Memory In Female Rats Research Articles

Acute glyphosate and aminomethylphosphonic acid (AMPA), its major metabolite, impaired spatial orientation, navigation, learning and/or memory in female rats

Human exposure to glyphosate-based herbicides (GBH) has been associated with a range of toxicological effects involving the central nervous system (CNS) such as alterations in learning and memory. Nevertheless, the effects of aminomethylphosphonic acid (AMPA), the main metabolite of glyphosate, remain essentially obscure. Previous preclinical reports suggest that acute intoxication with AMPA and glyphosate exerts decrease on hippocampal acetylcholinesterase activity and produces more metabolomic alterations in the female brain over the male one. Therefore, this work explored the effects of acute AMPA and glyphosate on spatial learning, memory and navigation in female rats. Sprague Dawley rats received a single injection (i.p.) of: (i) vehicle; (ii) 10 or 100mg/kg of AMPA; or (iii) 10 or 100mg/kg of glyphosate; subsequently, the Barnes maze paradigm was performance. Animals from the control group decreased latency and the attempts to solve the Barnes maze; and increased the degree of orientation when compared first training sessions (S1) vs. the last one (S4; p < 0.05). In contrast, both 10 and 100mg/kg of glyphosate and 100mg/kg of AMPA prevented the decrease in latency and attempts; and the increase of orientation (p>0.05 S1 vs. S4). Both treatments decreased the use of the spatial navigation strategy (p < 0.05). Besides, glyphosate at the higher dose but not AMPA impaired the spatial memory during the test. Our findings suggest that acute exposure to glyphosate and AMPA similarly affected spatial orientation, navigations, learning and/or memory.

Cocaine diminishes consolidation of cued fear memory in female rats through interactions with ventral hippocampal D2 receptors

In addition to cocaine's addictive properties, cocaine use may lead to heightened risk-taking behavior. The disruptive effects of cocaine on aversive memory formation may underlie this behavior. The present study investigated the effects of cocaine on fear memory using a cued fear conditioning paradigm in female Sprague Dawley rats, and further determined the role of D2 receptors in modulating the effect of cocaine on cued fear expression. Animals received six evenly spaced shocks preceded by a tone. The following day, rats were returned to the fear chamber where tones, but no shocks, were delivered. In Experiment 1, separate or concurrent administrations of cocaine (15 mg/kg; i.p.) and the D2 receptor antagonist eticlopride (0.1 mg/kg; i.p.) were given immediately after conditioning trials. It was determined that cocaine administration during the consolidation period diminished the expression of cued fear during the subsequent test day. Concurrent eticlopride administration attenuated this effect, indicating the involvement of D2 receptors in the deleterious effects of cocaine on fear memory consolidation. In Experiment 2, eticlopride (0.05 μg) was infused directly into the ventral hippocampus (VH) after fear conditioning and before cocaine administration. Cocaine continued to disrupt consolidation of cued and contextual fear memory, and concurrent intra-VH eticlopride blocked this effect, thereby demonstrating that VH D2 receptors mediate cocaine-induced impairment of fear memory consolidation. Overall, the present study provides evidence that acute cocaine administration impairs aversive memory formation and establishes a potential circuit through which cocaine induces its detrimental effects on fear memory consolidation.

The association of caffeine and nandrolone decanoate modulates aversive memory and nociception in rats

Caffeine and anabolic–androgenic steroids (AAS) are commonly used to improve muscle mass and athletic performance. Nandrolone Decanoate (ND) is one of the most abused AAS worldwide, leading to behavioral changes in both humans and rodents. Caffeine, the most widely consumed psychostimulant globally, is present in various thermogenic and gym supplements. Low and moderate doses of caffeine antagonize adenosine receptors and have been linked to improved memory and pain relief. We have previously demonstrated that consuming caffeine prevents the risk-taking behavior triggered by nandrolone. In this study, we aimed to investigate the long-term effects of ND and caffeine, either alone or in combination, on passive avoidance memory and nociception. We used the step-down and hot-plate tasks in male and female Lister Hooded rats. Our results confirmed the antinociceptive effect of caffeine and indicated that chronic administration of the ND-caffeine association promotes the evocation of aversive memory in female rats.

