like behavior ↓ | FST, TST, and sucrose preference test | Siopi et al. (2023) |
| VNS | Gain (+) | Fear extinction ↑ | Auditory fear conditioning | Noble et al. (2017) | ||||||
| SDA | Loss (−) | Conditioned Fear extinction ↓ | Auditory fear conditioning | Klarer et al. (2014) | ||||||
| Motivational behaviors | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| E. Normal conditions | F. Pathological conditions | |||||||||
| Methods | Gain/Loss | Phenotype | Behavioral tests | Ref. | Models | Methods | Gain/Loss | Phenotype | Behavioral tests | Ref. |
| Optogenetic stimulation of gut-innervating vagal sensory pathways | Gain (+) | Reward-related preference ↑ | RTPP | Sahasrabudhe et al. (2024) | Amphetamine or cocaine administration | SDV | Loss (−) | Drug-induced place preference ↓ | CPP | Onimus et al. (2026) |
| Optogenetic stimulation of right NG neurons innervating the upper gut | Gain (+) | Reward-related preference ↑ | Operant conditioning task and RTPP | Han et al. (2018) | ||||||
| SDV | Loss (−) | Reward preference, Reward discrimination, and motivation ↓ | T-maze test; operant conditioning task (lever pressing; FR and PR schedules) | Onimus et al. (2026) | ||||||
Summary of vagal pathway-related studies in emotion-related and motivational behaviors.
Avil, advillin; CCK-SAP, cholecystokinin-saporin; Chat, choline acetyltransferase; ChR2, channelrhodopsin-2; CPP, conditioned place preference; DREADDs, designer receptors exclusively activated by designer drugs; DSS, dextran sodium sulfate; ENS, enteric nervous system; EPM, elevated plus maze; FD, functional dyspepsia; FR, fixed ratio; FST, forced swim test; LDB, light–dark box; NG, nodose ganglion; NSF, novelty-suppressed feeding; OFT, open field test; Oxtr, oxytocin receptor; PR, progressive ratio; PTSD, post-traumatic stress disorder; RTPP, real-time place preference; SDV, subdiaphragmatic vagotomy; TST, tail suspension test; VNS, vagus nerve stimulation.
1.1.1 Anxiety
Anxiety-like behaviors in rodents are commonly assessed as innate responses using behavioral assays such as the open field test (OFT), elevated plus maze (EPM), light–dark box (LDB), and food neophobia test, which assesses avoidance or reduced intake of novel food or solutions. Several studies have examined the role of vagal signaling in the regulation of anxiety-like behavior (Table 1). Rats treated with VNS exhibited increased time spent in the open arms of the EPM, indicating an anxiolytic-like effect (Noble et al., 2019). Likewise, rats subjected to SDV displayed anxiolytic-like behaviors in the OFT, EPM, and food neophobia test (Klarer et al., 2014). These rats also exhibited increased gamma-aminobutyric acid (GABA) levels in the ventral prefrontal cortex (vPFC) and decreased noradrenaline levels in the vPFC and nucleus accumbens (NAc). Similarly, rats receiving CCK-SAP injections into the NG exhibited anxiolytic-like behaviors in the OFT, acoustic startle reflex test, and food neophobia test in male rats, whereas in female rats, these effects were limited to the food neophobia test (Krieger et al., 2022). In the same study, transcriptomic analysis of neurons within the central nucleus of the amygdala (CeA), identified by transsynaptic tracing from the vagus nerve, revealed gene expression changes associated with anxiety disorders together with enhanced inhibitory synaptic transmission. Moreover, intra-CeA administration of the GABAA receptor antagonist bicuculline abolished the anxiolytic-like behavior induced by CCK-SAP injection into the NG (Krieger et al., 2022). In contrast, cervical vagotomy induced anxiety-like behavior in the EPM, together with altered synchrony of neural oscillatory activity between the prefrontal cortex (PFC) and amygdala, resembling patterns observed in chronic stress-induced anxiety models (Okonogi et al., 2024). Together, these results suggest that vagal afferent signaling regulates anxiety-like behavior through polysynaptic circuits linking the gastrointestinal tract to limbic regions.
More direct evidence has emerged from studies using Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic approaches. Chemogenetic activation of NG neurons innervating the stomach and duodenum induced anxiety-like behavior in the OFT, EPM, and food neophobia test (Krieger et al., 2022). In addition, activation of oxytocin receptor-expressing NG neurons (NGOxtr) has been reported to induce vigilance-related behavioral responses together with marked hypometabolic changes, suggesting that distinct vagal sensory subtypes may regulate stress-related internal states (Scott et al., 2025).
