Acute stress persistently enhances estrogen levels in the female rat

Here we tested whether exposure to either tailshock or swim stress alters ovarian hormone levels, estrogen and progesterone, in females and whether the effects are persistent. Adrenal hormone levels were also measured in males and females. Estradiol levels were elevated in unstressed females during proestrus relative to females in other stages of estrous, and exposure to the stressors enhanced estradiol beyond basal levels. For females stressed during diestrus 2, estradiol levels were elevated immediately after stressor cessation and up to 24 hrs. Exposure to tailshock, but not swim-stress, transiently enhanced progesterone in females stressed during the stage of proestrus and estrus. Glucocorticoid levels were elevated in response to both stressors and were supraelevated in females under both basal and stress conditions relative to males, particularly in blood from females exposed to acute swim stress. These results indicate that exposure to a relatively acute stressful event immediately and persistently enhances serum estradiol and are discussed in the context of reports that exposure to the same stressors immediately and persistently impairs associative learning in the female rat.     

Hippocampal gene expression profiling in spatial discrimination learning

Learning and long-term memory are thought to involve temporally defined changes in gene expression that lead to the strengthening of synaptic connections in selected brain regions. We used cDNA microarrays to study hippocampal gene expression in animals trained in a spatial discrimination-learning paradigm. Our analysis identified 19 genes that showed statistically significant changes in expression when comparing Nai;ve versus Trained animals. We confirmed the changes in expression for the genes encoding the nuclear protein prothymosin(alpha) and the delta-1 opioid receptor (DOR1) by Northern blotting or in situ hybridization. In additional studies, laser-capture microdissection (LCM) allowed us to obtain enriched neuronal populations from the dentate gyrus, CA1, and CA3 subregions of the hippocampus from Nai;ve, Pseudotrained, and spatially Trained animals. Real-time PCR examined the spatial learning specificity of hippocampal modulation of the genes encoding protein kinase B (PKB, also known as Akt), protein kinase C(delta) (PKC(delta)), cell adhesion kinase(beta) (CAK(beta), also known as Pyk2), and receptor protein tyrosine phosphatase(zeta/beta) (RPTP(zeta/beta)). These studies showed subregion specificity of spatial learning-induced changes in gene expression within the hippocampus, a feature that was particular to each gene studied. We suggest that statistically valid gene expression profiles generated with cDNA microarrays may provide important insights as to the cellular and molecular events subserving learning and memory processes in the brain.     

Sex differences in spatial and non-spatial Y-maze performance after chronic stress

Chronic restraint is known to alter hippocampal CA3 dendritic morphology and spatial memory in male rats. The present study examined whether female rats, which exhibit different anatomical adaptations to chronic stress than those of males, would also show spatial memory impairments. Male and female Sprague-Dawley rats were restrained for 6 h/day for 21 days, a time frame previously demonstrated to cause hippocampal CA3 dendritic atrophy. The day after the last restraint session, rats were tested on a Y-maze, a habituation task that can be used to assess spatial memory. Chronic stress impaired Y-maze performance in both sexes without affecting levels of locomotion as measured by total arm entries in the first minute. However, Y-maze performance of stressed females improved in 2-5 min when chronically stressed males continued to show poor Y-maze performance. The enhanced Y-maze performance of chronically stressed females occurred when total arm entries were higher compared to the entries made by males. Therefore, correlations were performed between total arm entries and spatial memory in 1 and 2-5 min. In the first minute when control females demonstrated functional spatial memory, female controls with the lowest locomotor levels exhibited the best performance. The correlations for stressed females were not significant, and neither were the correlations for any group in 2-5 min. Overall, these results show important sex differences in response to chronic stress with females exhibiting an ability to recover quickly from deficits in Y-maze performance.     

Teaching multiply controlled intraverbals to children and adolescents with autism spectrum disorders

Reciprocal conversations, instructional activities, and other social interactions are replete with multiply controlled intraverbals, examples of which have been conceptualized in terms of conditional discriminations. Although the acquisition of conditional discriminations has been examined extensively in the behavior‐analytic literature, little research has evaluated procedures to establish multiply controlled intraverbals. Thus, the purpose of this investigation was to evaluate the effects of procedures based on conditional discrimination training on the acquisition of multiply controlled intraverbals with 7 participants who had been diagnosed with autism spectrum disorders. We evaluated the effects of prompt delay with error correction, a differential observing response (DOR), and a DOR plus blocked trials on the acquisition of intraverbals using a multiple baseline design. Accuracy of intraverbal performance increased for at least 1 set of stimuli for all participants under prompt delay with error correction conditions; however, 4 participants required additional teaching (i.e., DOR, modified DOR, modified prompt delay with error correction). Based on these findings, when prompt delay with error correction is not sufficient to establish multiply controlled intraverbals, prompted DORs may be an effective alternative.     

