Review articleRapid effects on memory consolidation and spine morphology by estradiol in female and male rodents
Introduction
The principal ovarian estrogen, estradiol, is implicated in long term regulation of cognition (Luine, 2014), mood (Altemus, 2017) and some psychiatric disorders (Bangasser and Valentino, 2014). Effects on these neural functions have been found following changes in circulating gonadal hormones including after ovariectomy, over the menstrual and estrus cycle, during menopause or estropause and after administration of hormones to gonadectomized subjects. These estrogenic effects are manifested over days or months. More recently, estrogens have been shown to affect neural functions, including learning and memory, within minutes, providing support for the idea that they act as neurosteroids (Luine and Frankfurt, 2012). Within minutes following estrogen and/or receptor agonist treatments female rats and mice show enhanced performance on memory tasks such as recognition memory (Inagaki et al., 2012; Inagaki et al., 2010; Jacome et al., 2016; Luine et al., 2003; Phan et al., 2012; Phan et al., 2015; Walf et al., 2006). Moreover, current studies show that estrogen's action is not limited to females but also affects cognition in males (Jacome et al., 2016). The goal of this review is to describe findings of rapid, neurosteroid-like effects of estrogens on memory in male and female rodents. First, a short description of memory testing is provided. Then, we show how these behavioral changes are related to rapid estrogenic effects on dendritic spine density, the distribution of spine types and the trafficking of PSD95 and GluA2 within spines in the hippocampus and medial prefrontal cortex (mPFC), two areas critical for learning and memory. Overall, these data lead to the conclusion that estrogens are capable of exerting rapid and potent influences on memory in both sexes.
Section snippets
Recognition memory tasks
Many neuroscientists have recently adopted recognition memory tasks to investigate memory processes and to determine possible effects of drugs and hormones on memory (Ennaceur and Meliani, 1992). Most memory tasks utilize positive (food or water) or negative (shock or possibility of drowning) reinforcements, which can confound results. However, recognition tasks utilize the innate, novelty seeking and exploratory nature of rodents and thereby largely eliminate many confounding influences found
Chronic, genomic effects of estrogens on memory
In assessing effects of drugs or hormones using recognition memory tasks, agents to be tested can be given before the training trial (Pre-T1 injection) or after the training trial (Post T1 injection) which is known as a post-training protocol (see Fig. 2, top). Classically, most studies using estrogens gave treatments before T1, then gave T1 trials, an inter-trial delay and then tested for effects in the recognition trial. On the left side of Fig. 2, results of a Pre-T1 treatment experiment are
Rapid enhancements in memory tasks – pre-training estradiol treatments
During the 1990's, evidence accumulated that receptor(s) for estrogens were also present outside of the cell nucleus in membranes of cell bodies and in axons, spines, presynaptic terminals, and near post-synaptic neurotransmitter receptors (see Almey et al., 2015 for review). Brain regions mediating reproductive function such as the hypothalamus as well as regions mediating cognition, including the mPFC and the hippocampus, were shown to contain non-nuclear receptors. Thus, we and others began
Post training trial injections rapidly enhance memory consolidation
In subsequent studies, we and others utilized post training protocols, post T1 injections (Fig. 2), as advanced by McGaugh and colleagues (McGaugh, 1989), for assessing memory. Post T1 treatments are given after subjects acquire information such as searching for a submerged platform in water maze tasks or having explored objects in recognition tasks. Following the acquisition or training trial, new information requires consolidation, and drugs or hormones can influence memory storage processes
Rapid enhancements of memory consolidation by estradiol: males
Gonadal hormones also influence cognition in males. Castration of rats impairs consolidation of memory on both OR and OP tasks (Aubele et al., 2008; Luine, 2015; Tuscher et al., 2015) and on working memory during acquisition of the radial arm maze (Daniel et al., 2003). Few studies, however, have examined males for rapid hormonal effects. Thus, we recently investigated rapid influences of gonadal hormones in castrated male rats (Jacome et al., 2016) and, as shown in Fig. 3, both E2 and
Acute estradiol increases spine density in both female and male rats
Increasing evidence shows that dendritic remodeling is a general mechanism underlying learning and memory. The acquisition of new memories in a conditioning paradigm is associated with increases in dendritic spine density in the CA1 region of the hippocampus (CA1) in both male (Jedlicka et al., 2008; Leuner et al., 2003) and female rats (Beltran-Campos et al., 2011). In addition, existing spines undergo structural alterations that result in long term potentiation (LTP) (Bourne and Harris, 2008;
Role of neurally derived estradiol on hippocampal function
The source of estrogens which maintain cognitive function and spine stability in the hippocampus of female rodents has been assumed, until recently, to be ovarian. However, many studies suggest that estradiol maybe acting as a neurosteroid, a steroid synthesized in the brain which acts locally, to modulate neuronal excitability by rapid non-genomic actions. In support of this idea, levels of estradiol in the hippocampus are higher than in the circulation over the rat estrous cycle: for example,
Estrogen induced spinogenesis in CA1: potential mechanisms
While it is accepted that E2 promotes increased dendritic spine plasticity in brain areas implicated in memory, the molecular mechanisms underlying plasticity are only beginning to emerge. The discovery that mERs could functionally couple to the metabotropic glutamate receptors, mGluR1 and 2, in the hippocampus (Boulware et al., 2005) provided the first indication of how estrogen signaling might alter spinogenesis. Since then, Mermelstein's group has documented the interaction between estrogen
Acknowledgments
Recent experimental work from our laboratories discussed in this review was supported by The City University of New York, PSC-CUNY, NIH grants RR003037 from the National Center for Research Resources (HC); Training Grants GM060665 (VL) and NS080686 (HC) and DA012136-13 (PAS).
References (76)
- et al.
Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females
Horm. Behav.
(2015) Neuroendocrine networks and functionality
Psychiatr. Clin. North Am.
(2017)- et al.
Effects of gonadectomy and hormone replacement on a spontaneous novel object recognition task in adult male rats
Horm. Behav.
(2008) - et al.
The importance of neural aromatization in the acquisition, recall, and integration of song and spatial memories in passerines
Horm. Behav.
(2015) - et al.
Sex differences in stress-related psychiatric disorders: neurobiological perspectives
Front. Neuroendocrinol.
(2014) - et al.
Do thin spines learn to be mushroom spines that remember?
Curr. Opin. Neurobiol.
(2007) - et al.
Increase of mushroom spine density in CA1 apical dendrites produced by water maze training is prevented by ovariectomy
Brain Res.
(2011) - et al.
Assessing rodent hippocampal involvement in the novel object recognition task. A review
Behav. Brain Res.
(2015) - et al.
The rodent hippocampus is essential for nonspatial object memory
Curr. Biol.
(2013) - et al.
A new one-trial test for neurobiological studies of memory in rats. III. Spatial vs. non-spatial working memory
Behav. Brain Res.
(1992)