Enhanced Memory Formation Research Articles

Therapies Using Anti-Diabetics to Prevent and Manage Progression of Parkinson's Disease

<p>Currently, a significant proportion of older individuals have demonstrated connections between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM). Emerging evidence from cohort studies, clinical data, and preclinical meta-analyses reveals that T2DM patients have an increased risk of developing PD, often accompanied by more severe disease progression. These two chronic conditions are believed to share common pathways. The pathways that likely connect the neurodegenerative process of PD include autophagy, mitochondrial dysfunction, dysregulated insulin signaling, inflammation, and insulin resistance. Preclinical PD models highlight the importance of cerebral insulin signaling, which confers numerous neuroprotective benefits. Several ongoing phase II and phase III trials are being conducted in PD-affected populations. These trials reflect the potential of existing anti-diabetic medications to improve PD motor symptoms and halt the progression of neurodegeneration. Brain insulin resistance plays a crucial role in the pathophysiology of PD. The insulin signaling pathway represents a promising novel target for disease modification in both diabetic and non-diabetic PD. Incretin receptors in the brain have emerged as the most promising targets for repurposing existing drugs in PD treatment. Targeting these receptors mitigates inflammation, apoptosis, toxic protein aggregation, long-term potentiation, autophagy, and insulin signaling failure. </p><p> Presently, various novel anti-diabetic targets are available that can regulate the insulin signaling pathway in dopaminergic neurons, suggesting improvements in cognitive function and significant neuroprotective effects in PD. Throughout neurodegenerative processes, insulin and incretins exert therapeutic effects in multiple manners. Preclinical studies have demonstrated that glucagon-- like peptide 1 (GLP-1) receptor agonists reduce neuroinflammation, tau phosphorylation, and amyloid deposition while increasing synaptic function and enhancing memory formation. Incretin mimetics may act through the restoration of insulin signaling pathways, inducing further neuroprotective effects. </p><p> This review examined the reported shared cellular and molecular pathologies between PD and T2DM, and explored the repurposing of anti-diabetic drugs for the prevention of PD progression through the regulation of insulin signaling pathways.</p>

Acetate enhances spatial memory in females via sex- and brain region-specific epigenetic and transcriptional remodeling.

Metabolic control of chromatin and gene expression is emerging as a key, but largely unexplored aspect of gene regulation. In the brain, metabolic-epigenetic interactions can influence critical neuronal functions. Here, we use a combination of behavioral, proteomic and genomic approaches to demonstrate that the intermediary metabolite acetate enhances memory in a brain region- and sex-specific manner. We show that acetate facilitates the formation of dorsal hippocampus-dependent spatial memories in female but not in male mice, while having no effect on cortex-dependent non-spatial memories in either sex. Acetate-enhanced spatial memory is driven by increased acetylation of histone variant H2A.Z, and upregulation of genes implicated in spatial learning in the dorsal hippocampus of female mice. In line with the sex-specific behavioral outcomes, the effect of acetate on dorsal hippocampal histone modifications and gene expression shows marked differences between the sexes during critical windows of memory formation (consolidation and recall). Overall, our findings elucidate a novel role for acetate, a ubiquitous and abundant metabolite, in regulating dorsal hippocampal chromatin, gene expression and learning, and outline acetate exposure as a promising new approach to enhance memory formation.

How to reduce fear in a snail: Take an aspirin, call me in the morning

Aspirin (Acetylsalicylic acid, ASA), one of the widely used non-steroid anti-inflammatory drugs can easily end up in sewage effluents and thus it becomes necessary to investigate the effects of aspirin on behaviour of aquatic organisms. Previous studies in mammals have shown ASA to alter fear and anxiety-like behaviours. In the great pond snail Lymnaea stagnalis, ASA has been shown to block a ‘sickness state’ induced by lipopolysaccharide injection which upregulates immune and stress-related genes thus altering behavioural responses. In Lymnaea, eliciting physiological stress may enhance memory formation or block its retrieval depending on the stimulus type and intensity. Here we examine whether ASA will alter two forms of associative-learning memory in crayfish predator-experienced Lymnaea when ASA exposure accompanies predator-cue-induced stress during the learning procedure. The two trainings procedures are: 1) operant conditioning of aerial respiration; and 2) a higher form of learning, called configural learning, which here is dependent on evoking a fear response. We show here that ASA alone does not alter homeostatic aerial respiration, feeding behaviour or long-term memory (LTM) formation of operantly conditioned aerial respiration. However, ASA blocked the enhancement of LTM formation normally elicited by training snails in predator cue. ASA also blocked configural learning, which makes use of the fear response elicited by the predator cue. Thus, ASA alters how Lymnaea responds cognitively to predator detection.

