Syracuse University
Exercise Science
Downstream regulatory element antagonist modulator (DREAM)/calsenilin(C)/K+ channel interacting protein 3 (KChIP3) is a multifunctional Ca2+-binding protein highly expressed in the hippocampus that inhibits hippocampus-sensitive memory... more
Downstream regulatory element antagonist modulator (DREAM)/calsenilin(C)/K+ channel interacting protein 3 (KChIP3)
is a multifunctional Ca2+-binding protein highly expressed in the hippocampus that inhibits hippocampus-sensitive memory
and synaptic plasticity in male mice. Initial studies in our lab suggested opposing effects of DR/C/K3 expression in female
mice. Fluctuating hormones that occur during the estrous cycle may affect these results. In this study, we hypothesized that
DR/C/K3 interacts with 17b-estradiol, the primary estrogen produced by the ovaries, to play a role in hippocampus function.
We investigated the role of estradiol and DR/C/K3 in learning strategy in ovariectomized (OVX) female mice. OVX
WT and DR/C/K3 knockout (KO) mice were given three injections of vehicle (sesame oil) or 17b-estradiol benzoate (0.25
mg in 100 mL sesame oil) 48, 24, and 2 h before training and testing. DR/C/K3 and estradiol had a time-dependent effect on
strategy use in the female mice. Male KO mice exhibited enhanced place strategy relative to WT 24 h after pre-exposure.
Fear memory formation was significantly reduced in intact female KO mice relative to intact WT mice, and OVX reduced
fear memory formation in the WT, but had no effect in the KO mice. Long-term potentiation in hippocampus slices from
female mice was enhanced by circulating ovarian hormones in both WT and DR/C/K3 KO mice. Paired-pulse depression
was not affected by ovarian hormones but was reduced in DR/C/K3 KO mice. These results provide the first evidence that
DR/C/K3 plays a timing-dependent role in estradiol regulation of learning, memory, and plasticity.
is a multifunctional Ca2+-binding protein highly expressed in the hippocampus that inhibits hippocampus-sensitive memory
and synaptic plasticity in male mice. Initial studies in our lab suggested opposing effects of DR/C/K3 expression in female
mice. Fluctuating hormones that occur during the estrous cycle may affect these results. In this study, we hypothesized that
DR/C/K3 interacts with 17b-estradiol, the primary estrogen produced by the ovaries, to play a role in hippocampus function.
We investigated the role of estradiol and DR/C/K3 in learning strategy in ovariectomized (OVX) female mice. OVX
WT and DR/C/K3 knockout (KO) mice were given three injections of vehicle (sesame oil) or 17b-estradiol benzoate (0.25
mg in 100 mL sesame oil) 48, 24, and 2 h before training and testing. DR/C/K3 and estradiol had a time-dependent effect on
strategy use in the female mice. Male KO mice exhibited enhanced place strategy relative to WT 24 h after pre-exposure.
Fear memory formation was significantly reduced in intact female KO mice relative to intact WT mice, and OVX reduced
fear memory formation in the WT, but had no effect in the KO mice. Long-term potentiation in hippocampus slices from
female mice was enhanced by circulating ovarian hormones in both WT and DR/C/K3 KO mice. Paired-pulse depression
was not affected by ovarian hormones but was reduced in DR/C/K3 KO mice. These results provide the first evidence that
DR/C/K3 plays a timing-dependent role in estradiol regulation of learning, memory, and plasticity.
The multiple memory systems hypothesis proposes that different types of learning strategies are mediated by distinct neural systems in the brain. Male and female mice were tested on a water plus-maze task that could be solved by either a... more
The multiple memory systems hypothesis proposes that different types of learning strategies are mediated by distinct
neural systems in the brain. Male and female mice were tested on a water plus-maze task that could be solved by either
a place or response strategy. One group of mice was pre-exposed to the same context as training and testing (PTC) and
the other group was pre-exposed to a different context (PDC). Our results show that the PTC condition biased mice
to place strategy use in males, but this bias was dependent on the presence of ovarian hormones in females.
neural systems in the brain. Male and female mice were tested on a water plus-maze task that could be solved by either
a place or response strategy. One group of mice was pre-exposed to the same context as training and testing (PTC) and
the other group was pre-exposed to a different context (PDC). Our results show that the PTC condition biased mice
to place strategy use in males, but this bias was dependent on the presence of ovarian hormones in females.