Acute physical exercise enhances memory persistence in female rats

Memory is a complex cognitive process with distinct stages, such as acquisition, consolidation, and retrieval. The hippocampus plays a crucial role in memory consolidation and retrieval. Physical exercise (PE) has been shown to enhance memory and cognitive functions, but the available research is mainly developed with males. So, there is limited knowledge about acute PE's effects on females' memory. This study aimed to investigate the impact of acute PE on memory in female rats and explore potential sex differences in PE memory modulation. Forty-two female Wistar rats were subjected to a novel object recognition (NOR) task, with half of them undergoing a single session of 30 min of PE after the learning session (memory acquisition). Behavioral assessments showed that acute PE improved memory persistence in female rats, with increased discrimination of novel objects. Biochemical analysis revealed elevated noradrenaline levels in the hippocampus following acute PE and NOR training. Notably, the positive effects of acute PE on female rats’ memory were similar to those previously observed in male rats. These findings suggest that acute PE can enhance memory in female rats and underscore the importance of considering sex differences in cognitive research. PE may offer a non-invasive strategy to promote cognitive health in both males and females.

The role of avoidance in modulating single prolonged stress effects on emotional memory in male and female rats

The incidence of post traumatic stress disorder (PTSD) is greater in women than men, but mechanisms via which this difference manifests remain under explored. The single prolonged stress (SPS) rodent model of traumatic stress has been used to identify mechanisms through which traumatic stress leads to deficits in retaining extinction (a core PTSD symptom), but has been mostly utilized in male model systems. Recent studies have observed that SPS leads to changes in persistent fear memory in female rats, though these results are variable. This variability could be driven by changes in behavioral strategy in females during extinction, but this possibility has not been sufficiently explored. To address this, we examined the impact of SPS on freezing and avoidance (a core PTSD symptom) during extinction in male and female rats. In male rats, SPS enhanced acquisition of conditioned freezing, but did not enhance freezing during extinction training or testing. SPS also decreased avoidance during extinction training, but not extinction testing. In female rats, SPS had no impact on conditioned freezing. Avoidance was not observed in control rats, but emerged in SPS/female rats during extinction testing. Furthermore, avoidance was negatively correlated with freezing in female rats (high avoidance associated with lower freezing), but this relationship was disrupted with SPS. The results suggest that introducing avoidance during extinction negates SPS effects on extinction retention in male and female rats, control/female rats engage in avoidance to regulate fear expression, and this relationship is disrupted with SPS.

The role of estrogen receptor manipulation during traumatic stress on changes in emotional memory induced by traumatic stress

Traumatic stress leads to persistent fear, which is a core feature of post-traumatic stress disorder (PTSD). Women are more likely than men to develop PTSD after trauma exposure, which suggests women are differentially sensitive to traumatic stress. However, it is unclear how this differential sensitivity manifests. Cyclical changes in vascular estrogen release could be a contributing factor where levels of vascular estrogens (and activation of estrogen receptors) at the time of traumatic stress alter the impact of traumatic stress. To examine this, we manipulated estrogen receptors at the time of stress and observed the effect this had on fear and extinction memory (within the single prolonged stress (SPS) paradigm) in female rats. In all experiments, freezing and darting were used to measure fear and extinction memory. In Experiment 1, SPS enhanced freezing during extinction testing, and this effect was blocked by nuclear estrogen receptor antagonism prior to SPS. In Experiment 2, SPS decreased conditioned freezing during the acquisition and testing of extinction. Administration of 17β-estradiol altered freezing in control and SPS animals during the acquisition of extinction, but this treatment had no effect on freezing during the testing of extinction memory. In all experiments, darting was only observed to footshock onset during fear conditioning. The results suggest multiple behaviors (or different behavioral paradigms) are needed to characterize the nature of traumatic stress effects on emotional memory in female rats and that nuclear estrogen receptor antagonism prior to SPS blocks SPS effects on emotional memory in female rats.

