搜索结果：Neurobiology of learning and memory

Translational inhibition has been suggested to impair long-term memory (LTM) while leaving short-term memory (STM) unaffected. However, intracranial infusions of protein synthesis inhibitors such as anisomycin (ANI), cycloheximide, and emetine have been shown to profoundly suppress both spontaneous and evoked neural activity, likely due to impairments of mitochondrial function and cellular metabolic loss. Given this neural suppressive effect, we wanted to re-examine the influence of translational inhibition on acquiring and retaining novel information with a direct comparison to agents that simply inactivate neural activity (without affecting protein synthesis). Our model was the widely-used cued-fear conditioning paradigm which is known to be dependent on the basolateral amygdala complex (BLA). Using male rats, we compared the behavioral deficits in cue fear conditioning induced by intra-BLA infusions of ANI to other commonly used neural inactivators, including the GABAA agonist muscimol (MUSC) and the sodium channel blocker tetrodotoxin (TTX). We confirmed that intra-BLA infusions of ANI and MUSC suppressed neural activity by examining effects on spiking activity in the BLA. In behavioral experiments, pre-training bilateral BLA infusions of ANI impaired both short-term (2 h) and long-term (24 h) cue fear memory similarly to the effects observed with both MUSC and TTX. Our results suggest that reductions in neural activity, whether via GABAA agonism, sodium channel blockade, or translational inhibition, are essential for both short- and long-term memory. Consequently, the influence of translational inhibitors may be better understood as being mediated via neural inactivation rather than solely the result of the absence of de novo synthesis of plasticity-related proteins. Previous work that interprets results using translational inhibitors as being purely protein-synthesis-dependent must to be reconsidered. SIGNIFICANCE STATEMENT: The axiomatic idea that protein synthesis can distinguish between phases of memory, namely short- versus long-term forms, is entirely based on work purporting to show differential disruptive effects of translational inhibitors on retrieval tested at long, but not short-term delays. However, protein synthesis inhibitors profoundly suppress neural activity as well, which should have an equivalent detrimental effect on both short- and long-term memory. In this study, we demonstrate that the translational inhibitor anisomycin suppresses neural activity in the basolateral amygdala which results in deficits in both short- and long-term memory for conditioned fear, similarly to agents that ONLY block neural activity. These findings are consistent with an important and under-appreciated role of neural activity in memory processes and argue for a critical re-evaluation of the strict de novo protein hypothesis of memory consolidation.

Understanding the neural mechanisms underlying the formation, retrieval, and extinction of taste memory is crucial for elucidating learning and memory processes. Using the conditioned taste aversion (CTA) model, we investigated the roles of the amygdala and gustatory cortex (GC), key structures consistently implicated in taste memory. Our study focused on the plastic changes associated with both appetitive and aversive taste memories, emphasizing the importance of extinction in promoting adaptive behavior and counteracting maladaptive responses. Memory processes elicit synaptic plasticity, often reflected in increased expression of neuronal remodeling markers such as growth-associated protein 43 (GAP-43) and synaptophysin (SYN). We examined the involvement of GAP-43 and SYN in taste memory by immunohistochemical analysis in male rats subjected to the formation of appetitive and aversive memories. During memory retrieval, GAP-43 expression was significantly upregulated in the basolateral amygdala (BLA), particularly under aversive conditions. In contrast, memory extinction induced a robust increase in GAP-43 expression in the central amygdala of overtrained animals, accompanied by elevated SYN expression in both the basolateral and central nuclei. These findings highlight the critical roles of GAP-43 and SYN in mediating synaptic changes during memory extinction, supporting the view of extinction as a dynamic, plastic process essential for behavioral adaptation. Our results advance understanding of the molecular substrates of taste memory and suggest potential targets for interventions aimed at modifying maladaptive memory traces, with implications for therapeutic strategies addressing aversive experiences and enhancing adaptive learning.