Potassium channel interacting proteins (KChIPs) are members of a family of calcium binding proteins that interact with Kv4 potassium (K+) channel primary subunits and also act as transcription factors. The Kv4 subunit is a primary K+... more
Potassium channel interacting proteins (KChIPs) are members of a family of calcium binding proteins that interact with
Kv4 potassium (K+) channel primary subunits and also act as transcription factors. The Kv4 subunit is a primary K+
channel pore-forming subunit, which contributes to the somatic and dendritic A-type currents throughout the nervous
system. These A-type currents play a key role in the regulation of neuronal excitability and dendritic processing of
incoming synaptic information. KChIP3 is also known as calsenilin and as the transcription factor, downstream
regulatory element antagonist modulator (DREAM), which regulates a number of genes including prodynorphin.
KChIP3 and Kv4 primary channel subunits are highly expressed in hippocampus, an area of the brain important for
learning and memory. Through its various functions, KChIP3 may play a role in the regulation of synaptic plasticity and
learning and memory. We evaluated the role of KChIP3 in a hippocampus-dependent memory task, contextual fear
conditioning. Male KChIP3 knockout (KO) mice showed significantly enhanced memory 24 hours after training as
measured by percent freezing. In addition, we found that membrane association and interaction with Kv4.2 of KChIP3
protein was significantly decreased and nuclear KChIP3 expression was increased six hours after the fear conditioning
training paradigm with no significant change in KChIP3 mRNA. In addition, prodynorphin mRNA expression was
significantly decreased six hours after fear conditioning training in wild-type (WT) but not in KO animals. These data
suggest a role for regulation of gene expression by KChIP3/DREAM/calsenilin in consolidation of contextual fear
conditioning memories.
Kv4 potassium (K+) channel primary subunits and also act as transcription factors. The Kv4 subunit is a primary K+
channel pore-forming subunit, which contributes to the somatic and dendritic A-type currents throughout the nervous
system. These A-type currents play a key role in the regulation of neuronal excitability and dendritic processing of
incoming synaptic information. KChIP3 is also known as calsenilin and as the transcription factor, downstream
regulatory element antagonist modulator (DREAM), which regulates a number of genes including prodynorphin.
KChIP3 and Kv4 primary channel subunits are highly expressed in hippocampus, an area of the brain important for
learning and memory. Through its various functions, KChIP3 may play a role in the regulation of synaptic plasticity and
learning and memory. We evaluated the role of KChIP3 in a hippocampus-dependent memory task, contextual fear
conditioning. Male KChIP3 knockout (KO) mice showed significantly enhanced memory 24 hours after training as
measured by percent freezing. In addition, we found that membrane association and interaction with Kv4.2 of KChIP3
protein was significantly decreased and nuclear KChIP3 expression was increased six hours after the fear conditioning
training paradigm with no significant change in KChIP3 mRNA. In addition, prodynorphin mRNA expression was
significantly decreased six hours after fear conditioning training in wild-type (WT) but not in KO animals. These data
suggest a role for regulation of gene expression by KChIP3/DREAM/calsenilin in consolidation of contextual fear
conditioning memories.
Topology deals with qualitative representations of space whereas metric relationships rely on quantitative measures of distances and angles (Gallistel, 1990). Through specific lesion approaches, topological information processing has been... more
Topology deals with qualitative representations of space whereas metric relationships rely on quantitative measures of distances and angles (Gallistel, 1990). Through specific lesion approaches, topological information processing has been linked to parietal cortex function, while metric information processing relies on intact hippocampus function (Goodrich-Hunsaker et al., 2008). Models of hippocampal function and disruption of function following lesions suggest that the dentate gyrus of the hippocampus is engaged during pattern separation (Rolls and Kesner, 2006). We previously showed that higher levels of circulating estradiol biased female rats toward using hippocampal-sensitive and away from using striatal-sensitive learning strategies (Korol, 2004). In this study, we first investigated the effect of estrous cycle on detection of metric change in object location (MCOL), a pattern separation task. In this task rats are allowed to explore two objects for three study sessions. Following the last study session, the metric distance between the objects is symmetrically changed for the test trial. We found that proestrous female rats were able to detect the metric change in object location during test session more efficiently than diestrous or estrous rats. We then tested the effects of 17-estradiol replacement to ovariectomized rats on MCOL. Rats treated with estradiol detected the metric change in object location, whereas vehicle-injected controls did not. Our data suggest that relatively higher levels of circulating estradiol in female rats enhance detection of subtle metric changes in object locations improving performance in pattern separation perhaps through more efficient processing of information through the hippocampus.