Chronic treatment with hormonal contraceptives alters hippocampal BDNF and histone H3 post-translational modifications but not learning and memory in female rats

Hormonal contraceptives prevent ovulation with subsequent reduction in endogenous levels of estradiol, progesterone and its neuroactive metabolite allopregnanolone. These neurosteroids modulate several brain functions, including neuronal plasticity, cognition and memory. We hypothesized that hormonal contraceptives might affect synaptic plasticity, learning and memory, as a consequence of suppressed endogenous hormones levels. Female rats were orally treated with a combination of ethinyl estradiol (EE, 0.020 mg) and levonorgestrel (LNG, 0.060 mg) once daily for four weeks. Decreased hippocampal brain-derived neurotrophic factor (BDNF) levels and altered histone H3 post-translational modifications (PTMs) were observed 14 days after discontinuation from chronic EE-LNG treatment. These effects were not accompanied by alterations in long-term plasticity at glutamatergic synapses, recognition memory in the novel object and novel place location tests, or spatial learning, memory, and behavioral flexibility in the Morris water maze test. Thus, decreased BDNF content does not affect synaptic plasticity and cognitive performance; rather it might be relevant for the occurrence of certain psychiatric symptoms, reported by some women using hormonal contraceptives. These results provide the first evidence of hippocampal epigenetic changes induced by hormonal contraceptives and complement previous studies on the neurobiological actions of hormonal contraceptives; the finding that effects of chronic EE-LNG treatment on BDNF content and histone PTMs are observed 14 days after drug discontinuation warrants further investigation to better understand the implications of such long-term consequences for women's health.

Progesterone rapidly alters the use of place and response memory during spatial navigation in female rats

17β-Estradiol (E2) and progesterone (P) influence place and response memory in female rats in spatial navigation tasks. Use of these memory systems is associated with the hippocampus and the dorsal striatum, respectively. Injections of E2 result in a well-established bias to use place memory, while much less is understood about the role of P. A total of 120 ovariectomized female rats were tested within a dual-solution T-maze task and treated with either low E2 (n = 24), high E2 (10 μg/kg; n = 24), or high E2 in combination with P (500 μg/kg) at three time points before testing: 15 min (n = 24), 1 h (n = 24), and 4 h (n = 24). Given alone, high E2 biases rats to the use of place memory, but this effect is reversed when P is given 1 h or 4 h before testing. This indicates that P may be playing an inhibitory role in the hippocampus during spatial tasks, which is consistent with past findings. Our findings show that P acts rapidly (within an hour) to affect performance during spatial tasks.

Intranasal oxytocin compensates for estrus cycle-specific reduction of conditioned safety memory in rats: Implications for psychiatric disorders

Stress and anxiety disorder patients frequently fail to benefit from psychotherapies which often consist of inhibitory fear learning paradigms. One option to improve the therapy outcome is medication-enhanced psychotherapy. Research in humans and laboratory rodents has demonstrated that oxytocin (OT) reduces fear and facilitates fear extinction. However, the role of OT in conditioned safety learning, an understudied but highly suitable type of inhibitory fear learning, remains to be investigated. The present study aimed at investigating the effect of intranasal OT on conditioned safety. To test this, Sprague Dawley rats (♂n = 57; ♀n = 72) were safety conditioned. The effects of pre-training or pre-testing intranasal OT on conditioned safety and contextual fear, both measured by the acoustic startle response, and on corticosterone plasma levels were assessed. Furthermore, the involvement of the estrous cycle was analyzed. The present data show that intranasal OT administration before the acquisition or recall sessions enhanced conditioned safety memory in female rats while OT had no effects in male rats. Further analysis of the estrus cycle revealed that vehicle-treated female rats in the metestrus showed reduced safety memory which was compensated by OT-treatment. Moreover, all vehicle-treated rats, regardless of sex, expressed robust contextual fear following conditioning. Intranasal OT-treated rats showed a decrease in contextual fear, along with reduced plasma corticosterone levels. The present data demonstrate that intranasal OT has the capacity to compensate deficits in safety learning, along with a reduction in contextual fear and corticosterone levels. Therefore, add-on treatment with intranasal OT could optimize the therapy of anxiety disorders.

The Impact of Neonatal Methamphetamine on Spatial Learning and Memory in Adult Female Rats.