The contribution of vagal pathways to anxiety-like behavior has also been reported in pathological conditions (Table 1). In a social defeat stress model, VNS restored EPM behavior toward baseline levels, indicating an anxiolytic effect (Okonogi et al., 2024). Similarly, VNS produced anxiolytic-like effects in the OFT, EPM, and novelty-suppressed feeding (NSF) test in a rat model of post-traumatic stress disorder (PTSD) (Souza et al., 2020). In dextran sodium sulfate (DSS)-induced colitis models, gastrointestinal vagal afferent signaling contributed to heightened anxiety-like behavior, and bilateral gastrointestinal vagal afferent ablation prevented the emergence of these behavioral abnormalities (Chen et al., 2023). Subsequent microbiome-based intervention studies further supported the involvement of vagal pathways in gut-brain communication. In particular, the anxiolytic effect of Bifidobacterium longum NCC3001 depended on intact vagal pathways (Bercik et al., 2011). Consistent with this, SDV also exerted anxiolytic-like effects in functional dyspepsia (FD) models (Cordner et al., 2021). In addition, the anxiolytic effect of Lactobacillus rhamnosus administration was abolished by SDV, further supporting the idea that intact vagal signaling is required for microbiota-dependent modulation of anxiety-like behavior (Bravo et al., 2011). Moreover, stress-induced alterations in the gut microbiota have been shown to require intact vagal signaling to influence affective behavior (Siopi et al., 2023). In addition, selective ablation of liver-innervating vagal sensory neurons induced anxiolytic-like behaviors in a high-fat diet-induced obesity model (Hwang et al., 2025).
Taken together, these findings indicate that vagal afferent signaling influences anxiety-like behavior in a context-dependent manner. Activation or disruption of gastrointestinal vagal afferents can produce different outcomes depending on physiological, inflammatory, metabolic, or microbiota-related states. These effects may involve anatomically and molecularly distinct NG neuron subtypes rather than a single uniform vagal pathway.
The divergent effects of SDV, CCK-SAP-mediated gastrointestinal vagal deafferentation, and cervical vagotomy may also reflect differences in anatomical specificity and affected fiber populations. SDV and CCK-SAP preferentially disrupt abdominal or gastrointestinal vagal afferents, whereas cervical vagotomy affects broader vagal afferent and efferent fibers from multiple organs. Species, sex, behavioral assays, and physiological or pathological conditions may further contribute to these contrasting outcomes. Thus, anxiety-like behaviors should be interpreted carefully when feeding, energy expenditure, pain, locomotor activity, or other physiological states may be altered.
1.1.2 Depression
VNS has demonstrated therapeutic efficacy in patients with depression, and its clinical application continues to expand (Conway et al., 2025). However, preclinical studies directly examining the contribution of gastrointestinal-brain interactions to depression-like behavior remain relatively limited. Current evidence from animal studies is mixed. Whereas one study reported an antidepressant-like effect of VNS (Krahl et al., 2004), another found no significant effect in the forced swim test (FST), despite detecting VNS-induced neuronal plasticity in the hippocampus (Biggio et al., 2009) (Table 1). In an FD model, SDV reduced immobility time in the FST, indicating an antidepressant-like effect (Cordner et al., 2021) (Table 1). Moreover, administration of Lactobacillus rhamnosus produced an antidepressant-like effect and altered GABAB1b and GABAAα2 mRNA expression in multiple brain regions; both the behavioral and molecular effects were abolished by SDV (Bravo et al., 2011). Consistent with this, stress-induced alterations in the gut microbiota have also been shown to require intact vagal signaling to promote hippocampal plasticity changes and depressive-like behaviors (Siopi et al., 2023). These findings suggest that gastrointestinal signals transmitted through the vagus nerve may influence depression-like behavior and neuronal plasticity in the brain.
The mixed preclinical evidence for vagal regulation of depression-like behavior may reflect differences in stimulation parameters, VNS duration, behavioral assays, and disease models. Because conventional VNS is not specific to gastrointestinal afferent pathways, organ- and cell-type-specific manipulations will be needed to determine whether gut-derived vagal signals causally regulate depression-like behaviors.
