Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex
Open accessAbstract
The mechanisms and neural circuits that drive emotion and cognition are inextricably linked. Activation of the hypothalamic-pituitary-adrenal (HPA) axis as a result of stress or other causes of arousal initiates a flood of hormone and neurotransmitter release throughout the brain, affecting the way we think, decide, and behave. This review will focus on factors that influence the function of the prefrontal cortex (PFC), a brain region that governs higher-level cognitive processes and executive function. The PFC becomes markedly impaired by stress, producing measurable deficits in working memory. These deficits arise from the interaction of multiple neuromodulators, including glucocorticoids, catecholamines, and gonadal hormones; here we will discuss the non-human primate and rodent literature that has furthered our understanding of the circuitry, receptors, and signaling cascades responsible for stress-induced prefrontal dysfunction.
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Written from the paper’s full text.
TL;DR
This review synthesizes non-human primate and rodent literature showing that stress impairs prefrontal cortex (PFC)-dependent working memory through interacting neuromodulators, principally catecholamines (dopamine and norepinephrine) acting via D1, alpha-1, and alpha-2 receptors, with glucocorticoids and estrogen modulating these effects. It proposes that stress pushes catecholamine signaling to the impairing end of inverted-U curves and that high estrogen may place females "ahead of the curve," increasing stress sensitivity.
Key findings
- Working memory depends on a balanced neurochemical milieu in the PFC; both insufficient and excessive D1 stimulation impair performance, producing the classic "inverted-U" relationship. Stress-induced HPA activation stimulates the VTA, causing excess DA release into the PFC, and these impairments can be reversed by intra-PFC D1 antagonist infusion or by cAMP and PKA inhibitors.
- Under stress, excess NE binds the lower-affinity alpha-1 receptor (rather than the high-affinity alpha-2 receptor active under non-stress conditions), impairing working memory and silencing PFC network activity; alpha-1 antagonists restore PFC function during stress, and PKC inhibition also reverses stress-related working memory impairments.
- Mechanistically, elevated D1 signaling opens HCN channels (via cAMP) on dendritic spines, shunting incoming excitation and suppressing both "noise" and "signal" neurons; alpha-2 receptor activation (Gi-coupled, lowering cAMP) slows HCN conductance and strengthens signal. Pharmacological HCN blockade restores working memory performance and PFC network tuning during stress.
- Glucocorticoids impair PFC working memory directly via GRs (systemic corticosterone reduces Delayed Alternation accuracy; intra-PFC RU 28362 impairs working memory; intra-PFC RU 38486 reverses stress-induced DSWS impairments) and indirectly by blocking extraneuronal catecholamine transporters and by locally driving stress-induced DA efflux in the PFC.
- In female rats, stress sensitivity is driven by high-estrogen phases: females became impaired after lower doses of FG7142 than males, driven by proestrus females; OVX + estrogen rats show impairments similar to proestrus females while OVX + blank-capsule rats perform more like males. A guanfacine dose that rescues stress-induced impairments in males and OVX females has no effect in OVX + estrogen rats.
Methods
- Narrative review of non-human primate and rodent literature on stress-induced PFC dysfunction, covering electrophysiology, pharmacology (receptor agonists/antagonists, cAMP/PKA/PKC inhibitors), microdialysis, lesion, and behavioral studies.
- Behavioral paradigms discussed: Delayed Response task (monkeys), Delayed Alternation and delayed spatial win-shift (DSWS) tasks (rodents); stressors include loud white noise, brief restraint stress, and the anxiogenic drug FG-7142.
- Sex-difference evidence drawn from dose-response studies with FG7142 and restraint stress in male and female rats, including ovariectomized rats with and without estrogen replacement.
Limitations
- The paper states that the vast majority of behavioral neuroscience research is conducted in male animals, so general understanding of stress effects in the PFC is within the context of the male brain, which is problematic from a translational standpoint given that stress-related illnesses like PTSD and major depressive disorder are twice as prevalent in women.
- The paper states that the mechanisms by which estrogen modulates stress-induced impairments are not known, and that estrogen-glucocorticoid interactions have not been investigated in the context of stress-induced working memory impairments.
- Evident from the text: the review is based entirely on animal (non-human primate and rodent) literature, and the estrogen "ahead of the curve" hypothesis is presented as a model (Figure 2) rather than a directly tested mechanism.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
4 of 9 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured
- Interpretationnone given
Stress-induced working memory deficits arise from the interaction of multiple neuromodulators, including glucocorticoids, catecholamines, and gonadal hormones.
“These deficits arise from the interaction of multiple neuromodulators, including glucocorticoids, catecholamines, and gonadal hormones; here we will discuss the non-human primate and rodent literature that has furthered our understanding of the circuitry, receptors, and signaling cascades responsible for stress-induced prefrontal dysfunction.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from non-human primate and rodent studies of stress-induced prefrontal dysfunction generalize to humans.