The present study was aimed at evaluating cognitive changes following neonatal methamphetamine exposure in combination with repeated treatment in adulthood of female Wistar rats. Pregnant dams and their pups were used in this study. One half of the offspring were treated indirectly via the breast milk of injected mothers, and the other half of pups were treated directly by methamphetamine injection. In the group with indirect exposure, mothers received methamphetamine (5 mg/ml/kg) or saline (1 ml/kg) between postnatal days (PD) 1–11. In the group with direct exposure, none of the mothers were treated. Instead, progeny were either: (1) treated with injected methamphetamine (5 mg/ml/kg); or (2) served as controls and received sham injections (no saline, just a needle stick) on PD 1–11. Learning ability and memory consolidation were tested on PD 70–90 in the Morris Water Maze (MWM) using three tests: Place Navigation Test, Probe Test, and Memory Recall Test. Adult female progeny were injected daily, after completion of the last trial of MWM tests, with saline or methamphetamine (1 mg/ml/kg). The effects of indirect/direct neonatal methamphetamine exposure combined with acute adult methamphetamine treatment on cognitive functions in female rats were compared. Statistical analyses showed that neonatal drug exposure worsened spatial learning and the ability to remember the position of a hidden platform. The study also demonstrated that direct methamphetamine exposure has a more significant impact on learning and memory than indirect exposure. The acute dose of the drug did not produce any changes in cognitive ability. Analyses of search strategies (thigmotaxis, scanning) used by females during the Place Navigation Test and Memory Recall Test confirmed all these results. Results from the present study suggested extensive deficits in learning skills and memory of female rats that may be linked to the negative impact of neonatal methamphetamine exposure.

Effects of ∆9-THC on memory in ovariectomized and intact female rats

The effects of marijuana's major psychoactive cannabinoid, ∆9-tetrahydrocannibinol (∆9-THC), were examined on memory in female rats by training subjects to respond under a repeated acquisition and delayed-performance procedure. During this task, subjects acquired a different 4-response sequence each session, which was then recalled after a delay. Sequence retention was tested following various delays, and quantified by a percent savings measure. Response rate and percent errors were also recorded. Subsequent to training, subjects underwent an ovariectomy (OVX) or sham surgery (intact). The OVX group then underwent implantation of subcutaneous 17β-estradiol capsules while the intact group received chronic administration of 1 mg/kg of the estrogen receptor modifier, tamoxifen. Increasing delays from 1 min to 24 h produced delay-dependent decreases in percent savings in both OVX and intact rats. Acute administration of ∆9-THC (0.32–3.2 mg/kg) dose-dependently decreased retention, increased percent errors, and decreased response rate in both groups when the delay was 1 h. However, intact rats showed a significantly lower percent savings than OVX rats at the 0.56-mg/kg dose. Delays of 3 h enhanced the disruptive effects of ∆9-THC more in intact than OVX rats; furthermore, implantation of 17β-estradiol attenuated ∆9-THC-induced disruptions in OVX rats and significantly increased estradiol levels and uterine weight as compared to intact rats. Although chronic tamoxifen administration did not alter ∆9-THC's effects on memory in intact rats, it did significantly decrease response rate. These results demonstrate the capacity of chronic 17β-estradiol for attenuating ∆9-THC's acute memory-disrupting effects in OVX female rats.

G protein-coupled oestrogen receptor stimulation ameliorates iron- and ovariectomy-induced memory impairments through the cAMP/PKA/CREB signalling pathway.

Iron accumulation in the brain has been associated with neurodegenerative disorders, and imaging studies in humans indicate that iron content in brain regions correlates with poor performance in cognitive tasks. In rats, iron overload impairs memoryretention in a variety of memorytasks. Although the effects of iron on cognition in rodents are extensively reported, no previous study has been conducted in female rats. The incidence of certain dementias, such as Alzheimer's disease, is higher in women after menopause compared to aged-matched men. The role of oestrogen depletion in memory deficits in menopausal women is still a matter of debate. The present study aimed to characterise the effects of iron overload on memory in female rats by investigating the effects of ovariectomy (OVX, an experimental model of oestrogen depletion) in rats submitted to iron overload, as well as examining the effects of G protein-coupled oestrogen receptor (GPER) agonism on memory impairments induced by iron and OVX. Female rats received iron (30mgkg-1 , orally) or vehicle at postnatal days 12-14 and were submitted to OVX in adulthood. Results showed that either iron or OVX impaired memory for object placement and inhibitory avoidance. The selective GPER agonist G1, administered immediately after training, reversed both iron- and OVX-induced memory impairments. G1 effects were abolished by protein kinase A (PKA) inhibition, suggesting the involvement of the cAMP/PKA/CREB signalling pathway. The search for novel oestrogen agonists with positive effects on cognition may be promising for the development of treatments for memory disorders.

