Effects of sex steroid hormones on memory.

Many evidences have elucidated relevant mechanisms of action of estrogen, progesterone, and testosterone on cognition, including learning and memory processes, both in animal models and humans. This influence may depend on their modulator role on several neurotransmitter systems, and the extensive presence of their receptors in cerebral areas, involved in cognitive functions, including the amygdala, hippocampal formation, and cerebral cortex. The present brief review summarizes data of our research and others with the aim of clarifying, in mammals, the involvement of sex hormones on memory. In particular, after an introduction illustrating the general mechanisms of sex hormones modulation on memory processes, the specific role of estrogen, progesterone and testosterone in memory is described in three different sections. Besides summarizing the most relevant actions of sex steroid hormones in the modulation of learning and memory, in this review is also emphasized that many aspects and mechanisms are still not completely\r\nunderstood and extensive future research is necessary to elucidate them.

Electrophysiological and Behavioral Indices of the Role of Estrogens on Memory Processes for Emotional Faces in Healthy Young Women.

It is well known that estrogens influence cognitive activities, such as memory, and emotional states. The objective of the present study was to investigate the role of estrogens in the short-term memory processing of basic emotional face expressions, by means of event-related potentials (ERPs) and a recognition memory (RM) behavioral task. Healthy young women were divided into a periovulatory (PO) group, characterized by high levels of estrogens and low levels of progesterone, and an early follicular (EF) group, characterized by low levels of both estrogens and progesterone. During the RM task, all subjects viewed images of faces expressing six basic emotions (happiness, anger, disgust, sadness, surprise, fear) and one neutral expression while their electrophysiological activity was recorded. We considered P300 components, amplitude, and latency in response to each stimulus. Soon after the presentation of each stimulus face, a target image was presented, consisting of two faces, one of which was the same, while the other was a chimerical face, obtained by mixing the upper or lower halves of the faces of the stimulus image with a different emotion. The subjects had to choose between the two alternatives, and the reaction time (RT) and accuracy of response (RM errors) were measured. The main findings of this study showed that P300 amplitudes are significantly higher in response to the expressions of happiness, but significantly lower for sadness, in PO compared to EF. The P300 data are consistent with performance in the RM task and with the measures of RT. The interest in the emotion of happiness, unlike sadness, during the PO phase may reflect the evolutionary significance of female sex hormones linked to mating behavior.

Transitionality in addiction: A "temporal continuum" hypotheses involving the aberrant motivation, the hedonic dysregulation, and the aberrant learning.

Addiction is a chronic compulsion and relapsing disorder. It involves several brain areas and circuits, which encode vary functions such as reward, motivation, and memory. Drug addiction is defined as a "pathological pattern of use of a substance", characterized by the loss of control on drug-taking-related behaviors, the pursuance of those behaviors even in the presence of negative consequences, and a strong motivated activity to assume substances. Three different theories guide experimental research on drug addiction. Each of these theories consider singles features, such as an aberrant motivation, a hedonic dysregulation, and an aberrant habit learning as the main actor to explain the entire process of the addictive behaviors. The major goal of this study is to present a new hypotheses of transitionality from a controlled use to abuse of addictive substances trough the overview of the three different theories, considering all the single features of each single theory together on the same "temporal continuum" from use to abuse of addictive substances. Recently, it has been suggested that common neural systems may be activated by natural and pharmacological stimuli, raising the hypotheses that binge-eating disorders could be considered as addictive behaviors. The second goal of this study is to present evidences in order to highlight a possible psycho-bio-physiological superimposition between drug and "food addiction". Finally, interesting questions are brought up starting from last findings about a theoretical/psycho-bio-physiological superimposition between drug and "food addiction" and their possibly same transitionality along the same "temporal continuum" from use to abuse of addictive substances in order to investigate new therapeutic strategies based on new therapeutic strategies based on the individual moments characterizing the transition from the voluntary intake of substances to the maladaptive addictive behavior.

Corrigendum: Editorial: Serotonin and Memory.

[This corrects the article DOI: 10.3389/fphar.2016.00008.].

Evidence of estrogen modulation on memory processes for emotional content in healthy young women.

PURPOSE: It is well accepted that emotional content can affect memory, interacting with the encoding and consolidation processes. The aim of the present study was to verify the effects of estrogens in the interplay of cognition and emotion. METHODS: Images from the International Affective Pictures System, based on valence (pleasant, unpleasant and neutral), maintaining arousal constant, were viewed passively by two groups of young women in different cycle phases: a periovulatory group (PO), characterized by high level of estrogens and low level of progesterone, and an early follicular group (EF), characterized by low levels of both estrogens and progesterone. The electrophysiological responses to images were measured, and P300 peak was considered. One week later, long-term memory was tested by means of free recall. FINDINGS: Intra-group analysis displayed that PO woman had significantly better memory for positive images, while EF women showed significantly better memory for negative images. The comparison between groups revealed that women in the PO phase had better memory performance for positive pictures than women in the EF phase, while no significant differences were found for negative and neutral pictures. According to the free recall results, the subjects in the PO group showed greater P300 amplitude, and shorter latency, for pleasant images compared with women in the EF group. CONCLUSION: Our results showed that the physiological hormonal fluctuation of estrogens during the menstrual cycle can influence memory, at the time of encoding, during the processing of emotional information.