Estradiol enhances the induction of homosynaptic long-term depression in the CA1 region of the adult, ovariectomized rat

An ovarian steroid-dependent cycle of synaptogenesis and synapse shedding occurs naturally in the hippocampus of the adult female rat. The newly formed axospinous synapses in CA1 may differ functionally from extant axospinous synapses, e.g., in terms of their modifiability. Here we assess whether estradiol alters the induction of homosynaptic long-term depression of the Schaffer collateral-CA1 synapses in vitro. Sprague-Dawley rats were bilaterally ovariectomized and, beginning 6-8 days later, received a series of injections of either 17beta-estradiol or sesame oil sc. Field potentials were recorded in hippocampal slices. In estradiol-treated animals, asynchronous, low-frequency stimulation led to significant long-term depression of the activated synapses in CA1 s. radiatum and no change of the inactive synapses in s. oriens. In contrast, this conditioning stimulation did not significantly alter any CA1 responses in oil-treated control animals. Subsequent high-frequency conditioning stimulation significantly potentiated the activated s. radiatum synapses in both estradiol- and oil-treated animals. Thus, given the stimulation conditions used here, estradiol enables the induction of homosynaptic long-term depression at the CA3-CA1 synapses in adult females.     

Embedding an identity-matching task within a prompting hierarchy to facilitate acquisition of conditional discriminations in children with autism

Least-to-most prompting hierarchies (e.g., progressing from verbal to modeled to physical prompts until the target response occurs) may be ineffective when the prompts do not cue the individual to attend to the relevant stimulus dimensions. In such cases, emission of the target response persistently requires one or more of the higher level prompts, a condition called prompt dependence (Clark & Green, 2004). Reinforcement of differential observing responses (DORs) has sometimes been used to ensure that participants attend to the relevant stimulus dimensions in matching-to-sample (MTS) tasks (e.g., Dube & McIlvane, 1999). For 2 participants with autism, we embedded an identity-matching task within a prompting hierarchy as a DOR to increase the likelihood that the participants attended to and discriminated the relevant features of the comparison stimuli in an MTS task. This procedure was compared with a traditional least-to-most prompting hierarchy and a no-reinforcement control condition in a multielement design. Results for both participants indicated that mastery-level acquisition of spoken-word-to-picture relations occurred only under the identity-matching condition. Findings are discussed relative to the use of DORs to facilitate acquisition of conditional discriminations in persons with autism or other conditions who do not attend to the comparison stimuli.     

Ovarian steroids and cognitive function

The ovarian steroids, estrogen and progesterone, not only govern reproductive events in mammalian females but also influence an array of other processes. Of particular clinical interest is the potential of ovarian steroids to facilitate storage of new memories and to protect neurons from various threats. Research during the past decade confirms that estrogen and progesterone influence the biochemical, electrical, and structural properties of neurons in brain regions that subserve learning and memory. These mechanisms form the biological foundations for the complex effects of ovarian steroids on cognitive functions in various species, including humans. Despite significant progress in our understanding of the roles of hormonal factors in cognitive function and neuronal survival, the value of hormone replacement as a treatment and deterrent for cognitive impairments associated with age, disease, and injury remains uncertain as we enter the new century.     

Endogenous opioid peptides contribute to associative LTP in the hippocampal CA3 region

The medial and lateral perforant path projections to the hippocampal CA3 region display distinct mechanisms of long-term potentiation (LTP) induction, N-methyl-d-aspartate (NMDA) and opioid receptor dependent, respectively. However, medial and lateral perforant path projections to the CA3 region display associative LTP with coactivation, suggesting that while they differ in receptors involved in LTP induction they may share common downstream mechanisms of LTP induction. Here we address this interaction of LTP induction mechanisms by evaluating the contribution of opioid receptors to the induction of associative LTP among the medial and lateral perforant path projections to the CA3 region in vivo. Local application of the opioid receptor antagonists naloxone or Cys2-Tyr3-Orn5-Pen7-amide (CTOP) normally block induction of lateral perforant path-CA3 LTP. However, these opioid receptor antagonists failed to block associative LTP in lateral perforant path-CA3 synapses when it was induced by strong coactivation of the medial perforant pathway which displays NMDAR-dependent LTP. Thus strong activation of non-opioidergic afferents can substitute for the opioid receptor activation required for lateral perforant path LTP induction. Conversely, medial perforant path-CA3 associative LTP was blocked by opioid receptor antagonists when induced by strong coactivation of the opioidergic lateral perforant path. These data indicate endogenous opioid peptides contribute to associative LTP at coactive synapses when induced by strong coactivation of an opioidergic afferent system. These data further suggest that associative LTP induction is regulated by the receptor mechanisms of the strongly stimulated pathway. Thus, while medial and lateral perforant path synapses differ in their mechanisms of LTP induction, associative LTP at these synapses share common downstream mechanisms of induction.     

