Biomedical subjects

T J Shors

Publications and source records attributed to T J Shors.

At least 19 recordsLinked to original sources

PubMed2004

High levels of estrogen enhance associative memory formation in ovariectomized females.

The ovarian hormone estrogen is presumed to modulate processes of learning and memory in adulthood. In this study, we examined the effects of short-term estrogen replacement on associative memory formation. Adult ovariectomized female rats received two injections of estradiol (10, 20 or 40 microg) 24 h apart and were trained 4 h following each injection on the hippocampal-dependent task of trace eyeblink conditioning. Only the highest dose of estrogen, which produced plasma estradiol levels >250 pg/ml, enhanced conditioned responding. One day after the last injection, estrogen treated rats continued to exhibit elevated levels of conditioning and extinguished responding when the conditioned stimulus was no longer presented. Exposure to estrogen did not alter pain sensitivity or activity levels, but did greatly increase uterine weight. These results provide additional support to the view that that ovarian steroids are beneficial to the performance of certain forms of learning and memory tasks, albeit at supraphysiological doses. They are discussed with reference to hormone replacement and its effects on cognitive processes.

Animals↗

PubMed2004

The opposite effects of stress on dendritic spines in male vs. female rats are NMDA receptor-dependent.

Dendritic spines in the hippocampus are sources of synaptic contact that may be involved in processes of learning and memory [Moser (1999) Cell. Mol. Life Sci., 55, 593-600]. These structures are sensitive to sex differences as females in proestrus possess a greater density than males and females in other stages of the estrous cycle [Woolley et al. (1990) J. Neurosci., 10, 4035-4039]. Moreover, exposure to an acute stressful event increases spine density in the male hippocampus but decreases spine density in the female hippocampus [Shors et al. (2001) J. Neurosci., 21, 6292-6297]. Here we demonstrate that antagonism of N-methyl-d-aspartate (NMDA) receptors prevents the increase in spine density as females transition from diestrus 2 to proestrus, when estrogen levels are rising. Antagonism of NMDA receptors during exposure to the stressful event also prevented the changes in spine density in males and females, despite differences in the direction of these effects. Thus, the stress-induced increase in spine density was prevented in the male hippocampus as was the stress-induced decrease in spine density in the female hippocampus. NMDA receptor antagonism during exposure to the stressful event did not alter corticosterone levels or the corticosterone response to stress. These data suggest that both increases and decreases in spine density can be dependent on NMDA receptor activation.

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PubMed2001

Sex differences and opposite effects of stress on dendritic spine density in the male versus female hippocampus.

Dendritic spines are postsynaptic sites of excitatory input in the mammalian nervous system. Despite much information about their structure, their functional significance remains unknown. It has been reported that females in proestrus, when estrogen levels are elevated, have a greater density of apical dendritic spines on pyramidal neurons in area CA1 of the hippocampus than females in other stages of estrous (Woolley et al., 1990). Here we replicate these findings and in addition, show that females in proestrus have a greater density of spines in area CA1 of the hippocampus than males. Moreover, this sex difference in spine density is affected in opposite directions by stressful experience. In response to one acute stressful event of intermittent tailshocks, spine density was enhanced in the male hippocampus but reduced in the female hippocampus. The decrease in the female was observed for those that were stressed during diestrus 2 and perfused 24 hr later during proestrus. The opposing effects of stress were not evident immediately after the stressor but rather occurred within 24 hr and were evident on apical and to a lesser extent on basal dendrites of pyramidal cells in area CA1. Neither sex nor stress affected spine density on pyramidal neurons in somatosensory cortex. Sex differences in hippocampal spine density correlated with sex hormones, estradiol and testosterone, whereas stress effects on spine density were not directly associated with differences in the stress hormones, glucocorticoids. In summary, males and females have different levels of dendritic spine density in the hippocampus under unstressed conditions, and their neuronal anatomy can respond in opposite directions to the same stressful event.

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PubMed2001

Neurogenesis in the adult is involved in the formation of trace memories.