- Premisecitation
High estrogen levels confer sensitivity to stress-induced working memory impairments.
“When the authors divided the females based on estrus cycle phase, they found that this stress sensitivity was driven by females in proestrus, when estrogen levels are highest.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shansky et al., 2004 source
- May combine two claims. 6
May combine two claims.
PremisecitationD1 receptor activity has an inverted-U effect on working memory: both blockade and excessive stimulation impair performance, and stress causes excess dopamine release that impairs working memory via D1 signaling.
“While a lack of D1 activity can impair working memory performance, high levels of D1 stimulation also produce cognitive deficits—the classic “inverted-U” relationship.”
- Also stated in: § Dopamine and norepinephrine · plain
“During stress, HPA axis activation leads to stimulation of the VTA, causing excess DA release into the PFC (Murphy et al., 1996). When this DA binds to the D1 receptor, its downstream signaling cascades lead to working memory impairment (Taylor et al., 1999).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Murphy et al., 1996 source
- cites Taylor et al., 1999 source
The section “Possible relevance of PKA activation to stress-induced PFC dysfunction” reports that high D1 stimulation impairs working memory and contributes to stress-induced deficits. It does not establish that D1 blockade impairs working-memory performance, so it does not support both sides of the claimed inverted-U relationship. The section also does not explicitly say that stress causes excess dopamine release. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Also stated in: § Dopamine and norepinephrine · plain
May combine two claims.
InterpretationcitationStress-related mental illnesses like PTSD and major depressive disorder are twice as prevalent in women, suggesting a distinct neurobiology may underlie the stress response in female brains.
“stress-related mental illnesses like post-traumatic stress disorder (PTSD) and major depressive disorder are twice as prevalent in women (Becker et al., 2007), suggesting a distinct neurobiology may underlie the stress response in female brains.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Becker et al., 2007 source
The “Stress and affective disorders” section says women experience depression at approximately twice the rate of men. The “Sex differences in clinical studies” section discusses sex differences in PTSD risk but does not give a twofold prevalence figure for PTSD. The citation therefore supports the depression figure, not its extension to both disorders. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationExposure to stress disrupts prefrontal cortex function, markedly impairing working memory.
“Exposure to stress, however, can disrupt PFC function, markedly impairing working memory (Arnsten, 2009; Arnsten et al., 2012).”
- Also stated in: § Abstract · plain
“The PFC becomes markedly impaired by stress, producing measurable deficits in working memory.”
Quote in the paperSubstantial claim2 of 2 sources checked- Rests on an assumption: Findings from non-human primate and rodent studies of stress-induced prefrontal dysfunction generalize to humans.
- Also stated in: § Abstract · plain
May combine two claims.
PremisecitationAlpha-2 receptor stimulation enhances working memory, while alpha-1 receptor stimulation during stress impairs working memory and silences prefrontal cortex network activity.
“Pharmacological stimulation of the alpha-2 receptor can increase firing in PFC neurons that code for relevant information, enhancing working memory in monkeys and rodents (Wang et al., 2007).”
- Also stated in: § Dopamine and norepinephrine · plain
“Stimulation of this receptor—either pharmacologically or because of stress-induced NE release—leads to working memory impairment and a silencing of PFC network activity (Arnsten et al., 1999).”
Quote in the paperSubstantial claim0 of 2 sources checked- Also stated in: § Dopamine and norepinephrine · plain
May combine two claims.
InterpretationreasoningStress-induced working memory impairment is driven by increased catecholamine signaling, which may be further modulated or exacerbated by changes in steroid hormone levels.
“Research in non-human primates and rodents has shown that this impairment is driven by increased catecholamine signaling, which may be further modulated or exacerbated by changes in steroid hormone levels.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from non-human primate and rodent studies of stress-induced prefrontal dysfunction generalize to humans.
May combine two claims.
InterpretationreasoningGlucocorticoid actions in the prefrontal cortex impair working memory and may indirectly exacerbate working memory impairments through interactions with catecholamine systems.
“While this release is critical to the enhancement of long term memories associated with the event (Rodrigues et al., 2009), glucocorticoid actions in the PFC impair working memory.”
- Also stated in: § Glucocorticoids · hedged
“These findings suggest that glucocorticoids can impair PFC function through direct actions at GRs, but glucocorticoids may also indirectly exacerbate working memory impairments through interactions with the catecholamine systems described above.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rodrigues et al., 2009 source
- Also stated in: § Glucocorticoids · hedged
The paper relies on this without support.
Findings from non-human primate and rodent studies of stress-induced prefrontal dysfunction generalize to humans.
“here we will discuss the non-human primate and rodent literature that has furthered our understanding of the circuitry, receptors, and signaling cascades responsible for stress-induced prefrontal dysfunction.”