The role of estrogens in anxiety-like behavior and memory of female rats

The role of estrogens in anxiety-like behavior and memory of female rats

REM deprivation but not sleep fragmentation produces a sex-specific impairment in extinction

REM sleep is essential for learning and memory processes, particularly emotional learning. Manipulations of REM sleep impair learning and memory and sleep architecture is often altered following a learning experience; for example, short term REM deprivation immediately after fear conditioning results in impaired extinction. In light of research demonstrating sex-dependent differences in fear conditioning as well as differences in sleep architecture, the present study investigated the effects of short term REM deprivation on the extinction of conditioned fear in male and female rats. In addition, given evidence that sleep fragmentation, which is a consequence of REM deprivation, can negatively impact learning and memory, this manipulation was compared to REM deprivation and a control condition. Male and female rats were exposed to fear conditioning followed by 6 h of REM deprivation, sleep fragmentation, or a control condition. Two extinction sessions were conducted at 48 h intervals after conditioning. REM deprivation, but not sleep fragmentation or the control condition, impaired extinction of conditioned fear. However, this effect was seen only in male rats. This study is the first to explore the effects of sleep manipulations on memory in female rats and suggests that female rats are more resilient to the deleterious effects of REM deprivation. In addition, it demonstrates that REM deprivation but not fragmentation of sleep is responsible for impairment in extinction of conditioned fear.

The Effect of Flutamide on Spatial Working Memory and Serum Estrogen Levels in Female Rats

In the absence of testosterone, the brain, by default, differentiates into a female brain. Sex differentiation of the rat brain occurs during the perinatal period (four days prior to and four days after birth) during which time both estrogen and androgen receptors are expressed in the female brain. However, the role of androgen receptors in the differentiation of the female brain during the perinatal period is unknown. Our purpose of this study was to examine the effects of blockade of androgen receptors on circulating estrogen levels and spatial working memory. Four timed‐pregnant Long Evans rats were divided into two groups: one group (N=2) received flutamide during perinatal period whereas the other group (N=2) served as control receiving vehicle (95% Olive oil‐5% ethanol). Female pups from the flutamide group (N=8) continued to receive flutamide whereas the pups from the control group received vehicle for the additional four days (N=15). Prior to performing Radial Arm Maze test to assess their spatial working memory, adult animals were placed on a 60 % food restriction to bring their body weights close to 85% of their original weight. spatial working memory testing involved a three‐day habituation, three‐day training, and one testing day. During the habituation period, all eight arms of the Radial Arm Maze contained food. During the training and the testing periods, however, four of the eight arms contained food and the other four did not. Any‐maze software linked to a video‐tracking device tracked the amount of time each animal spent in the arms with or without food. Flutamide‐treated animals spent more time in the arms with food compared to the control group suggesting greater choice accuracy or modestly improved spatial working memory (p= 0.06). At the end of the behavioral study, animals were sacrificed and trunk blood was collected to measure serum estrogen levels using ELISA. Flutamide‐treated animals showed an increase in serum estrogen levels (p&lt;0.05) implying a relationship between improved spatial working memory and increased levels of estrogen. Thus, this study suggests that the blockade of androgen receptors during perinatal period increases serum estrogen levels and marginally improves spatial working memory in female rats.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Estrogen‐ and Delay‐Dependent Effects of Δ9‐THC on Memory in Female Rats

The cannabinoid receptor agonist, Δ9‐tetrahydrocannabinol (Δ9‐THC), is a psychoactive constituent of marijuana, and has been shown to produce sex‐dependent changes in learning and memory. This study examined the effects of estrogen on memory, and how these effects alter the acute disruptive effects of Δ9‐THC (0.32–3.2 mg/kg) on memory in female rats. To do this, female rats were trained to respond under a repeated acquisition and delayed‐performance procedure and then ovariectomized. During the acquisition phase of this procedure, rats acquired a 4‐response sequence on three response keys (center, left and right), and sequences changed daily (CRLC, LRCL, RLCR, etc). Sequence acquisition was followed by a delay phase (1 minute to 24 hours), and a delayed‐performance phase in which rats were required to emit the previously acquired sequence. Responding in the acquisition and delayed‐performance phases was maintained under a second‐order fixed‐ratio 3 schedule of food presentation. Δ9‐THC or vehicle (control) was administered 30 minutes prior to the delayed‐performance phase, regardless of delay duration, in order to specifically assess memory, which was quantified by a percent savings measure. Response rate and the percentage of errors were also recorded. To further examine the effects of estrogen, OVX female rats were chronically administered estradiol using a subcutaneous capsule containing a 25/75% ratio of estradiol to cholesterol. The disruptive effects of Δ9‐THC on memory were assessed prior to and during estradiol administration. Prior to estradiol administration, increasing delays ranging from 1 minute to 24 hours produced delay‐dependent decreases in percent savings. When the delay was 1 hour, acute administration of Δ9‐THC produced dose‐dependent decreases in response rate and percent savings, and increases in percent errors, that were significantly attenuated by estradiol administration. Increasing the delay from 1 to 3 hours enhanced the effects of low doses of Δ9‐THC (e.g., 0.56 mg/kg) and produced a significant decrease in percent savings. These results demonstrate the delay‐dependent effects of Δ9‐THC on memory and the involvement of estrogen in modulating Δ9‐THC's acute memory‐disrupting effects in female rats.Support or Funding Information–NIH‐NIDA: R01‐DA037255‐02S1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Consequences of Adolescent Exposure to the Cannabinoid Receptor Agonist WIN55,212-2 on Working Memory in Female Rats.

