Behavioral Neuroendocrinology: Cognition

The demonstration of steroid binding proteins in brain areas outside of the hypothalamus was a key neuroendocrine discovery in the 1980s. These findings suggested that gonadal hormones, estradiol and testosterone, may have additional functions besides controlling reproduction through the hypothalamic–pituitary–gonadal axis (HPG) and that glucocorticoids may also influence neural functions not related to the hypothalamic–pituitary–adrenal axis (HPA). In the past 30 years, since the early 1990s, a body of neuroendocrine studies in animals has provided evidence for these hypotheses, and in 2020, it is generally accepted that steroid hormones exert robust influences over cognition—both learning and memory. Gonadal hormones, predominantly estrogens, enhance learning and memory in rodents and humans and influence cognitive processes throughout the lifespan. Gonadal hormones bind to classical nuclear estrogen receptors and to membrane receptors to influence cognition. In contrast to the generally positive effects of gonadal hormones on learning and memory, adrenal hormones (glucocorticoids in rodents or cortisol in primates) released during chronic stress have adverse effects on cognition, causing impairments in both learning and memory. However, emerging evidence suggests that impairments may be limited only to males, as chronic stress in females does not usually impair cognition and, in many cases, enhances it. The cognitive resilience of females to stress may result from interactions between the HPG and HPA axis, with estrogens exerting neuroprotective effects against glucocorticoids at both the morphological and neurochemical level. Overall, knowledge of the biological underpinnings of hormonal effects on cognitive function has enormous implications for human health and well-being by providing novel tools for mitigating memory loss, for treating stress-related disorders, and for understanding the bases for resilience versus susceptibility to stress.

Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action

Biologically active steroids are transported in the blood by albumin, sex hormone-binding globulin (SHBG), and corticosteroid-binding globulin (CBG). These plasma proteins also regulate the non-protein-bound or ‘free’ fractions of circulating steroid hormones that are considered to be biologically active; as such, they can be viewed as the ‘primary gatekeepers of steroid action’. Albumin binds steroids with limited specificity and low affinity, but its high concentration in blood buffers major fluctuations in steroid concentrations and their free fractions. By contrast, SHBG and CBG play much more dynamic roles in controlling steroid access to target tissues and cells. They bind steroids with high (~nM) affinity and specificity, with SHBG binding androgens and estrogens and CBG binding glucocorticoids and progesterone. Both are glycoproteins that are structurally unrelated, and they function in different ways that extend beyond their transportation or buffering functions in the blood. Plasma SHBG and CBG production by the liver varies during development and different physiological or pathophysiological conditions, and abnormalities in the plasma levels of SHBG and CBG or their abilities to bind steroids are associated with a variety of pathologies. Understanding how the unique structures of SHBG and CBG determine their specialized functions, how changes in their plasma levels are controlled, and how they function outside the blood circulation provides insight into how they control the freedom of steroids to act in health and disease.

Corticosteroid-binding globulin contributes to the neuroendocrine phenotype of mice selected for extremes in stress reactivity

Increasing evidence indicates an important role of steroid-binding proteins in endocrine functions, including hypothalamic–pituitary–adrenal (HPA) axis activity and regulation, as they influence bioavailability, local delivery, and cellular signal transduction of steroid hormones. In the plasma, glucocorticoids (GCs) are mainly bound to the corticosteroid-binding globulin (CBG) and to a lesser extend to albumin. Plasma CBG levels are therefore involved in the adaptive stress response, as they determine the concentration of free, biologically active GCs. In this study, we investigated whether male mice with a genetic predisposition for high-reactivity (HR), intermediate-reactivity (IR), or low-reactivity (LR) stress-induced corticosterone (CORT) secretion present different levels of free CORT and CORT-binding proteins, basally and in response to stressors of different intensity. Our results suggest a fine control interaction between plasma CBG expression and stress-induced CORT release. Although plasma CBG levels, and therefore CBG binding capacity, were higher in HR animals, CORT secretion overloaded the CBG buffering function in response to stressors, resulting in clearly higher free CORT levels in HR compared with IR and LR mice (HR>IR>LR), resembling the pattern of total CORT increase in all three lines. Both stressors, restraint or forced swimming, did not evoke fast CBG release from the liver into the bloodstream and therefore CBG binding capacity was not altered in our three mouse lines. Thus, we confirm CBG functions in maintaining a dynamic equilibrium between CBG-bound and unbound CORT, but could not verify its role in delaying the rise of plasma free CORT immediately after stress exposure.

Specific binding sites for progesterone and 17beta-estradiol in cells of Triticum aestivum L.

The presence and location of specific binding sites for progesterone and 17beta-estradiol in cells of wheat were estimated using radioligand binding assay. Membrane and cytosolic fractions of non-vernalized and vernalized plants were tested using tritium-labelled ligands. Specific binding of [(3)H]progesterone and [(3)H]17beta-estradiol occurs in wheat cells. The binding sites are located in membranes and in the cytosol. Specific binding of [(3)H]17beta-estradiol is higher in the membranes than in the cytosol. Specific binding of both ligands in the cytosolic fraction is higher in vernalized plants than in non-vernalized ones. The possibility of the occurrence of steroid binding proteins specific for progesterone and 17beta-estradiol, putative steroid receptors for these steroids in Triticum aestivum L., is discussed.