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Analyzing the Impact of Chronic Stress on Hippocampal Function: A Systematic Review

Ibero-American Journal of Exercise and Sports Psychology

Research Article - (2025) Volume 20, Issue 4

Analyzing the Impact of Chronic Stress on Hippocampal Function: A Systematic Review

Mawadah Mohammed Hassan jannah1* and Moamen Abdelfadil Ismail2
*Correspondence: Mawadah Mohammed Hassan jannah, Neurology resident, KFAFH, Saudi Arabia, Email:
1Neurology resident, KFAFH, Saudi Arabia
2Consultant, King Abdulaziz specialist hospital-Sakaka-Aljouf, Saudi Arabia

Received: 12-Jun-2025 Published: 17-Jul-2025

Abstract

Background: Chronic stress alters hippocampal structure and function, leading to memory deficits and increased vulnerability to psychiatric disorders (McEwen, 2000; Lupien et al., 2009). Purpose: This systematic review synthesizes evidence from 25 peer-reviewed studies to examine how chronic stress impacts the hippocampus at morphological, molecular, and behavioral levels.

Methods: A comprehensive search was conducted across PubMed, PsycINFO, and Google Scholar using keywords such as “chronic stress,” “hippocampus,” “HPA axis,” and “memory impairment.” Studies were included if they were empirical (spanning animal models, human neuroimaging, and clinical cohorts) and measured specific hippocampal outcomes. Data extraction and quality assessments were performed by two independent reviewers, and results were integrated using a narrative synthesis approach (Kim & Diamond, 2002; Sapolsky, 1996).

Results: The review revealed that chronic stress is associated with reduced hippocampal volume, impaired synaptic plasticity, and deficits in memory performance. Elevated glucocorticoid levels appear to play a pivotal role in initiating neurotoxic effects that lead to morphological and functional changes (Bremner et al., 2003; Vyas et al., 2002).

Discussion: Findings from both animal and human studies converge on the detrimental effects of chronic stress on hippocampal integrity, highlighting the role of stress hormones and the potential reversibility of some alterations with timely interventions.

Conclusion: The accumulated evidence underscores the importance of early stress management strategies and suggests therapeutic targets for alleviating hippocampal dysfunction in stress-related disorders.

Keywords

Chronic Stress. Hippocampus. Memory Impairment. Glucocorticoids. Neuroplasticity

Introduction

Chronic stress is a pervasive factor that exerts profound neurobiological effects on the brain, particularly within the hippocampus-a region paramount to learning, memory, and emotional regulation. The hippocampus is notably sensitive to stress hormones, with both animal models and human studies documenting structural and functional changes following prolonged stress exposure (McEwen, 2000; Lupien, McEwen, Gunnar, & Heim, 2009). This sensitivity makes it a critical focus area for understanding stress-related cognitive deficits and potential psychiatric outcomes.

At the core of these neurobiological changes is the sustained activation of the hypothalamic-pituitary-adrenal (HPA) axis. Chronic activation of this system results in elevated levels of glucocorticoids, such as cortisol in humans and corticosterone in rodents, which have been linked to morphological alterations in the hippocampus (Sapolsky, 1996; Kim & Diamond, 2002). These hormonal changes are believed to drive dendritic retraction, interfere with synaptic plasticity, and ultimately impair the processes of learning and memory.

Research has consistently demonstrated that repeated exposure to stress can lead to a reduction in hippocampal volume. Animal studies have revealed that chronic stress protocols, such as restraint stress, are associated with dendritic atrophy and reduced neurogenesis (Sapolsky, 1996; Vyas et al., 2002). Similarly, human neuroimaging research has indicated that individuals with prolonged stress exposure, including those suffering from post-traumatic stress disorder (PTSD) and depression, frequently exhibit smaller hippocampal volumes compared to control groups (Bremner et al., 2003; Teicher, Anderson, & Polcari, 2012).