The paper relies on this without support.
Working memory tasks in animals measure the same executive function as human working memory.
“Working memory in animals is assessed using delay-based tasks, which require an animal to keep a piece of information in mind over the course of a delay period, in order to make an accurate choice when the delay ends.”
The paper relies on this without support.
The prefrontal cortex helps to shut down the stress response.
“Because the PFC also helps to shut down the stress response, this loss of PFC function can lead to prolonged glucocorticoid release, which can exacerbate working memory impairments.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Opposite directions given for ion flow through open HCN channels
MinorThe text first says that open HCN channels allow positive ions into the cell, then says that opening the same channels lets Na+ and K+ flow out. It does not explain the reversal in direction.
“Traditionally, HCN channels serve to normalize neuronal membrane potential, opening to allow positive ions into the cell to combat post-firing hyperpolarization (Wahl-Schott and Biel, 2009).”
“when cAMP increases (as happens when D1 receptors are over-activated), HCN channels open, letting Na+ and K+ flow out of the cell (Chen et al., 2007).”
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“Under stress, however, the LC releases NE throughout the brain and excess NE in the PFC binds instead to the loweraffinity alpha-1 receptor (Mohell et al., 1983).”
BackgroundPickel, V., Colago, E. E., Mania, I., Molosh, A., & Rainnie, D. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.06.059 · Cited by 59 · cited 1× · see citing works
“Electron micrographs show that D1 receptors co-localize with glutamate receptors on dendritic spines (Pickel et al., 2006, and see Figure 1), making them strategically positioned to modulate incoming excitatory information.”
BackgroundChen, S., Wang, J., Zhou, L., et al. (2007) · The Journal of General Physiology · doi:10.1085/jgp.200609585 · Cited by 55 · cited 1× · see citing works
“But as their name implies, HCN channels are also sensitive to changes in cAMP levels, and when cAMP increases (as happens when D1 receptors are over-activated), HCN channels open, letting Na+ and K+ flow out of the cell (Chen et al., 2007).”
BackgroundEffects of benzodiazepines receptor agonists on the hypothalamic–pituitary–adrenocortical axis
Mikkelsen, J. D., Søderman, A., Kiss, A., & Mirza, N. R. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2005.06.049 · Cited by 50 · see citing works
Goldman-Rakic, P. S. (2003) · The MIT Press eBooks · doi:10.7551/mitpress/2834.003.0032 · Cited by 48 · see citing works
Shansky, R., Bender, G., & Arnsten, A. (2009) · Stress · doi:10.1080/10253890802520988 · Cited by 29 · cited 4× · see citing works
“…no-stress conditions, but mild stress shifts high-estrogen animals down into the far end of the D1 inverted U, while only pushing low-estrogen animals slightly across the middle. impairments in males and OVX female rats has no effect in OVX rats with estrogen replacement (Shansky et al., 2009).”
BackgroundInfluentialSelf-citationReceptor Phosphorylation Mediates Estradiol
Ansonoff, M. A., & Etgen, A. M. (2001) · Endocrine · doi:10.1385/endo:14:2:165 · Cited by 29 · cited 1× · see citing works
“Estrogen uncouples the alpha-2a receptor from its G-protein (Ansonoff and Etgen, 2001), thus potentially disrupting the delicate balance of D1 and alpha-2a activity that is required for optimal PFC function.”
BackgroundNeurobiology of Attention Regulation and Its Disorders
Arnsten, A. F. T., & Castellanos, F. X. (2010) · Oxford University Press eBooks · doi:10.1093/med/9780195398212.003.0007 · Cited by 15 · cited 2× · see citing works
“INTRODUCTION Our ability to manage, update, and act on information in the absence of external cues—executive functions collectively known as working memory—is critical to daily functioning (Arnsten and Castellanos, 2002).”
BackgroundPharmacologic Alternatives to Antidepressants in Posttraumatic Stress Disorder: A Systematic Review
Berger, W. L., Portella, C. M., Mendlowicz, M. V., et al. (2008) · PsycEXTRA Dataset · doi:10.1037/e517302011-305 · Cited by 13 · see citing works
THIERRY, A. M., GODBOUT, R., MANTZ, J., PIROT, S., & GLOWINSKI, J. (1992) · Clinical Neuropharmacology · doi:10.1097/00002826-199201001-00075 · Cited by 7 · cited 2× · see citing works
“hormone-neurotransmitter interactions in the prefrontal cortex”
BackgroundArnsten, A. F. T., & Goldman-Rakic, P. S. (1998) · Archives of General Psychiatry · doi:10.1001/archpsyc.55.4.362 · Cited by 6 · see citing works
Neurobiology of attention regulation and its disorders
Arnsten, A. F. T., & Castellanos, F. X. (2002) · doi:10.1093/oso/9780195141733.003.0008 · Cited by 3 · see citing works
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Shields, G. S., Sazma, M. A., & Yonelinas, A. P. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.038 · Cited by 818 · see citing works
The effects of acute stress on episodic memory: A meta-analysis and integrative review.
