Stress facilitates classical conditioning in males, but impairs classical conditioning in females through activational effects of ovarian hormones

Stress facilitates classical conditioning in males, but impairs classical conditioning in females through activational effects of ovarian hormones Gwendolyn E. Wood Tracey J. Shors

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Stress facilitates classical conditioning in males, but impairs classical conditioning in females through activational effects of ovarian hormones 1998 Proceedings of the National Academy of Sciences 10.1073/pnas.95.7.4066 wood1998-stress-facilitates-classical-condi wood1998-stress-facilitates-classical-condi.txt, the project's staged copy 56585c5aa5a9f41f023833d5a2c057f4f97e9971 open-access neuroscience

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0 spans located by searching the stored text for the quote's exact words, allowing any whitespace between them the effect of an acute stressor on acquisition of the classically conditioned eyeblink response in male and female rats, and the role of ovarian hormones in the female effect Quotation withheld because this record is not cleared for redistribution. does stress enhance classical eyeblink conditioning in females as it does in males Quotation withheld because this record is not cleared for redistribution. shows that the same stressor has opposite effects on associative learning in males and females, and that the female impairment requires ovarian hormones and available estrogen receptors Quotation withheld because this record is not cleared for redistribution. mechanism Quotation withheld because this record is not cleared for redistribution. sexually dimorphic stress effects on classical eyeblink conditioning Quotation withheld because this record is not cleared for redistribution. behavioural-experiment behavioural-experiment Quotation withheld because this record is not cleared for redistribution. mechanisms Stress impairs female conditioning by acting through circulating estrogen binding to available estrogen receptors, so removing either the hormone or the receptor blocks the impairment Quotation withheld because this record is not cleared for redistribution. mechanisms Stress disrupts ovarian hormone levels, and that disruption in turn impairs learning Quotation withheld because this record is not cleared for redistribution. mechanisms Stress raises glucocorticoids through a sexually dimorphic hypothalamic-pituitary-adrenal response, and the glucocorticoid rise disrupts estrogen and progesterone Quotation withheld because this record is not cleared for redistribution. mechanisms Estrogen changes intracellular calcium through L-type calcium channels and NMDA receptor activation, altering synaptic density and efficacy and thereby the rate of learning Quotation withheld because this record is not cleared for redistribution. the paper's premise is a stated absence: the experiment exists because the question had never been asked of females Quotation withheld because this record is not cleared for redistribution. the ceiling explanation is not argued away but engineered away: the CS intensity is lowered until unstressed females start where unstressed males started, and the impairment survives Quotation withheld because this record is not cleared for redistribution. two independent routes to the same conclusion: take out the organ that makes the hormone, then leave the organ and block the receptor instead Quotation withheld because this record is not cleared for redistribution. the two converging routes do not agree in every detail, and the paper reports the disagreement rather than resolving it by preference Quotation withheld because this record is not cleared for redistribution. a ladder of nonspecific explanations is eliminated one at a time with its own control — pseudoconditioning, sensitization, spontaneous blinking, first-trial responding, analgesia and motor activity Quotation withheld because this record is not cleared for redistribution. the first trial is used as a control on the manipulation itself: if the stressor made animals respond to the tone directly, it would show before any learning was possible Quotation withheld because this record is not cleared for redistribution. the reflex itself is used as an argument that motor differences cannot explain the result, since every animal must produce the unconditioned response Quotation withheld because this record is not cleared for redistribution. the hormonal state is read out independently of the manipulation, by vaginal cytology, so the antagonist's effect can be confirmed rather than assumed Quotation withheld because this record is not cleared for redistribution. a continuous cycle is collapsed into three stages by the authors, chosen to correspond to circulating hormone levels rather than to the underlying cytological detail Quotation withheld because this record is not cleared for redistribution. a transient effect and a persistent one are separated by