The gut-brain axis and cognitive control: a role for the vagus nerve

Abstract

Survival requires the integration of external information and interoceptive cues to effectively guide advantageous behaviors, particularly foraging and other behaviors that promote energy acquisition and consumption. The vagus nerve acts as a critical relay between the abdominal viscera and the brain to convey metabolic signals. This review synthesizes recent findings from rodent models and humans revealing the impact of vagus nerve signaling from the gut on the control of higher-order neurocognitive domains, including anxiety, depression, reward motivation, and learning and memory. We propose a framework where meal consumption engages gastrointestinal tract-originating vagal afferent signaling that functions to alleviate anxiety and depressive-like states, while also promoting motivational and memory functions. These concurrent processes serve to favor the encoding of meal-relevant information into memory storage, thus facilitating future foraging behaviors. Modulation of these neurocognitive domains by vagal tone is also discussed in the context of pathological conditions, including the use of transcutaneous vagus nerve stimulation for the treatment of anxiety disorders, major depressive disorder, and dementia-associated memory impairments. Collectively, these findings highlight the contributions of gastrointestinal vagus nerve signaling to the regulation of neurocognitive processes that shape various adaptive behavioral responses.

INTRODUCTION

‘Survival of the fittest’ is driven by a species’ constant adaptation to a changing environment, which requires both awareness of environmental demands and the ability to engage in the appropriate actions to address them. While external pressures such as rising temperatures or loss of natural habitat drive long-term evolutionary changes, dynamic interoceptive demands also necessitate rapid shifts in behaviors. For example, fluctuations in metabolic hormones can orient towards or away from foraging and ingestive behaviors [1] and social interactions can be heavily guided by reproductive state [2]. This ability to integrate internal signals to guide relevant actions results from extensive lines of communications between the visceral organs and the central nervous system through various humoral and neural signaling pathways. One critical gut-to-brain pathway centers on the vagus nerve, which serves as a key relay between metabolic signals arising from the abdominal viscera and the caudal brainstem [3]. Mechanoreceptors and chemoreceptors on vagal afferent terminals innervating the gut communicate various within-meal signals (e.g., stomach distension, paracrine endocrine signals) to the brainstem to regulate meal size [4]. Within the brain, visceral gut-derived vagal signaling is communicated via diffuse neural projections from the brainstem to the forebrain, including to various hypothalamic, limbic, and cortical regions that regulate energy balance control more broadly.

In addition to being critical in determining food intake regulatory behaviors, emerging findings reveal that the gut-vagal-brain axis modulates various complex cognitive and behavioral processes. Indeed, gut functions have been intrinsically linked to affective states such as anxiety and depression [5–7], as well as neural processes that regulate learning and memory [8,9] and motivation [10]. Connections between the gut and cognitive processes were highlighted in the medical community by 19^th Century British physicians, who would commonly refer to the stomach as “the great abdominal brain” and a strong regulator of emotional well-being [11,12]. Interest in a functional connection between the gut and cognitive function has re-emerged based on several recent basic science findings from humans and mechanistic rodent models. This review will synthesize these recent findings emphasizing the contribution of vagus nerve signaling, particularly that originating from the gastrointestinal (GI) tract, in modulating several neurocognitive domains. Results from the literature included are also considered with regards to the relevance of these phenomena from an evolutionary perspective.

ANXIETY

Animal models

Anxiety is a state of worry and tension where the need to protect oneself from external and/or internal demands can interfere with efforts to engage in behaviors meeting other competing needs. In rodents, manipulations of vagus nerve signaling have been shown to impact anxiety-like measures in behavioral assays opposing exploratory drive to preference for dark enclosed “safe” spaces. For example, in male rats, surgical ablation of gut-originating vagal afferent/sensory signaling through subdiaphragmatic vagal deafferentation (SDA) reduces anxiety-like behaviors via an increase in exploration of open areas in the elevated plus maze (EPM) and open field (OF) assays [13], including in a rodent model of 0.1% iodoacetamide oral gavage-induced functional dyspepsia characterized by heightened anxiety [14]. Similarly, reversible chemogenetic silencing of gut-originating vagal afferences reduces anxiety-like behaviors in the EPM and OF in both male and female rats offered 1h access to food following an overnight fast – a metabolic state associated to an elevated anxiety phenotype [15]. Consistent with this model, male mice exposed to chronic unpredictable mild stress, a model of chronic anxiety, display hypersensitivity of gastric vagal afferences to mechanical stimulation [16], suggesting that chronic stress can dysregulate vagal tone, which is consistent with loss of vagal function reducing anxiety behaviors.