Episodic memory is the conscious recalling of past experiences. The neural underpinnings of this skill have long been of clinical interest, as deficits can be debilitating, including to those with temporal lobe pathology. This study sought to improve the assessment of those with unilateral temporal lobe pathology by comparing the localisation and lateralisation of successful spatial and verbal associative recognition memory using 3D time-frequency analysis and connectivity analysis of EEG data, while reducing perceptual confounds. Twenty right-handed participants aged 18 to 33 years were included. Average band-power analysis in eLORETA was used to compare verbal associative memory, spatial associative memory, and the resting state to identify the regions of interest for subsequent analyses. Time-frequency analyses were conducted for the inferior temporal, parahippocampal, inferior frontal, and middle occipital gyri. Phase-synchronisation was compared between conditions between 32 regions of interest. Material specific differences in neural synchrony were identified, with peak synchronisation around 1000 ms that was unique to verbal associative memory and mildly left-lateralised, compared with temporally diffuse and bilateral desynchronisation during spatial associative memory. However, overall, levels of local synchrony during verbal and spatial associative memory were more similar than different, with no compelling evidence for dissociation by material type or hemisphere. Differences in phase-synchronisation between verbal and spatial associative memory for theta and alpha oscillations suggested their role in long-range rather than local synchrony. Future research should focus on replication, further explore connectivity, and assess material-specific deficits in perceptual processing to identify deficits in memory processing.

Positive and negative schizotypy reflect distinct patterns of subclinical traits in the general population associated with neurodevelopmental and schizophrenia-spectrum pathologies. Yet, a comprehensive characterization of the unique and shared neuroanatomical signatures of these schizotypy dimensions is lacking. Leveraging 3D brain MRI data from 2730 unmedicated healthy individuals, we identified neuroanatomical profiles of positive and negative schizotypy and systematically compared them with disorder-specific, microarchitectural, neurotransmitter-level, and connectome measures. Positive and negative schizotypy were associated with distinct cortical signatures, of predominantly thinner frontal and thicker paralimbic cortical areas, respectively. These cortical signatures of positive and negative schizotypy were differentially linked to brain-wide cortical patterns of schizophrenia-spectrum (clinical high-risk for psychosis, schizophrenia) and neurodevelopmental conditions (ADHD, autism spectrum disorder and 22q11.2 deletion syndrome). Additionally, the positive and negative schizotypy-related cortical profiles mapped onto different local attributes of gene expression, cortical myelination, D1, and histamine receptor distributions. Network models further showed that positive and negative schizotypy cortical signatures were spatially associated with cortical hubs, suggesting that highly interconnected regions are more vulnerable to the morphological differences associated with both schizotypy dimensions. Finally, predominantly sensorimotor-to-association and paralimbic areas emerged as epicenters with connectivity profiles significantly linked to the schizotypy-related cortical patterns. Collectively, this study identified cortical signatures of positive and negative schizotypy traits that are embedded along multiple scales of cortical organization and neuropsychiatric pathologies. Our work yields novel insights into how neurobiology and brain architecture may guide neuroanatomical vulnerability and resilience to psychopathology in the general population.

In this work, we develop a mathematical model that captures both the early and late phases of Long-Term Potentiation (LTP) and Long-Term Depression (LTD), incorporating NMDAR-dependent induction and changes in AMPAR conductance. The model combines multiple essential properties. First, it emphasizes a detailed representation of biochemical processes within the postsynaptic neuron, thereby illustrating the interaction between LTD and distinct forms of LTP. Second, the dynamic modulation of postsynaptic AMPA receptor conductance is represented through nonlinear differential equations and algebraic relations. Third, the model incorporates input specificity, associativity, and cooperativity, allowing synaptic changes at one site to influence the strength of neighboring synapses. These features provide a comprehensive description of synaptic dynamics, allowing the simulation of plasticity at both the cellular and the network levels. Overall, the model offers a valuable framework for studying NMDAR-dependent LTP and LTD by explicitly incorporating changes in AMPAR conductance. We believe that this model provides deeper insights into the molecular mechanisms of synaptic plasticity and paves the way for the construction of network-level models by linking multiple cells through AMPA receptor conductance. Significance statement: We present a comprehensive mathematical framework that integrates early (E-LTP), late (L-LTP), and LTD by incorporating NMDAR-dependent signaling and changes in AMPAR conductance. By combining and extending established biochemical models, our approach links molecular signaling, receptor trafficking, and postsynaptic membrane dynamics to changes in synaptic strength. The model reproduces key experimental phenomena, including input specificity, associativity, and cooperativity, and clarifies how pathways, such as CaMKII and PKA govern the stability of synaptic modifications. By capturing both cellular- and network-level properties, this framework provides a foundation for building scalable neural models grounded in the biophysics of learning and memory.