Behavioral and transcriptional effects of carnosine in the central ring ganglia of the pond snail Lymnaea stagnalis.

Carnosine is a naturally occurring endogenous dipeptide with well-recognized anti-inflammatory, antioxidant, and neuroprotective effects at the central nervous system level. To date, very few studies have been focused on the ability of carnosine to rescue and/or enhance memory. Here, we used a well-known invertebrate model system, the pond snail Lymnaea stagnalis, and a well-studied associative learning procedure, operant conditioning of aerial respiration, to investigate the ability of carnosine to enhance long-term memory (LTM) formation and reverse memory obstruction caused by an immune challenge (i.e., lipopolysaccharide [LPS] injection). Exposing snails to 1 mM carnosine for 1 h before training in addition to enhancing memory formation resulted in a significant upregulation of the expression levels of key neuroplasticity genes (i.e., glutamate ionotropic receptor N-methyl-d-aspartate [NMDA]-type subunit 1-LymGRIN1, and the transcription factor cAMP-response element-binding protein 1-LymCREB1) in snails' central ring ganglia. Moreover, pre-exposure to 1 mM carnosine before an LPS injection reversed the memory deficit brought about by inflammation, by preventing the upregulation of key targets for immune and stress response (i.e., Toll-like receptor 4-LymTLR4, molluscan defense molecule-LymMDM, heat shock protein 70-LymHSP70). Our data are thus consistent with the hypothesis that carnosine can have positive benefits on cognitive ability and be able to reverse memory aversive states induced by neuroinflammation.

Want to learn? think again!

One of the best ways to improve new learning and increase memory strength is by reprocessing the recently acquired information, for example, by thinking of it again. Synaptic plasticity, the process by which neurons change the strength of their connections with each other, is fundamental for learning and memory formation. Yet, at present, it is unclear how reprocessing information drives synaptic plasticity to support memory improvement. A new study suggests that reprocessing enhances memory formation by recruiting more synapses to represent the new memory, thus increasing its strength.

Sleep-like State in Pond Snails Leads to Enhanced Memory Formation.

To test the hypothesis that a sleep-like quiescent state enhances memory consolidation in the pond snail Lymnaea stagnalis, we interposed a period in which snails experienced either a quiescent, sleeping state or an active, non-sleeping state following escape behavior suppression learning (EBSL). During EBSL training, the number of escapes made by a snail from a container was significantly suppressed using an external aversive stimulus (punishment). After training, the snails were divided into two groups. One group of snails was allowed to move freely and to experience a sleep-like quiescent state for 3 h in distilled water. The other group was stimulated with a sucrose solution every 10 min to keep them active (i.e., non-sleeping). In the memory test, escape behavior was suppressed in the group that experienced the quiescent state, whereas the suppression was not observed in snails that were kept active. Additionally, the latency of the first escape in the memory test was shorter in the snails kept active than in those that experienced the quiescent state. Together, these data are consistent with the hypothesis that a sleep-like quiescent state enhances EBSL memory consolidation in L. stagnalis.

Tocotrienol-rich fraction enhances cell proliferation and memory formation in hippocampal HT22 neuronal cells through BDNF/TrkB pathway

Memory formation is influenced by neurogenesis and long-term potentiation (LTP) of neurons in the hippocampus. In this study, we aimed to elucidate the mechanism of action of tocotrienol-rich fraction (TRF) involved in memory formation. Two cell models were employed, differentiated and undifferentiated HT22 neuronal cells. Our findings demonstrated that treatment with TRF increased cell proliferation of undifferentiated HT22 cells in a time-dependent manner by activating the brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) pathway. Elevated levels of cyclin D and E were also observed, indicating an increase in cell cycle progression and proliferation. In differentiated HT22 cells, TRF upregulated expressions of BDNF, phosphorylation of glutamate receptor 1 and Ca2+/calmodulin-dependent protein kinase II, potentially leading to stronger synaptic strength and contributing to LTP. Taken together, these findings suggest that TRF supplementation may enhance memory formation in HT22 cells through modulation of the BDNF/TrkB pathway.