Interestingly, gain of vagal function with stimulation of the left vagus nerve at the cervical level in male rats reduces anxiety-like behaviors in the EPM [17–21]. In light of these findings, it is possible that extreme perturbations of vagal tone in either direction (surgical ablation, electrical stimulation) dampens anxiety levels and allows for flexibility in behavioral responses. Consistent with this framework, left vagus nerve stimulation facilitates the extinction of a conditioned fear response to an auditory stimulus paired with food shock [18–25], and this effect is dependent on stimulation intensity in an inverted-U shape manner [22]. Further, stimulation of the left vagus nerve in male mice bidirectionally influences fear extinction learning, a proxy of anxiety-like behavior, dependent on the animal’s freezing levels during conditioning [26]. These findings suggest that the complex influence of vagal signaling on anxiety-like and fear-oriented behaviors may be modulated by baseline levels of stress and/or anxiety. It may be the case that increased vagal tone drives exploration over anxiety-like behaviors when animals are not in a state of heightened anxiety or metabolic stress, whereas reduced vagal tone has a similar effect in various models of acute or chronic stress, although this hypothesis requires further exploration.

Clinical findings

Work conducted in human participants has also investigated the impact of vagus nerve signaling on fear extinction learning using transcutaneous vagus nerve stimulation (tVNS), which, in the context of this review, refers to either cervical or auricular tVNS. For example, tVNS in healthy participants facilitates the extinction of a conditioned fear response relative to sham treatment [27–29]. Another study failed to observe an improvement in fear extinction but did report dampened shock expectancy to an auditory cue that was not associated with presentation of a spider picture in the tVNS group, indicating that stimulation of the vagus nerve may limit fear generalization [30]. Thus, augmenting vagal tone could minimize the consequences of fear conditioning by both facilitating extinction learning and reducing fear generalization.

Vagus nerve stimulation might serve as a promising tool to appease symptoms in those suffering from anxiety disorders. tVNS reduced autonomic responses following trauma stress relative to the sham condition in both healthy participants [31] and individuals suffering from post-traumatic stress disorder [32]. These results are highly encouraging for the development of adjunct therapies for the treatment of anxiety disorders, including the combination of virtual reality with vagus nerve stimulation [33]. Therefore, similarly to the findings from rodent studies, vagal tone appears to promote fear extinction learning in humans and attenuate the autonomic responses to stress recall. Given that rodent model work indicates that, similar to vagal stimulation, loss of gut-originating vagal signaling also has anxiolytic effects, it is likely that the influence of vagal tone on anxiety is complex and is dependent on baseline levels of stress and/or anxiety, the magnitude of stimulation or ablation, and other potential factors that have not yet been systematically investigated.

DEPRESSION

Animal models

Depression is a state of negative affect often associated to a dampened ability to experience pleasure from or willingness to engage in previously enjoyable activities. In rodents, vagus nerve signaling can influence depressive-like behaviors by restoring an animal’s innate preference for natural rewards, such as consuming palatable sweetened solutions, social interactions with a conspecific, or by reducing passive coping strategies associated to behavioral despair. For example, loss of gut-originating vagal afferent fibers through SDA in male rats promotes depressive-like behaviors by dampening preference for a sucrose solution and increasing immobility in the forced swim test (FST), an established rodent model of depressive-like behavior [34]. Consistent with these findings, stimulation of the vagus nerve at the cervical level in male rats reduces depressive-like behaviors by decreasing immobility in the FST [35–37]. These findings that vagal tone dampens depressive-like behaviors also extend to models of enhanced susceptibility to depression. For instance, stimulation of the vagus nerve at the cervical level decreases immobility time in the FST in Wistar Kyoto rats [38,39] and Zucker Diabetic Fatty rats [40–42]; two rat models with elevated depressive-like behaviors, and in rats exposed to cage flooding [43] and chronic restraint stress [44]. Vagus nerve stimulation also restores preference for a sweetened solution in male rats exposed to chronic unpredicted mild stress (alternating between tail clipping, swimming in cold water, food or water deprivation, overnight illumination and electric shock) [45,46], chronic pain-induced stress [47], and in a kainic acid model of epilepsy [48]. Thus, vagus nerve signaling appears to reduce depressive-like behaviors, both in naïve animals and in models of depression.