Most widely studied option evaluation strategies rely on knowledge accumulated across repeated experiences. But how should options be evaluated in unfamiliar environments, in which knowledge is sparse? In these situations, how do decision makers make efficient use of limited past experience to guide their choices? One possible strategy is episodic sampling, in which a decision maker retrieves a small number of past decisions from memory to estimate the value of present options. By virtue of their age, children and adolescents have less experience than adults, making episodic sampling a particularly useful strategy for them. At the same time, the effectiveness of episodic sampling derives from memory's precision and context sensitivity-properties that continue to develop into adolescence and young adulthood. This tension raises a key question: are developmental differences in episodic memory associated with differences in episodic sampling? To address this question, 106 participants, ages 8 to 25, completed a 2-d choice task that dissociated the influence of a single episodic memory from the influence of multiple episodes sharing a common context. At all ages, single episodes biased choices. But, only adults were sensitive to the broader evoked context. Further clarifying the relationship between episodic memory and decision making, differences in memory precision predicted differences in episodic sampling, even after taking into account age, while episodic sampling, in turn, accounted for individual differences in forward planning. Together, these findings suggest that episodic memory guides decision making throughout development, but the character of its influence evolves as memory becomes more precise and richly structured.

Normal explicit/declarative memory requires a system of anatomically related structures in the medial temporal lobe that includes the hippocampus and the entorhinal, perirhinal, and parahippocampal cortex. Although extensive medial temporal lobe damage in primates causes robust anterograde amnesia, defining the contribution of the hippocampus proper has proved challenging. We revisited that enduring puzzle here, directly addressing a number of factors suspected to contribute to conflicting results across earlier studies. Among them, we explored the effects of selective hippocampus lesions produced by two common excitotoxin methods, ibotenic acid and N-methyl-D-aspartic acid. Sample sizes were substantial, and all behavioral testing was conducted postoperatively. Performance was assessed on several standard procedures designed for monkeys, including multiple variants of the delayed nonmatching-to-sample test of visual object recognition, a series of rapidly acquired two-choice object discriminations, and a delayed response test of spatiotemporal memory. We used task-specific parametric manipulations (e.g., increasing retention intervals and reduced stimulus set size) to systematically vary demands on memory and test/retest analyses to enhance sensitivity for detecting impairment. Although both lesion groups sustained substantial hippocampal damage, their performance failed to differ from that of intact controls on any task, under any key test condition, regardless of data analytic strategy. The findings constrain plausible accounts of extant discrepancies in the literature and, moreover, highlight the need for fresh perspectives on the core operating characteristics of memory mediated by the primate hippocampus. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

The precise coordination of slow oscillations (SO) and sleep spindles during non-rapid eye movement (NREM) sleep supports memory consolidation and may serve as a sensitive marker of cognitive aging. However, longitudinal changes in their oscillatory dynamics in midlife and older age remain poorly understood. Using polysomnography with high-density EEG at two timepoints over ~2.5 years, we examined changes in local NREM slow wave (SW), sleep spindle (occurring in the 11-16 Hz sigma range), and SO-sigma coupling strength in cognitively unimpaired middle-aged to older adults at risk for Alzheimer's disease. Fronto-central SO-sigma power coupling strength significantly declined over time, independent of changes in multiple measures of SW and sleep spindle expression. Local declines in multiple sleep spindle measures were also observed. Greater baseline levels of cerebrospinal fluid (CSF) neurogranin, a postsynaptic protein abundantly expressed in the dendritic spines of the hippocampus and cerebral cortex and implicated in calcium-dependent synaptic plasticity, predicted the magnitude of longitudinal decline in SO-fast sigma coupling strength, which in turn predicted episodic memory performance changes. These findings suggest that longitudinal changes in local sleep oscillatory dynamics are related to decreased synaptic integrity and may serve as an early indicator of memory decline in older adults at risk for Alzheimer's disease.

Acute physical exercise (PE) is known to influence the expression of many neurobiological markers and cognitive functions, but the time course and domain-specificity of such effects remain under debate. This study investigated whether a single bout of maximal incremental exercise can increase serum brain-derived neurotrophic factor (BDNF) levels, improving cognitive performance in healthy adults. Twenty-eight physically active males underwent a maximal incremental cycling test. BDNF serum concentrations were measured at three timepoints: before exercise, 15 min after, and 24 h post-exercise. Cognitive performance in verbal and visuo-spatial memory and convergent creative thinking was assessed before and 24 h post-exercise. Results showed a significant increase in serum BDNF 24 h after exercise, while no significant change was observed 15 min post-exercise. Cognitive assessments revealed improvements in verbal immediate recall and visuo-spatial working memory, but not in long-term verbal memory, visuo-spatial short-term memory, and convergent creative thinking. No significant correlations emerged between BDNF changes and cognitive performance changes. The dissociation between BDNF and behavior points to complex and likely time-dependent mechanisms underlying exercise-induced cognitive enhancements. These results support the effectiveness of acute PE as stimulus for BDNF neurotrophin production and as a non-pharmacological tool to boost specific cognitive functions, with implications for optimizing learning and cognitive performance in healthy populations.

