Summary of the major findings on ER distribution in the adult brain
The diversity of approaches taken when investigating ER distribution in the brain are illustrated. Some studies present data throughout the brain, whereas others focus on specific areas, with variations in the use of intact and gonadectomized rodents and the sex of the subjects under investigation. Along with difficulties inherent in the absolute quantification of immunoreactivity (IR) and in situ hybridization (ISH) signals, this complicates direct comparisons between studies. Overall, however, there is a strong consistency for the anatomical organization of ERs in the brain: it is clear that across species, ERα and ERβ are widely distributed in brain regions that are and are not principally associated with reproductive functions. Although overlapping in many brain regions, ERα and ERβ have distinct patterns of distribution. In humans and rodents, the hypothalamus (especially the VMN) and amygdala emerge as ERα-dominant regions (Shughrue et al., 1997; Osterlund et al., 2000a,c), providing neuroanatomical evidence for a role in regulating neuroendocrine, autonomic, emotional, affective, and motivational responses. Both ERα and ERβ are found in the hippocampus in rodents and humans, ERβ being the dominant form in the human subiculum (where information leaves the hippocampus to influence amygdala, cortical, and subcortical structures). ERs are thus well placed to influence learning and memory. The basal ganglia are notable by their relative lack of classical ERs. The distribution patterns of ERs are remarkably similar in adult male and female brains. However, sex differences are present in the relative levels of expression in hypothalamic subnuclei involved in reproductive processes, which may be determined early in life (Khünemann et al., 1994; Orikasa et al., 2002; Ikeda et al., 2003). In the human hypothalamus, sex differences were also revealed by closer analysis of their subcellular distribution to the nucleus, cytoplasm, and nerve terminals (Kruijver et al., 2002). In contrast, a lack of overall sex differences in ER expression levels was notable in the hippocampal regions, where estradiol-responsiveness is known to be sexually dimorphic (Weiland et al., 1997). Sex differences are also absent in the cortex (Kritzer, 2002), but finer analysis revealed that males and females did exhibit differences in the cytoarchitectural localization of ERs in the mesocortical neurons supplying different regions of the PFC (Kritzer and Creutz, 2008).
| Species | Protein/Immunoreactivity | mRNA (In Situ Hybridization) |
|---|---|---|
| ERα | ||
| Rat | Gonad-intact, male and female cerebral cortex: wide neuronal distribution (distinct from ERβ); no sex differences (Kritzer, 2002). | Twelve days post-OVX: exclusively in the VMN and subfornical organ; also in perikarya in cerebral cortex and hippocampus (weak compared with ERβ), as well as other brain regions, including the BNST, medial and cortical amygdaloid nuclei, POA, lateral habenula, periaqueductal gray, parabrachial nucleus, LC, NTS, spinal trigeminal nucleus, superficial laminae of the spinal cord (Shughrue et al., 1997). |
| Gonad-intact, male and female dopaminergic neurones of the mesocortical system: no overall sex differences, but sex differences revealed at cytoarchitectural level (Kritzer and Creutz, 2008). | Intact males and females; olfactory cortex, hippocampus, amygdala, septum, BNST, thalamus, POA, AVPV, SCN, ARC, PeN, SNc, NTS, LC, midbrain raphe nuclei; no sex differences (Laflamme et al., 1998). | |
| Mouse | Two weeks post-OVX; widely distributed throughout brain; predominant subtype in hippocampus, POA, and most of the hypothalamus; sparse or absent from cerebral cortex and cerebellum (Mitra et al., 2003). | CX; widely expressed throughout brain; few positive cells in striatum; none in SNc (Shughrue, 2004). |