The vagus nerve may influence depressive-like behaviors through its function as a relay between peripheral inflammation in the abdominal viscera and the central nervous system (CNS). For example, loss of gut-originating vagal fibers through subdiaphragmatic vagotomy (SDV), which is less selective than SDA as it eliminates 100% instead of 50% of gut vagal efferent/motor signaling, prevents the reduction in social interactions induced by peripheral administration of the inflammatory cytokine interleukin-1 in male mice [49] and rats [50,51]. SDV also dampens measures of behavioral despair in the FST following systemic administration of the bacterial toxin lipopolysaccharide in male mice [52]. In addition to communicating peripheral inflammation to the brain, the vagus nerve may also influence depressive-like behaviors by acting as a relay between the gut microbiome and the CNS. For instance, SDV blocks the pro-depressant effects of Lactobacillus reuteri and Lactobacillus intestinalis or Filobacterium rodentium - bacterial populations enriched in the gut microbiome of male mice exposed to chronic social defeat stress [53,54]. Lactobacillus reuteri also rescues social deficits in a vagally-dependent manner in a mouse model of autism disorder [55]. Similarly, the depression phenotype exhibited by transgenic mice lacking the alpha-7 nicotinic receptors in the tail suspension test (TST), FST, and dampened sucrose preference, is blunted by SDV [56,57]. Additionally, SDV in male mice prevents the antidepressant effects of Lactobacillus rhamnosus in the FST [58]. Collectively, these findings suggest that vagus nerve signaling can modulate depressive-like behaviors by communicating both the pro- and antidepressant effects of gut molecules to the brain.

Clinical findings

Clinical trials conducted in individuals suffering from major depressive disorder (MDD) reveal that tVNS is effective in reducing depressive symptoms [59–63]. These improvements in depressive symptomatology correlate with changes in functional connectivity between limbic regions, including the precuneus and orbitofrontal cortex [64], the amygdala and dorsolateral prefrontal cortex [65], the medial hypothalamus and rostral anterior cingulate cortex [62], and the nucleus accumbens and rostral anterior cingulate cortex [66]. In addition, tVNS has been shown to increase cerebrospinal fluid levels of homovanillic acid, suggesting greater metabolism of monoamines [67]. This latter result may identify a potential mechanism for the beneficial effects of tVNS on MDD, as the leading antidepressant pharmacotherapies target the monoamine serotonin. Therefore, tVNS is emerging as a promising avenue for the treatment of MDD, perhaps through adaptations in brain connectivity and/or enhancement of monoaminergic neurotransmission.

Interestingly, vagus nerve signaling appears to be intrinsically linked to emotional processing more broadly. For example, individuals suffering from MDD present heightened cardiac vagal responses to negatively arousing stimuli [68] and blunted vagal regulation of heart rate after crying [69]. In healthy participants, tVNS reduces reactivity to emotionally charged stimuli [70,71], yet improves visual attention towards facial features [72], and overall emotional recognition [73,74]. Interestingly, tVNS in individuals with temporal lobe epilepsy enhances cooperation in a prisoner’s dilemma scenario [75], suggesting that boosting vagal tone favors prosocial interactions. Acute tVNS also augments positive mood ratings following physical and cognitive effort in healthy individuals [76]. Changes in scores of well-being following tVNS versus sham stimulation have also been associated to reduced blood-oxygen-level-dependent signal in limbic regions, including the amygdala and hippocampus [77]. Altogether, these results indicate that vagal tone contributes to emotional processing by reducing depressive-like behaviors and facilitating the engagement in positive valence actions that have been advantageous throughout evolution.