1.1.3 Fear
In rodents, fear-related behavior is commonly evaluated using Pavlovian fear conditioning paradigms, in which freezing responses to conditioned stimuli serve as a primary behavioral measure. Studies in rats have consistently shown that VNS facilitates the extinction of conditioned fear following auditory fear conditioning (Noble et al., 2019; Peña et al., 2013; Peña et al., 2014; Alvarez-Dieppa et al., 2016; Noble et al., 2017) (Table 1). This VNS-mediated effect was abolished by vagotomy (Klarer et al., 2014), supporting the involvement of vagal pathways. Although the underlying mechanisms remain to be fully elucidated, VNS appears to promote neuronal plasticity in brain regions critically involved in fear processing, including the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). Indeed, VNS has been reported to alter synaptic plasticity between the BLA and mPFC, and to modulate the expression of plasticity-related molecules such as activity-regulated cytoskeleton-associated protein (Arc), Ca2+/calmodulin-dependent protein kinase II, and GluN2B-containing NMDA receptors in the BLA (Peña et al., 2014; Alvarez-Dieppa et al., 2016). In rat models of PTSD, extinction of conditioned freezing responses was delayed relative to controls. However, when VNS was paired with extinction training, it reduced freezing behavior during training and decreased freezing responses during subsequent recall tests, indicating that VNS can restore impaired fear extinction (Souza et al., 2020; Noble et al., 2017; Souza et al., 2021) (Table 1). Taken together, these findings suggest that VNS promotes extinction of conditioned fear memory. Nevertheless, direct validation using genetic and other circuit-specific approaches remains limited, and the precise role of vagal signaling in fear regulation has yet to be fully defined.
1.1.4 Reward, preference, and motivation
Recent studies have demonstrated that gastrointestinal vagal afferents also contribute to reward, preference, and motivation. Here, we use “motivation” to refer to internal drives that energize goal-directed behavior rather than to an emotional state itself. Optogenetic activation of gut-innervating vagal sensory pathways has been shown to increase time spent on the stimulated side in the real-time place preference (RTPP) test, indicating a role in reward-related preference (Sahasrabudhe et al., 2024) (Table 1). Likewise, optogenetic activation of right-sided NG neurons innervating the upper gut enhanced both self-stimulation behavior and place preference, as assessed by operant conditioning paradigms and RTPP. This manipulation was accompanied by increased dopamine signaling in the dorsal striatum, suggesting recruitment of positive reinforcement circuits (Han et al., 2018). By contrast, activation of left-sided NG neurons did not produce similar behavioral changes or alterations in dopamine signaling. These findings indicate that even NG neurons innervating the same organ can exhibit lateralized functional specialization. Consistent with this idea, SDV reduced preference for water and food and impaired reward discrimination in the T-maze test (Onimus et al., 2026). Although SDV did not affect operant learning itself, it reduced the number of trials completed under both fixed-ratio and progressive-ratio schedules, suggesting reduced motivation. A recent study further extended this concept by showing that post-ingestive sugar and fat signals recruit spatially distinct dorsal hippocampal neuronal ensembles through a vagal pathway, thereby regulating nutrient-specific preference, contextual memory, and motivation (Yang et al., 2025). SDV also suppressed drug-induced place preference behavior, further suggesting that gastrointestinal interoceptive signals contribute to both natural reward processing and addiction-related behavioral phenotypes (Onimus et al., 2026) (Table 1).
1.2 ENS and spinal afferent pathways
The ENS is an autonomous neural network that regulates gastrointestinal function independently of the brain. In addition to this intrinsic role, ENS-derived signals may influence gut-to-brain communication through vagal pathways, spinal afferent pathways mediated by dorsal root ganglion (DRG) neurons, epithelial intermediates, immune mediators, and humoral routes. The causal contribution of the ENS itself to emotion-related behavioral regulation remains poorly understood. Recent advances in single-cell RNA sequencing and genetic manipulation techniques have enabled detailed characterization of enteric neurons and glial cells, as well as precise recording and manipulation of their activity (Shi et al., 2025; Millett et al., 2025). Here, we highlight two studies using DSS-induced colitis model mice that directly examined the relationship between ENS activity and affective-like behaviors through genetic and pharmacological manipulation of enteric neurons and glial cells. These ENS-related findings are summarized in Table 2.
Table 2
| Pain, aversion, and emotion-related behaviors | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| A. Normal conditions | B. Pathological conditions | |||||||||
| Methods | Gain/Loss | Phenotype | Behavioral tests | Ref. | Models | Methods | Gain/Loss | Phenotype | Behavioral tests | Ref. |
| ChR2 (Chat+ ENS neurons in the distal colon) | Gain (+) | Pain-related behavior ↑, aversion → | Back-hunching behavior and step-down test | Wang Z. et al. (2026) | DSS-induced colitis | ChR2 (Chat+ ENS neurons in the distal colon) | Gain (+) | Aversion ↑ | Step-down test | Wang Z. et al. (2026) |
| DSS-induced colitis | DL-fluorocitrate barium salt (glial inhibitor) | Loss (−) | Anxiety-like behavior ↓, depression-like behavior ↓ | OFT, EPM, and TST | Li et al. (2024) | |||||
Summary of ENS-related mechanisms in emotion-related behaviors.
Chat, choline acetyltransferase; ChR2, channelrhodopsin-2; DRG, dorsal root ganglion; DSS, dextran sodium sulfate; ENS, enteric nervous system; EPM, elevated plus maze; OFT, open field test; TST, tail suspension test.