Shields, G. S., Sazma, M. A., McCullough, A. M., & Yonelinas, A. P. (2017) · Psychological Bulletin · doi:10.1037/bul0000100 · Cited by 450 · see citing works
“For example, stress first exerts rapid effects in the brain by producing a surge in both dopaminergic and noradrenergic activity within the prefrontal cortex (Arnsten, 2009; Shansky & Lipps, 2013).”
Gonadal steroid hormones and the hypothalamo–pituitary–adrenal axis
Handa, R. J., & Weiser, M. J. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2013.11.001 · Cited by 408 · see citing works
“Moreover, the changes in glucocorticoids that arise following environmental perturbations can also impact numerous behaviors through actions at other brain regions (Weiser and Handa, 2009, for review see: (Shansky and Lipps, 2013)).”
BackgroundPatki, G., Solanki, N., Atrooz, F., Allam, F., & Salim, S. (2013) · Brain Research · doi:10.1016/j.brainres.2013.09.033 · Cited by 380 · see citing works
Sex differences in anxiety disorders: Interactions between fear, stress, and gonadal hormones
Maeng, L. Y., & Milad, M. R. (2015) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.04.002 · Cited by 374 · see citing works
James, K. A., Stromin, J., Steenkamp, N., & Combrinck, M. I. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1085950 · Cited by 461 · see citing works
Okon-Singer, H., Hendler, T., Pessoa, L., & Shackman, A. J. (2015) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2015.00058 · Cited by 371 · see citing works
“The molecular basis of emotion’s deleterious impact on working memory is reviewed by Shansky and Lipps (2013).”
BackgroundCortisol and DHEA in development and psychopathology
Kamin, H. S., & Kertes, D. A. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2016.11.018 · Cited by 311 · see citing works
“For instance, stress-induced cortisol release in the prefrontal cortex (PFC) leading to overstimulation of dopamine D1 and α1 noradrenergic receptors has been linked to impaired PFC function and deficits in working memory (Shansky and Lipps, 2013).”
BackgroundPsychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and naïve adult mice
Liu, Y.-W., Liu, W., Wu, C.-C., Juan, Y.-C., Wu, Y.-C., Tsai, H.-P., Wang, S. Z., & Tsai, Y.-C. (2015) · Brain Research · doi:10.1016/j.brainres.2015.11.018 · Cited by 290 · see citing works
“PFC is known to be a highly evolved brain region that is responsible for regulating working memory, decision-making, and emotions, including stress response (Shansky and Lipps, 2013).”
Effect of acute hypoxia on cognition: A systematic review and meta-regression analysis
McMorris, T., Hale, B. J., Barwood, M. J., Costello, J. T., & Corbett, J. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.019 · Cited by 265 · see citing works
“The activation of α1-adrenoceptors 313 reduces neuronal firing, while increased stimulation of D1-receptors and β-adrenoceptors induces 314 even greater activity of the second messenger, cyclic adenosine monophosphate, which dampens 315 all neuronal activity, thus weakening the signal to ‘noise’ ratio (Arnsten, 2011).”
Radley, J., Morilak, D., Viau, V., & Campeau, S. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.06.018 · Cited by 339 · see citing works
“…length and branching, and decreases in spine density in the apical dendritic tree (Cook and Wellman, 2004; Liston et al., 2006; Liu and Aghajanian, 2008; Martin and Wellman, 2011; Radley et al., 2005; Radley et al., 2006b; Radley et al., 2008a; Radley et al., 2004; Shansky and Lipps, 2013).”
BackgroundNeural Circuit Motifs in Valence Processing
Tye, K. M. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.001 · Cited by 247 · see citing works
McMorris, T. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.08.011 · Cited by 188 · see citing works
“Furthermore, within the PFC, 329 glucocorticoids further stimulate activation of α1-adrenoceptors and D1-receptors [98].”
Calhoun, C. D., Stone, K. J., Cobb, A. R., Patterson, M. W., Danielson, C. K., & Bendezú, J. J. (2022) · Psychiatric Quarterly · doi:10.1007/s11126-022-10003-w · Cited by 199 · see citing works
“, ventromedial prefrontal cortex) [55].”
The neurobiology of alcohol consumption and alcoholism: An integrative history
Tabakoff, B., & Hoffman, P. L. (2013) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2013.10.009 · Cited by 135 · see citing works
McLaughlin, R. J., Hill, M. N., & Gorzalka, B. B. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.02.006 · Cited by 130 · see citing works
Hwang, J., Brothers, R. M., Castelli, D. M., Glowacki, E. M., Chen, Y. T., Salinas, M. M., Kim, J., Jung, Y., & Calvert, H. G. (2016) · Neuroscience Letters · doi:10.1016/j.neulet.2016.07.033 · Cited by 126 · see citing works
“cerebral blood flow [18], arousal level [9], and neurotransmitters [23].”