MOTIVATION

Animal models

In the context of this review, motivation refers to actions or processes that are directed towards rewarding (i.e., positive reinforcing) outcomes. Early work in cats reveals that lateral hypothalamus self-stimulation from lever pressing, a phenomenon known as “brain stimulation reward”, suppressed vagal electrical activity initially, but activity reappeared and increased during subsequent responses. The same study also reported that vagus nerve stimulation interrupts self-stimulatory operant behavior while vagotomy enhances the rate of self-stimulation [78,79]. In contrast, however, multiple studies show that SDV in male rats reduces responding for stimulation of the lateral hypothalamus [80,81]. It is unclear whether these conflicting findings are based on species differences and/or electrical stimulation parameters. Regardless, these studies clearly identify a role for vagal tone in mediating motivational processes stemming from hypothalamic brain stimulation reward.

More recent results from rodents indicate that increased vagal tone is inherently rewarding. For example, male mice will nose poke repeatedly for optogenetic stimulation of the right nodose ganglia neurons (cell bodies of the afferent vagus nerve) innervating the gut and this optical stimulation can induce place and flavor preferences and nigrostriatal dopamine release [82]. In addition, chronic vagus nerve stimulation in male rats influences lipid composition and protein structure in key regions of the brain involved in reward-mediated dopamine signaling, including the ventral tegmental area, the substantia nigra, and the striatum [83]. Collectively, results from rodents suggest that enhanced vagus nerve signaling is positively reinforcing, potentially via increased dopaminergic neurotransmission, and that loss of vagal tone interrupts brain reward signaling induced by hypothalamic stimulation.

Vagal tone contributes to the regulation of meal size via brainstem signaling, yet vagus nerve signaling could also modulate eating behaviors by altering higher-order motivational processes. For example, capsaicin-mediated ablation of gut-originating vagal afferent unmyelinated C-fibers (which comprises ~70% of all vagal afferents) impairs the acquisition of flavor preference learning induced by gut nutrient infusions in male rats [84]. Vagal signaling may also influence binge eating and food-motivated operant behavior, as the ability of peripheral endocannabinoid signaling to promote binge eating is dampened by SDV in male mice [85] and VNS paired with lever pressing for food reward reduces overall calories earned and consumed in both male and female rats [86]. Under pathological conditions that reduce food motivation, such as following intraperitoneal administration of lipopolysaccharide or interleukin-1β in male mice, the reduction in nose pokes for food rewards is alleviated by SDV [87], indicating that vagus nerve signaling might facilitate dampening of motivational processes by systemic inflammation. The collective findings indicate that vagal tone can promote food-motivated behaviors, although the extent to which these effects are entangled with its actions on energy intake remains elusive and requires further investigation. The complexity regarding vagal influences on food reward is underlined by the fact that meal consumption involves both an early phase positive feedback process (appetition), as well as a later phase negative feedback process (satiation). Future work could disentangle whether the effects of surgical vagal ablation or VNS on food reward-motivated behaviors are dependent on short- and long-term changes in energy state.

Alcohol and drugs of abuse also recruit the brain reward circuitry and preclinical work suggests that vagus nerve signaling contributes to consumption of these substances. For example, in rats bred for high ethanol consumption, SDV drastically decreases voluntary ethanol intake by 75% [88]. Accordingly, left vagus nerve ablation at the cervical level prevents relapse in ethanol consumption in female rats [89]. In male rats, VNS facilitates the extinction and dampens the reinstatement of cocaine [90,91] and heroin-seeking behaviors [92]. Altogether, these studies suggest that vagus nerve signaling promotes behaviors associated to alcohol and drug consumption, which is consistent with studies discussed above indicating that vagal signaling promotes food reward learning and food-motivated behavioral responses.