Allosteric inhibition of phosphodiesterase 4D induces biphasic memory-enhancing effects associated with learning-activated signaling pathways.

Phosphodiesterase 4D negative allosteric modulators (PDE4D NAMs) enhance memory and cognitive function in animal models without emetic-like side effects. However, the relationship between increased cyclic adenosine monophosphate (cAMP) signaling and the effects of PDE4D NAM remains elusive. To investigate the roles of hippocampal cAMP metabolism and synaptic activation in the effects of D159687, a PDE4D NAM, under baseline and learning-stimulated conditions. At 3mg/kg, D159687 enhanced memory formation and consolidation in contextual fear conditioning; however, neither lower (0.3mg/kg) nor higher (30mg/kg) doses induced memory-enhancing effects. A biphasic (bell-shaped) dose-response effect was also observed in a scopolamine-induced model of amnesia in the Y-maze, whereas D159687 dose-dependently caused an emetic-like effect in the xylazine/ketamine anesthesia test. At 3mg/kg, D159687 increased cAMP levels in the hippocampal CA1 region after conditioning in the fear conditioning test, but not in the home-cage or conditioning cage (i.e., context only). By contrast, 30mg/kg of D159687 increased hippocampal cAMP levels under all conditions. Although both 3 and 30mg/kg of D159687 upregulated learning-induced Fos expression in the hippocampal CA1 30min after conditioning, 3mg/kg, but not 30mg/kg, of D159687 induced phosphorylation of synaptic plasticity-related proteins such as cAMP-responsive element-binding protein, synaptosomal-associated protein 25kDa, and the N-methyl-D-aspartate receptor subunit NR2A. Our findings suggest that learning-stimulated conditions can alter the effects of a PDE4D NAM on hippocampal cAMP levels and imply that a PDE4D NAM exerts biphasic memory-enhancing effects associated with synaptic plasticity-related signaling activation.

The influence of learning history on anterograde interference

Classically interpreted as a competition between opposite memories (A vs B), anterograde interference (AI) also emerges in the absence of competing memories (A vs A), suggesting that mechanisms other than those involved in memory competition contribute to AI. To investigate this, we tested the hypothesis that extending motor practice would enhance a first memory, but come at the cost of reduced learning capabilities when subsequently exposed to a second learning session of the same task. Based on converging biological evidence, AI was expected to depend upon the degree of extended practice of the initial exposure. During a first Session, four conditions were carried out where participants (n = 24) adapted to a gradually introduced −20° visual deviation while the extent of the initial exposure was manipulated by varying the duration or type of the performance asymptote. Specifically, the performance asymptote at −20° was either Short (40 trials), Moderate (160 trials), Long (320 trials), or absent due to continuously changing perturbations around the mean of −20° (Jagged; 160 trials). After a 2-min interval, participants re-adapted to the same (-20°) visual deviation, which was meant to probe the effect of extended practice in the first Session on the learning capabilities of a second identical memory (A vs A). The results first confirmed that the duration of exposure in the first Session enhanced immediate aftereffects in the Moderate, Long, and Jagged conditions as compared to the Short condition, suggesting that extended practice enhanced retention of the first memory. When comparing the second Session to the first one, results revealed a different pattern of re-adaptation depending on the duration of initial exposure: in the Short condition, there was evidence for facilitated re-adaptation and similar aftereffects. However, in the Moderate, Long and Jagged conditions, re-adaptation was similar and aftereffects were impaired, suggestive of AI. This suggests that extended practice initially enhances memory formation, but comes at the cost of reduced subsequent learning capabilities. One possibility is that AI occurs because extended practice induces the emergence of network-specific homeostatic constraints, which limit subsequent neuroplastic and learning capabilities in the same neural network.

CD4 Effector TCR Avidity for Peptide on APC Determines the Level of Memory Generated.