When chocolate seeking becomes compulsion: gene-environment interplay.

BACKGROUND: Eating disorders appear to be caused by a complex interaction between environmental and genetic factors, and compulsive eating in response to adverse circumstances characterizes many eating disorders. MATERIALS AND METHODS: We compared compulsion-like eating in the form of conditioned suppression of palatable food-seeking in adverse situations in stressed C57BL/6J and DBA/2J mice, two well-characterized inbred strains, to determine the influence of gene-environment interplay on this behavioral phenotype. Moreover, we tested the hypothesis that low accumbal D2 receptor (R) availability is a genetic risk factor of food compulsion-like behavior and that environmental conditions that induce compulsive eating alter D2R expression in the striatum. To this end, we measured D1R and D2R expression in the striatum and D1R, D2R and α1R levels in the medial prefrontal cortex, respectively, by western blot. RESULTS: Exposure to environmental conditions induces compulsion-like eating behavior, depending on genetic background. This behavioral pattern is linked to decreased availability of accumbal D2R. Moreover, exposure to certain environmental conditions upregulates D2R and downregulates α1R in the striatum and medial prefrontal cortex, respectively, of compulsive animals. These findings confirm the function of gene-environment interplay in the manifestation of compulsive eating and support the hypothesis that low accumbal D2R availability is a "constitutive" genetic risk factor for compulsion-like eating behavior. Finally, D2R upregulation and α1R downregulation in the striatum and medial prefrontal cortex, respectively, are potential neuroadaptive responses that parallel the shift from motivated to compulsive eating.

Zaprinast impairs spatial memory by increasing PDE5 expression in the rat hippocampus.

In this work, we report the effect of post-training intraperitoneal administration of zaprinast on rat memory retention in the Morris water maze task that revealed a significant memory impairment at the intermediate dose of 10mg/kg. Zaprinast is capable of inhibiting both striatal and hippocampal PDE activity but to a different extent which is probably due to the different PDE isoforms expressed in these areas. To assess the possible involvement of cyclic nucleotides in rat memory impairment, we compared the effects obtained 30 min after the zaprinast injection with respect to 24h after injection by measuring both cyclic nucleotide levels and PDE activity. As expected, 30 min after the zaprinast administration, we observed an increase of cyclic nucleotides, which returned to a basal level within 24h, with the exception of the hippocampal cGMP which was significantly decreased at the dose of 10mg/kg of zaprinast. This increase in the hippocampal region is the result of a cGMP-specific PDE5 induction, confirmed by sildenafil inhibition, in agreement with literature data that demonstrate transcriptional regulation of PDE5 by cAMP/cGMP intracellular levels. Our results highlight the possible rebound effect of PDE inhibitors.

Facial emotion recognition in schizophrenia: an event-related potentials study.

Previous studies extensively reported an impaired ability to recognize emotional stimuli in patients with schizophrenia. We used pictures from Ekman and Friesen in an event-related potentials study to investigate the neurophysiological correlates of the fear emotional processing compared with happiness in patients with schizophrenia versus healthy subjects. A significant lower P300 amplitude for fear processing but not for P100, N170 and N250 amplitude was found in schizophrenics compared to controls. These data suggest that the ability of basic visual processing is preserved in schizophrenia, whereas facial affect processing is impaired.

Habit learning and memory in mammals: behavioral and neural characteristics.

Goal-direct behavior and habit learning represent two forms of instrumental learning; whereas the former is rapidly acquired and regulated by its outcome, the latter is reflexive, elicited by antecedent stimuli rather than their consequences. Habit learning can be generally defined as the acquisition of associations between stimuli and responses. Habits are acquired via experience-dependent plasticity, occurring repeatedly over the course of days or years and becoming remarkably fixed. The distinction between habit learning, as a product of a procedural learning brain system, and a declarative learning system for encoding facts and episodes is based on the hypothesis that memory is composed of multiple systems that have distinct neuroanatomy and operating principles. Here we review recent research analyzing the main behavioral and neural characteristics of habit learning. In particular, we focus on the distinction between goal-directed and habitual behavior, and describe the brain areas and neurotransmitters systems involved in habit learning. The emotional modulation of habit learning in rodents and primates is reviewed, and the implications of habit learning in psychopathology are briefly described.

