Steroid hormones influence a variety of physiological behaviours, including sexual behaviour, anxiety, learning and memory (Bidmon, 2003). As a result, many studies strive to correlate aspects of those behaviours; they are attempting to determine whether or not the hormones are causing the behaviours to influence each other. Based on the literature, steroid hormones such as cortisol are believed to enhance learning and memory, and this relationship is thought to be time-dependent. When the activity of these hormones occurs close in time to a particular behaviour or situation, they enhance learning and memory surrounding the event. This may be due to hormonal modulation of the AMPA and NMDA receptors; AMPA and NMDA receptors are involved in synaptic plasticity.
It also may be attributed to hormone receptors in circuits and areas of the brain that are specifically associated with learning and memory. The particular amount of the hormone is crucial: high levels of stress can be condusive to learning, but low levels of stress has shown to be detrimental. Further proving this relationship, the lesioning of areas associated with learning in ablation studies of mice blocks the stress-induced inversion of serial memory retrieval.
The steroid hormones of the adrenal cortex (the glucocorticoids and the mineralocorticoids) have been implicated in learning and memory. The glucocorticoids include cortisol and corticosterone, among others; what the glucocorticoids do is modulate carbohydrate metabolism by converting stored proteins into carbohydrates (Brown, 1994). Glucocorticoids (corticosteroids in rats) are released in response to stressful stimuli, and this response has been shown to have an effect on learning and memory. The hypothalamus produces corticotropin releasing hormone (CRH), which in turn stimulates adrenocorticotropic hormone (ACTH) release. ACTH is a pituitary hormone of the pars distalis, which then stimulates glucocorticoid release from the adrenal cortex. It is produced in the corticotroph cells of the adenohypophysis. Because of the three structures involved, these hormones are said to operate in a third-order feedback loop known as the hypothalamic-pituitary-adrenal (H-P-A) axis (Brown, 1994).
As shown by Akirav et al. (2004), the activation of this system causes emotionally charged experiences to alter memory storage. Glucocorticoids and mineralocorticoids bind to receptors in areas of the forebrain which play a role in emotional regulation, learning and memory processes (Berger, 2009). These receptors also “act as transcription factors and mediate complementary but also in part overlapping actions of corticosterone in endocrine and behavioural functions” (Berger, 2009). The effects of these the steroid hormones on LTP is presumed to be time-dependent; previous experiments in the hippocampal CA1 area describe the glucocorticoid corticosterone's facilitation of long-term potentiation in a rapid non-genomic fashion. This same hormone suppresses LTP that is induced several hours after the hormone's application (Krugers, 2007).
Bidmon et al. (2003) show in their research that certain changes in learning and memory may occur through the steroid hormones inducing the alteration of AMPA and NMDA receptor densities, particularly in the glutamatergic intrahippocampal pathway. During estrus and diestrus periods in adult rats of both sexes, steroid hormones appear to affect the densities of AMPA and NMDA receptors in the hippocampus. These receptor types are both crucial for LTP: AMPA receptors depolarize the post-synaptic cell, and NMDA receptors allow the induction of LTP (Rudy, 2007). The location of these receptors in the hippocampus is also important, as the hippocampus plays a major role in memory. Bidmon et al. conducted research on in vivo steroid hormone impact on the density of these receptors in adult rats. They found that the density of AMPA receptors are significantly reduced in hippocampal regions of the female rats in estrus, when compared to females in diestrus; although there were differences in NMDA receptors, they were not significant. They also found ovariectomy to be associated with stress, and that overiectomized rats show changes in plasma levels of glucocorticoids and mineralocorticoids due to altered activity of the adrenal cortex. In these ovariectomized rats, it is the upregulation of NMDA receptor densities that is described as being sensitive to changing hormonal levels. These results show that an increase of glucocorticoids and mineralocorticoids in the blood has an affect on the density of NMDA receptors. NMDA receptors have been implicated in LTP; based on these results, it can be hypothesized that an increase in stress (hormonally) is condusive to learning (based on an increase in receptor density).
The binding sites of the steroid hormones have also shown to play a role in learning and memory. The adrenal steroid hormones bind to glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the hippocampus, and modulate stress responses. The hippocampus as been implicated in spatial memory, and as such it can be hypothesized that there is a relationship between stress hormones and memory.
Akirav et al. (2004) found that high doses of stress induced before training or testing led to an impairment in spatial performance and memory. This study showed that rats that performed well in a spatial task in cold water, which induced moderate stress, deteriorated following the suppression of corticosterone levels. Rats trained in warm water, inducing mild stress, who did not perform as well, on average, as the cold water-trained animals, improved following the rise in corticosterone levels. The relationship between the particular level of stress is important, as high levels hormones have been shown to have a positive effect on spatial memory, whereas moderate levels appear to be less effective.