The vertebrate brain continues to produce new neurons throughout life. In the rat hippocampus, several thousand are produced each day, many of which die within weeks. Associative learning can enhance their survival; however, until now it was unknown whether new neurons are involved in memory formation. Here we show that a substantial reduction in the number of newly generated neurons in the adult rat impairs hippocampal-dependent trace conditioning, a task in which an animal must associate stimuli that are separated in time. A similar reduction did not affect learning when the same stimuli are not separated in time, a task that is hippocampal-independent. The reduction in neurogenesis did not induce death of mature hippocampal neurons or permanently alter neurophysiological properties of the CA1 region, such as long-term potentiation. Moreover, recovery of cell production was associated with the ability to acquire trace memories. These results indicate that newly generated neurons in the adult are not only affected by the formation of a hippocampal-dependent memory, but also participate in it.

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PubMed2001

Acute stress rapidly and persistently enhances memory formation in the male rat.

Previous studies, as well as the present one, report that acute exposure to intermittent tailshocks enhances classical eyeblink conditioning in male rats when trained 24 h after stressor cessation. In Experiment 1, it was determined that the facilitating effect of stress on conditioning could also be obtained in response to a stressor of acute inescapable swim stress but not inescapable noise or the unconditioned stimulus of periorbital eyelid stimulation. These selective responses arose despite comparable enhancements of the stress-related hormone corticosterone in response to tailshocks, periorbital eyelid stimulation, noise stress, and supraelevation in response to swim stress. Although corticosterone is necessary for the enhanced learning in response to stress (Beylin & Shors, 1999), these results suggest that it is not sufficient. In addition, the results suggest that the enhancement is not dependent on common characteristics between the stressor and the conditioning stimuli (stimulus generalization). In Experiment 2, it was determined that the facilitating effect of the stressor on conditioning occurs within 30 min of stressor cessation. Thus, the mechanism responsible for facilitating memory formation is rapidly induced as well as persistently expressed. In Experiment 3, it was determined that exposure to the stressor does not enhance performance of the conditioned response after the response has been acquired. Thus, exposure to the stressor enhances the formation of new associations rather than affecting retention or performance of the motor response. These studies extend the circumstances under which stress is known to enhance associative learning and implicate neural mechanisms of memory enhancement that are rapidly induced and persistently expressed.

Acute Disease↗

PubMed2001

The role of the hippocampus in trace conditioning: temporal discontinuity or task difficulty?

It is well established that the hippocampal formation is critically involved in the acquisition of trace memories, a paradigm in which the conditioned (CS) and unconditioned stimuli (US) are separated by a temporal gap (Solomon et al., 1986). The structure is reportedly not critical for the acquisition of delay memories, where the CS and the US overlap in time (Berger & Orr, 1983; Schmaltz & Theios, 1972). Based on these results, it is often stated that the hippocampus is involved in "filling the gap" or otherwise associating the two stimuli in time. However, in addition to the presence of a temporal gap, there are other differences between trace and delay conditioning. The most apparent difference is that animals require many more trials to learn the trace task, and thus it is inherently more difficult than the delay task. Here, we tested whether the hippocampus was critically involved in delay conditioning, if it was rendered more difficult such that the rate of acquisition was shifted to be analogous to trace conditioning. Groups of rats received excitotoxic lesions to the hippocampus, sham lesions or were left intact. Using the same interstimulus intervals (ISI), control animals required more trials to acquire the trace than the delay task. As predicted, animals with hippocampal lesions were impaired during trace conditioning but not delay conditioning. However, when the delay task was rendered more difficult by extending the ISI (a long delay task), animals with hippocampal lesions were impaired. In addition, once the lesioned animal learned the association between the CS and the US during delay conditioning, it could learn and perform the trace CR. Thus, the role of the hippocampus in classical conditioning is not limited to learning about discontiguous events in time and space; rather the structure can become engaged simply as a function of task difficulty.

Animals↗

PubMed2001

The contribution of adrenal and reproductive hormones to the opposing effects of stress on trace conditioning in males versus females.

Exposure to an acute stressful experience facilitates classical conditioning in male rats but impairs conditioning in female rats (T. J. Shors, C. Lewczyk, M. Paczynski, P. R. Mathew, & J. Pickett, 1998; G. E. Wood & T. J. Shors, 1998). The authors report that these effects extend to performance on the hippocampal-dependent task of trace conditioning. The stress-induced impairment of conditioning in females was evident immediately, 24 hr and 48 hr after stress, depending on the stage of estrus. Moreover, the effect could be reactivated days later by reexposure to the stressful context. Corticosterone levels correlated with overall performance in males but not in females. Unlike the effect seen in males, adrenalectomy did not prevent the stress-induced effect on conditioning in females. These data indicate that exposure to the same experience can have opposite effects on learning in males versus females and that these opposing effects are mediated by differing hormonal systems.

