Hysterectomy Uniquely Impacts Spatial Memory in a Rat Model: A Role for the Nonpregnant Uterus in Cognitive Processes

Koebele, Stephanie V.; Palmer, Justin M.; Hadder, Bryanna; Melikian, Ryan; Fox, Carly; Strouse, Isabel Martha; DeNardo, Dale F.; George, Christina; Daunis, Emily; Nimer, Adrianna; Mayer, Loretta P.; Dyer, Cheryl A.; Bimonte‐Nelson, Heather A.

doi:10.1210/en.2018-00709

Cited by 35 publications

(33 citation statements)

References 84 publications

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“…Prominent in the rodent literature is the use of the radial-arm maze (RAM) (Olton and Samuelson, 1976 ; Ward et al, 1999 ; Bimonte-Nelson et al, 2004 ; Braden et al, 2011 ; Prakapenka et al, 2018 ; Koebele et al, 2019 ; see reviews: Olton, 1979 ; Bimonte-Nelson et al, 2010 , 2015 ), a multi-arm apparatus requiring rodents to locate a reinforcer at the ends of particular arms, often by navigating through space using distinctive extramaze cues for optimal performance. The RAM is a win-shift task, with optimal performance involving the animal receiving a reinforcer in one location and then “shifting” away to a new location for the next reinforcer, rather than returning to the initial site of reinforcement within a testing session; this is accomplished by presenting reinforcement only upon first entry into a given arm (Bimonte-Nelson et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

“…Using the WRAM, we have found that errors made into working and reference memory arms typically occur in concert, indicating that working and reference memory demands impact each other (Braden et al, 2011 , 2017 ; Mennenga et al, 2015b , c ; Prakapenka et al, 2018 ; Koebele et al, 2019 ). Here, we evaluate relationships between working and reference memory by systematically testing working memory performance with and without the presence of reference memory demands.…”

Section: Introductionmentioning

confidence: 99%

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Age Impacts the Burden That Reference Memory Imparts on an Increasing Working Memory Load and Modifies Relationships With Cholinergic Activity

Bernaud

Hiroi

Poisson

et al. 2021

Front. Behav. Neurosci.

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Rodent aging research often utilizes spatial mazes, such as the water radial-arm-maze (WRAM), to evaluate cognition. The WRAM can simultaneously measure spatial working and reference memory, wherein these two memory types are often represented as orthogonal. There is evidence, however, that these two memory forms yield interference at a high working memory load. The current study systematically evaluated whether the presence of a reference memory component impacts handling of an increasing working memory load. Young and aged female rats were tested to assess whether aging impacts this relationship. Cholinergic projections from the basal forebrain to the hippocampus and cortex can affect cognitive outcomes, and are negatively impacted by aging. To evaluate whether age-related changes in working and reference memory profiles are associated with cholinergic functioning, we assessed choline acetyltransferase activity in these behaviorally-tested rats. Results showed that young rats outperformed aged rats on a task testing solely working memory. The addition of a reference memory component deteriorated the ability to handle an increasing working memory load, such that young rats performed similar to their aged counterparts. Aged rats also had challenges when reference memory was present, but in a different context. Specifically, aged rats had difficulty remembering which reference memory arms they had entered within a session, compared to young rats. Further, aged rats that excelled in reference memory also excelled in working memory when working memory demand was high, a relationship not seen in young rats. Relationships between cholinergic activity and maze performance differed by age in direction and brain region, reflecting the complex role that the cholinergic system plays in memory and attentional processes across the female lifespan. Overall, the addition of a reference memory requirement detrimentally impacted the ability to handle working memory information across young and aged timepoints, especially when the working memory challenge was high; these age-related deficits manifested differently with the addition of a reference memory component. This interplay between working and reference memory provides insight into the multiple domains necessary to solve complex cognitive tasks, potentially improving the understanding of complexities of age- and disease- related memory failures and optimizing their respective treatments.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Age Impacts the Burden That Reference Memory Imparts on an Increasing Working Memory Load and Modifies Relationships With Cholinergic Activity

Bernaud

Hiroi

Poisson

et al. 2021

Front. Behav. Neurosci.

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“…Several studies have reported that differences between male and female rats in evoked AMPAR/NMDAR signaling in hippocampal synapses, along with differences in the magnitude of evoked LTP, may underlie sex differences in spatial memory (Monfort et al, 2015;Qi et al, 2016). Estrous has been shown to modulate diffusion of AMPARs to the surface in female mice (Palomero-Gallagher et al, 2003;Tada et al, 2015;Bechard et al, 2018), which may underlie part of the reported importance of estrogenic mechanisms for memory in females (Cordeira et al, 2018;Frick et al, 2018;Koss et al, 2018;Wang et al, 2018;Koebele et al, 2019). However, the sex-specific role of AMPARs in memory may also be specific to the type of memory task being tested, as a study by Dachtler et al concluded that the GluA1 subunit was necessary only for male, not female, mice in fear conditioning memory, but that hippocampal GluA1 was necessary for spatial learning in both sexes (Dachtler et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Cornichon Homolog-3 (CNIH3) Modulates Spatial Memory in Female Mice