looking at where each has gone by the end of training: the baseline sex difference washes out, the stress effect does not Quotation withheld because this record is not cleared for redistribution. an unexpected reversal is reported rather than buried: ovariectomised females responded MORE after stress, putting them on the male side of the effect Quotation withheld because this record is not cleared for redistribution. Sex and stress each independently affect performance in learning tasks, which complicates attributing the observed differences to learning. what this limits: any attribution of the effect to sex or to stress singly: EVALUATING THE CONTRIBUTION OF SEX AND STRESS TO LEARNING IS COMPLICATED BY THE FACT THAT BOTH VARIABLES ALTER PERFORMANCE IN LEARNING TASKS Quotation withheld because this record is not cleared for redistribution. The ovariectomy result may reflect progesterone rather than estrogen, since removal of the hormone and blockade of its receptor gave different outcomes. what this limits: the estrogen interpretation of the ovariectomy result: THE RESULTS MAY SUGGEST A CRITICAL ROLE FOR PROGESTERONE IN THE IMPAIRED PERFORMANCE ASSOCIATED WITH OVARIECTOMY Quotation withheld because this record is not cleared for redistribution. Hormone removal and receptor blockade did not have equivalent consequences for learning, so the cellular route of the effect is unresolved. what this limits: any inference that treats hormone removal and receptor blockade as the same evidence: REMOVAL OF ESTROGEN HORMONE AND BLOCKADE OF ITS RECEPTOR DO NOT NECESSARILY HAVE SIMILAR CONSEQUENCES ON LEARNING AND MAY ACTIVATE DIFFERENT CELLULAR PROCESSES Quotation withheld because this record is not cleared for redistribution. the two hormones cannot be separated by ovariectomy, which removes both estrogen and progesterone what this limits: the same scope as limitations[1] - ovariectomy removes estrogen and progesterone together, so the two hormones cannot be separated by it Quotation withheld because this record is not cleared for redistribution. the antagonist is not clean at the receptor-subtype level what this limits: the receptor-specificity of the pharmacological result: ESTROGEN HAS AT LEAST TWO TYPES OF NUCLEAR RECEPTORS ... AND TAM HAS BINDING AFFINITY FOR BOTH TYPES OF RECEPTORS TO VARYING DEGREES Quotation withheld because this record is not cleared for redistribution. the estrous stage was not controlled in the main experiments, so the effect may be carried by one phase of the cycle what this limits: the main stress effect, which may be carried by one phase of the cycle: THE EFFECTS OF STRESS ON ACQUISITION OF THE CR [may be] MEDIATED BY THE STAGE OF ESTROUS AND LEVELS OF CIRCULATING ESTROGEN Quotation withheld because this record is not cleared for redistribution. ovariectomy itself was not inert — it raised sensitized responding, and the paper has to argue that the increase is too small to matter what this limits: the sensitization comparison specifically: OVARIECTOMY ALONE ENHANCED THE NUMBER OF SENSITIZED RESPONSES ... [called] THIS MINOR INCREASE - the surgery moved the baseline it was meant to hold still Quotation withheld because this record is not cleared for redistribution. sex and stress are entangled as explanatory variables because each alters performance on its own duplicate of: limitations[0] · what this limits: the same scope as limitations[0] - sex and stress are entangled because each alters performance on its own Quotation withheld because this record is not cleared for redistribution. the mechanism linking stress to the hormones is proposed, not shown what this limits: the mechanistic account only: THE STRESS-INDUCED IMPAIRMENT OF LEARNING IN FEMALES MAY BE MEDIATED BY A STRESS-INDUCED DISRUPTION OF OVARIAN HORMONES - proposed, not shown Quotation withheld because this record is not cleared for redistribution. vaginal smear staging, imported as an independent readout of hormonal state so that a behavioural manipulation can be checked against circulating estrogen Quotation withheld because this record is not cleared for redistribution. tamoxifen, a clinical antiestrogen, repurposed as a laboratory tool for asking whether a behaviour requires estrogen receptors Quotation withheld because this record is not cleared for redistribution. sham surgery reproducing every part of the ovariectomy except the removal itself eliminates: the surgery, anaesthesia and handling as the cause of any difference attributed to loss of the ovaries - the single difference is named in the sentence · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. measurements of spontaneous blinking, sensitization and pseudoconditioning alongside the conditioning result eliminates: three alternatives at once - nonspecific effects of stressor exposure on blinking, sensitization, and pseudoconditioning · outcome: held Quotation withheld because this record is not cleared for redistribution. comparison of analgesia following tailshock between males and females eliminates: a