BackgroundCognitive enhancement by transcranial laser stimulation and acute aerobic exercise
Hwang, J., Castelli, D. M., & Gonzalez-Lima, F. (2016) · Lasers in Medical Science · doi:10.1007/s10103-016-1962-3 · Cited by 118 · see citing works
Munshi, S., Loh, M. K., Ferrara, N., DeJoseph, M. R., Ritger, A., Padival, M., Record, M. J., Urban, J. H., & Rosenkranz, J. A. (2020) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2019.11.023 · Cited by 117 · see citing works
“(ii) Stress causes cognitive impairment (Yuen et al., 2012; Shansky and Lipps, 2013).”
Age-dependent postoperative cognitive impairment and Alzheimer-related neuropathology in mice
Xu, Z., Dong, Y., Wang, H., Culley, D. J., Marcantonio, E. R., Crosby, G. J., Tanzi, R. E., Zhang, Y., & Xie, Z. (2014) · Scientific Reports · doi:10.1038/srep03766 · Cited by 106 · see citing works
Moser, J. S., Moran, T. P., Kneip, C., Schroder, H. S., & Larson, M. J. (2016) · Psychophysiology · doi:10.1111/psyp.12509 · Cited by 96 · see citing works
“Sex differences in cognition and emotion are particularly active areas of research (Bangasser & Valentino, 2014; Cahill, 2006, 2012, 2014; Ingalhalikar et al., 2014; Shansky & Lipps, 2013).”
Epperson, C. N., Sammel, M. D., Bale, T. L., Kim, D. R., Conlin, S. E., Scalice, S., Freeman, K., & Freeman, E. W. (2017) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.16m10662 · Cited by 96 · see citing works
Acute stress impairs cognitive flexibility in men, not women
Shields, G. S., Trainor, B. C., Lam, J. C., & Yonelinas, A. P. (2016) · Stress · doi:10.1080/10253890.2016.1192603 · Cited by 93 · see citing works
“Similarly, sex differences in dopaminergic activity exist, and dopamine is important for executive functioning (Shansky & Lipps, 2013).”
BackgroundCorticotropin-Releasing Factor (CRF) circuit modulation of cognition and motivation
Hupalo, S., Bryce, C. A., Bangasser, D. A., Berridge, C. W., Valentino, R. J., & Floresco, S. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.06.010 · Cited by 90 · see citing works
“fear conditioning and memory) dependent on subcortical regions (Wingard and Packard, 2008; Arnsten, 2009; Luethi et al., 2009; Roozendaal et al., 2009; Barsegyan et al., 2010; Shansky and Lipps, 2013).”
BackgroundWong, J. C., Scott, T. M., Wilde, P., Li, Y.-G., Tucker, K. L., & Gao, X. (2016) · Journal of Nutrition · doi:10.3945/jn.115.228700 · Cited by 84 · see citing works
Helpman, L., Zhu, X., Suarez-Jimenez, B., Lazarov, A., Monk, C., & Neria, Y. (2017) · Current Psychiatry Reports · doi:10.1007/s11920-017-0854-y · Cited by 82 · see citing works
“These sex differences appear not only to involve HPA response but also interaction with hypothalamic-pituitary-gonadal (HPG) axis activations, whereas estrogen, a gonadal steroid hormone, appears to modulate effects of both GC [104] and PAC1 [105].”
BackgroundCórdova, A., Caballero-García, A., Drobnic, F., Roche, E., & Noriega, D. C. (2023) · Healthcare · doi:10.3390/healthcare11121787 · Cited by 108 · see citing works
“It has rapid effects by producing an increase in dopaminergic and noradrenergic activity in the prefrontal cortex [44,45].”
BackgroundLucantonio, F., Caprioli, D., & Schoenbaum, G. M. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.05.033 · Cited by 76 · see citing works
“Interestingly, similar to what we have shown with cocaine exposure, stress seems to modulate prefrontal cortex mechanisms and dorsolateral striatum processes in a way that biases towards model-free strategies (Shansky and Lipps, 2013).”
BackgroundDifferences in Coping Strategies Between Young and Older Adults: The Role of Executive Functions
Nieto, M., Ayuso, D. M. R., Ros, L., Zabala, C., Martínez, M., Ricarte, J. J., Serrano, J. P., & Latorre, J. M. (2019) · The International Journal of Aging and Human Development · doi:10.1177/0091415018822040 · Cited by 73 · see citing works
“Stress is generally thought to impair executive functioning (Diamond, 2013; Shansky & Lipps, 2013).”