The hippocampus and striatum are two memory systems studied for their respective participation in navigation tasks that require place and response learning in water or land-based mazes. To avoid stress responses of swim tasks and food... more
The hippocampus and striatum are two memory systems studied for their respective participation in navigation tasks that require place and response learning in water or land-based mazes. To avoid stress responses of swim tasks and food restriction in appetitive tasks, we developed two pattern separation tasks that allowed us to determine the selective involvement of hippocampus and striatum. The metric change in object location (MCOL) task measures the ability of rats to perform pattern separation using the distance between two objects. Damage to the hippocampus impairs the ability to detect MCOL (Goodrich-Hunsaker et al., 2008). The double object replacement (DOR) task examines the ability to detect the presence of two novel objects that have replaced familiar ones. Importantly, these tasks do not require extrinsic motivators or extensive locomotor activity. In the current study, we tested the role of the hippocampus or striatum in these tasks with direct microinjections of drugs that disrupt normal physiological function into these brain areas. Young adult male rats were randomly assigned to drug or vehicle control infusions and tested on either the MCOL or DOR task. Rats were allowed to explore the arena with two objects placed on opposite sides during three study sessions followed by a 30-min delay prior to the test trial. Bilateral infusions were made 10 min prior to the test trial, during which the two objects were either moved closer together for the MCOL task or replaced with new objects for the DOR task. Compared to controls, rats with disrupted hippocampal functions displayed impaired memory on the MCOL task but not on the DOR task. Conversely, rats with disrupted striatal functions displayed impaired memory on the DOR task, but not on the MCOL task. These results suggest that the MCOL task is hippocampus-sensitive while the DOR task is striatum-sensitive. In addition to demonstrating novel dissociations between the hippocampus and striatum, these tasks allow us to examine the metabolic and biochemical pathways involved in learning and memory without changing baseline metabolism due to stress or food/water restriction. These findings offer new behavioral methods to investigate cognitive shifts with changing hormonal states, across healthy aging, and in models of neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease.
Pattern separation allows the distinction of similar events, places, or objects by integrating topological qualitative representations of space and metric relationships (Gallistel, 1990). Recent findings suggest that metric information... more
Pattern separation allows the distinction of similar events, places, or objects by integrating topological qualitative representations of space and metric relationships (Gallistel, 1990). Recent findings suggest that metric information processing relies on intact hippocampus function (Goodrich-Hunsaker et al., 2008). We previously showed that elevations in circulating estradiol biased female rats toward using hippocampus-sensitive and away from using striatum-sensitive learning strategies. The converse is also true: low levels of estrogens promote the use of striatum-sensitive strategies and impair the use of hippocampus-sensitive strategies (Korol, 2004). Thus, it is likely that shifts in pattern separation abilities will follow changes in estradiol levels. To test how estradiol modulates pattern separation, we investigated the effects of estradiol on detection of metric change in object location, a pattern separation task. Three-month-old female Long-Evans rats were ovariectomized three weeks prior to behavioral testing. 48 and 24 h prior to testing, rats received either 17-estradiol (45mg/kg) or vehicle (oil) injections. Rats were allowed to explore two objects constructed of colored Legos for three 5-min study sessions with an inter-session interval of 3 min. Following the third study session, the objects were moved apart symmetrically to increase the metric distance between them for the 5 min test session. The total amount spent exploring both objects was recorded. Rats treated with 17-estradiol detected the metric change during the test session significantly more than did control rats. We then tested the effects of 17-estradiol replacement to ovariectomized rats on a modified object recognition task. This task is similar to the metric change in object location task except that in place of a metric change, objects were modified by adding Lego bricks of different color to the top of each original object. All rats detected the modification to the objects regardless of treatment condition, showing that rats with low estradiol maintained the ability to perceive changes in objects. Our data suggest that estradiol enhances pattern separation but not object recognition. We are currently developing additional versions of the metric change in object location tasks to determine whether these tasks will tap different memory systems, using the findings to evaluate the role of estrogens in different aspects of pattern separation.