Adrenalectomy↗

PubMed2000

The modulation of Pavlovian memory.

Exposure to stressful experiences as well as sex differences in the brain are known to influence the acquisition of new memories. This review focuses on acquisition of two types of Pavlovian learning paradigms: hippocampal-independent delay conditioning and hippocampal-dependent trace conditioning and their modulation by exposure to stressful experience and sex differences in the brain. We concentrate on two sets of findings: the first is that exposure to an acute stressful experience enhances Pavlovian conditioning in the male rat, while exposure to the very same experience dramatically impairs conditioning in female rat. The sexually-opposed effects of stress on conditioning are mediated by differing hormonal substrates (adrenal versus ovarian steroids) and possibly by differing anatomical and biochemical pathways. The second set of findings is that training with hippocampal-dependent trace conditioning enhances the survival of newly generated neurons in the adult hippocampal formation. The same amount of training with hippocampal-independent delay conditioning does not affect their survival. In addition, females acquire the trace task faster than males and generate more new neurons. As with the stress effects on learning, these sex effects are influenced by hormonal status. It is our contention that identifying the hormonal and neuronal processes that modulate associative memory formation will provide insight into the processes of memory formation itself.

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PubMed2000

Postnatal decrease in transforming growth factor alpha is associated with enlarged ventricles, deficient amygdaloid vasculature and performance deficits.

It is well established that transforming growth factor alpha is involved prenatally in development of the nervous system, but its role in the postnatal brain is less well understood. Here, we document the occurrence of late-onset, morphological and behavioral deficits in the naturally occurring murine mutant, Waved-1 (Wa-1), whose transforming growth factor alpha levels decrease naturally between early postnatal and adolescent ages. Morphological analyses suggest that reduction in the growth factor postnatally is associated temporally with the onset of enlarged lateral ventricles, a reduction in vasculature in the region of the amygdala and a reduction in size of the central nucleus. Onset of the morphological deficits corresponds to the appearance of a performance deficit in contextual fear conditioning. In contrast, the transforming growth factor alpha gene-targeted null mutants exhibit neither morphological nor performance deficits. These data suggest that transforming growth factor alpha during postnatal maturation of the brain may contribute to maintenance of limbic morphology and vasculature, which may in turn affect some behaviors associated with these specific brain structures.

Age Factors↗

PubMed1999

Acute stress and re-exposure to the stressful context suppress spontaneous unit activity in the basolateral amygdala via NMDA receptor activation.

Exposure to an acute stressor of intermittent tail-shocks enhances acquisition of the classically conditioned eyeblink response and the enhancement is dependent on NMDA receptor activation in the basolateral nucleus of the amygdala. In the present study, multiple units (spikes/s) were recorded from the basolateral amygdala in response to the stressor of intermittent tailshocks (thirty, 1 mA, 1 s, 1/min) and upon re-exposure to the context in which the stress was administered. Exposure to the stressor suppressed multiple unit activity in the basolateral/lateral amygdala (67% of baseline) which, in some cases, persisted for 48 h after stressor cessation. Re-exposure to the stressful context reactivated the suppression in unit activity (69% of baseline). In a second experiment, it was determined that the stress-induced suppression of neuronal activity was prevented by NMDA receptor antagonism during stressor exposure. It is proposed that the stress-induced suppression of background unit activity enhances the neural representation of environmental cues by enhancing their signal/background noise ratio and thereby facilitates the formation of associations between those cues.

2-Amino-5-phosphonovalerate↗

PubMed1999

Learning enhances adult neurogenesis in the hippocampal formation.

Thousands of hippocampal neurons are born in adulthood, suggesting that new cells could be important for hippocampal function. To determine whether hippocampus-dependent learning affects adult-generated neurons, we examined the fate of new cells labeled with the thymidine analog bromodeoxyuridine following specific behavioral tasks. Here we report that the number of adult-generated neurons doubles in the rat dentate gyrus in response to training on associative learning tasks that require the hippocampus. In contrast, training on associative learning tasks that do not require the hippocampus did not alter the number of new cells. These findings indicate that adult-generated hippocampal neurons are specifically affected by, and potentially involved in, associative memory formation.