Initial TCR affinity for peptide Ag is known to impact the generation of memory; however, its contributions later, when effectors must again recognize Ag at 5-8 d postinfection to become memory, is unclear. We examined whether the effector TCR affinity for peptide at this "effector checkpoint" dictates the extent of memory and degree of protection against rechallenge. We made an influenza A virus nucleoprotein (NP)-specific TCR transgenic mouse strain, FluNP, and generated NP-peptide variants that are presented by MHC class II to bind to the FluNP TCR over a broad range of avidity. To evaluate the impact of avidity invivo, we primed naive donor FluNP in influenza A virus-infected host mice, purified donor effectors at the checkpoint, and cotransferred them with the range of peptides pulsed on activated APCs into second uninfected hosts. Higher-avidity peptides yielded higher numbers of FluNP memory cells in spleen and most dramatically in lung and draining lymph nodes and induced better protection against lethal influenza infection. Avidity determined memory cell number, not cytokine profile, and already impacted donor cell number within several days of transfer. We previously found that autocrine IL-2 production at the checkpoint prevents default effector apoptosis and supports memory formation. Here, we find that peptide avidity determines the level of IL-2 produced by these effectors and that IL-2Rα expression by the APCs enhances memory formation, suggesting that transpresentation of IL-2 by APCs further amplifies IL-2 availability. Secondary memory generation was also avidity dependent. We propose that this regulatory pathway selects CD4 effectors of highest affinity to progress to memory.

Independent effects of emotional arousal and reward anticipation on episodic memory formation.

Events that elicit emotional arousal or are associated with reward are more likely remembered. Emotional arousal activates the amygdala and the central noradrenergic system, whereas reward anticipation results in an activity in the mesocorticolimbic dopaminergic system. The activation of both pathways enhances memory formation in the hippocampus where their effects are based on similar neural substrates, e.g. tagging of active hippocampal synapses. Moreover, emotional arousal and reward anticipation both enhance attention, which can also affect memory formation. In addition, both neuromodulators interact on the cellular level. Therefore, we tested in the current functional magnetic resonance imaging study whether simultaneously occurring emotional arousal and reward anticipation might have interacting effects on memory formation. We did not find evidence for such an interaction, neither on the behavioral nor on the neural level. Our results further suggest that reward anticipation enhances memory formation rather by an increase in anticipation-related arousal-reflected in activity in the dorsal anterior cingulate cortex-and not dopaminergic midbrain activity. Accompanying behavioral experiments indicated that the effect of reward anticipation on memory is (i) caused at least to some extent by anticipating the speeded response to obtain the reward and not by the valance of the outcome and (ii) can be observed already immediately after encoding, i.e. before consolidation.

Reappraisal enhances memory formation for a stressful episode

Emotion regulation strategies have been shown to modify the physiological response to stress, yet whether these strategies can modulate also cognitive responses to stress is largely unknown. A prominent cognitive response to stress is the enhanced memory formation for the stressful event, which is an adaptive mechanism to prepare for similar events in the future. Thus, the present study aimed to investigate whether emotion regulation strategies impact the memory formation for a stressful episode. In a two-day study, participants (n = 124) underwent an enriched stressful episode or a control episode. Critically, before the exposure to the stressor, they were instructed to use a suppression or reappraisal strategy during the stressful episode. One week later, participants completed a memory test for central and peripheral details of this episode. Our results show that reappraisal enhanced not only the cortisol response to the stressor but also the memory formation for central features of the stressful episode. This reappraisal-related boost of memory for the stressor was particularly pronounced in participants’ with high working memory capacity. These findings show that reappraisal may not only impact the physiological response to a stressful event but also the cognitive representation of this event in memory.

The Assimilation of Novel Information into Schemata and Its Efficient Consolidation.

Schemata enhance memory formation for related novel information. This is true even when this information is neutral with respect to schema-driven expectations. This assimilation of novel information into schemata has been attributed to more effective organizational processing that leads to more referential connections with the activated associative schema network. Animal data suggest that systems consolidation of novel assimilated information is also accelerated. In the current study, we used both multivariate and univariate fMRI analyses to provide further support for these proposals and to elucidate the neural underpinning of these processes. Twenty-eight participants (5 male) overlearned fictitious schemata for 7 weeks and then encoded novel related and control facts in the scanner. These facts were retrieved both immediately and 2 weeks later, also in the scanner. Our results conceptually replicate previous findings with respect to enhanced vmPFC-hippocampus coupling during encoding of novel related information and point to a prior knowledge effect that is distinct from situations where novel information is experienced as congruent or incongruent with a schema. Moreover, the combination of both multivariate and univariate results further specified the proposed contributions of the vmPFC, precuneus and angular gyrus network to the more efficient encoding of schema-related information. In addition, our data provide further evidence for more efficient systems consolidation of such novel schema-related and potentially assimilated information.SIGNIFICANCE STATEMENT Our prior knowledge in a certain domain, often termed schema, heavily influences whether and how we form memories for novel information that can be related to them. The results of the current study show how a ventromedial prefrontal-precuneal-angular network contributes to the more efficient encoding of novel related information. Furthermore, the observed increase in prefrontal-hippocampal coupling during this process points to a critical distinction from the previously described mechanisms supporting the encoding of information that is experienced as congruent with schema-driven expectations. In addition, we find further support for the proposal based on animal data that prior knowledge enhances also the consolidation of schema-related information.