Posttraumatic stress disorder (PTSD) is a psychiatric condition that may develop after trauma exposure. PTSD is characterized by considerable clinical heterogeneity. The amygdala's key role in fear conditioning makes it an important focus for investigating the neurobiology of PTSD. However, associations between amygdala volume and PTSD have been inconsistent. The amygdala consists of functionally distinct nuclei. Specific associations between amygdala nuclei volumes and PTSD may account for previous discrepancies between PTSD and whole amygdala volume. This study investigates the associations between amygdala nuclei volumes, PTSD diagnosis, severity, symptom cluster scores, age of onset and childhood trauma. Individuals with a PTSD diagnosis (n = 771) and controls (n = 1 081, 72% trauma-exposed) were sourced from the Enhancing Neuro-Imaging Genetics through Meta-Analysis and Psychiatric Genomics Consortium (mean age = 32.4 years, (SD = 13 years), 60% male). Nine amygdala nuclei volumes were compared to PTSD diagnosis, age of onset, overall severity, symptom cluster scores (re-experiencing, arousal, and avoidance/emotional numbing), and childhood trauma subscales. Analyses were performed using ordinary least-squares regression, corrected for age, sex, intracranial volume, and whole amygdala volume. PTSD diagnosis was not significantly associated with amygdala nuclei volumes. PTSD severity scores were associated with smaller right lateral nucleus volume (β = -0.26, pBON = 0.01). Smaller right lateral nucleus volume was also associated with re-experiencing (β = -1.01, pBON = 0.04) and arousal (β = -0.9, pBON = 0.04), smaller left paralaminar nucleus volume was associated with re-experiencing (β = -0.1, pBON = 0.04), smaller left corticoamygdaloid transition area volume was associated with avoidance (β = -0.31, pBON = 0.02). Larger left and right central nucleus volumes were significantly associated with childhood physical abuse (β = 0.24, pBON = 9 × 10-3) and neglect (β = 0.29, pBON = 0.04), respectively. Differences in select amygdala nuclei volumes among adults are associated with PTSD severity, symptom cluster scores, and childhood physical abuse and neglect. These findings demonstrate nuclei-specific patterns consistent with their functional roles in fear learning and expression.

Since Ivan Pavlov first demonstrated classical conditioning by pairing a neutral stimulus with a reinforcer, researchers have applied this approach to understand not only direct associations, but also more complex learning processes, such as sensory preconditioning and second-order conditioning. Despite their relative immaturity, very young mammals such as newborn rabbits exhibit robust classical and higher-order conditioning. However, the neuromodulatory systems involved in these different types of neonatal conditioning remain to be identified. Here, we compared the role played by the noradrenergic and the endocannabinoid systems in classical conditioning, sensory preconditioning and second-order conditioning in newborn rabbits. Intraperitoneal injections of Propranolol, an antagonist of beta-adrenergic receptors, blocked classical conditioning promoted by the mammary pheromone in newborn rabbits but had no effect on sensory preconditioning or second-order conditioning. Conversely, intraperitoneal injections of Rimonabant, an antagonist of the main cannabinoid receptor CB1, had no effect on classical conditioning but blocked sensory preconditioning and second-order conditioning, indicating a specific impact on unreinforced association. Moreover, an effect of Rimonabant on memory reconsolidation was also revealed. These findings demonstrate a double dissociation in the role of noradrenergic and endocannabinoid modulations in first- and higher-order conditioning in newborn rabbits. Whereas our results indicate the noradrenergic system specifically promotes reinforced association in pups, they also establish that the endocannabinoid system selectively mediates higher-order conditioning by regulating unreinforced association in newborns. This also highlights that the rabbit is an excellent model for further investigating the neurobiology of neonatal first- and higher-order memory.