Clinical findings

A growing body of work has examined whether stimulation of the vagus nerve can influence motivated behavior in humans. In healthy participants, tVNS promotes invigoration of effort, defined as how quickly a participant energizes effortful button-pressing behavior, without affecting wanting ratings for either food or monetary reward. This effect was specific to responses for food rewards following stimulation of the left vagus nerve, suggesting a possible functional laterality dissociation [93]. Consistent with these findings, ratings of pleasantness following consumption of low-fat food items are increased in women receiving acute tVNS, although no effects were observed on scores for ‘wanting’ using visual analog scales [94]. Intriguingly, no effects of tVNS were observed for stimuli varying in sugar content, which corroborates the research from animal models indicating a vagally mediated connection between dietary fat and food reward [82,95]. A recent study in healthy human participants indicates that tVNS fails to impact subjective ratings of food, thus suggesting that tVNS is unlikely to be the mechanism for longer-term effects of VNS on body weight [96]. Finally, correlational analyses from a small male participant group with extensive histories of using both alcohol and cocaine indicate that alcohol consumption is associated with reduced vagal tone and a dysregulated state in which heart rate is uncoupled from vagal activity [97]. One interpretation of these results is that alcohol consumption may be used as a coping mechanism for instances when there is a mismatch between interoceptive cues and behavioral responses.

Collective results from humans and animal models suggest that increased vagal tone, particularly from the gut, is inherently reinforcing and can promote operant responses directed towards food reward, vagal stimulation, or lateral hypothalamic stimulation. In light of these findings together with those discussed in the previous sections, the efficacy of tVNS in humans for the treatment of anhedonia warrants further investigation.

Learning and Memory

Animal models

Learning is the acquisition and maintenance of knowledge or skill through experience or observation, and memory is the process referring to information storage and recall. Memory can be categorized into different systems (e.g., procedural memory, short-term memory) that are regulated by distinct brain substrates. The hippocampus and its interconnected circuitry are critical for specific memory domains, including visuospatial memory for navigation, episodic memory for navigation, and episodic memory for specific past experiences. An accumulating body of evidence indicates a functional connection between vagal signaling from the gut and the hippocampus. For example, vagally-mediated within-meal signals from the GI tract, including gastric distension of the stomach and intestinal nutrient infusion, robustly increase cerebral blood flow in the dorsal subregion of the hippocampus in rats [98,99]. This connection is function with regards to hippocampal-dependent memory as, both SDV and a cholecystokinin-conjugated saporin-mediated ablation of gut-originating vagal afferents impair contextual episodic memory and spatial working memory in male rats [100]. Further, both surgical approaches significantly reduced protein expression of brain-derived neurotrophic factor (BDNF) and the neurogenic marker, doublecortin (DCX) in the dorsal hippocampus, and performance in the hippocampal-dependent memory tasks was correlated with hippocampal BDNF and DCX expression. The stomach-derived “hunger hormone”, ghrelin, is a functional node in the gut-hippocampus axis, as nodose ganglion-specific knockdown of the ghrelin receptor (growth hormone secretagogue receptor 1A) also yields contextual episodic memory impairments and reduced hippocampal BDNF expression in male rats [101]. Consistent with these findings, a separate study also revealed reductions in BDNF and DCX expression in the hippocampus as a result of SDV in male mice, as well as reductions in the birth of new neurons in the dentate gyrus marked by a reduction of KI-67+ and BrdU+ cells [102]. Thus, vagal afferent tone appears to play a critical role in hippocampal function, potentially by promoting neurotrophic and neurogenic signaling via a multi-synaptic pathway connecting the nucleus of the solitary tract to the dorsal hippocampus via the medial septum, as revealed through neuroanatomical pathway tracing in rats [100].

Several lines of evidence suggest that some neurodegenerative disorders are connected to gut physiology through vagus nerve signaling. For example, in female and male mice, duodenal injection of alpha-synuclein preformed fibrils (PFF), a pathogenic hallmark of Parkinson’s disease, results in dense propagation of PFFs throughout the brain and memory impairments in the novel object recognition and Y-maze tasks, yet these effects are prevented by SDV [103]. Furthermore, SDV also blocks the progression of amyloid beta (Aβ) and Tau deposits in the brain, characteristic of Alzheimer’s Disease (AD) models, and deficits in fear conditioning in female and male mice inoculated with Aβ and Tau fibrils in the colon [104]. Thus, under both normal (discussed above) and pathological conditions, the vagus nerve may promote learning and memory impairments through its function as a relay between the gut and the central nervous system.