Frye

Williams

Trousdale

et al. 2019

Preprint

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Cornichon homolog-3 (CNIH3) is an AMPA receptor (AMPAR) auxiliary protein that traffics AMPARs to the postsynaptic membrane and potentiates AMPAR signaling. AMPARs are key components of hippocampal synaptic plasticity and memory formation, however the role of CNIH3 in memory has yet to be elucidated. To study the role of CNIH3 on mouse behavior, we bred and characterized a line of Cnih3 -/mice from C57BL/6 Cnih3 tm1a(KOMP)Wtsi mice obtained from the Knockout Mouse Project (KOMP). In agreement with previous studies of CNIH3 in the brain, we observed concentrated expression of Cnih3 in the dorsal hippocampus, a region associated with spatial learning and memory. Therefore, we tested Cnih3 +/+ , Cnih3 +/-, and Cnih3 -/mice in the Barnes maze paradigm to measure spatial memory. We observed no change in spatial memory in male Cnih3 +/and Cnih3 -/mice compared to male Cnih3 +/+ controls, however, Cnih3 -/female mice made significantly more primary errors, had a higher primary latency, and took less efficient routes to the target in the maze compared to Cnih3 +/+ female mice. Next, to investigate an enhancement of spatial memory by Cnih3 overexpression, specifically in the dorsal hippocampus, we developed an AAV5 viral construct to express wild-type Cnih3 in excitatory neurons. Female mice overexpressing Cnih3 made significantly fewer errors, had a lower primary latency to the target, and took more efficient routes to the maze target compared to YFP expressing control females. No change in spatial memory was observed in male Cnih3 overexpression mice. This study, the first to identify sex-specific effects of the AMPAR auxiliary protein CNIH3 on spatial memory, provides the groundwork for future studies investigating the role of CNIH3 on sexually dimorphic AMPAR-dependent behavior and hippocampal synaptic plasticity.

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“…For WRAM treatment effects, WRAM testing was split into three blocks, Block 1 (days 2-5) to represent the early acquisition phase, Block 2 (days 6-9) to represent the late acquisition phase, and Block 3 (days 10-12) to represent the asymptotic phase (Koebele et al, 2019). A priori comparison repeated measures ANOVA was run for each Block to directly compare oil-control and blank-PLGA treatments to evaluate vehicle effects.…”

Section: Statistical Analysesmentioning

confidence: 99%

Poly(lactic-co-glycolic Acid) Nanoparticle Encapsulated 17β-Estradiol Improves Spatial Memory and Increases Uterine Stimulation in Middle-Aged Ovariectomized Rats

Prakapenka

Quihuis

Carson

et al. 2020

Front. Behav. Neurosci.

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Hormone therapy that contains 17β-estradiol (E2) is used commonly for treatment of symptoms associated with menopause. E2 treatment has been shown to improve cognitive function following the decrease in ovarian hormones that is characteristic of menopause. However, once in circulation, the majority of E2 is bound to serum hormone binding globulin or albumin, becoming biologically inactive. Thus, therapeutic efficacy of E2 stands to benefit from increased bioavailability via sustained release of the hormone. Here, we focus on the encapsulation of E2 within polymeric nanoparticles composed of poly(lactic-co-glycolic) acid (PLGA). PLGA agent encapsulation offers several delivery advantages, including improved bioavailability and sustained biological activity of encapsulated agents. We hypothesized that delivery of E2 from PLGA nanoparticles would enhance the beneficial cognitive effects of E2 relative to free E2 or non-hormone loaded nanoparticle controls in a rat model of menopause. To test this hypothesis, spatial learning and memory were assessed in middle-aged ovariectomized rats receiving weekly subcutaneous treatment of either oil-control, free (oil-solubilized) E2, blank (non-hormone loaded) PLGA, or E2-loaded PLGA. Unexpectedly, learning and memory differed significantly between the two vehicle control groups. E2-loaded PLGA nanoparticles improved learning and memory relative to its control, while learning and memory were not different between free E2 and its vehicle control. These results suggest that delivery of E2 from PLGA nanoparticles offered cognitive benefit. However, when evaluating peripheral burden, E2-loaded PLGA was found to increase uterine stimulation compared to free E2, which is an undesired outcome, as estrogen exposure increases uterine cancer risk. In sum, a weekly E2 treatment regimen of E2 from PLGA nanoparticles increased cognitive efficacy and was accompanied with an adverse impact on the periphery, effects that may be due to the improved agent bioavailability and sustained biological activity offered by PLGA nanoparticle encapsulation. These findings underscore the risk of non-specific enhancement of E2 delivery and provide a basic framework for the study and development of E2's efficacy as a cognitive therapeutic with the aid of customizable polymeric nano-carriers.

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Hysterectomy Uniquely Impacts Spatial Memory in a Rat Model: A Role for the Nonpregnant Uterus in Cognitive Processes

Cited by 35 publications

References 84 publications

Age Impacts the Burden That Reference Memory Imparts on an Increasing Working Memory Load and Modifies Relationships With Cholinergic Activity

Age Impacts the Burden That Reference Memory Imparts on an Increasing Working Memory Load and Modifies Relationships With Cholinergic Activity

Cornichon Homolog-3 (CNIH3) Modulates Spatial Memory in Female Mice

Poly(lactic-co-glycolic Acid) Nanoparticle Encapsulated 17β-Estradiol Improves Spatial Memory and Increases Uterine Stimulation in Middle-Aged Ovariectomized Rats

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