sex difference in stress-induced analgesia as the reason the conditioning effects run in opposite directions · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. conditioning — classical versus operant/instrumental; stress moves them in opposite directions, which is the dissociation the paper is built on Quotation withheld because this record is not cleared for redistribution. eyeblink — conditioned response (at least 80 ms after CS onset, before US onset) versus sensitized response (within 80 ms of CS onset); the same movement counted as two different things by latency Quotation withheld because this record is not cleared for redistribution. impairment — as a stress effect within females, versus as an ovariectomy effect in unstressed females; the paper finds both and keeps them apart Quotation withheld because this record is not cleared for redistribution. removing estrogen — by taking out the source (ovariectomy) versus by blocking the receptor (tamoxifen); the paper shows these are not equivalent operations Quotation withheld because this record is not cleared for redistribution. sex difference — the baseline one (unstressed females learn faster, and it washes out with training) versus the stress-induced one (opposite signs, and it persists) Quotation withheld because this record is not cleared for redistribution. estrous stage — the full cytological sequence versus the simplified three-stage scheme the authors impose to track circulating hormone levels Quotation withheld because this record is not cleared for redistribution. hormone effects — activational, depending on what circulates in the adult, as against the organisational sense implied by the title's contrast Quotation withheld because this record is not cleared for redistribution. claim_type: existence a second reading DIFFERING from the recorded value. Recorded: mechanism — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. method: classical eyeblink conditioning in rats with implanted periorbital electrodes, 24 h after restraint-and-tailshock stress, crossed with ovariectomy and with estrogen-receptor blockade a second reading DIFFERING from the recorded value. Recorded: behavioural-experiment — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. phenomenon: sexually dimorphic effects of stress on associative learning a second reading DIFFERING from the recorded value. Recorded: sexually dimorphic stress effects on classical eyeblink conditioning — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. extends → the male-only literature on stress-induced facilitation of classical conditioning (refs 10–15), by asking the same question of females for the first time Quotation withheld because this record is not cleared for redistribution. extends → reports that stress-induced helplessness is reduced or absent in females (refs 6–9) Quotation withheld because this record is not cleared for redistribution. contradicts → the expectation, stated as the paper's own hypothesis, that stress would enhance conditioning in females as it does in males Quotation withheld because this record is not cleared for redistribution. supports → the body of evidence implicating estrogen in memory formation, including clinical work on estrogen and Alzheimer's Quotation withheld because this record is not cleared for redistribution. supports → a later study establishing that the female impairment occurs preferentially in proestrus Quotation withheld because this record is not cleared for redistribution. critiques → an activity-difference explanation of sex effects in learning tasks Quotation withheld because this record is not cleared for redistribution. classical conditioning —contrasted-with→ instrumental conditioning classical conditioning instrumental conditioning strength of the relation: 0.95 Quotation withheld because this record is not cleared for redistribution. learned helplessness —operationalised-as→ operant conditioning learned helplessness operant conditioning strength of the relation: 0.85 Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but endpoint by anaphora: 'The impairment' = learned helplessness (previous sentence); operationalised-as is loose. Quotation withheld because this record is not cleared for redistribution. estrogen —part-of→ ovarian hormones estrogen ovarian hormones strength of the relation: 0.95 Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but the span writes 'Female sex hormones ... produced by the ovaries', not 'ovarian hormones'. Quotation withheld because this record is not cleared for redistribution. conditioned eyeblink response —distinct-from→ sensitized responses conditioned eyeblink response sensitized responses strength of the relation: 1 Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but the span writes 'Conditioned responses (CRs)', not 'conditioned eyeblink response'. Quotation withheld because this record is not cleared for redistribution. estrous cycle —operationalised-as→ vaginal cytology estrous cycle vaginal cytology strength of the relation: 