BackgroundNegrón-Oyarzo, I., Aboitiz, F., & Fuentealba, P. (2016) · Neural Plasticity · doi:10.1155/2016/7539065 · Cited by 75 · see citing works
“Therefore, connecting this evidence, it has been suggested that chronic stress affects the accurate functioning of the PFC [33, 34], which is expressed as the maladaptive generation of behavioral responses observed in neuropsychiatric disorders.”
BackgroundStress and cognition: A user’s guide to designing and interpreting studies
Shields, G. S. (2020) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2019.104475 · Cited by 80 · see citing works
Acute psychosocial stress effects on memory performance: Relevance of age and sex
Hidalgo, V., Pulopulos, M. M., & Salvador, A. (2018) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2018.11.013 · Cited by 69 · see citing works
Glucocorticoids and cognitive function: a walkthrough in endogenous and exogenous alterations
Alcubierre, D. D., Ferrari, D., Mauro, G. C. D., Isidori, A. M., Tomlinson, J., & Pofi, R. (2023) · Journal of Endocrinological Investigation · doi:10.1007/s40618-023-02091-7 · Cited by 71 · see citing works
“This has to be taken into account both from a functional and structural point of view [129, 130], as degeneration of hippocampal neurons [131], and related impaired performance on declarative memory tasks [132] have been described in AI patients.”
BackgroundPatki, G., Solanki, N., Atrooz, F., Ansari, A., Allam, F., Jannise, B., Maturi, J., & Salim, S. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.04.011 · Cited by 67 · see citing works
Corrêa, M. S., Vedovelli, K., Giacobbo, B. L., de Souza, C. E. B., Ferrari, P., Argimon, I. I. D. L., Walz, J. C., Kapczinski, F. P., & Bromberg, E. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.11.052 · Cited by 67 · see citing works
Alcohol Effects on Stress Pathways
Blaine, S. K., Milivojevic, V., Fox, H. C., & Sinha, R. (2016) · The Canadian Journal of Psychiatry · doi:10.1177/0706743716632512 · Cited by 60 · see citing works
Solianik, R., Sujeta, A., Terentjevienė, A., & Skurvydas, A. (2016) · BioMed Research International · doi:10.1155/2016/1503956 · Cited by 58 · see citing works
“It is well established that the brain is a target of stress and that the prefrontal cortex is the brain area that is most sensitive to its effects [14, 15]; the prefrontal complex is responsible for highest-order cognitive abilities, such as executive functions [14, 16].”
BackgroundBrazaitis, M., Eimantas, N., Daniusevičiūtė, L., Mickevičienė, D., Steponavičiūtė, R., & Skurvydas, A. (2014) · PLoS ONE · doi:10.1371/journal.pone.0109020 · Cited by 57 · see citing works
“Stressful events can lead to immediate and marked impairments in working memory, which is an executive function [57].”
BackgroundAcute Stress Attenuates Cognitive Flexibility in Males Only: An fNIRS Examination
Kalia, V., Vishwanath, K., Knauft, K. M., Vellen, B. V. D., Luebbe, A. M., & Williams, A. L. (2018) · Frontiers in Psychology · doi:10.3389/fpsyg.2018.02084 · Cited by 57 · see citing works
Role of epigenetic factors in the development of mental illness throughout life
Guintivano, J., & Kaminsky, Z. A. (2014) · Neuroscience Research · doi:10.1016/j.neures.2014.08.003 · Cited by 54 · see citing works
Chauhan, N. R., Kumar, R., Gupta, A., Meena, R. C., Nanda, S., Mishra, K. P., & Singh, S. B. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112895 · Cited by 54 · see citing works
Tai, F., Wang, C., Xin, D., Li, R., Guo, Z., Quan, H., & Li, S. (2020) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2020.08.025 · Cited by 53 · see citing works
Royer, M. F., Guerithault, N., Braden, B. B., Laska, M. N., & Bruening, M. M. (2021) · International Journal of Translational Medicine · doi:10.3390/ijtm1030015 · Cited by 50 · see citing works
Valros, A., Palander, P., Heinonen, M., Munsterhjelm, C., Brunberg, E., Keeling, L. J., & Piepponen, P. T. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2015.02.049 · Cited by 47 · see citing works
“The function of the prefrontal cortex, which governs higher-level cognitive processes, can be negatively altered by stress, causing changes in behavior [40].”
Mizuki, D., Matsumoto, K., Tanaka, K., Le, X. T., Fujiwara, H., Ishikawa, T., & Higuchi, Y. (2014) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2014.08.014 · Cited by 46 · see citing works
“…anti-depressant-like effect in UCMS animals, we first analyzed the serum corticosterone level as a biomarker of excess activation of the HPA axis (Shansky and Lipps, 2013) since it plays an important role not only in therapeutic mechanisms of antidepressant drugs (Kim et al., 2013) but also in…”
BackgroundRole of neuroinflammation and sex hormones in war-related PTSD.