Dopamine modulations of reward-driven music memory consolidation.

Music listening provides one of the most significant abstract rewards for humans because hearing music activates the dopaminergic mesolimbic system. Given the strong link between reward, dopamine, and memory, we aimed here to investigate the hypothesis that dopamine-dependent musical reward can drive memory improvements. Twenty-nine healthy participants of both sexes provided reward ratings of unfamiliar musical excerpts that had to be remembered following a consolidation period under three separate conditions: after the ingestion of a dopaminergic antagonist, a dopaminergic precursor, or a placebo. Linear mixed modeling of the intervention data showed that the effect of reward on memory-i.e., the greater the reward experienced while listening to the musical excerpts, the better the memory recollection performance-was modulated by both dopaminergic signaling and individual differences in reward processing. Greater pleasure was consistently associated with better memory outcomes in participants with high sensitivity to musical reward, but this effect was lost when dopaminergic signaling was disrupted in participants with average or low musical hedonia. Our work highlights the flexibility of the human dopaminergic system, which can enhance memory formation not only through explicit and/or primary reinforcers but also via abstract and aesthetic rewards such as music.

Formaldehyde and De/Methylation in Age-Related Cognitive Impairment.

Formaldehyde (FA) is a highly reactive substance that is ubiquitous in the environment and is usually considered as a pollutant. In the human body, FA is a product of various metabolic pathways and participates in one-carbon cycle, which provides carbon for the synthesis and modification of bio-compounds, such as DNA, RNA, and amino acids. Endogenous FA plays a role in epigenetic regulation, especially in the methylation and demethylation of DNA, histones, and RNA. Recently, epigenetic alterations associated with FA dysmetabolism have been considered as one of the important features in age-related cognitive impairment (ARCI), suggesting the potential of using FA as a diagnostic biomarker of ARCI. Notably, FA plays multifaceted roles, and, at certain concentrations, it promotes cell proliferation, enhances memory formation, and elongates life span, effects that could also be involved in the aetiology of ARCI. Further investigation of and the regulation of the epigenetics landscape may provide new insights about the aetiology of ARCI and provide novel therapeutic targets.

4R Tau Modulates Cocaine-Associated Memory through Adult Dorsal Hippocampal Neurogenesis.

The development, persistence and relapse of drug addiction require drug memory that generally develops with drug administration-paired contextual stimuli. Adult hippocampal neurogenesis (AHN) contributes to cocaine memory formation; however, the underlying mechanism remains unclear. Male mice hippocampal expression of Tau was significantly decreased during the cocaine-associated memory formation. Genetic overexpression of four microtubule-binding repeats Tau (4R Tau) in the mice hippocampus disrupted cocaine memory by suppressing AHN. Furthermore, 4R Tau directly interacted with phosphoinositide 3-kinase (PI3K)-p85 and impaired its nuclear translocation and PI3K-AKT signaling, processes required for hippocampal neuron proliferation. Collectively, 4R Tau modulates cocaine memory formation by disrupting AHN, suggesting a novel mechanism underlying cocaine memory formation and provide a new strategy for the treatment of cocaine addiction.SIGNIFICANCE STATEMENT Drug memory that generally develops with drug-paired contextual stimuli and drug administration is critical for the development, persistence and relapse of drug addiction. Previous studies have suggested that adult hippocampal neurogenesis (AHN) plays a role in cocaine memory formation. Here, we showed that Tau was significantly downregulated in the hippocampus in the cocaine memory formation. Tau knock-out (KO) promoted AHN in the hippocampal dentate gyrus (DG), resulting in the enhanced memory formation evoked by cocaine-cue stimuli. In contrast, genetically overexpressed 4R Tau in the hippocampus disrupted cocaine-cue memory by suppressing AHN. In addition, 4R Tau interacted directly with phosphoinositide 3-kinase (PI3K)-p85 and hindered its nuclear translocation, eventually repressing PI3K-AKT signaling, which is essential for hippocampal neuronal proliferation.