Sex-dependent effects of neonatally administered morphiceptin and D-ala-D-leu-enkephalin on maze learning in rats

Newborn rats were injected (ip) with morphiceptin [72.7 micrograms/kg (a mu-type opioid receptor agonist)], D-alanine2-D-leucine5-enkephalin [79.4 micrograms/kg (a delta-receptor agonist)], or saline for 7 days after birth. Testing on a complex maze on Day 25 revealed a significant sex-dependent facilitation of performance by the opioid peptides. Peptide-treated females performed better than the males on the first day of training as measured by errors. Opioid treatment increased mortality, as three times as many peptide-treated animals died in comparison to the saline control group. Peptide treatment did not affect locomotor activity measured in an open field. Weight at Day 24 was also affected by the peptide treatment, females and males injected with the opioids being lighter and heavier, respectively, than the control group.     

Differential roles for hippocampal areas CA1 and CA3 in the contextual encoding and retrieval of extinguished fear

Recent studies demonstrate that context-specific memory retrieval after extinction requires the hippocampus. However, the contribution of hippocampal subfields to the context-dependent expression of extinction is not known. In the present experiments, we examined the roles of areas CA1 and CA3 of the dorsal hippocampus in the context specificity of extinction. After pairing an auditory conditional stimulus (CS) with an aversive footshock (unconditional stimulus or US), rats received extinction sessions in which the CS was presented without the US. In Experiment 1, pretraining neurotoxic lesions in either CA1 or CA3 eliminated the context dependence of extinguished fear. In Experiment 2, lesions of CA1 or CA3 were made after extinction training. In this case, only CA1 lesions impaired the context dependence of extinction. Collectively, these results reveal that both hippocampal areas CA1 and CA3 contribute to the acquisition of context-dependent extinction, but that only area CA1 is required for contextual memory retrieval.     

Role of neonatal androgens in sexual differentiation of brain structure, scent marking, and gonadotropin secretion in gerbils

Gerbils display a sexually dimorphic scent marking behavior that responds to testosterone (T) in adulthood and develops under the influence of testosterone perinatally. A complex of cell groups between the preoptic area and anterior hypothalamus of the gerbil brain is also sexually dimorphic and responsive to testosterone. One of these cell groups, the sexually dimorphic area pars compacta (SDApc), usually exists only in males. Even when given testosterone, adult female gerbils rarely have an SDApc. To determine if the SDApc develops under the influence of testosterone, male gerbils were castrated or given sham operations on the day they were born or 1 day later, or were not manipulated. Female gerbils were injected subcutaneously with 0, 50, or 100 micrograms testosterone propionate (TP) on the day after birth. When given ovarian transplants as adults, neonatally castrated males scent marked at low levels typical of females. Neonatally androgenized females given testosterone as adults scent marked at high levels typical of males. Neonatal castration did not affect the probability that the SDApc would develop, but neonatal androgenization did. Half the females given either dose of TP as neonates had SDApcs bilaterally. The sizes of the SDApcs present in females depended on the dose of testosterone given neonatally. The larger dose produced larger SDApcs. The 100-micrograms dose of TP also defeminized gonadotropin secretion, but the 50-micrograms dose did not. The castration of males neonatally prevented the defeminization normally caused by endogenous testosterone. Both groups of neonatally castrated males formed corpora lutea in their ovarian transplants, but control males did not.     

The Anomaly Among Sexually Abusive Youth: The Juvenile Sex Trafficker

A hypothesized sketch of the atypical juvenile sex offender who engages in human sex trafficking is extrapolated from empirical data from the findings of victims of sex traffickers, juvenile sex offenders, and from one of the largest (N = 1056) cross-validation studies of a risk assessment tool in the field for sexually abusive youth. The tool, MEGA^?, assesses risk level of sexually abusive youth (4–19 years, males and females, adjudicated and non-adjudicated, including youth with low intellectual functioning). The compiled empirical data supports a paradigm describing one of the least known, or studied type of sexually abusive youth: the sexually abusive juvenile who engages in sex trafficking.     