Such neuroanatomical changes have significant implications for cognitive function, particularly memory consolidation and retrieval. Studies have shown that reduced hippocampal volume correlates with deficits in memory performance and may also contribute to the ethology of affective disorders (Lupien et al., 2009; Kim & Diamond, 2002). By impairing synaptic plasticity-an essential mechanism for learning—the chronic release of stress hormones not only affects cellular integrity but may also predispose individuals to longer-term psychological challenges.

Understanding the multifaceted impact of chronic stress on hippocampal function is further complicated by the use of diverse methodologies. Researchers have employed a variety of experimental approaches, including animal models that allow for controlled stress exposure and neuroimaging studies that confirm these effects in humans. Reviews and longitudinal studies have been particularly valuable in demonstrating consistent patterns across species and methods, thus highlighting the translational potential of this line of inquiry (McEwen, 2000; Joëls et al., 2004).

Given the central role of the hippocampus in both cognitive and emotional domains, a systematic synthesis of the current literature is essential. This review aims to integrate evidence from 25 studies to explore the associations between chronic stress and hippocampal structure and function. By clarifying the underlying neurobiological mechanisms and identifying gaps in current research, this review seeks to inform both clinical practice and future investigations into therapeutic strategies.

Objectives

  • To evaluate the effects of chronic stress on hippocampal structure and function.
  • To identify key neural mechanisms and pathways implicated in stress-induced hippocampal alterations.
  • To synthesize findings from 25 studies using diverse research methodologies and populations.
  • To discuss the clinical implications of hippocampal changes in stress-related psychopathologies.

Methods

Search Strategy

A comprehensive literature search was conducted using databases such as PubMed, PsycINFO, and Google Scholar. Key search terms included “chronic stress,” “hippocampus,” “HPA axis,” “glucocorticoids,” “synaptic plasticity,” and “memory impairment.” Only studies published in English between 1995 and 2025 were considered.

Inclusion and Exclusion Criteria

  • Inclusion: Empirical studies (clinical, neuroimaging, animal models) addressing chronic stress and hippocampal outcomes; articles that reported quantifiable changes in hippocampal volume or function; review articles that aggregated previous findings.
  • Exclusion: Studies that investigated only acute stress responses; articles with non-empirical commentaries; studies without clear identification of hippocampal outcomes.

Data Extraction

Data extraction was carried out independently by two reviewers to minimize bias and ensure consistency across the selected studies. Extracted data covered authorship, publication year, sample characteristics, study design, specific outcome measures (e.g., hippocampal volume via MRI, synaptic plasticity assays, behavioural cognitive tests), and a summary of the main findings. Any discrepancies between reviewers were resolved through discussion and consultation with a third expert where necessary (Joëls et al., 2004).

Each study’s methodological quality was evaluated using a standardized quality assessment tool that considered sample size, control of extraneous variables, and statistical analysis clarity. This quality check was essential in confirming that studies included in the review provided reliable data regarding the impact of chronic stress on the hippocampus. Studies ranging from animal research with controlled experimental conditions to longitudinal neuroimaging studies in humans were deemed acceptable if they met these quality criteria.

In addition, meta-data concerning stress paradigms (e.g., restraint stress, chronic occupational stress, early life adversity) were recorded to explore potential variations in outcomes. The extracted data were then organized into thematic groups that allowed for a comparative analysis of hippocampal outcomes across different populations and methods. Such thematic synthesis ensured that the review captured both the molecular mechanisms (e.g., glucocorticoid-induced alterations in BDNF expression) and the broader neurobehavioral correlates of chronic stress (Sapolsky, 1996; Teicher et al., 2012).

Finally, data synthesis involved a narrative approach aimed at integrating the findings into a coherent theoretical framework. This framework considers the complex interactions between stress, hippocampal morphology, and behavioural outcomes. The goal was to create a model that identifies not only the direct effects of chronic stress but also the potential moderating influences of genetic, environmental, and developmental factors (McEwen, 2000; Lupien et al., 2009) (Figure 1).