| CX: concentrated in many brain regions, especially hypothalamus (POA, ARC, VMN), BNST, amygdala; scattered positive cells in striatum; few in lateral SN, not SNc (not located in dopamine neurons) (Shughrue, 2004). | ||
| Monkey | OVX; present in hippocampus and hypothalamus at a relatively high ERβ/ERα ratio (Register et al., 1998) | RT-PCR; widely distributed in males and females; exclusive subtype in frontal cortex, caudate nucleus and cerebellum; no sex differences (Pau et al., 1998). |
| Human | Hypothalamic region; 5 men and 5 women (20–39 years old); strong sub-regional sex differences in staining intensity and cellular location (nuclear, cytoplasmic, nerve terminals) (Kruijver et al., 2002) | Forebrain (three men, two women); abundant in amygdala and hypothalamus, lower in cerebral cortex and hippocampus; similar in monkey (two males) but differs in part from rat (Osterlund et al., 2000c). |
| Forebrain (seven men, two women) alternative ERα promoter expression in distinct forebrain populations; suggests multiple promoter usage may underlie differentiated regulation of expression (Osterlund et al., 2000a). | ||
| Dominates in amygdala, hypothalamus (Ostlund et al., 2003). | ||
| ERβ | ||
| Rat | Twelve days post-OVX brain; nuclear IR in neurons colocalizes with mRNA; includes the olfactory nuclei, laminae IV–VI of the cerebral cortex, medial septum, POA, BNST, SON, PVN, ZI, medial and cortical amygdaloid nuclei, cerebellum, NTS, VTA, and spinal trigeminal nucleus (Shughrue and Merchenthaler, 2001). | Twelve days post-OVX hypothalamus; dense expression in mPOA and BNST (similar to ERα mRNA), PVN and SON (vs. little/negligible ERα); weak in ARC, VMN (vs. abundant ERα) (Shughrue et al., 1996). |
| Gonad-intact, male and female cerebral cortex; wide neuronal distribution; distinct from ERα; no sex differences (Kritzer, 2002). | Twelve days post-OVX brain; exclusively in neurons of the olfactory bulb, SON, PVN, SCN, tuberal nuclei, ZI, VTA, cerebellum (Purkinje cells), laminae III–V, VIII, and IX of the spinal cord, and pineal gland. Also in perikarya in cerebral cortex and hippocampus, as well as other brain regions, including the BNST, medial and cortical amygdaloid nuclei, POA, lateral habenula, periaqueductal gray, parabrachial nucleus, LC, NTS, spinal trigeminal nucleus, superficial laminae of the spinal cord (Shughrue et al., 1997). | |
| Similar wide distribution in male and female rat brains, including cerebral cortex, LC (high); SN, amygdala (moderate); hypothalamic subnuclei (weak): sex differences in IR intensity in hippocampus (female dominant) and BNST, mPOA, LC (male dominant); also sex differences in intracellular (nuclear, cytoplasmic, terminal) distribution (Zhang et al., 2002). | Intact males and females; exclusive to SON and PVN magnocellular and autonomic subdivisions; also in olfactory cortex, hippocampus, amygdala, BNST, substantia inominata, POA, AVPV, ARC, SNc, NTS, cerebellum; no sex differences (Laflamme et al., 1998). | |
| VMN: females have significantly more IR cells than males at postnatal days 5–14; sex difference was not significant by P21; confirmed by ISH; remarkably higher expression levels in neonatal VMN compared with adult (Ikeda et al., 2003). | Sex differences in AVPV and mPOA from first week of birth to adulthood; confirmed by ICC (Orikasa et al., 2002). | |
| Gonad-intact-intact female brain: compared with young rats (10 weeks), numbers of ERβ mRNA-positive cells were reduced in the olfactory bulb, cerebral cortex, hippocampus, N.Acc, parts of the amygdala and raphe nuclei in middle-age (12 months), but did not decline further in aged animals (24 months); by contrast, numbers in hippocampus, striatum, claustrum, SN and cerebellum did not change by middle-age, but decreased in old rats: age-dependent changes are region specific (Yamaguchi-Shima and Yuri, 2007). | ||