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PubMed1999

Acute stress persistently enhances estrogen levels in the female rat.

Here we tested whether exposure to either tailshock or swim stress alters ovarian hormone levels, estrogen and progesterone, in females and whether the effects are persistent. Adrenal hormone levels were also measured in males and females. Estradiol levels were elevated in unstressed females during proestrus relative to females in other stages of estrous, and exposure to the stressors enhanced estradiol beyond basal levels. For females stressed during diestrus 2, estradiol levels were elevated immediately after stressor cessation and up to 24 hrs. Exposure to tailshock, but not swim-stress, transiently enhanced progesterone in females stressed during the stage of proestrus and estrus. Glucocorticoid levels were elevated in response to both stressors and were supraelevated in females under both basal and stress conditions relative to males, particularly in blood from females exposed to acute swim stress. These results indicate that exposure to a relatively acute stressful event immediately and persistently enhances serum estradiol and are discussed in the context of reports that exposure to the same stressors immediately and persistently impairs associative learning in the female rat.

Acute Disease↗

PubMed1998

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

Exposure to restraint and brief intermittent tailshocks facilitates associative learning of the classical conditioned eyeblink response in male rats. Based on evidence of sex differences in learning and responses to stressful events, we investigated sexually dimorphic effects of a stressor of restraint and intermittent tailshock on classical eyeblink conditioning 24 h after stressor cessation. Our results indicate that exposure to the acute stressor had diametrically opposed effects on the rate of acquisition of the conditioned response in male vs. female rats. Exposure to the stressor facilitated acquisition of the conditioned response in males, whereas exposure to the same stressful event dramatically impaired acquisition in females. We further demonstrate that the stress-induced impairment in female conditioning is dependent on the presence of ovarian hormones. Conditioning of stressed sham-ovariectomized females was significantly impaired relative to the unstressed controls, whereas conditioning in stressed ovariectomized females was not impaired. We present additional evidence that estrogen mediates the stress-induced impairment in female acquisition. Females administered sesame oil vehicle and then stressed were significantly impaired relative to their unstressed controls, whereas females administered the estrogen antagonist tamoxifen prior to stress were not impaired. In summary, these results indicate that exposure to the same aversive event can induce opposite behavioral responses in males vs. females. These effects underscore sex differences in associative learning and emotional responding, and implicate estrogen in the underlying neuronal mechanism.

Animals↗

PubMed1998

Stages of estrous mediate the stress-induced impairment of associative learning in the female rat.

Exposure to a stressful event facilitates classical eyeblink conditioning in male rats and impairs conditioning in females. The contribution of stages of estrous to the stress-induced impairment of eyeblink conditioning was evaluated. Females in proestrus, estrus and diestrus were either exposed to an acute stressor of intermittent tailshocks or swim stress and compared to unstressed females in the three stages. Females in proestrus, when estrogen levels are high, acquired the conditioned response at a facilitated rate relative to females in other stages. However, exposure to a stressor of either intermittent tailshocks or inescapable swim stress severely impaired acquisition in females during proestrus. These results suggest that the enhancing effect of estrogen on procedural memory formation is disrupted by previous exposure to a stressful event.

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PubMed1998

Stress enhances excitatory trace eyeblink conditioning and opposes acquisition of inhibitory conditioning.

Exposure to a brief, stressful event is reported to facilitate classical eyeblink conditioning in the male rat (Rattus norvegicus) by use of a delay paradigm in which the conditioned stimulus (CS) and unconditioned stimulus (US) overlap and coterminate. This study examined the effects of stress on trace conditioning, a task in which the CS and US were separated by 500 ms. Experiment 1 showed that exposure to brief (1 s), low-intensity (1 mA) tailshocks facilitated acquisition 24 hr later. Experiment 2 showed that stressor exposure did not affect retention or extinction of trace conditioning in rats that were stressed after acquisition. Experiment 3 showed that exposure to the same stressor opposed acquisition of inhibitory conditioning. These results suggest that exposure to a stressful event persistently facilitates acquisition of trace conditioning and enhances a bias toward acquiring positive versus negative associations.