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Figure 1. Prisma Flow Chart 2020.

Results

Overview

The systematic search yielded 25 eligible studies. The studies ranged from controlled animal experiments examining molecular changes to longitudinal clinical studies using high-resolution magnetic resonance imaging (MRI) to assess hippocampal volumes in stressed populations. Most studies reported that chronic stress corresponded with significant declines in hippocampal volume, disrupted synaptic plasticity, and cognitive impairments.

Table of Results

(Table 1) The aggregated evidence suggests that chronic stress has a deleterious effect on hippocampal structure and function. Key trends include:

  • Morphological Changes: Multiple studies (e.g., Sapolsky, 1996; Lupien et al., 2009; Teicher et al., 2012) have reported significant reductions in hippocampal volume associated with chronic stress.
  • Molecular Mechanisms: Changes in BDNF expression, elevated glucocorticoid levels, and reduced neurogenesis appear central to the hippocampal alterations observed (Cordero et al., 2003; Lindholm et al., 2012).
  • Functional Outcomes: Functional MRI studies have consistently demonstrated altered connectivity and activation patterns in the hippocampus during memory tasks in stressed individuals (Dedovic et al., 2009; Liston et al., 2006).

Table 1: The aggregated evidence suggests that chronic stress has a deleterious effect on hippocampal structure and function.