Chromatin-modifying and -remodeling machineries are important for learning-induced transcriptional activity, yet it remains unclear how they coordinate to drive de novo gene expression for memory formation. Here, we examine the transcription factor known as calcium-responsive transactivator (CREST) in memory formation, synaptic plasticity, and learning-induced gene expression. CREST is known to bind major chromatin-modifying and -remodeling machineries via interaction with CREB-binding protein (CBP) and brahma-related gene 1 (BRG1), respectively. In silico modeling of CREST identified tyrosine 397 (Y397) within the CBP-binding domain. Expression of a CREST Y397F point mutant impairs long-term potentiation and memory. Conversely, expression of a CREST Y397D point mutant enhances memory in a CBP-dependent manner. Differential gene expression analysis reveals distinct CREST Y397-regulated signatures during memory consolidation. CBP acts through CREB and post-translation modifications to affect memory, but the findings of this study argue for consideration of the CREST-CBP interaction and Y397 accessibility as factors in memory processes.

Recent studies suggest pigeons undergo age-related changes in hippocampal function and cognitive decline. The present research compared the behavior of six young and six old homing pigeons that were trained to locate food in an open-field task. The availability of the food varied by location between two different conditions: in one condition, the risky location (75% chance of food) yielded more total reward compared to a food bowl that delivered a small amount of food on all trials; in the other, the risky location (25% chance of food) yielded less total reward compared to a food bowl that delivered a small amount of food on all trials. There was no significant difference between the two experimental groups with respect to error rates (choosing an empty food location). However, while older pigeons preferred the small, constant reward location in both the low and high variable conditions, young pigeons only preferred the small, constant reward location in the low variable condition. In the high (75%) variable condition, younger, but not older, pigeons preferred the large, variable reward location, which yielded a larger long-term food gain. The behavior of the older pigeons indicates a deviation from rational decision-making and a greater aversion to risk. Further research will be necessary to probe how the avian hippocampus and related structures evaluate risk and reward, and how that evaluation may change as a function of age.

Although learning over multiple days is more effective than a single day of training, the underlying cellular mechanisms of repeated training trials remain poorly understood. With a combination of empirical and computational approaches, we determined a critical time window for a second stimulus block of a multiday training protocol to augment long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse and long-term enhancement of neuronal excitability (LTEE), two cellular correlates of learning and memory. A second stimulus block delivered 24 h after the first block significantly enhanced LTF and LTEE, but was without effect at 18 or 32 h. This spacing effect appears due, at least in part, to the dynamics of competition between the transcription activator cAMP response element-binding protein 1 (CREB1) and repressor CREB2. The timer mechanism is intrinsic to individual neurons, as LTEE exhibited this critical temporal window in isolated sensory neurons. These findings suggest the dynamics of transcription factors function as a cellular timer that establishes a window of eligibility for a second learning trial to enhance memory.

Genetic tracing revealed that subsets of neurons in the medial amygdala (MeA) were labeled with the transneuronal tracer tWGA-DsRed originating from bitter taste receptor cells in male mice, suggesting the locations of bitter taste-relaying neurons in the MeA. Although not many studies have reported the involvement of MeA neurons in taste information processing, several studies clearly indicated that the MeA neurons play an important role in taste neophobia that refers to a reduction in consumption of a novel taste. On the other hand, several amygdaloid nuclei of the amygdala also operate to acquire conditioned taste aversion (CTA), which taste novelty determines the efficiency and strength for, while processing the conditioned stimulus (CS) followed by the unconditioned one (US) to elicit behavioral aversion to the CS. Here we combined genetic tracing and immunohistochemical analyses to examine whether subpopulations of tWGA-DsRed-labeled MeA neurons which inherently receive aversive bitter input can induce changes in responses to the novelty of saccharin and the CS saccharin during CTA learning. Immunohistochemical detection of Zif268 induction revealed that saccharin activated more tWGA-DsRed-labeled MeA neurons of mice that experienced saccharin at the first time than it did in mice experiencing saccharin multiple times. The CS saccharin activated a larger number of tWGA-DsRed-labeled MeA neurons after mice acquired CTA memory, compared with those detected in mice without CTA. Our results also suggest that the increased population of the CS-activated neurons among tWGA-DsRed-labeled MeA neurons may remain unchanged and activated by the CS after the subsequent extinction of CTA memory.