Marijuana is a prevalent illicit substance used by adolescents, and several studies have indicated that adolescent use can lead to long-term cognitive deficits including problems with attention and memory. However, preclinical animal studies that observe cognitive deficits after cannabinoid exposure during adolescence utilize experimenter administration of doses of cannabinoids that may exceed what an organism would choose to take, suggesting that contingency and dose are critical factors that need to be addressed in translational models of consequences of cannabinoid exposure. Indeed, we recently developed an adolescent cannabinoid self-administration paradigm in male rats, and found that prior adolescent self-administration of the cannabinoid receptor agonist WIN55,212-2 (WIN) resulted in improved working memory performance in adulthood. In addition, the doses self-administered were not as high as those that are found to produce memory deficits. However, given known sex differences in both drug self-administration and learning and memory processes, it is possible that cannabinoid self-administration could have different cognitive consequences in females. Therefore, we aimed to explore the effects of self-administered vs. experimenter-administered WIN in adolescent female rats on adult cognitive function. Female rats were trained to self-administer WIN daily throughout adolescence (postnatal day 34–59). A control group self-administered vehicle solution. The acute effects of adolescent WIN self-administration on memory were determined using a short-term spatial memory test 24 h after final SA session; and the long-term effects on cognitive performance were assessed during protracted abstinence in adulthood using a delayed-match-to-sample working memory task. In a separate experiment, females were given daily intraperitoneal (IP) injections of a low or high dose of WIN, corresponding to self-administered and typical experimenter-administered doses, respectively, or its vehicle during adolescence and working memory was assessed under drug-free conditions in adulthood. While self-administration of WIN in adolescence had no significant effects on short-term spatial memory or adult working memory, experimenter administration of WIN resulted in improved adult working memory performance that was more pronounced in the low dose group. Thus, low-dose adolescent WIN exposure, whether self-administered or experimenter-administered, results in either improvements or no change in adult working memory performance in female rats, similar to previous results found in males.

Interactive Effects of Hormone Status and Δ9‐THC Administration on Memory in Female Rats

The cannabinoid receptor agonist, Δ9‐tetrahydrocannabinol (Δ9‐THC), is a psychoactive constituent of marijuana, and a popular recreational drug that has been shown to produce disruptions in learning and memory. Conversely, estrogen has been found to produce a positive effect on learning and memory in female rats. The purpose of this study was to examine the effects of hormone status on memory, and how these effects alter the acute disruptive effects of Δ9‐THC (0.32–3.2 mg/kg) on memory in female rats. To do this, intact and ovariectomized (OVX) female rats were trained on a repeated acquisition and delayed‐performance procedure. During the acquisition phase of this procedure, rats acquired a 4‐response sequence (CRLC, LRCL, RLCR, etc.) that changed daily. Responding was maintained under a second‐order fixed‐ratio 3 schedule of food presentation. Sequence acquisition was followed by a delay phase and a delayed‐performance phase in which rats emitted the previously acquired sequence. Delay phase under baseline conditions was 1 hour. In order to examine the effect of delay, delays ranging from 1 minute to 24 hours were used. Δ9‐THC or vehicle was administered 30 minutes prior to the delayed‐performance phase in order to specifically target retention, which was assessed by percent savings. Response rate and the percentage of errors were also recorded. When the delay was varied under non‐drug conditions, delay‐dependent decreases in percent savings were observed in intact and OVX rats. However, the disruption of retention was greater in OVX than intact rats. Acute administration of Δ9‐THC produced dose‐dependent decreases in response rate and percent savings, and increases in percent errors in both intact and OVX rats under baseline conditions. After administration of 0.56 mg/kg Δ9‐THC, intact rats showed less sequence retention than OVX rats. Increasing the delay to 3 hours produced a leftward shift in the percent‐savings curve for both intact and OVX rats. These results suggest that hormone status directly impacts retention under an acquisition and delayed‐performance procedure, and acute administration of Δ9‐THC produces both delay‐dependent and dose‐dependent effects on memory in intact and OVX female rats.Support or Funding InformationNIH grant R01‐DA037255‐02S1