Study Authors (Year) Design & Sample Key Measures Findings Limitations
1 McEwen, B. S. (2000) Review; Animal and human data Glucocorticoid levels; hippocampal morphology Chronic exposure to glucocorticoids reduced hippocampal volume in animal models and correlated with memory deficits in humans. Heterogeneity in study designs.
2 Sapolsky, R. M. (1996) Animal study; Rodent models Histological hippocampal changes; stress biomarkers High corticosterone levels led to dendritic retraction in the hippocampus. Limited generalizability to humans.
3 Lupien, S. J. et al. (2009) Longitudinal human study; Elderly subjects MRI hippocampal volume; cognitive function tests Elevated cortisol associated with hippocampal atrophy and reduced memory performance over time. Confounding factors such as comorbidity.
4 Bremner, J. D. et al. (2003) Clinical; PTSD patients vs. controls MRI-based hippocampal volume; PTSD severity PTSD patients showed smaller hippocampal volumes relative to controls. Retrospective design.
5 Kim, J. J., & Diamond, D. M. (2002) Animal study; Rats with chronic stress exposure Synaptic plasticity measures; LTP/LTD assays Chronic stress impaired long-term potentiation (LTP) in the hippocampus. Limited behavioral correlation.
6 Joëls, M. et al. (2004) Review; Animal and human models Neural plasticity; neuroendocrine responses Integrated evidence linking stress-induced neural remodeling in the hippocampus. Mixed methodologies across studies.
7 Dedovic, K. et al. (2009) Human fMRI study; Healthy volunteers undergoing stress tasks fMRI activation patterns; cortisol levels Acute and chronic stress altered hippocampal activation patterns during memory tasks. Small sample size.
8 McLaughlin, K. A. et al. (2014) Longitudinal; At-risk adolescents Cortisol measures; structural MRI Early life stress predicted reduced hippocampal volume in adolescence. Limited follow-up duration.
9 Cordero, M. I. et al. (2003) Animal study; Rat models under restraint stress Neural plasticity; BDNF expression in the hippocampus Chronic restraint stress decreased BDNF levels, impairing synaptic function. Translational limitations.
10 Conrad, C. D. (2008) Review; Synthesis of behavioral and neuroendocrine studies Hippocampal function markers; behavioral outcomes Chronic stress disrupts hippocampal-dependent learning and memory. Heterogeneity of stress paradigms.
11 McLaughlin, K. A. et al. (2017) Longitudinal human study; Adolescents with early adversity Structural MRI; cortisol assays Early adversity linked with lower hippocampal volume and elevated cortisol. Stress measurement variability.
12 Vaccarino, V. et al. (2007) Clinical; Cardiovascular patients with stress comorbidity MRI hippocampal volume; depressive symptom scales Chronic stress in cardiovascular conditions associated with hippocampal shrinkage. Comorbid condition influence.
13 Vyas, A. et al. (2002) Animal study; Chronic stress rat models Dendritic remodeling; synaptic density measures Stress induced dendritic retraction in hippocampal neurons. Focused solely on morphological changes.
14 McEwen, B. S. & Gianaros, P. J. (2011) Review; Human neuroimaging studies Structural and functional MRI Chronic stress is linked to hippocampal volume loss and cognitive deficits. Review-based synthesis.
15 Hanson, J. L. et al. (2015) Longitudinal study; Childhood adversity MRI; cognitive function tests Early stress predicted smaller hippocampal volumes and poorer memory performance. Potential recall bias in reporting stress.
16 Teicher, M. H. et al. (2012) Clinical; Adults with histories of childhood maltreatment Structural MRI; neuropsychological assessments Childhood maltreatment linked with hippocampal volume reductions and impaired memory. Retrospective design.
17 Frodl, T. et al. (2002) Clinical; Depressed patients under chronic stress MRI hippocampal volume; depression scales Depressed patients with high stress levels had reduced hippocampal volumes. Cross-sectional design.
18 O’Carroll, C. et al. (2011) Human fMRI study; Healthy volunteers under stress paradigms fMRI; hippocampal connectivity analysis Chronic stress altered functional connectivity between the hippocampus and prefrontal cortex. Limited external validity.
19 Pruessner, J. C. et al. (2005) Longitudinal human study; Middle-aged subjects Cortisol levels; hippocampal volume via MRI Elevated cortisol predicted hippocampal volume loss over time. Variability in cortisol measurements.
20 Lindholm, K. et al. (2012) Animal study; Chronic unpredictable stress in mice BDNF expression; hippocampal neurogenesis Chronic unpredictable stress reduced hippocampal neurogenesis and BDNF levels. Direct human comparison limited.
21 Snyder, J. S. et al. (2011) Animal study; Rodent behavioral assays with chronic stress exposure Cognitive behavioral tests; neurogenesis markers Chronic stress impaired spatial memory and reduced hippocampal neurogenesis. Behavioral tests may lack sensitivity.
22 Vythilingam, M. et al. (2002) Clinical; Patients with major depressive disorder MRI hippocampal volume; stress hormone assays Severe chronic stress in depressed individuals was associated with hippocampal atrophy. Potential medication effects.
23 Hanson, J. L. et al. (2012) Pediatric study; Children exposed to chronic family stress MRI; cognitive assessments Chronic family stress correlated with smaller hippocampal volumes in children. Sociodemographic confounds.
24 Gourley, S. L. et al. (2010) Animal study; Stressed rodents tested on memory tasks Synaptic markers; behavioral performance Synaptic alterations in the hippocampus mediated stress-related cognitive deficits. Specific stress models deployed.
25 Liston, C. et al. (2006) Human fMRI study; Adult subjects exposed to chronic occupational stress fMRI; working memory tasks Occupational stress was associated with diminished hippocampal activation during memory tasks. Occupational stress measurement limitations.

Discussion

The corpus of reviewed studies consistently supports that chronic stress leads to both structural and functional impairments in the hippocampus. Animal research highlights that prolonged exposure to stress hormones causes dendritic retraction and a decrease in neurogenesis (Sapolsky, 1996; Vyas et al., 2002). Similarly, human studies utilizing high-resolution MRI have repeatedly demonstrated reductions in hippocampal volume among individuals experiencing chronic stress, such as those with post-traumatic stress disorder or major depressive disorder (Bremner et al., 2003; Teicher et al., 2012). Research investigating the molecular underpinnings of this phenomenon indicates that chronic exposure to glucocorticoids disrupts cellular processes and neurotrophic support, leading to decreased levels of molecules like brain-derived neurotrophic factor that are essential for neuron survival and plasticity (McEwen, 2000; Lupien et al., 2009).

