Gonadal Hormones Rapidly Enhance Spatial Memory and Increase Hippocampal Spine Density in Male Rats

Abstract

17β-estradiol (E2) rapidly, within minutes, activates behaviors and cognition by binding to membrane estrogen receptors, activating cell signaling cascades and increasing dendritic spines. In female rodents, E2 enhances spatial memory within 2-4 hours, and spine density is increased in the CA1 area of the hippocampus within 30-60 minutes. Although chronic gonadal hormone treatments in male rats alter cognition and spines/spine synapses and acute hormone effects occur in hippocampal slices, effects of acute, in vivo hormone administration in males are unknown. Therefore, we assessed rapid effects of E2 (20 μg/kg) and testosterone (T) (750 μg/kg) on spatial memory using the object placement task and on hippocampal spine density using Golgi impregnation. Orchidectomized rats received hormones immediately after the training trial and were tested for retention 2 hours later. Vehicle-injected orchidectomized males spent equal time exploring objects in the old and new locations, but E2- or T-treated subjects spent more time exploring objects at the new location, suggesting enhanced memory. Both hormones also increased spine density in CA1, but not the dentate gyrus, by 20%-40% at 30 minutes and 2 hours after injections. This report is the first, to our knowledge, to show E2 and T enhancements of memory and spine density within such a short time frame in male rats.

Why estrogens matter for behavior and brain health

“…In particular, dendritic spines, the site of most excitatory synapses, respond very rapidly to estrogen treatment. In the hippocampus, 17β-estradiol administration results in a transient increase in density and length (Jacome et al, 2016; MacLusky et al, 2005; Mukai et al, 2007; Murakami et al, 2006; Mendez et al, 2011; Srivastava, et al, 2008; Tuscher et al, 2016). In behaviorally naïve ovariectomized female mice, it was also found that systemic treatment with 17β-estradiol (Phan et al, 2012), ERα agonist PPT (Phan et al, 2011) and GPER agonist G1 (Gabor, Lymer et al, 2015) rapidly increased dendritic spine density in CA1 field of the hippocampus, while ERβ agonist DPN decreased it (Phan et al, 2011).…”

Rapid nongenomic modulation by neurosteroids of dendritic spines in the hippocampus: Androgen, oestrogen and corticosteroid

“…Although rapid spine modulation via in vivo androgen treatment has not been studied extensively, the rapid increase in CA1 spines was observed 0.5‐2 hours after s.c. injection of testosterone (750 μg kg ‐1 ) in castrated male rats …”

“…Numerous investigations have been performed regarding the rapid E 2 effects on spines, in addition to isolated slices. In vivo E 2 treatment via s.c. injection rapidly increased (within 15‐40 minutes) the spine density in CA1 hippocampal neurones of ovariectomised (OVX) mice . The injection of E 2 rapidly (~30 minutes) increased the spine‐synapse density as a result of synaptic rearrangements in OVX female rats .…”

“…The same study group reported that the injection of a selective agonist for ERα (PPT) but not for ERβ (DPN) rapidly (approximately 1 hour) increased dendritic spines and improved learning in OVX female mice . Subcutaneous injection of E 2 rapidly (30‐60 minutes) induced not only hippocampus‐dependent memory performance, but also spine increases in the hippocampus in OVX female rats . In OVX female rats, relatively rapid E 2 effects (approximately 4 hours after s.c. injection) were observed on object recognition and object placement tests .…”

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…Therefore, the intuitive reasoning is that reducing Aβ levels should protect synapses, ameliorate neuronal plasticity and translate into beneficial effects on memory function. Thus, interventions that ameliorate spine density and plasticity also boost memory function (170)(171)(172). Conversely, manipulations that reduce neuronal connectivity and spine density subsequently alter memory (173,174).…”