In contrast to loss of function models discussed above, acute stimulation of the vagus nerve at the cervical level in rodents can improve learning and memory functions. For example, VNS improves performance in cross-maze rule-shifting and T-maze tasks in male rats [105] and in the novel object recognition task in both male rats [105] and male mice [106]. Acute VNS also enhances long-term potentiation in the dentate gyrus and elevates spike amplitude, both of which are biological correlates of learning, in male rats [107] and in hippocampal slices [108]. Vagal modulation of memory function may involve CNS cholinergic signaling, as improvements in motor learning following VNS engage cholinergic signaling from the basal forebrain to the motor cortex [109]. This is consistent with another study reporting that VNS modulates hippocampal theta rhythm type II through muscarinic M1 receptor containing cholinergic neurons of the medial septum [110], as well as neuroanatomical data discussed above identifying the medial septum, a CNS hub for cholinergic signaling, as an anatomical relay between gut vagal signaling and the hippocampus [101]. Altogether, these studies indicate that learning and memory functions can be enhanced by acute VNS and that this process likely involves cholinergic neurotransmission through multiple neural pathways.

Enhancing vagal tone could potentially be an effective form of treatment for neurodegenerative disorders and neurological conditions associated with cognitive decline. For example, 6-month-old AD transgenic mice expressing the amyloid precursor protein and presenilin-1 gene mutations receiving VNS display dampened spatial working memory impairments and Aβ load in the hippocampus, potentially through greater microglial phagocytic actions on Aβ [111]. Additionally, chronic VNS rescues deficits observed in a passive avoidance task in male rats induced by central administration of Aβ deposits [112]. Not limited to models of dementia, VNS was also found to have anti-inflammatory effects within the CNS in models of cerebral ischemia/reperfusion and postoperative procedures by reducing inflammatory cytokine expression [113–115]. Collective results support the potential of VNS as a treatment avenue for brain disorders and injury, although additional critical translational studies are of course needed and are ongoing [116].

Clinical findings

Similar to rodents, the hippocampus is engaged by gut vagal stimulation in humans, as evidenced by results showing that electrical stimulation of the gastric vagal trunk in humans increases metabolic activity in the hippocampus [117]. Further, tVNS is used for pharmaco-resistant epilepsy and tVNS-treated patients display enhanced word retention memory capability [118]. Similarly, acute tVNS improves lexical recognition in healthy adults when stimulation is paired with lexical training [119] and promotes associative and spatial working memory in healthy aged individuals [120] and young adults [121]. These cognitive improvements could be related to vagally-mediated cardiac function, as changes in vagal modulation of heart rate was found to be associated with memory performance in patients with chronic fatigue syndrome [122].

From medical records of a Taiwanese cohort of 155,944 patients who underwent truncal vagotomies for the treatment of severe gastric ulcers, results identify an association of vagotomy and onset of dementia in women or individuals under the age of 65 [123]. To our knowledge, this is the only population study conducted assessing the relationship between vagotomy and predisposition to dementia later in life, thus calling for more investigations of this kind more broadly in other populations. Collectively, these studies identify the vagus nerve as an integral constituent in the regulation of several different memory processes in animal models and humans, particularly through a cholinergic pathway that connects with the hippocampus. Moreover, stimulation of the vagus nerve has evidenced to be effective in the treatment of neurodegenerative disorders in animal models, and can enhance cognitive function in healthy adult humans. The potential efficacy of tVNS for treatment of Mild Cognitive Impairment and dementia warrants further mechanistic investigation.

EVOLUTIONARY PERSPECTIVE AND CONCLUSIONS

While data from tVNS in humans, as well as cervical VNS in rodents were included in this review, we posit that the ability of vagal signaling to modulate neurocognitive function arises predominantly from gut-originating vagal signaling. For example, many of the critical mechanistic results from the rodent literature involve surgical approaches that leave vagal signaling partially or completely intact above the diaphragm, including SDV, SDA, cholecystokinin-conjugated saporin-mediated ablation of gut-originating vagal afferents, subdiaphragmatic capsaicin treatment, and optogenetic targeting of gut-innervating nodose ganglia. That electrical stimulation above the diaphragm can recapitulate gut-vagal mediated effects is not surprising as such treatments should influence nodose ganglia neuron activity indiscriminately, including presumable activation of gut-innervating neurons in concert with other vagal afferent neurons.