Furthermore, several studies have provided evidence that these structural alterations translate into tangible cognitive deficits. Reduced hippocampal volume has been closely linked with impairments in memory performance and learning, reinforcing the connection between stress-induced neurobiological changes and behavioural outcomes (Kim & Diamond, 2002). The consistency of these findings across both animal and human models underscores the centrality of the hippocampus in stress-related neurocognitive impairments. Although differences in experimental paradigms and measurement techniques complicate direct comparisons, the overall narrative remains that chronic stress disrupts the delicate balance of synaptic plasticity, thereby impairing memory and other hippocampal-dependent functions (Joëls et al., 2004).

The discussion of therapeutic implications is equally critical. Some studies suggest that interventions-ranging from behavioural therapies to pharmacological agents aimed at modulating the HPA axis-could help mitigate or even reverse these hippocampal changes (Conrad, 2008; Snyder et al., 2011). Such findings offer promise for developing targeted strategies that not only reduce stress but also promote neuroplasticity. However, issues such as the timing of the intervention, dosage of treatments, and individual differences in stress reactivity must be considered to optimize therapeutic outcomes.

These findings also call attention to the complexity of stress responses, which are influenced by genetic, environmental, and developmental factors. Early exposure to stress, for example, has been shown to predispose individuals to more profound hippocampal deficits later in life (Hanson et al., 2012; Teicher et al., 2012). This highlights the potential benefits of early prevention and intervention programs. Despite the robust associations observed, the heterogeneity in stress paradigms and methodological approaches across studies necessitates caution in generalizing these results.

Future research should adopt longitudinal frameworks and standardized stress protocols to better delineate the trajectory of hippocampal changes. Integrative approaches combining neuroimaging, molecular assays, and behavioural tests will be instrumental in unravelling the multifactorial relationship between chronic stress and hippocampal dysfunction. Ultimately, the goal is to develop interventions that can protect or restore hippocampal integrity, thereby mitigating the cognitive and emotional deficits associated with prolonged stress (Lupien et al., 2009; McEwen, 2000).

Limitations

While the reviewed studies provide strong evidence, several limitations are noted:

  • Heterogeneity in Stress Models: Variability in chronic stress paradigms (e.g., restraint stress, occupational stress, early life adversity) may influence the generalizability of results.
  • Methodological Variability: Differences in imaging techniques, sample sizes, and analytical methods create challenges in synthesizing findings.
  • Causality: Many studies are correlational or cross-sectional, which limits causal inferences.

Future Directions

Further research should aim to

  • Employ large-scale, longitudinal designs to better establish causal relationships.
  • Utilize standardized stress paradigms across studies for improved comparability.
  • Explore the reversibility of hippocampal alterations with stress reduction interventions or pharmacotherapies.
  • Incorporate multi-modal imaging combined with molecular assays to link structural changes with functional outcomes.

Conclusion

The review synthesizes evidence that chronic stress exerts a significant negative impact on hippocampal structure and function. Elevated levels of stress hormones such as cortisol lead to reduced hippocampal volume, impaired neurogenesis, and disturbances in synaptic plasticity, all of which jointly contribute to deficits in memory and learning. The converging evidence from both animal models and human clinical studies highlights the importance of considering the hippocampus as a critical mediator of stress-related cognitive decline, urging the development of both preventative measures and targeted interventions.

In light of these findings, future research should focus on refining stress paradigms and employing longitudinal designs to more clearly establish the causality and reversibility of hippocampal changes. It is imperative to explore early intervention strategies and pharmacological treatments that modulate the HPA axis and enhance neuroplasticity. Such advances could not only improve our understanding of stress-induced neural mechanisms but also lead to more effective clinical strategies in addressing the neurocognitive sequelae of chronic stress.

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