1 Quotation withheld because this record is not cleared for redistribution. analgesia —operationalised-as→ tailflick response analgesia tailflick response strength of the relation: 1 Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but the span writes 'analgesic responses', not 'analgesia'. Quotation withheld because this record is not cleared for redistribution. EVIDENCE CORRECTED (RE-GROUNDED) · estrogen —causes→ dendritic spine density estrogen dendritic spine density EVIDENCE CORRECTED: RE-GROUNDED. The old span said 'the density of…', which does not attest the endpoint 'dendritic spine density' as a word. This sentence uses the paper's own compact form and states the effect: estrogen 'is reported to ENHANCE…'. — strength of the relation: 0.9 Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but attributed/hedged: estrogen is REPORTED to enhance spine density. Quotation withheld because this record is not cleared for redistribution. ovarian hormones —causes→ hypothalamic-pituitary-adrenal axis ovarian hormones hypothalamic-pituitary-adrenal axis strength of the relation: 0.7 Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but endpoint by anaphora: 'these sex differences in the stress response' = HPA axis activation (previous sentence); the span says DEPENDENT ON, causes is loose. Quotation withheld because this record is not cleared for redistribution. classical conditioning —operationalised-as→ delay paradigm classical conditioning delay paradigm strength of the relation: 0.95 Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but the span writes 'A delay paradigm was used', not 'classical conditioning'. Quotation withheld because this record is not cleared for redistribution. active avoidance —contrasted-with→ passive avoidance active avoidance passive avoidance strength of the relation: 0.95 Quotation withheld because this record is not cleared for redistribution. ANOVA ANOVA Quotation withheld because this record is not cleared for redistribution. interaction effect interaction effect Quotation withheld because this record is not cleared for redistribution. post hoc multiple comparison test post hoc multiple comparison test Quotation withheld because this record is not cleared for redistribution. Cochran's Q test Cochran's Q test Quotation withheld because this record is not cleared for redistribution. standard deviation standard deviation Quotation withheld because this record is not cleared for redistribution. p-value p-value Quotation withheld because this record is not cleared for redistribution. F F Quotation withheld because this record is not cleared for redistribution. Newman–Keuls comparison test Newman–Keuls comparison test Quotation withheld because this record is not cleared for redistribution. Cochran Q test Cochran Q test Quotation withheld because this record is not cleared for redistribution. significant interaction significant interaction Quotation withheld because this record is not cleared for redistribution. SD SD Quotation withheld because this record is not cleared for redistribution. The same stressor had opposite effects by sex: it speeded acquisition of the conditioned eyeblink response in males and slowed it in females, each relative to its own unstressed controls. Quotation withheld because this record is not cleared for redistribution. Without stress, females acquired the conditioned response faster than males. Quotation withheld because this record is not cleared for redistribution. Removing the ovaries abolished the stress-induced impairment: stress impaired acquisition in females with intact ovaries but not in ovariectomized females. Quotation withheld because this record is not cleared for redistribution. Blocking estrogen receptors with tamoxifen also abolished the impairment: stress impaired acquisition in vehicle-injected females but not in tamoxifen-injected females. Quotation withheld because this record is not cleared for redistribution. The opposite effects of stress on the two sexes were not caused by changes in spontaneous blinking, sensitization or pseudoconditioning. Quotation withheld because this record is not cleared for redistribution. After stressor exposure, females remained significantly impaired relative to unstressed females. Quotation withheld because this record is not cleared for redistribution. Stressed males and stressed females did not differ in pain sensitivity as measured by tailflick latency, so the sex-opposite learning effects were not caused by differences in analgesia. Quotation withheld because this record is not cleared for redistribution. Late in training, stressed ovariectomized females actually responded more than unstressed ovariectomized females, that is, they showed the male-like facilitation once ovarian hormones were gone. Quotation withheld because this record is not cleared for redistribution. Ovariectomy on its own impaired learning in unstressed females during the later part of acquisition. Quotation withheld because this record is not cleared for