Endocrine Mediators of Masculinization in Female Mammals

ABSTRACT— Most mammal species show traditional patterns of sexual dimorphism (e.g., greater male size and aggression), the proximal mechanism of which involves the male's greater pre- and postnatal exposure to circulating androgens. But in several species, females diverge from the traditional pattern, converging on the male form or even reversing sexual dimorphisms. Such "masculinized" females might show elongation of the clitoris, enhanced body size, and aggressively mediated social dominance over males, and they are interesting case studies for examining the role of androgens in females. This review addresses our understanding of the mediating mechanisms of morphological and behavioral development in both traditional and exceptional mammal species. Although certain lines of evidence implicate testosterone in female masculinization, the role for sex steroids in female development remains unclear. The results call for continued study of both hormonal and nonhormonal mechanisms of sexual differentiation, particularly focused on active processes of feminine development.     

Biobehavioral responses to stress in females: tend-and-befriend, not fight-or-flight

The human stress response has been characterized, both physiologically and behaviorally, as "fight-or-flight." Although fight-or-flight may characterize the primary physiological responses to stress for both males and females, we propose that, behaviorally, females' responses are more marked by a pattern of "tend-and-befriend." Tending involves nurturant activities designed to protect the self and offspring that promote safety and reduce distress; befriending is the creation and maintenance of social networks that may aid in this process. The biobehavioral mechanism that underlies the tend-and-befriend pattern appears to draw on the attachment-caregiving system, and neuroendocrine evidence from animal and human studies suggests that oxytocin, in conjunction with female reproductive hormones and endogenous opioid peptide mechanisms, may be at its core. This previously unexplored stress regulatory system has manifold implications for the study of stress.     

Sex-dependent changes induced by prenatal stress in cortical and hippocampal morphology and behaviour in rats: an update

Recent prospective studies have shown that gestational stress in humans is more likely to cause cognitive and emotional problems in the offspring if it occurs during weeks 12-20 of pregnancy. There are also suggestions that such problems may be gender dependent. This review describes recent studies that found sex differences in the behaviour and brain morphology of rats stressed prenatally during the equivalent period of neuronal development in humans. Learning deficits are more prevalent in males and anxious behaviour in females but their appearance depends also on the timing and intensity of the stress and the age when the offspring were tested. Cognitive deficits and anxiety are linked to a sex-dependent reduction in neurogenesis and in measures of dendritic morphology in the prefrontal cortex and hippocampal formation. Maternal adrenalectomy prior to the stress prevents the anxiety in both sexes and learning deficits in males. Corticosterone administration to the dam to mimic levels induced by stress reinstates only the anxiety, indicating that it arises from foetal exposure to corticosterone from the maternal circulation. Learning deficits in males may result from a combination of a reduction in testosterone and in aromatase activity, together with the action of other adrenal hormones.     

Using immediate-early genes to map hippocampal subregional functions

Different functions have been suggested for the hippocampus and its subdivisions along both transversal and longitudinal axes. Expression of immediate-early genes (IEGs) has been used to map specific functions onto neuronal activity in different areas of the brain including the hippocampus (IEG imaging). Here we review IEG studies on hippocampal functional dissociations with a particular focus on the CA3 subregion. We first discuss the cellular functions of IEGs and the brain system interactions that govern their dynamic expression in hippocampal neurons to provide a more solid framework for interpreting the findings from IEG studies. We show the pitfalls and shortcomings of conventional IEG imaging studies and describe advanced methods using IEGs for imaging of neuronal activity or functional intervention. We review the current IEG evidence of hippocampal function, subregional-specific contribution to different stages of memory formation, systems consolidation, functional dissociation between memory and anxiety/behavioral inhibition along the septotemporal axis, and different neural network properties of hippocampal subregions. In total, IEG studies provide support for (1) the role of the hippocampus in spatial and contextual learning and memory, (2) its role in continuous encoding of ongoing experience, (3) septotemporal dissociations between memory and anxiety, and (4) a dynamic relationship between pattern separation and pattern completion in the CA3 subregion. In closing, we provide a framework for how cutting-edge IEG imaging and intervention techniques will likely contribute to better understanding of the specific functions of CA3 and other hippocampal subregions.     

Sex differences in assertive achievement patterns

Observations in mathematics and social studies classrooms were made of 40 sixth-grade children of average and high ability to investigate whether males and females differ in assertive achievement behavior. The prediction of less assertive achievement behavior for females than males was supported only among average-ability children. Particularly in social studies, average-ability females participated less in the classroom than average-ability males and either high-ability males or females. Average-ability females' deficit of assertive behavior became more pronounced as the behavior category increased in degree of assertiveness. High-ability females demonstrated a deficit only in the most assertive behavior category.     