Mendoza, C., Barreto, G., Avila-Rodriguez, M. F., & Echeverría, V. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.05.016 · Cited by 43 · see citing works
Landau, A. M., Dyve, S., Jakobsen, S., Alstrup, A. K. O., GJEDDE, A. H., & Doudet, D. J. (2015) · Brain stimulation · doi:10.1016/j.brs.2015.02.003 · Cited by 43 · see citing works
Geissler, C. F., Friehs, M. A., Frings, C., & Domes, G. (2022) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2022.105998 · Cited by 44 · see citing works
Sex-related differences in attention and memory
Solianik, R., Brazaitis, M., & Skurvydas, A. (2016) · Medicina · doi:10.1016/j.medici.2016.11.007 · Cited by 44 · see citing works
“Furthermore, it is known that sex hormones can affect neurotransmitter levels responsible for cognition [2,18,21], thus women were tested during the early follicular phase when estradiol and progesterone levels are low.”
Backgroundd-serine prevents cognitive deficits induced by acute stress
Guercio, G. D., Bevictori, L. E., Vargas-Lopes, C., Madeira, C., Oliveira, A. F., Carvalho, V. F., d’Avila, J. C., & Panizzutti, R. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.06.021 · Cited by 41 · see citing works
“In fact, stress is a known regulator of many other pathways in the brain, including the dopaminergic and the endocannabinoid systems (Hill and McEwen 2010; Shansky and Lipps, 2013).”
Plieger, T., Felten, A., Splittgerber, H., Duke, É., & Reuter, M. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2017.10.020 · Cited by 40 · see citing works
Acute stress and working memory in older people
Pulopulos, M. M., Hidalgo, V., Almela, M., Puig‐Pérez, S., Villada, C., & Salvador, A. (2015) · Stress · doi:10.3109/10253890.2015.1004538 · Cited by 40 · see citing works
Chanana, P., & Kumar, A. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00084 · Cited by 37 · see citing works
Effect of Cold Stress on Neurobehavioral and Physiological Parameters in Rats
Elmarzouki, H., Aboussaleh, Y., Najimi, M., Chigr, F., & Ahami, A. O. T. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.660124 · Cited by 38 · see citing works
Successful voluntary recruitment of cognitive control under acute stress
Plessow, F., Schade, S., Kirschbaum, C., & Fischer, R. (2017) · Cognition · doi:10.1016/j.cognition.2017.06.016 · Cited by 36 · see citing works
“Currently, the most common view on how stress affects cognitive control converges on the assumption that acute uncontrollable stress impairs prefrontal cortex (PFC)-dependent cognitive functions, including cognitive control (Arnsten, 2009; Shansky & Lipps, 2013; Shields, Sazma, & Yonelinas, 2016).”
Corrêa, M. S., de Lima, D. B., Giacobbo, B. L., Vedovelli, K., Argimon, I. I. D. L., & Bromberg, E. (2018) · Stress · doi:10.1080/10253890.2018.1510485 · Cited by 35 · see citing works
“…and BDNF levels seem to play a key role on prefrontal and hippocampal dysfunctions, leading to the impairment of cognitive components such as attention, executive function and different memory types (Kim, Pellman, & Kim, 2015; Lu, Nagappan, & Lu, 2014; Pluchino et al., 2015; Shansky & Lipps, 2013).”
BackgroundSleep, cognition and cortisol in addison’s disease: a mechanistic relationship
Henry, M., Thomas, K. G. F., & Ross, I. L. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.694046 · Cited by 34 · see citing works
Cognitive emotion regulation and stress: a multiple mediation approach
Miklósi, M., Martos, T., Szabó, M., Kocsis-Bogár, K., & Forintos, D. P. (2014) · Translational Neuroscience · doi:10.2478/s13380-014-0207-9 · Cited by 33 · see citing works
“Executive functions depend on the structural and functional integrity of the prefrontal cortex (PFC) [19], which guides emotions and behaviour through projections to subcortical regions like the hypothalamus and the amygdala [20].”
BackgroundBrazaitis, M., Eimantas, N., Daniusevičiūtė, L., Vitkauskienė, A., Paulauskas, H., & Skurvydas, A. (2015) · International Journal of Hyperthermia · doi:10.3109/02656736.2015.1004135 · Cited by 32 · see citing works
“High environmental temperature impairs neuromuscular [1–4], aerobic [5], and cognitive performance [1,6,7,8–10] and the ability to activate skeletal muscles [1,11].”
