Estrogen effects on the brain: actions beyond the hypothalamus via novel mechanisms

Abstract

From its origins in how the brain controls the endocrine system via the hypothalamus and pituitary gland, neuroendocrinology has evolved into a science that now includes hormone action on many aspects of brain function. These actions involve the whole central nervous system and not just the hypothalamus. Advances in our understanding of cellular and molecular actions of steroid hormones have gone beyond the important cell nuclear actions of steroid hormone receptors to include signaling pathways that intersect with other mediators such as neurotransmitters and neuromodulators. This has, in turn, broadened the search for and identification of steroid receptors to include nonnuclear sites in synapses, dendrites, mitochondria, and glial cells, as well as cell nuclei. The study of estrogen receptors and estrogen actions on processes related to cognition, mood, autonomic regulation, pain, and neuroprotection, among other functions, has led the way in this new view of hormone actions on the brain. In this review, we summarize past and current work in our laboratory on this topic. This exciting and growing field involving many laboratories continues to reshape our ideas and approaches to neuroendocrinology both at the bench and the bedside.

Figure 1

Representation of CA1 pyramidal neurons in the female rat hippocampus during the 4-5 day estrous cycle: (A) diestrus, when estradiol levels begin to gradually increase; (B) proestrus, before ovulation; (C) estrus, after ovulation. From McEwen and Schmeck The Hostage Brain Rockefeller University Press, 1994. Drawing by Lidia Kibiuk.

Figure 2

Schematic summaries of the postulated role of estrogen stimulation of two pathways that can lead to spine synapse formation and maturation. First, estradiol signaling activates PI3 kinase and leads to phosphorylation of Lim Kinase 1 (LIMK1) leading, in turn, to phosphorylation of cofilin. This phosphorylation disinhibits actin polymerizatin and leads to filopodia formation that leads, in turn, to contacts with presynaptic elements that can lead to new, stable synaptic contact. In addition, PI3K increased phosphorylation of AKT and subsequent phosphorylation of 4E-BP1 leading to increased PSD95 translation. This effect promotes spine and synapse maturation.

Fig. 3

LIMK is activated during proestrus. (A) Images of peroxidase labeling of phosphorylated LIMK in the dorsal hippocampal formation of representative sections from one proestrus and one diestrus mouse. pLIMK-ir is darker throughout the hippocampus in proestrus than in diestrus. (B) Quantification of pLIMK-ir in four hippocampal subregions across the estrous cycle. pLIMK-ir was significantly higher in proestrus than in estrus (P<0.01) or diestrus. From (Spencer et al 2008). (P<0.0001) by permission.

Fig. 4

Akt is activated during proestrus and inactivated during estrus. (A) Images of peroxidase labeling of phosphorylated Akt in the dorsal hippocampal formation of representative sections from one proestrus and one estrus mouse. pAkt-ir is darker throughout the hippocampus inproestrus than in estrus. (B) Quantification of pAkt-ir in four hippocampal subregions across the estrus cycle. pAkt-ir was significantly higher in proestrus compared with estrus (P<0.0001), and in diestrus compared with estrus (P<0.0001). From (Spencer et al 2008) by permission.

Figure 5

BDNF Val66Met mice have increased hippocampal BDNF and TrkB expression. (A) Optical density of BDNF mRNA in the CA3 pyramidal cell layer (box) from in situ hybridization films. (B) Optical density of TrkB mRNA in the CA1 pyramidal cell layer (box) from in situ hybridization films. *, P < 0.05 for genotype. n = 6 for Val proestrus, 4 for Val diestrus, 5 for Met proestrus, and 4 for Met diestrus. Error bars represent SEM. (Scale bars: 100 μm.) From (Spencer et al 2010) by permission.

Figure 6

Schematic diagram of distribution of steroid receptors in autonomic circuits. The baroreceptor reflex is formed by projections from the NTS to CVL to RVLM to the interomedial lateral cell column (IML) of the spinal cord. The NTS projects directly to the RVLM (chemoreceptor pathway) and PVN. The PVN projects directly to the RVLM and IML. ERα and PR predominate in neurons in the autonomic regions of the NTS, ERβ predominates in the PVN and RVLM neurons, and AR predominates in the PVN.

Figure 7

Schematic diagram of the subcellular distributions of steroid receptors in the RVLM. ERa is found in the nuclei of catecholaminergic (CA) RVLM neurons and in afferent terminals, possibly arising from the NTS or hypothalamus. ERβ is mostly found on the plasma membranes or affiliated with mitochondria of CA neurons and sometimes in terminals. PR is almost exclusively in axons, some colocalized with GABA which possibly arise from the CVL. ARs are in large afferent terminals resembling NTS and hypothalamic afferents and in glia.