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PubMed1997

Stress persistently increases NMDA receptor-mediated binding of [3H]PDBu (a marker for protein kinase C) in the amygdala, and re-exposure to the stressful context reactivates the increase.

The long-term consequences of acute stress on [3H]phorbol 12,13-dibutyrate ([3H]PDBu) binding, a marker for protein kinase C (PKC) activity, were investigated. In the first experiment, exposure to acute restraint and intermittent tail-shock increased [3H]PDBu binding in the amygdala but not in the hippocampus or cerebral cortex. The increase was persistent, lasting at least 24 h after stressor cessation. In the second experiment, it was determined that the stress-induced increase in binding in the amygdala was dependent on NMDA receptor activation; rats injected with a competitive NMDA receptor antagonist prior to the stressor did not exhibit the increased binding in the amygdala 24 h later. In the third experiment, re-exposure to the stressful context 96 h after stressor cessation reactivated the stress-induced increase the binding of [3H]PDBu in the amygdala. Re-exposure to the context also increased binding in the thalamus and area CA1 of the hippocampus. [3H]PDBu binds preferentially to PKC in the membrane and, therefore, these results suggest that stress induces the translocation of PKC from its resting compartments in the cytosol to the membrane. Its dependence on NMDA receptor activation implicates isoforms of PKC that are sensitive to intracellular calcium, such as PKC gamma. The results further suggest that a "psychological' manipulation, viz. context re-exposure, can reactivate the persistent increase in [3H]PDBu binding in the amygdala.

2-Amino-5-phosphonovalerate↗

PubMed1997

Transient and persistent consequences of acute stress on long-term potentiation (LTP), synaptic efficacy, theta rhythms and bursts in area CA1 of the hippocampus.

Previous studies reported that exposure to an acute stressor of restraint and intermittent tailshock impairs long-term potentiation (LTP) in area CA1 of the rat hippocampus. In the first experiment, the longevity of the stress-induced impairment of LTP was determined. LTP of the excitatory postsynaptic potential (EPSP) was impaired 2 but not 4 days after stressor cessation. Exposure to the stressor also persistently enhanced the synaptic response to the tetanic stimulation patterned after theta rhythm activity (10, 100 Hz bursts delivered at 5 Hz). In a second experiment, we tested the hypothesis that exposure to the stressor enhanced synaptic efficacy itself. EPSPs were recorded from freely moving rats before, during and after stressor exposure. The synaptic response was not enhanced during stressor exposure. Instead, cessation of the stressor (and perhaps movement associated with release from restraint) induced a transient (< 2 min) decrease in synaptic efficacy. To determine whether exposure to the stressor enhances endogenous theta rhythms in area CA1, electroencephalographic (EEG) recordings were obtained from freely moving rats before, during and after exposure to the stressor. The power of theta (4-8 Hz) and low frequency (0.1-3.9 Hz) activity was enhanced in response to the tailshock aspect of the stressor. Together, the results indicate that exposure to an acute stressful event increases theta activity and its cessation transiently decreases synaptic efficacy. These transient effects are succeeded by a persistently sensitized response to theta burst stimulation and impaired LTP.

Acute Disease↗

PubMed1997

The contribution of stressor intensity, duration, and context to the stress-induced facilitation of associative learning.

Exposure to an acute stressor of restraint and intermittent tailshock facilitates acquisition of the classically conditioned eye-blink response 24 h after stressor cessation. The contribution of stressor intensity, duration, and context was determined. Male rats exposed to 90 or 30 1-mA tailshocks exhibited sensitization to an auditory cue of 86 dB and facilitated acquisition of the conditioned response, whereas rats exposed to 90 0.5-mA tailshocks or restraint alone only exhibited sensitization. Rats exposed to the 5 1.0-mA tailshocks (and 5 min of restraint) exhibited neither sensitization nor facilitated acquisition. Rats stressed in the same context 48 and 96 h earlier exhibited sensitization and facilitated acquisition relative to those stressed in a different context. Neither stressed group exposed to unpaired stimuli responded to the CS, and thus there was no pseudodconditioning. Together, these results dissociate the stress-induced sensitization from the facilitated learning. They also indicate that the facilitated learning is particularly sensitive to stressor intensity and contextual cues.

Animals↗