Serotonergic 5-HT7 receptors and cognition.

The abundant distribution of serotonin (5-HT) in different areas of the central nervous system can explain the involvement of this neurotransmitter in the regulation of several functions, such as sleep, pain, feeding, and sexual and emotional behaviors. Moreover, the serotonergic system is also involved in other more complex roles, such as cognition, including learning and memory processes. Recent studies led to the discovery of various types and subtypes of receptors differentially associated to cognitive mechanisms. 5-HT7 is the most recently discovered receptor for 5-HT; therefore, it is also one of the least well characterized. Studies exist hypothesizing the role of 5-HT7 on the modulation of learning and memory processes and other cognitive functions. Moreover, much attention has been devoted to the possible role of 5-HT7 receptors in psychiatric disorders. Therefore, the aim of this review is to clarify the behavioral role of the recently discovered 5-HT7 type receptor and highlight its involvement in the cognitive functions, with particular attention to the modulation of learning and memory processes, thus providing a basis to obtain new therapeutic agents and strategies for the treatment of cognitive disorders.

Age-related differences in cortical activity during a visuo-spatial working memory task with facial stimuli.

Emotion, importantly displayed by facial expressions, is one of the most significant memory modulators. The interaction between memory and the different emotional valences change across lifespan, while young adults (YA) are expected to better recall negative events (Negativity Bias Hypothesis), older adults (OA) tend to focus on positive stimuli (Positivity Effect Hypothesis). This research work aims at verifying whether cortical electrical activity of these two age groups would also be differently influenced by emotional valences in a visuo-spatial working memory task. 27 YA (13 males) and 25 OA (14 males), all healthy volunteers, underwent electroencephalographic recordings (21 scalp electrodes montage), while performing the Spatial Delayed Recognition Span Task using a touch screen with different stimuli categories: neutral, positive and negative faces and geometric pictures. YA obtained higher scores than OA, and showed higher activation of theta and alpha bands in the frontal and midline regions, besides a more evident right-hemispheric asymmetry on alpha band when compared to OA. For both age groups, performance in the task was worse for positive faces than to negative and to neutral faces. Facial stimuli induced a better performance and higher alpha activation on the pre-frontal region for YA, and on the midline, occipital and left temporal regions for OA when compared to geometric figures. The superior performance of YA was expected due to the natural cognitive deficits connected to ageing, as was a better performance with facial stimuli due to the evolutionary importance of faces. These results were related to cortical activity on areas of importance for action-planning, decision making and sustained attention. Taken together, they are in accordance with the Negativity Bias but do not support the Positivity Effect. The methodology used was able to identify age-related differences in cortical activity during emotional mnemonic processing and may be interesting to future investigations.

Role of nicotine on cognitive and behavioral deficits in sepsis-surviving rats.

Sepsis and its complications are important causes of mortality in intensive care units and sepsis survivors may present long-term cognitive and emotional impairments, including memory deficits and anxiety symptoms. In the present study, we investigated whether repeated nicotine administration can affect the behavioral changes in sepsis-surviving rats. Male Wistar rats were divided in two groups: sham-operated and experimental sepsis induced by cecal ligation and puncture (CLP). The animals were injected subcutaneously with nicotine (0.1 mg/kg) or vehicle once a day during 1 week before and/or 1 week after sepsis induction. Thirty minutes after the last administration (i.e., 7 days after surgery), the animals were tested in the open field, elevated plus-maze and step-down inhibitory avoidance tasks. The repeated nicotine treatment did not affect the survival rate in the sepsis group (50%). Moreover, no significant changes on locomotor activity were observed in the sepsis group while the treatment with nicotine during 1 week after surgery reduced the locomotion of sepsis-surviving rats in the open field. It is important to note that both schedules of nicotine treatment (prior and/or after CLP) improved the sepsis-induced anxiogenic-like responses. Interestingly, nicotine was able to improve short- and long-term inhibitory avoidance memory impairments, observed in sepsis survivors, only when administered during 2 consecutive weeks (i.e., prior and after CLP). Taken together, these results indicate that repeated nicotine administration does not alter the survival rate in rats submitted to CLP and provide new evidence that nicotine can improve long-lasting memory impairments and anxiogenic-like responses in sepsis-surviving animals.

Estrogen, cognitive functions and emotion: an overview on humans, non-human primates and rodents in reproductive years.