redistribution. By the last 100 trials, unstressed males performed at a similar rate to unstressed females. Quotation withheld because this record is not cleared for redistribution. the same stressor had opposite effects by sex — facilitating acquisition in males and impairing it in females Quotation withheld because this record is not cleared for redistribution. unstressed females outperformed unstressed males Quotation withheld because this record is not cleared for redistribution. the baseline sex difference was gone by the last 100 trials Quotation withheld because this record is not cleared for redistribution. after stressor exposure females were still significantly impaired relative to unstressed females Quotation withheld because this record is not cleared for redistribution. stress impaired acquisition in females with intact ovaries but not in ovariectomised females Quotation withheld because this record is not cleared for redistribution. ovariectomised females went the other way late in training, responding more after stress — the male pattern Quotation withheld because this record is not cleared for redistribution. blocking estrogen receptors with tamoxifen prevented the stress-induced impairment, while the injections alone had no effect on acquisition Quotation withheld because this record is not cleared for redistribution. removing ovarian hormones impaired performance in the last 100 trials of training Quotation withheld because this record is not cleared for redistribution. no sex difference in spontaneous blink rate, in responses to the tone before training, or to explicitly unpaired stimuli Quotation withheld because this record is not cleared for redistribution. stressed males and stressed females did not differ in tailflick analgesia, so the effect is not a pain-sensitivity difference Quotation withheld because this record is not cleared for redistribution. unstressed females reached 72% responding in the first 20 trials against 37% for unstressed males Quotation withheld because this record is not cleared for redistribution. tamoxifen produced a diestrus cytology in 20 of 21 females, confirming the intended low-estrogen state Quotation withheld because this record is not cleared for redistribution. ovariectomy alone roughly doubled sensitized responding, from under 1 in 10 to 2 in 10 Quotation withheld because this record is not cleared for redistribution. the stressor did not produce responses to the tone on the very first trial, before learning was possible Quotation withheld because this record is not cleared for redistribution. learned helplessness learned helplessness Quotation withheld because this record is not cleared for redistribution. conditioned response conditioned response Quotation withheld because this record is not cleared for redistribution. sensitized response sensitized response Quotation withheld because this record is not cleared for redistribution. learned helplessness learned helplessness Quotation withheld because this record is not cleared for redistribution. Conditioned responses Conditioned responses Quotation withheld because this record is not cleared for redistribution. sensitized responses sensitized responses Quotation withheld because this record is not cleared for redistribution. delay paradigm delay paradigm Quotation withheld because this record is not cleared for redistribution. eyeblinks eyeblinks Quotation withheld because this record is not cleared for redistribution. Sham surgery Sham surgery Quotation withheld because this record is not cleared for redistribution. pseudopregnancy pseudopregnancy Quotation withheld because this record is not cleared for redistribution. ceiling effect ceiling effect Quotation withheld because this record is not cleared for redistribution. Proestrus Proestrus Quotation withheld because this record is not cleared for redistribution. estrus estrus Quotation withheld because this record is not cleared for redistribution. diestrus diestrus Quotation withheld because this record is not cleared for redistribution. sex sex Quotation withheld because this record is not cleared for redistribution. acquisition of the conditioned eyeblink response acquisition of the conditioned eyeblink response Quotation withheld because this record is not cleared for redistribution. analgesic responses analgesic responses Quotation withheld because this record is not cleared for redistribution. spontaneous blink rate spontaneous blink rate Quotation withheld because this record is not cleared for redistribution. Sham surgery Sham surgery Quotation withheld because this record is not cleared for redistribution. intertrial interval intertrial interval Quotation withheld because this record is not cleared for redistribution. rate of acquisition of the conditioned response rate of acquisition of the conditioned response Quotation withheld because this record is not cleared for redistribution. sex sex Quotation withheld because this record is not cleared for redistribution. stressor exposure stressor