The hippocampus and striatum are memory systems studied for their respective participation in place and response learning. Considerable evidence from our and other laboratories demonstrates that higher levels of circulating estradiol... more
The hippocampus and striatum are memory systems studied for their respective participation in place and response learning. Considerable evidence from our and other laboratories demonstrates that higher levels of circulating estradiol bias female rats towards using hippocampus-sensitive learning strategies and away from using striatum-sensitive learning strategies. In this study, we developed two pattern separation tasks allowing us to determine site-specific regulation of learning and memory by estrogens without food restriction, extensive locomotion, or extrinsic stressors like those used in aversive tasks. The hippocampus-sensitive metric change in object location (MCOL) task measures the ability to perform pattern separation using the distance between two objects. The double object replacement (DOR) task assesses the ability to detect the presence of two novel objects that have replaced familiar ones; whether intact functioning of the hippocampus and/or striatum is required for DOR is unknown. Using lidocaine infusions in 3-mo-old male rats, inactivation of the striatum selectively impaired the ability to detect DOR while inactivation of the hippocampus selectively impaired the ability to detect MCOL. In addition, two days of 17-estradiol benzoate (EB) treatment to ovariectomized young adult rats enhanced detection of MCOL and impaired detection of DOR. Finally, we are currently assessing whether both selective ER (PPT) and ER (DPN) agonists can enhance MCOL and impair DOR. Our data suggest that estrogens bidirectionally modulate recognition memory but not habituation in a task- and brain-site-specific manner and may do so through both ERs. The findings also suggest that MCOL and DOR are powerful tools to study regulation of cognition when drive or movement may be compromised such as with hormone treatment or aging.
It is well established that estrogens modulate cognition in a task-dependent manner. Estrogen replacement generally improves hippocampus-sensitive learning although this effect can vary with age, stress status, and hormone regimen. Many... more
It is well established that estrogens modulate cognition in a task-dependent manner. Estrogen replacement generally improves hippocampus-sensitive learning although this effect can vary with age, stress status, and hormone regimen. Many dietary supplements contain estrogenic compounds, the efficacy and safety of which are poorly understood. This study investigated the efficacy of the commercially available botanical estrogenic compound isoliquiritigenin (ISL) to alter performance on a hippocampus-sensitive metric change in object location (MCOL) task. ISL is a compound found in licorice root that is currently used in over-the-counter dietary supplements. Because the Western diet is high in saturated fat, and high fat diets (HFD) have been shown to negatively impact cognition in rodent models, we also explored whether a HFD would impair performance on this hippocampus-sensitive task and whether ISL could mitigate the negative effects of the HFD. Thus, we included HFD as well as low fat (LFD) groups. Young adult (3-month old) Long-Evans female rats were ovariectomized and exposed to either a HFD (44.8% kcal from fat) or a LFD (17.2% kcal from fat) for five weeks prior to testing. A subset of rats on each diet was exposed to ISL at a concentration of 0.05% of the diet for three weeks prior to testing. Since estradiol improves performance on the MCOL task, we used an estradiol group as a positive control. Rats in the estradiol group were injected subcutaneously 48 and 24 hours prior to testing with 45 µg/kg of estradiol. In the MCOL task, rats were allowed to explore two objects in a black Plexiglas® chamber measuring 28x28x21 inches. Exploration time was recorded for three 5-min trials with a 3-min inter-trial interval in the rat’s home cage. For the fourth 5-min trial, the objects were moved closer together and exploration time was again recorded. An increase in object exploration time in the final trial suggests that the rat detected the change in object locations. ISL led to a significant increase in exploration time in the final trial relative to the third trial. To a lesser degree, estradiol also increased object exploration time on the final trial. Diet had no effect on its own and did not interact with ISL exposure. In this study we showed that ISL improved performance on a hippocampus-sensitive task that depends on the natural tendency to explore novel objects but avoids food restriction or aversive stimuli. We are currently using Western blot analysis to assess the levels of estrogen-sensitive synaptic proteins in the hippocampus, which could provide clues as to the mechanism of action for the improved performance in ISL exposed animals.
Context Female endurance athletes exhibit an increased risk of the female athlete triad (Triad) and relative energy deficiency in sport (RED-S). The triad and RED-S are conditions that involve the health and performance consequences of... more
Context Female endurance athletes exhibit an increased risk of the female athlete triad (Triad) and relative energy deficiency in sport (RED-S). The triad and RED-S are conditions that involve the health and performance consequences of low energy availability. Few authors of studies to date have assessed the knowledge that athletes, coaches, and athletic trainers (ATs) have regarding the Triad or RED-S. Proper education has been shown to be effective in increasing knowledge of sports medicine concerns for athletes, yet no known continuing education programs for the Triad or RED-S exist at collegiate institutions. Objective To assess the knowledge, confidence, and educational impact of identifying, screening, treating, and preventing the Triad or RED-S. Design Cross-sectional study. Setting An evidence-based online survey was developed and administered via Qualtrics. Patients or Other Participants Female collegiate cross-country athletes (n = 275, age = 20 ± 1 years), collegiate cros...