Machine learning methods employing neuroimaging data are useful for monitoring the activation of neural representations. Specifically, they can be used to discern the brain networks engaged in processing specific categories of items. This approach has been employed on neuroimaging data, including functional magnetic resonance imaging data and electroencephalography (EEG) data. Here, we present a task and an analytical pipeline for investigating category representations using EEG. Participants (N = 30) viewed a series of images and words of objects belonging to five categories (Animals, Tools, Food, Scenes, and Vehicles) and responded when items from the same category were presented consecutively. We trained support vector machines on EEG data within participants and found that both image trials and word trials yielded significant category classification accuracy, with image trials achieving higher accuracy than word trials. When comparing categories in a pair-wise fashion, all pairs were statistically distinguishable for image trials, whereas only one pair was distinguishable for word trials. Parietal and Left Temporal electrodes contributed more to image classification than Frontal and Right Temporal electrodes. Category-specific activity patterns also generalized across participants for image trials. Our data and analytic pipeline yielded high classification accuracies, primarily for image trials, providing support for the utility of EEG data for neural decoding. These methods can be instrumental for exploring the activation and reactivation of neural representations at the category level during wakefulness and, potentially, during offline states.

Pavlov's research on how arbitrary stimuli elicit conditioned reflexes has revolutionized the field of learning. His original work with the orienting response set the foundation for further investigations on the nature of Pavlovian conditioned responding.Where Pavlov's research may have lacked the ecological significance of Pavlovian conditioning, the behavior systems approach emerged later to capture how conditioning is embedded into a broader spectrum of naturalistic behaviors.The behavior systems approach proposes that behaviors evolved as organized systems designed to solve specific adaptive problems, and that learning interacts with these systems. The approach emphasizes the arrangement of responses to stimuli in the environment on a temporal and spatial continuum from an appetitive general search behavior at one end to focal and consummatory acts at the other end.During Pavlovian conditioning, a conditioned stimulus may become integrated along the continuum.The current paper describes several studies of Pavlovian conditioning that support the behavior systems approach with more detail in studies on sexual conditioning in male quail. Collectively, these studies demonstrate the importance of the form and relevance of the CS and the CS-US interval in determining where along the continuum the CS becomes integrated and thereby determine the nature or topography of the conditioned response.These studies, and many others, should serve as a reminder of how Pavlov's research set the framework for the conceptualization of behavior systems.

Remembering the identity and the location of distinct spatial elements is crucial for an animal's successful exploration of their environment. Locating food and shelter are but a few behaviors that rely on forming effective associations between the identity and location of spatial elements. Object-in-place (OiP) tasks are commonly used in rats to assess this identity-location association. While the availability of genetic resources has made the mouse an increasingly used animal model in neuroscience research, very few studies have successfully assessed OiP in mice. To address this limitation, we tested three distinct experimental designs of the spontaneous OiP preference task in adult C57/129 J and C57BL/6 J mice. C57BL/6 J, but not C57/129 J mice, displayed OiP preference in the four-object version of the OiP task. In contrast, mice of both strains successfully performed the two-object OiP task design, with retention intervals of five minutes and one hour. To broaden our task validation, we uncovered the ontogenetic profile of two-object OiP in C57/129 J mice, which emerges between postnatal day (P)25 and P28 in this mouse strain. Our data establish robust guidelines for successful assessment of OiP preference in mice across the lifespan, expanding the available behavioral toolbox for spatial memory research in mice.

Although running upright has been reported to have positive effects on both physical and mental health, the minimum running intensity/speed that would benefit mood and prefrontal cognition is not yet clear. Here, we tested the hypothesis that a brief bout of very slow running, which is classified as a very light intensity exercise, would enhance positive mood and executive function and increase activation in executive-function-related prefrontal subregions. Twenty-four healthy participants completed a 10-minute very slow running session on a treadmill at 35% V̇o2peak and a resting control session in randomized order. Executive function was measured using the Stroop task and mood state was measured using the Two-Dimensional Mood Scale (TDMS) before and after both sessions. Cortical hemodynamic changes while performing the task were monitored using functional near-infrared spectroscopy (fNIRS). The results show that 10 minutes of very slow running significantly enhanced mood, reduced Stroop interference time (i.e., enhanced executive function), and elicited left lateral PFC activation. Moreover, head acceleration, the magnitude of up-and-down oscillations, was measured during running, and a significant positive correlation with pleasant mood was found. Head acceleration is a remarkable characteristic of running and may be one of the factors related to a pleasant mood induced by very slow running. In conclusion, the current study reveals that a single bout of running, even at very slow speed, elicits a pleasant mood and improved executive function with enhancing activation in prefrontal subregions. This sheds light on the slow running benefits to brain health.