exposure Quotation withheld because this record is not cleared for redistribution. CS intensity CS intensity Quotation withheld because this record is not cleared for redistribution. spontaneous blink rate spontaneous blink rate Quotation withheld because this record is not cleared for redistribution. paired ( n = 7) or explicitly unpaired ( n = 4) conditioning stimuli paired ( n = 7) or explicitly unpaired ( n = 4) conditioning stimuli Quotation withheld because this record is not cleared for redistribution. tailflick response tailflick response Quotation withheld because this record is not cleared for redistribution. Forty-four — male and female rats used in the first sex-by-stress experiment Quotation withheld because this record is not cleared for redistribution. 30 shocks (1 s, 1 mA, 60 Hz, 1 per min for 30 min) — the stressor administered to stressed rats 24 h before conditioning Quotation withheld because this record is not cleared for redistribution. 300 trials a day for 2 days — the conditioning schedule in the first experiment Quotation withheld because this record is not cleared for redistribution. 72% ± 11 versus 37% ± 8% — conditioned responding over the first 20 trials in unstressed females versus unstressed males Quotation withheld because this record is not cleared for redistribution. 47% ± 7 — first-20-trial acquisition rate of unstressed females once the CS was lowered to 80 dB, close to the male rate of 37% Quotation withheld because this record is not cleared for redistribution. F (1, 36) = 14.28; P < 0.001 — the sex-by-stress interaction on acquisition of the conditioned response Quotation withheld because this record is not cleared for redistribution. F (1, 37) = 3.93; P = 0.05 — the effect of estrogen-receptor blockade on the stress-induced impairment of acquisition Quotation withheld because this record is not cleared for redistribution. 20 of 21 — tamoxifen-treated females whose vaginal cytology indicated diestrus and low estrogen Quotation withheld because this record is not cleared for redistribution. from <1 of 10, to 2 of 10 — increase in sensitized responses to the white-noise stimulus produced by ovariectomy alone Quotation withheld because this record is not cleared for redistribution. F (1, 36) = 14.28; P < 0.001 — the sex-by-stress interaction on acquisition, the paper's central result Quotation withheld because this record is not cleared for redistribution. 72% ± 11 vs 37% ± 8% — first-20-trial acquisition, unstressed females against unstressed males Quotation withheld because this record is not cleared for redistribution. 47% ± 7 — unstressed female acquisition after the CS was lowered to 80 dB, matched to the male rate Quotation withheld because this record is not cleared for redistribution. 30 shocks — the stressor: 1 s, 1 mA, 60 Hz, one per minute for 30 minutes Quotation withheld because this record is not cleared for redistribution. 24 h — delay between stressor cessation and conditioning Quotation withheld because this record is not cleared for redistribution. 300 trials a day for 2 days — training schedule in the first experiment Quotation withheld because this record is not cleared for redistribution. 85-dB, 240-ms — the white noise conditioned stimulus Quotation withheld because this record is not cleared for redistribution. 0.7-mA, 80-ms — the periorbital shock unconditioned stimulus Quotation withheld because this record is not cleared for redistribution. 20 ± 10 s — intertrial interval Quotation withheld because this record is not cleared for redistribution. 80 ms — the latency boundary separating conditioned from sensitized responses Quotation withheld because this record is not cleared for redistribution. F (1, 34)= 10.42; P < 0.005 — the ovariectomy-by-stress interaction Quotation withheld because this record is not cleared for redistribution. F (1, 37) = 3.93; P = 0.05 — the tamoxifen-by-stress interaction Quotation withheld because this record is not cleared for redistribution. 1.5 mg — daily tamoxifen dose in sesame oil, for 4 days Quotation withheld because this record is not cleared for redistribution. 44 male and female — sample in the first experiment Quotation withheld because this record is not cleared for redistribution. 37 adult female — sample in the ovariectomy experiment Quotation withheld because this record is not cleared for redistribution. 41 adult female — sample in the tamoxifen experiment Quotation withheld because this record is not cleared for redistribution. 20 of 21 — tamoxifen-treated females whose cytology indicated diestrus Quotation withheld because this record is not cleared for redistribution. 0.3–1.0 kHz, amplified 10,000× — electromyograph filter band and gain Quotation withheld because this record is not cleared for redistribution.

The full text of this article is not redistributable, so it is not included here. The evidence sentences are withheld with it; the tag layer and its grounding status remain. The article itself is at https://doi.org/10.1073/pnas.95.7.4066.