Assunta Pompili

Effect of 5-HT7 antagonist SB-269970 in the modulation of working and reference memory in the rat

It has been established that serotonergic pathways project to cerebral areas involved in learning and memory and that serotonin (5-HT) receptor agonists and antagonists modify these processes. Indeed, most of the 5-HT receptors characterized so far, i.e., 5-HT(1) through 5-HT(7), show a regional distribution in brain areas involved in learning and memory, such as hippocampal formation (HF), amygdala and cortex. Although 5-HT(7) receptor biological functions are still to be clarified, it was recently suggested that it may play a role in the control of learning and memory processes. The aim of our study was to assess the role of 5-HT(7) receptors antagonist SB-269970 on working and reference memory in a radial arm maze task, utilizing a two-phase procedure, comprising an acquisition and test phase, conducted to evaluate working and reference memory, respectively. Our results showed that 5-HT(7) receptors antagonist SB-269970 improved memory, decreasing the number of errors in test phase and, thus, affecting reference memory, while no effects were observed in working memory. These results could be explained taking into consideration the specific localization of 5-HT(7) receptors in the CNS. In fact, high concentrations of 5-HT(7) receptors were found in the HF, which exerts an important role on reference memory, while relatively low concentrations were present in the prefrontal cortex, involved in working memory. Thus, 5-HT(7) receptor blockade had procognitive effect, when the learning task implicated a high degree of difficulty. This conclusion has a major implication in the context that 5-HT receptors play an important role under amnesia states (e.g., Alzheimers disease) or when the learning is complex.

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 mammals 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.

The induction of cyclic nucleotide phosphodiesterase 4 gene (PDE4D) impairs memory in a water maze task.

In this study, the effects on memory of intraperitoneal post-training administration of cyclic nucleotide phosphodiesterase (PDE) inhibitors, DC-TA 46 and rolipram, were tested using a visible/hidden-platform water maze task. The effects of these compounds on cyclic nucleotide levels in the hippocampal formation (HF) and striatum (CP) were also assessed, by enzymatic immunoassay (EIA). The results obtained from rats trained in the visible-platform task were not significantly different from controls. On the contrary, the animals trained in the hidden-platform water maze task showed a memory impairment, when injected with DC-TA 46 at maximal dose of 20mg/kg and with rolipram at 3 and 30 mg/kg doses. The effects of these drugs on cyclic nucleotide levels in HF and CP were observed at 30 min and at 24h after drug administration. Thirty minutes after drug injection, we observed an increase of cAMP level, both in HF and in CP. Twenty-four hours after the retention test, we observed that in CP the cAMP intracellular level remained high, while in the HF at effective doses both inhibitors induced cAMP PDE activity, determining a decrease of cyclic nucleotide. Semi-quantitative RT-PCR analysis, together with Western blot immunodetection, showed a mRNA and protein induction of PDE4D PDE isoforms, that may account for the increase of PDE activity observed. Our data suggest that, despite cyclic nucleotide increase at 30 min, the fundamental event causing memory impairment, came from the subsequent long time decrease of cAMP levels, due to the post-translational PDE4D induction.

Working memory for emotional facial expressions: Role of the estrogen in young women.

Physiological hormonal fluctuations during the menstrual cycle, postpartum, and menopause have been implicated in the modulation of mood, cognition, and affective disorders. Taking into account that womens performance in memory tasks can also fluctuate with circulating hormones levels across the menstrual cycle, the cognitive performance in a working memory task for emotional facial expressions, using the six basic emotions as stimuli in the delayed matching-to-sample, was evaluated in young women in different phases of the menstrual cycle. Our findings suggest that high levels of estradiol in the follicular phase could have a negative effect on delayed matching-to-sample working memory task, using stimuli with emotional valence. Moreover, in the follicular phase, compared to the menstrual phase, the percent of errors was significantly higher for the emotional facial expressions of sadness and disgust. The evaluation of the response times (time employed to answer) for each facial expression with emotional valence showed a significant difference between follicular and luteal in reference to the emotional facial expression of sadness. Our results show that high levels of estradiol in the follicular phase could impair the performance of working memory. However, this effect is specific to selective facial expressions suggesting that, across the phases of the menstrual cycle, in which conception risk is high, women could give less importance to the recognition of the emotional facial expressions of sadness and disgust. This study is in agreement with research conducted on non-human primates, showing that fluctuations of ovarian hormones across the menstrual cycle influence a variety of social and cognitive behaviors. Moreover, our data could also represent a useful tool for investigating emotional disturbances linked to menstrual cycle phases and menopause in women.

Comparative effects of lesions to the ponto-cerebellar and olivo-cerebellar pathways on motor and spatial learning in the rat.

Emerging evidence supports the role of the cerebellum in motor learning and previous studies have also shown that olivary projections to the cerebellum are involved in motor learning. Since the pontine nuclei make up the other main relay centre in the cerebro-cerebellar pathway, the purpose of the present study was to verify the involvement of the ponto-cerebellar pathway in motor and spatial learning, by comparing these functions in intact animals and in rats with selective injury of the olivary or pontine neurons. Two groups of rats were used: the first was treated with 3-acetylpyridine to destroy the inferior olivary complex, the second received electrolytic lesions of the middle cerebellar peduncle to interrupt the ponto-cerebellar pathway. Control and lesioned rats were then submitted to three tasks: unrotated rod, rota-rod at 20 r.p.m., and Morris water maze. In the first task both 3-acetylpyridine-treated rats and rats with lesions of the middle cerebellar peduncle showed static equilibrium deficiencies. Through training, however, they reached the maximal score attained by the controls. The rats submitted to the rota-rod at 20 r.p.m. obtained scores significantly inferior to the controls. The Morris water maze results indicated that the lesion of inferior olivary complex and middle cerebellar peduncle both alter learning of the spatial task. These findings show that both the ponto- and olivo-cerebellar pathways are involved in learning complex motor sequences and spatial tasks. Since both projections converge onto Purkinje cells, our results suggest an integration of these two pathways in the cerebellar control of learning mechanism.

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 Alzheimers 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 lateralized effect of emotional content on declarative memory: an event related potential study.

Several studies suggest that emotional arousal can promote memory storage. In this study, we evaluated the effects of emotional content on declarative memory, utilizing an adaptation of two versions of the same story, with different arousing properties (neutral or emotional), which have been already employed in experiments involving the enhancing effects of emotions on memory retention. We used event related potentials (ERP) to evaluate whether there is a sex-related hemispheric lateralization of electrical potentials elicited by the emotional content of a story. We compared left and right hemisphere P300 waves, recorded in P3 and P4 electrode sites, in response to emotional or neutral stimuli in men and women. In the left hemisphere, emotional stimuli elicited a stronger P300 in women, compared to men, as indexed by both amplitude and latency measures; moreover, the emotional content of the story elicited a stronger P300 in the right hemisphere in men than in women. The better memory for the arousal material may be related to the differential P300 at encoding. These data indicate that both sex and cerebral hemisphere constitute important, interacting influences on neural correlates of emotion, and of emotionally influenced memory.

Serotonergic 5-HT7 receptors and cognition.

Abstract 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.

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.

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

Abstract 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 widespread presence of the two classes (α and β) 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.