Structural plasticity of the hippocampus in response to estrogens in female rodents

Abstract

It is well established that estrogens affect neuroplasticity in a number of brain regions. In particular, estrogens modulate and mediate spine and synapse formation as well as neurogenesis in the hippocampal formation. In this review, we discuss current research exploring the effects of estrogens on dendritic spine plasticity and neurogenesis with a focus on the modulating factors of sex, age, and pregnancy. Hormone levels, including those of estrogens, fluctuate widely across the lifespan from early life to puberty, through adulthood and into old age, as well as with pregnancy and parturition. Dendritic spine formation and modulation are altered both by rapid (likely non-genomic) and classical (genomic) actions of estrogens and have been suggested to play a role in the effects of estrogens on learning and memory. Neurogenesis in the hippocampus is influenced by age, the estrous cycle, pregnancy, and parity in female rodents. Furthermore, sex differences exist in hippocampal cellular and molecular responses to estrogens and are briefly discussed throughout. Understanding how structural plasticity in the hippocampus is affected by estrogens and how these effects can influence function and be influenced by other factors, such as experience and sex, is critical and can inform future treatments in conditions involving the hippocampus.

Keywords: Neurogenesis; aging; dendritic spines; depression; memory; parity; pregnancy; sex differences; stress.

Fig. 1

Hippocampal regions, strata, and neurogenesis. a Diagram of the major divisions of the hippocampus. Red box shows region depicted in B. Yellow box shows region depicted in C. b Image of Golgi-Cox stained hippocampal CA1 neurons from OVX female mouse, captured using 10x objective. Stratum oriens ~40-60% the length of basal dendrite. Stratum radiatum ~30-50% the length of the apical dendrite. Lacunosum-moleculare ~80-100% the length of the apical dendrite. c Diagram depicting the stages of adult neurogenesis in the dentate gyrus. DG, dentate gyrus; SO, stratum oriens; SR, stratum radiatum; LM, (stratum) lacunosum-moleculare

Fig. 2

Overview of behavioural tasks affected by estrogens and mentioned in this review. a Object recognition, b) social recognition, and c) object placement tasks take advantage of rodents’ innate preference for novelty. In each of task, a test rodent is presented with stimuli (typically two) to explore during training. Upon test, one stimulus is replaced with a novel stimulus (object/social recognition) or moved to a novel location. d In conditioned place preference, an animal is rewarded in one of two distinguishable contexts. A probe trial then explores the amount of time spent in the two contexts. e In the social transmission of food preferences, a “demonstrator” animal consumes a novel flavoured diet. They are then paired with an “observer” for an interaction period in which the observer will smell the novel flavoured diet on the demonstrator’s breath. When given a choice between the flavoured diet smelled on the demonstrator’s breath and another novel diet (both diets are novel to the observer), an animal with intact social learning will prefer the demonstrator’s diet. f In the win-shift version of the radial arm maze, rodents are placed in the maze and allowed to enter only a subset of the arms in order to receive rewards. Upon test phases, all arms are open, but rodents are only rewarded at the termini of formerly un-baited arms. Entries into previously baited arms are reference memory errors, whereas re-entry into arms entered during the test phase are working memory errors. Similarly, g) in the working/reference memory radial arm maze task, rodents are repeatedly rewarded in the same arms. Entries into never-baited arms are reference memory errors, whereas re-entries are working memory errors. h In the Morris water maze, an animal learns to swim to a hidden platform to escape. Probe trials then evaluate the amount of time the animal spends swimming in the quadrant previously containing the platform

Fig. 3

Suggested non-genomic, intracellular mechanisms driving dendritic spine changes and neurogenesis by estrogens. We hypothesize that estrogens bind to estrogen receptors (membrane bound or intracellular) which go on to activate cell signalling pathways, including, but not limited to the ERK, PI3K, JNK, and/or mTOR pathways. Cross-talk between these pathways is common. These have downstream effects on a number of intracellular mechanisms, including protein synthesis and actin polymerization. Through actin polymerization and protein synthesis, novel spines or “silent” synapses are created, which can become mature synapses following neuronal activity. If unused, the novel spines do not mature and are instead re-internalized. Other intracellular mechanisms, such as epigenetic or post-translational protein modifications and mediation of neurotransmitters and/or receptors, are likely also involved. The contributions of cell signalling pathways and other intracellular mechanisms in the effects of estrogens on neurogenesis remain to be explored