Slow oscillation-spindle coupling predicts enhanced memory formation from childhood to adolescence.

Precise temporal coordination of slow oscillations (SO) and sleep spindles is a fundamental mechanism of sleep-dependent memory consolidation. SO and spindle morphology changes considerably throughout development. Critically, it remains unknown how the precise temporal coordination of these two sleep oscillations develops during brain maturation and whether their synchronization indexes the development of memory networks. Here, we use a longitudinal study design spanning from childhood to adolescence, where participants underwent polysomnography and performed a declarative word-pair learning task. Performance on the memory task was better during adolescence. After disentangling oscillatory components from 1/f activity, we found frequency shifts within SO and spindle frequency bands. Consequently, we devised an individualized cross-frequency coupling approach, which demonstrates that SO-spindle coupling strength increases during maturation. Critically, this increase indicated enhanced memory formation from childhood to adolescence. Our results provide evidence that improved coordination between SOs and spindles indexes the development of sleep-dependent memory networks.

CD4+ T cells support polyfunctionality of cytotoxic CD8+ T cells with memory potential in immunological control of tumor.

Polyfunctionality/multifunctionality of effector T cells at the single cell level has been shown as an important parameter to predict the quality of T cell response and immunological control of infectious disease and malignancy. However, the fate of polyfunctional CD8+ CTLs and the factors that control the polyfunctionality of T cells remain largely unknown. Here we show that the acquisition of polyfunctionality on the initial stimulation is a sensitive immune correlate of CTL survival and memory formation. CD8+ T cells with high polyfunctionality, assessed with γ‐interferon and tumor necrosis factor‐α production and surface mobilization of the degranulation marker CD107a, showed enhanced Bcl‐2 expression, low apoptosis, and increased CD127highKLRG1low memory precursor phenotype. Consistent with these observations, CD8+ T cells were found to acquire high frequency of cells with polyfunctionality when stimulated in conditions known to enhance memory formation, such as the presence of CD4+ T cells, interleukin (IL)‐2, or IL‐21. Utilizing T‐cell receptor (TCR) transgenic mouse‐derived CD8+ T cells that express a TCR specific for a tumor‐derived neoantigen, we showed that polyfunctional tumor‐specific CTLs generated in the presence of CD4+ T cells showed long persistence in vivo and induced enhanced tumor regression when adoptively transferred into mice with progressing tumor. Acquisition of polyfunctionality thus impacts CTL survival and memory formation associated with immunological control of tumor.

The effect of intrinsic and extrinsic motivation on memory formation: insight from behavioral and imaging study

Motivation can be generated intrinsically or extrinsically, and both kinds of motivation show similar facilitatory effects on memory. However, effects of extrinsic and intrinsic motivation on memory formation have not been studied in combination and thus, it is unknown whether they interact and how such interplay is neurally implemented. In the present study, both extrinsic monetary reward and intrinsic curiosity enhanced memory performance, without evidence for an interaction. Functional magnetic resonance imaging revealed that curiosity-driven activity in the ventral striatal reward network appears to work cooperatively with the fronto-parietal attention network, while enhancing memory formation. In contrast, the monetary reward-modulated subsequent memory effect revealed deactivation in parietal midline regions. Thus, curiosity might enhance memory performance by allocation of attentional resources and reward-related processes; while, monetary reward does so by suppression of task-irrelevant processing.

Student Perception of Stress in Online and Face-to-Face Learning: The Exploration of Stress Determinants

ABSTRACT Stress during the learning process is thought to enhance memory formation while at the same time hinders memory retrieval. Together like a double-edged sword, stress can have both a positive and negative affect on student outcomes. Congruently, learning online brings unique challenges to students. Two distinct groups of learners at a northeastern (USA) college were measured. Each group was enrolled in the same information technology course. One group received instructional materials and course content online only, while the other group received the same learning materials in a traditional classroom. The overall results show a significant difference in the perceived level of stress associated with student learning in disparate learning environments. These findings suggest new avenues for exploring and understanding what aspects of course delivery modality associated with the student perception of stress and how stress modifies learning outcomes in various learning environments.