BackgroundA paradoxical switch: the implications of excitatory GABAergic signaling in neurological disorders
McArdle, C. J., Arnone, A. A., Heaney, C. F., & Raab‐Graham, K. F. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1296527 · Cited by 33 · see citing works
“For example, stress is associated with anxiety and substance use disorders (172, 173), cognitive dysfunction is present in both stress-related disorders and AD (174, 175), and epileptogenesis occurs in both autism spectrum disorders (ASD) and Alzheimer’s disease patients (176–178).”
BackgroundMualem, R., Morales-Quezada, L., Farraj, R. H., Shance, S., Bernshtein, D. H., Cohen, S., Mualem, L., Salem, N., Yehuda, R. R., Zbedat, Y., et al. (2024) · Frontiers in Public Health · doi:10.3389/fpubh.2024.1376075 · Cited by 48 · see citing works
Solianik, R., Skurvydas, A., Mickevičienė, D., & Brazaitis, M. (2014) · Cryobiology · doi:10.1016/j.cryobiol.2014.08.007 · Cited by 28 · see citing works
Episodic memory impairment in Addison’s disease: results from a telephonic cognitive assessment
Henry, M., & Thomas, K. G. F. (2014) · Metabolic Brain Disease · doi:10.1007/s11011-014-9511-x · Cited by 30 · see citing works
“The effects of cortisol on the hippocampus and PFC can affect memory processes because both of those regions play integral roles in memory processing, and both have dense concentrations of glucocorticoid receptors (Schacter and Wagner 1999; Alderson and Novack 2002; Kim and Diamond 2002; Shansky and Lipps 2013).”
Gargus, M., Ben‐Azu, B., Landwehr, A., Dunn, J., Errico, J. P., & Tremblay, M. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1527842 · Cited by 32 · see citing works
Solianik, R., Sujeta, A., & Čekanauskaitė, A. (2018) · Experimental Brain Research · doi:10.1007/s00221-018-5305-4 · Cited by 28 · see citing works
Empathy in pregnant women and new mothers: a systematic literature review
Boorman, R. J., Creedy, D. K., Fenwick, J., & Muurlink, O. T. (2018) · Journal of Reproductive and Infant Psychology · doi:10.1080/02646838.2018.1525695 · Cited by 29 · see citing works
“Cognitive deficits are apparent during periods of stress (Shansky & Lipps, 2013) as well as pregnancy and postpartum (Davies, Lum, Skouteris, Byrne, & Hayden, 2018).”
BackgroundPsychoneuroendocrinology of Stress
Gunnar, M., Doom, J., & Esposito, E. A. (2015) · Wiley eBooks · doi:10.1002/9781118963418.childpsy304 · Cited by 14 · see citing works
Missing expectations: Windlass tourniquet use without formal training yields poor results
Dennis, A. J., Bajani, F., Schlanser, V. L., et al. (2019) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0000000000002431 · Cited by 28 · see citing works
Albertini, G., Walrave, L., Demuyser, T., Massie, A., Bundel, D. D., & Smolders, I. J. (2017) · Epilepsia · doi:10.1111/epi.13943 · Cited by 28 · see citing works
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Dopamine effects on stress-induced working memory deficits
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“Additional complexity is added by the fact that a subset of midbrain DA neurons may also corelease the excitatory neurotransmitter glutamate (Stuber et al., 2010; Hnasko et al., 2010, 2012) or GABA (Stamatakis et al., 2013).”
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“Stress exposure induces several changes in the body, among which the most important is activation of the hypothalamo-pituitary-adrenal (HPA) axis (Shansky and Lipps 2013).”
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“With regard to E2 concentrations and task specificity, one possibility is that E2 influences cognitive function involving tasks reliant on the PFC, through the DA system (Shansky and Lipps, 2013).”
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Behavioral Neuroadaptation to Alcohol: From Glucocorticoids to Histone Acetylation
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- Authors
- Shansky, R. M., & Lipps, J.
- Affiliations
- Northeastern University (US)
- Corresponding author
- Shansky, Rebecca M.
- ORCID
- Shansky, Rebecca M.
- Venue
- Frontiers in Human Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2013
- Volume
- 7
- Pages
- 123-123
- ISSN
- 1662-5161 (ISSN-L)
- PMC
- PMC3617365
- OpenAlex
- W1977773662
- Semantic Scholar
- c29a390e82744bcb70b04e0c370134134cc8802f
- Cited by
- 205
- References
- 55
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 12 · 2023: 25 · 2022: 14 · 2021: 17 · 2020: 11 · 2019: 8 · 2018: 13 · 2017: 17 · 2016: 20 · 2015: 17 · 2014: 14 · 2013: 7
- FWCI
- 8.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Human Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- stress, cognitive impairment, prefrontal cortex, hypothalamic-pituitary-adrenal axis, glucocorticoids, catecholamines, gonadal hormones, working memory, executive function, neuromodulation, stress-induced neuroplasticity, receptor signaling
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-28.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-28.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
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