Optogenetic activation of choline acetyltransferase-positive (Chat+) enteric neurons innervating the colon induced back-hunching behavior, a pain-related defensive response, via an ENS-DRG circuit, but did not elicit aversive behavior in the step-down assay under physiological conditions. In contrast, in DSS-treated mice, activation of Chat+ enteric neurons altered step-down assay performance, suggesting that inflammatory conditions unmask a contribution of these neurons to aversive behavior. These findings suggest that inflammation alters the functional properties of Chat+ enteric neurons, enabling them to contribute not only to pain-related defensive responses but also to aversive behavior (Wang Z. et al., 2026) (Table 2).
In parallel, another study using DSS-treated mice reported an increased number of GFAP-positive enteric glial cells, together with marked morphological alterations. Importantly, inhibition of enteric glial cell activity ameliorated both anxiety- and depression-like behaviors (Li et al., 2024) (Table 2). Collectively, these findings suggest that inflammation-induced changes in enteric neurons and glial cells may contribute to negative affective states.
2 Discussion
Interoceptive signals from the gastrointestinal tract, conveyed through vagal pathways, spinal afferent pathways, ENS-related routes, and humoral/immune signaling, are increasingly recognized as important modulators of emotion-related and motivational states. Nevertheless, direct causal evidence linking these pathways to behavioral regulation remains limited, and rodent behavioral assays require careful interpretation. Many phenotypes described as anxiety-like, depression-like, aversion-related, or motivational may also reflect changes in arousal, sickness behavior, vigilance, metabolic state, visceral discomfort, pain, or locomotion. The studies reviewed here begin to narrow this gap by identifying candidate gut-derived signals and their associated cellular substrates. However, it remains unclear which specific molecular or cellular signals originating from the gut shape affective-like behaviors and how these signals are integrated into central circuits.
Although the ENS has been proposed as an important source of gut-derived signals, direct evidence linking ENS activity to emotion-related behavioral regulation remains limited. Multiple routes may connect the ENS and the central nervous system, including vagal pathways, spinal afferent pathways, epithelial intermediates, immune mediators, and humoral signaling. However, the relative contributions of these routes and how they are integrated to shape affective-like states remain to be clarified. Future studies should identify specific ENS-derived signals and dissect the neural circuits through which these signals are conveyed to and integrated in the brain. A comprehensive understanding of these mechanisms will be essential for clarifying how gastrointestinal physiology influences emotion-related behaviors and may provide new insights into the pathophysiology of psychiatric disorders.
Across these studies, several broader questions emerge. A key issue is whether distinct gut-to-brain pathways encode separable behavioral dimensions, such as negative valence, vigilance, reward, memory, or motivational drive. Gut-derived signals including nutrients, inflammatory mediators and microbiota-related factors may shape emotion-related and motivational behaviors through multiple routes. In particular, inflammatory signals may alter vagal and/or spinal afferent activity and increase visceral discomfort, thereby promoting or exacerbating anxiety- or depression-like behaviors.
An important future direction is to identify the molecular identities of these gut-derived signals and determine how they are integrated into central circuits. Future studies should combine gut-specific stimulation or inhibition with genetic manipulation of defined cell types and longitudinal activity recording. Careful behavioral controls will also be necessary to distinguish emotion-related changes from generalized physiological or motivational state changes.
Statements
Author contributions
TO: Conceptualization, Writing – original draft, Writing – review & editing. TI: Conceptualization, Funding acquisition, Supervision, Validation, Writing – original draft, Writing – review & editing, Visualization. MT: Funding acquisition, Writing – original draft, Writing – review & editing, Validation.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This study was supported by the Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science grant numbers: 24K02119 (TI) and 24K22181 (MT), and by JST PRESTO grant number: JPMJPR23S1 (TI).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Summary
Keywords
emotion, enteric nervous system, gut-brain axis, interoception, spinal afferents, vagal afferents
Citation
Otsuki T, Ichiki T and Terunuma M (2026) Gut-to-brain interoceptive pathways in emotion-related behaviors. Front. Syst. Neurosci. 20:1855213. doi: 10.3389/fnsys.2026.1855213
Received
14 April 2026
Revised
08 June 2026
Accepted
09 June 2026
Published
24 June 2026
Volume
20 - 2026
Edited by
Paola Bonsi, Santa Lucia Foundation (IRCCS), Italy
Reviewed by
Rebeca Mendez-Hernandez, Monell Chemical Senses Center, United States
Shiv Singh, Boston University, United States
Tongtong Wang, California Institute of Technology, United States
Updates
Copyright
© 2026 Otsuki, Ichiki and Terunuma.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Takako Ichiki, ichiki@dent.niigata-u.ac.jp
Disclaimer
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