Accumulating evidence has highlighted a number of important, global issues regarding the influence of estrogen on emotion and cognitive functions,including learning and memory processes, both in animal models and humans. The influence of estrogen on cognition and emotion can be explained by taking into account its modulator role on several neurotransmitter systems, acetylcholine in particular, but also catecholamines,serotonin and GABA in rodents, primates and humans. Another reason may lie in the wide spread presence of the two classes (a and~) of estrogen receptors in many brain regions involved in emotion and cognition, including the hippocampal formation, amygdala and cerebral cortex. The present review reports on research conducted in our laboratory and others with the objective of identifying the action of estrogens on cognition and emotion in rodents, monkeys and humans in youth. In particular, the first section,focused on the mechanisms of estrogens action in the brain, illustrates the involvement of estrogen receptors and neurotransmitters in the cognitive and emotional processes; the second section deals with the estrogen effects on cognitive and emotional mechanisms, with particular emphasis on memory and the involvement of estrogen in emotion and cognition across the estrous/menstrual cycle.

Estrogens and memory in physiological and neuropathological conditions.

Ovarian hormones can influence brain regions crucial to higher cognitive functions, such as learning and memory, acting at structural, cellular and functional levels, and modulating neurotransmitter systems. Among the main effects of estrogens, the protective role that they may play against the deterioration of cognitive functions occurring with normal aging is of essential importance. In fact, during the last century, there has been a 30 years increase in female life expectancy, from 50 to 83 years; however, the mean age of spontaneous menopause remains stable, 50-51 years, with variability related to race and ethnicity. Therefore, women are now spending a greater fraction of their lives in a hypoestrogenic state. Although many cognitive functions seem to be unaffected by normal aging, age-related impairments are particularly evident in tasks involving working memory (WM), whose deficits are a recognized feature of Alzheimer's disease (AD). Many studies conducted over the past two decades showed that the female gonadal hormone estradiol can influence performance of learning and memory tasks, both in animal and humans. There is a great deal of evidence, mostly from animal models, that estrogens can facilitate or enhance performance on WM tasks; therefore, it is very important to clarify their role on this type of memory. To this aim, in this review we briefly describe the most relevant neurobiological bases of estrogens, that can explain their effects on cognitive functioning, and then we summarize the results of works conducted in our laboratory, both on animals and humans, utilizing the menstrual/estrous cycle as a useful noninvasive model. Finally, we review the possible role of estrogens in neuropathological conditions, such as AD and schizophrenia.

Sex-related memory recall and talkativeness for emotional stimuli.

Recent studies have evidenced an increasing interest in sex-related brain mechanisms and cerebral lateralization subserving emotional memory, language processing, and conversational behavior. We used event-related-potentials (ERP) to examine the influence of sex and hemisphere on brain responses to emotional stimuli. Given that the P300 component of ERP is considered a cognitive neuroelectric phenomenon, we compared left and right hemisphere P300 responses to emotional stimuli in men and women. As indexed by both amplitude and latency measures, emotional stimuli elicited more robust P300 effects in the left hemisphere in women than in men, while a stronger P300 component was elicited in the right hemisphere in men compared to women. Our findings show that the variables of sex and hemisphere interacted significantly to influence the strength of the P300 component to the emotional stimuli. Emotional stimuli were also best recalled when given a long-term, incidental memory test, a fact potentially related to the differential P300 waves at encoding. Moreover, taking into account the sex-related differences in language processing and conversational behavior, in the present study we evaluated possible talkativeness differences between the two genders in the recollection of emotional stimuli. Our data showed that women used a higher number of words, compared to men, to describe both arousal and neutral stories. Moreover, the present results support the view that sex differences in lateralization may not be a general feature of language processing but may be related to the specific condition, such as the emotional content of stimuli.

Working and reference memory across the estrous cycle of rat: a long-term study in gonadally intact females.

The results of many studies conducted over the past two decades suggested a role of estrogen on mammal's ability to learn and remember. In the present paper, we analyzed the influence that the endogenous fluctuation of estrogen, naturally present across the different phases of estrous cycle of female rats, can exert over the performance of tasks utilized to assess memory. In particular, we analyzed the performances in an eight arms radial maze task, dependent upon working memory, and in a water maze (WM) task, dependent upon spatial reference memory. The water maze is aversively motivated by the desire to escape onto a safe platform, whereas the radial arm maze (RAM) is motivated by food reward. The difference in reinforcement may affect the speed of learning, the strategy adopted and the necessity for accurate navigation. Therefore, coherent results obtained through the two different tasks can be due to mnemonic factors. The study was conducted during a long period of time, 14 months, utilizing gonadally intact females, without pharmacological and surgical treatments. In order to evaluate the post-acquisition phase we first trained the animals to reach the criterion in performing tasks, and then we submitted them to experimental phase. Our results show that estrogen can have an effect on memory processes, and that this effect may be different in relation to different kinds of memory. In fact, in our study, estrogen selectively improved working memory, but not reference memory, during post-acquisition performance of a RAM task with four baited and four un-baited arms. Moreover, WM performances showed that estrogen have a negative effect on spatial reference memory.