Results discussed herein emphasize that vagus nerve signaling, particularly from the GI tract, reduces anxiety and depressive-like behavioral symptoms, promotes motivated behaviors for various domains of reinforcement, and enhances learning and memory function, especially hippocampal-dependent memory systems. Given the GI-derived vagal signaling is classically studied for its role in satiation and meal size control, it is important to consider why the vagus nerve also mediates these cognitive processes as well. We argue that one common element among these collective cognitive processes subserved by GI vagal signaling is that they are each likely to facilitate memory encoding for meal-associated events. This would be advantageous from an evolutionary perspective as a survival advantage among early humans and lower-order mammals is to accurately remember the physical location of a food source, and to efficiently navigate back to a shelter, and potentially back to the food source again in the future. Learning about other aspects of eating behavior is also advantageous, including social cues, which strongly influence food choice and amount consumed by conveying the safety and nutritive capacity of specific foods [124–127]. Both short- and longer-term temporal factors that affect vegetation status and predator-prey dynamics are also important variables to encode to facilitate successful foraging behavior. Our model is that vagus nerve signaling from the GI tract, which is engaged under endogenous conditions during and shortly after consuming a meal, influences multiple neurocognitive domains, in part, for the purpose of remembering meal-associated events.

Consistent with this model, both chronic and acute anxiety can negatively impact memory function independent of concomitant depression, including spatial working memory which is particularly relevant to foraging and is also impaired with gut-selective vagal ablation [128,129]. Thus, reduced anxiety levels in the prandial and postprandial state would be beneficial for meal-associated memory encoding. Similarly, rodent models of depression are associated with impaired hippocampal plasticity and memory function [130–132], indicating that optimal meal-associated memory encoding should involve suppression of depressive-like behaviors and emotional states. Beyond anxiety and depression, vagus nerve signaling is intrinsically tied with motivational processes, generally increasing motivated behaviors across multiple reinforcement domains, including food, drugs, and brain stimulation reward. The magnitude of the reinforcer is a critical variable in learning and memory theory that facilitates learning, and indeed, it intuitively makes sense that increased reinforcement from food, including during the early meal reinforcing process known as appetition when vagal afferents are engaged, would enhance meal-associated memory encoding. Finally, evidence was reviewed in which surgical ablation of gut-specific vagal afferent signaling impaired hippocampal-dependent contextual episodic and visuospatial memory in rats, both of which are critical mnemonic processes for foraging and meal-associated memory. Whether the vagus nerve preferentially promotes food-associated memory vs. memories not associated with eating requires further investigation. However, our preliminary unpublished results reveal that SDV in male rats impairs memory for a meal location, but not an object location in an otherwise analogous memory task. These findings warrant future work to decipher whether vagal signaling from the gut mediates memory capacity in a reinforcement-specific manner.

Under certain pathological conditions, however, such as in the event of systemic inflammation, the vagus nerve might serve as a conduit for deleterious molecules to reach the central nervous system. In these specific instances, unlike under healthy conditions, loss of gut-originating vagal afferents instead of gain-of-function (e.g., VNS) may improve neurocognitive functions. Thus, we posit that as a conduit of communication from the GI tract to the brain, the vagus nerve relays interoceptive information regarding changes in metabolic state (particularly when successful foraging results in meal consumption) as well as pathological systemic conditions to bidirectionally modulate neurocognitive processes.

In conclusion, the vagus nerve plays a vital role in integrating external and internal cues to subserve critical domains of neurocognition, with broad-reaching implications on evolutionary adaptations spanning the domains of anxiety, depression, motivation, and learning and memory. Collectively, the evidence connecting vagal signaling and these neurocognitive domains indicates an important role for the gut-brain axis in allowing a species to better respond to a changing environment, including relaying interoceptive dynamic changes. One critical catalyst for vagal signaling from the gut is meal consumption, and collectively the literature is consistent with a role for gut-derived vagal signaling in promoting neurocognition processes such to facilitate meal-associated memory encoding.