Estradiol shifts interactions between the infralimbic cortex and central amygdala to enhance fear extinction memory in female rats.

There is growing evidence that estradiol (E2) enhances fear extinction memory consolidation. However, it is unclear how E2 influences the nodes of the fear extinction network to enhance extinction memory. This study begins to delineate the neural circuits underlying the influence of E2 on fear extinction acquisition and consolidation in female rats. After fear conditioning (day 1), naturally cycling female rats underwent extinction learning (day 2) in a low-E2 state, receiving a systemic administration of either E2 or vehicle prior to extinction training. Extinction memory recall was then tested 24 hr later (day 3). We measured immediate early gene c-fos expression within the extinction network during fear extinction learning and extinction recall. During extinction learning, E2 treatment increased centrolateral amygdala c-fos activity and reduced lateral amygdala activity relative to vehicle. During extinction recall, E2-treated rats exhibited reduced c-fos expression in the centromedial amygdala. There were no group differences in c-fos expression within the medial prefrontal cortex or dorsal hippocampus. Examining c-fos ratios with the infralimbic cortex (IL) revealed that, despite the lack of group differences within the IL, E2 treatment induced greater IL activity relative to both prelimbic cortex and central amygdala (CeA) activity during extinction memory recall. Only the relationship between IL and CeA activity positively correlated with extinction retention. In conclusion, E2 appears to modify interactions between the IL and the CeA in females, shifting from stronger amygdalar modulation of fear during extinction learning to stronger IL control during extinction recall. © 2016 Wiley Periodicals, Inc.

How does Estrogen Influence Attention? Impact of 17‐beta Estradiol on Performance in an Attentional Set Shifting Task

Estrogens have been shown to affect learning and memory in female rats. ADHD is 3–9× more prevalent in males, suggesting that gonadal hormones may be in part responsible for the observed disparity between the sexes. In this disorder dopamine and norepinephrine levels in the ventromedial prefrontal cortex may be deficient, as evidenced by the use of stimulants to treat this disorder. Estrogen has been shown to inhibit dopamine reuptake in the prefrontal cortex this increasing extracellular levels of dopamine. Our previous work has suggested that in ovariectomized female rats, estradiol supplementation yielded higher levels of dopamine in the PFC than in male rats (1). The purpose of the present study was to evaluate the effect of estrogen in ovariectomized (OVX) female Long‐Evans rats in the attentional set‐shifting task (ASST)(2), a measure of attention which is strongly associated with monoamine levels in the vmPFC. Adult female rats were ovariectomized (OVX) or underwent a sham surgery. OVX rats were then randomized into two groups and given injections of 21 ug/kg 17‐B‐estradiol or vehicle every other day for the remainder of the study, while sham surgery animals were given vehicle injections. Rats were then tested in the ASST, wherein rats are trained to dig in pots for food reward. Pots are labeled with three dimensions, scent, digging material and texture of the pot and trained to dig for a food reward. Once the animal reaches criteria performance in a simple discrimination (SD) and then a complex discrimination (CD), the animal is then tested for performance in the intradimensional shift (ID), followed by a reversal (IDR). The animal is then exposed to an extradimensional shift (odor to digging material) (ED), followed by the reversal within this ED (EDR). This study found that OVX rats performed better in the ASST than sham or OVX + E animals, possibly reflecting a complicated dose‐response relationship to 17‐B‐estradiol administration. Further studies are underway to assess the levels of dopamine, norepinephrine, and serotonin in the ventromedial prefrontal cortex of these animals using in vivo microdialysis.Support or Funding InformationSC supported by a Morgane Research Fellowship from UNECOM.