An imbalance between the GRs and the MRs is thought to play a role in stress-related disorders; stress-related disorders may be attributed to learned stress. Using a fear conditioning experiment, Berger et al. (2009) showed that upregulation of GRs most likely contributes to the consolidation of fear behaviour. They tested mice with forebrain ablations of MRs in various behavioural tasks, including fear conditioning. This examines the adaptive effects of steroid hormone receptors on behaviour, as the relationship between stress and memory is important for learning about danger. Because MR has been shown to “mediate the regulation of basal corticosterone levels and the initial corticosterone secretion during the ultradian rhythm and after stress” (Berger, 2009) and GR has been attributed to consolidation of such memories, Berger et al. hypothesize a relationship between the function of the MRs and the GRs. MRCaMKCre mice showed enhanced fear during acquisition of the task, suggesting that the two receptor types work in a way which is complementary to one another. The MRs have a much greater affinity for the hormones, which could be useful with regards to the MRs being involved in the early acquisition of the memory. The results of Berger et al. show that after 4 days of training, the MRCaMKCre mice have a 40% higher concentration of corticosterone than the control group, showing the connection between learning and corticosterone.
The dentate gyrus of the hippocampus is particularly important, as Krugers et al. (2007) describe in the results of their study on the timing of hormone application in the dentate gyrus and the effects of timing on LTP.
They tested both rapid and delayed corticosterone activity on B-adrenergic-dependent changes in LTP. Their results show that the B-adrenergic agonist isoproterenol, when applied concurrently with corticosterone, enhanced synaptic strength, but when corticosterone was given in advance of isoproterenol, no potentiation was shown. These results describe timing-dependent nature of the synaptic plasticity involved in LTP, in relation to activity of the stress hormone corticosterone. In terms of behaviour, this is to say that stress enhances learning when the two occur close in time. The adaptive function of a such a system is that it “may promote encoding of the information associated with the stressful event” (Krugers, 2007).
The retrieval of memories can be disrupted by lesions or malfunction in the areas of the brain associated with learning. Beracochea et al. (2009) lesioned the mediodorsal thalamus, associated with diencephalic amnesia and found that it blocked stress-induced inversion of the serial memory retrieval in mice. These results are much like those observed in prior studies done regarding prefrontal cortex or amygdala-lesioned mice. Beracochea's 2009 study proposes a circuit which comprises these 3 structures to thus be involved in serial memory retrieval. “Long lasting synaptic changes have been observed in the thalamo-amygdala and thalamo-prefrontal pathways following associative emotional memory” (Beracochea, 2009), which would be related to activation of the amygdala. The activation of the amygdala in this experiment was also shown to suppress hippocampal plasticity. Beracochea et al. hypothesize that this is the result of a shift of strategy under certain conditions. They give several reasons why lesioning the mediodorsal thalamus may suppress stress-induced serial memory retrieval, one being that removal of this region eliminates a large portion of excitatory glutamatergic activity coming from the prefrontal cortex. This may cause a reduction in synaptic activity and thus a reduction in LTP.
The studies presented in this discussion on hormonal effects on learning reflect the current research being done in this field. There is a focus in current research on understanding the effects of steroid hormones on neural plasticity, such as that which occurs in LTP. It would be beneficial for future research to study the involvement of the processes which stimulate hormonal release, due to the time-dependency of the relationship between hormones and learning. Perhaps the mechanisms leading to hormonal secretion occur differently when in relation to learning, allowing faster activity of the hormone. Another area of study which could be useful would be to understand the connection between the different affinities of the two hormone receptor types (MRs and GRs), and their respective roles in memory acquisition and consolidation. This might lead to a greater understanding of the ways in which acquisition and consolidation differ on a molecular level. It would also be beneficial for future research to examine the effects of other types of hormones on learning, as most of the research appears to be concentrated on the stress hormones and the involvement of the H-P-A axis. Due to the interrelated nature of the endocrine system and the neural networks, it is probable that other hormones may have an influence learning and memory as well.
References
Akirav, I., Kozenicky, M., Richter-Levin, G., Sandi, C., Tal, D., Venero, C. (2004). A Facilitative Role for Corticosterone in the Acquisition of a Spatial Task Under Moderate Stress. Learning and Memory, 11, 188-195.
Beracochea, D., Celerier, A., Chauveau, F., Christophe, T., Guillou, J. L., Pierard, C., Vouimba, R. M. (2009). Mediodorsal thalamic lesions block the stress-induced inversion of serial memory retrieval pattern in mice. Behavioural Brain Research, 203, 270-278.
Berger, S., Brinks, V., Gass, P., de Kloet, E. R., Oitzl, M. S. (2009). Mineralocorticoid receptors in control of emotional arousal and fear memory. Hormones and Behaviour, 56, 232-238.
Bidmon, H., Palomero-Gallagher, N., Zilles, C. (2003). AMPA, Kainate, and NMDA Receptor Densities in the Hippocampus of Untreated Male Rats and Females in Estrus and Diestrus. The Journal of Comparative Neurology, 459, 468-474.
Brown, R. E. (1994). An Introduction to Neuroendocrinology. New York: Cambridge University Press.
Bulmer, S., Carlile, J., Corcoran, C., Ferrier, I. N., Gallagher, F. P., Horton, K., Watson, S. (2009). Effect of aspirin on hypothalamic–pituitary–adrenal function and on neuropsychological performance in healthy adults: a pilot study. Psychopharmacology, 205, 151-155.
Krugers, H. J., Joels, M., Pu, Z. (2007). Corticosterone time-dependently modulates B-adrenergic effects on long-term potentiation in the hippocampal dentate gyrus. Learning and Memory, 14,359-367.
Rudy, J. (2007) Neurobiology of Learning and Memory, Chapters 1-4.