| Mouse | Two weeks post-OVX; widely distributed throughout brain; primarily in cell nuclei in select regions of the brain, including the olfactory bulb, cerebral cortex, septum, POA, BNST, amygdala, PVN, thalamus, VTA, SN, dorsal raphe, LC, and cerebellum. Extranuclear-IR detected in several areas, including fibers of the olfactory bulb, areas CA3 and CA1 of the hippocampus, and the cerebellum. (Shughrue, 2004); CX males; concentration of positive cells in POA, BNST, PVN, amygdala; no positive cells in striatum or SN (Mitra et al., 2003). | CX males; widely expressed throughout brain; no positive cells in striatum or SN (Shughrue, 2004). |
| Monkey | OVX: present in hippocampus and hypothalamus at a relatively high ERβ/ERα ratio (Register et al., 1998). | RT-PCR: more widely distributed in female brains, including putamen, hippocampus and PVN, which lack mRNA in males (Pau et al., 1998). |
| Human | Five men, five women (20–39 years old); subregional sex differences in IR intensity and cellular location (nuclear, cytoplasmic, nerve terminals) (Kruijver et al., 2003). | Eight men and two women; most abundant in hippocampus, claustrum, and cerebral cortex; low in hypothalamus and amygdala (distinct from ERα) (Osterlund et al., 2000b). |
| Sex differences: 50-fold more IR neurons in the AVP-containing region of the dorsolateral SON in young women compared with men; no sex differences in ERα (Ishunina et al., 2000). | Dominates in hippocampal formation, entorhinal cortx, thalamus (Ostlund et al., 2003). | |
| GPR30 (proposed G protein-coupled receptor for estradiol) | ||
| Rat | Adult males and females; Island of Calleja, striatum (high density), PVN, SON, hippocampus, SN, brainstem autonomic nuclei (Brailoiu et al., 2007) | Adult males and females; PVN (particularly magnocellular region), SON (Hazell et al., 2009). |
| Mouse | Adult males and females; cortex, hypothalamus, hippocampus, pontine nuclei, LC, trigeminal nuclei and cerebellum; distinct from ERα and ERβ; no sex differences (Hazell et al., 2009). | Adult males and females; PVN (particularly magnocellular region), SON (Hazell et al., 2009). |
| No distinction between ERα or ERβ | ||
| Rat | Males and females; mRNA (ISH) widely distributed in hypothalamus and cortex; also in lateral septal nucleus, amygdala, hippocampus, BNST; no sex differences (Simerly et al., 1990). | |
| Gonad-intact male and female midbrain; ER-IR absent in SNc and present in subpopulations of VTA and retrorubral field; no sex differences (Kritzer, 1997). | ||
| Gonad-intact male and female hippocampal CA1 region; sex differences in estradiol responsiveness, but ER-IR levels in showed no sex differences (Weiland et al., 1997). | ||
| Quantitative in vitro autoradiography in developing rat hypothalamus; sex differences in some sub-regions are present around birth (mPOA), others emerge at 1–2 weeks (VMN), and persist into adulthood. Note well: Using ISH, sex differences in ER in mPOA disappear by postnatal day 10 (DonCarlos and Handa, 1994; Khünemann et al., 1994). | ||
| Mouse | ER transcriptional activity in the ERE-luciferase reporter mouse; no sex differences at diestrus; sex differences at proestrus (high estradiol) (Stell et al., 2008). | |
ARC, arcuate nucleus of the hypothalamus; AVPV, anteroventral paraventricular nucleus of the hypothalamus; BNST, bed nucleus of the stria terminalis; CX, castrated adult male; GPR30, proposed G protein-coupled receptor for estradiol; LC, locus ceruleus; NTS, nucleus tractus solitarius; OVX, ovariectomized adult female; PeN, periventricular nucleus of the hypothalamus; RT-PCR, reverse transcription-polymerase chain reaction; SCN, suprachiasmatic nucleus of the hypothalamus; SN, substantia nigra; SON, supraoptic nucleus of the hypothalamus; ZI, zona incerta.