Perforant path activation modulates the induction of long-term potentiation of the schaffer collateral--hippocampal CA1 response: theoretical and experimental analyses

In one computational model of hippocampal function, the entorhinal cortical input to CA1 is hypothesized to play a key role in the ability of CA1 to decode CA3 recodings. Here, we develop a modification of this CA1 decoder hypothesis that is applicable to several computational theories of hippocampal function, and then we electrophysiologically investigate one assumption of this new hypothesis. First, using biologically realistic estimates, we calculate that CA3-induced CA1 excitation is too high and that inhibition plausibly plays a role in this CA1 decoder model. Thus motivated, we turn to a physiological demonstration to substantiate the plausibility of the proposed mechanism. Using the rat hippocampal slice, we examine an interlaminar interaction between the distal perforant path input to hippocampal CA1 stratum moleculare and the more proximal Schaffer collateral input to stratum radiatum. Perforant path activation provides sufficient inhibition to block homosynaptic long-term potentiation elicited by a suitably strong stratum radiatum input. For this interlaminar interaction to be most effective, perforant path activation must both precede and follow Schaffer collateral activation. Perforant path-evoked inhibition in CA1 can thus serve as a viable mechanism in the learned decoder theory of hippocampal CA1.     

Hippocampal EEG and Unit Activity Responses to Modulation of Serotonergic Median Raphe Neurons in the Freely Behaving Rat

Hippocampal EEG, GABAergic interneurons, and principal cells were recorded simultaneously as rats foraged within one of three environments both before and after modulation of serotonergic inputs to the hippocampus. Median raphe microinjections of the 5-HT1a receptor agonist 8-OH-DPAT were made to produce inhibition of serotonergic neurons in this region. Such microinjections produced behavioral arousal and increases in the amplitude of hippocampal EEG theta. Consistent with the pattern of serotonergic innervation of the hippocampus, the GABAergic interneuron population was affected differentially by the microinjections. Principal cells were generally unaffected by the manipulation and maintained robust spatial firing correlates within the foraging environment. The results provide basic data on the relationship between serotonergic median raphe neurons and hippocampal activity in a behaving animal. The data suggest that behavioral responses to manipulation of the serotonergic system are mediated by brain regions other than the hippocampus or are mediated through changes in the activity of hippocampal interneurons.     

Sex differences in chronic stress effects on memory in rats

Recent studies in rodent models and in humans have shown that the status of both the gonadal and adrenal axes (hypothalamic-pituitary-gonadal, HPG and hypothalamic-pituitary-adrenal, HPA, respectively) can influence learning and memory function. In this article, the effects of activating the HPA axis (stress) on performance of memory tasks in rats are reviewed. More importantly, results are presented which show that chronic stress has a different impact on performance of these tasks depending upon the sex of the rat. These observations are novel and potentially important since few studies, animal or human, have utilized females as subjects in studies of the stress response. Sex differences in the effects of chronic stress on memory were investigated in rats using an object recognition task and two spatial memory tasks, radial arm maze and object location. Given the same chronic stress--21 days of restraint for 6 h each day--males were impaired in all of the memory tests while females showed enhanced performance of the spatial memory tasks and no changes in object recognition performance. Levels of neurotransmitters and metabolites were measured in brain areas important for cognition in the subjects in order to determine neural systems that may respond to stress and mediate the cognitive responses. These results show that responses of monoamine and amino acid containing neural systems may contribute to or underlie sex differences in stress effects on cognition. Stress decreased dopaminergic activity in the frontal cortex and amygdala of males but not females; whereas, in CA3 of the hippocampus, stress increased levels of 5-HT and norepinephrine in females, but not males, and increased GABA in males, but not females. Finally, a possible role for estradiol in mediating sexually differentiated responses to stress was examined. Behavioral and neurochemical evaluations in ovariectomized, stressed females, with or without estrogen replacement, suggest that sex differences in response to stress are influenced by both the organizing and activating effects of estradiol. A few, recent studies in humans, that show sexually dimorphic relationships between chronic stress and cognition, are also highlighted. These results in humans are consistent with the pattern of results in rats. Clearly, further studies are necessary to substantiate sex differences in stress effects on memory function in humans and to understand mechanisms whereby estrogen may influence the stress response in rats. Nonetheless, recent studies show sexually differentiated cognitive responses to chronic stress and underline the importance of considering the sex/gender of subjects when studying the stress response.