How far neuroscience is from understanding brains.

The cellular biology of brains is relatively well-understood, but neuroscientists have not yet generated a theory explaining how brains work. Explanations of how neurons collectively operate to produce what brains can do are tentative and incomplete. Without prior assumptions about the brain mechanisms, I attempt here to identify major obstacles to progress in neuroscientific understanding of brains and central nervous systems. Most of the obstacles to our understanding are conceptual. Neuroscience lacks concepts and models rooted in experimental results explaining how neurons interact at all scales. The cerebral cortex is thought to control awake activities, which contrasts with recent experimental results. There is ambiguity distinguishing task-related brain activities from spontaneous activities and organized intrinsic activities. Brains are regarded as driven by external and internal stimuli in contrast to their considerable autonomy. Experimental results are explained by sensory inputs, behavior, and psychological concepts. Time and space are regarded as mutually independent variables for spiking, post-synaptic events, and other measured variables, in contrast to experimental results. Dynamical systems theory and models describing evolution of variables with time as the independent variable are insufficient to account for central nervous system activities. Spatial dynamics may be a practical solution. The general hypothesis that measurements of changes in fundamental brain variables, action potentials, transmitter releases, post-synaptic transmembrane currents, etc., propagating in central nervous systems reveal how they work, carries no additional assumptions. Combinations of current techniques could reveal many aspects of spatial dynamics of spiking, post-synaptic processing, and plasticity in insects and rodents to start with. But problems defining baseline and reference conditions hinder interpretations of the results. Furthermore, the facts that pooling and averaging of data destroy their underlying dynamics imply that single-trial designs and statistics are necessary.

Brain Systems Underlying Fundamental Motivations of Human Social Conformity.

From birth to adulthood, we often align our behaviors, attitudes, and opinions with a majority, a phenomenon known as social conformity. A seminal framework has proposed that conformity behaviors are mainly driven by three fundamental motives: a desire to gain more information to be accurate, to obtain social approval from others, and to maintain a favorable self-concept. Despite extensive interest in neuroimaging investigation of social conformity, the relationship between brain systems and these fundamental motivations has yet to be established. Here, we reviewed brain imaging findings of social conformity with a componential framework, aiming to reveal the neuropsychological substrates underlying different conformity motivations. First, information-seeking engages the evaluation of social information, information integration, and modification of task-related activity, corresponding to brain networks implicated in reward, cognitive control, and tasks at hand. Second, social acceptance involves the anticipation of social acceptance or rejection and mental state attribution, mediated by networks of reward, punishment, and mentalizing. Third, self-enhancement entails the excessive representation of positive self-related information and suppression of negative self-related information, ingroup favoritism and/or outgroup derogation, and elaborated mentalizing processes to the ingroup, supported by brain systems of reward, punishment, and mentalizing. Therefore, recent brain imaging studies have provided important insights into the fundamental motivations of social conformity in terms of component processes and brain mechanisms.

Brain Systems Underlying Fundamental Motivations of Human Social Conformity / 神经科学通报·英文版

From birth to adulthood, we often align our behaviors, attitudes, and opinions with a majority, a phenomenon known as social conformity. A seminal framework has proposed that conformity behaviors are mainly driven by three fundamental motives: a desire to gain more information to be accurate, to obtain social approval from others, and to maintain a favorable self-concept. Despite extensive interest in neuroimaging investigation of social conformity, the relationship between brain systems and these fundamental motivations has yet to be established. Here, we reviewed brain imaging findings of social conformity with a componential framework, aiming to reveal the neuropsychological substrates underlying different conformity motivations. First, information-seeking engages the evaluation of social information, information integration, and modification of task-related activity, corresponding to brain networks implicated in reward, cognitive control, and tasks at hand. Second, social acceptance involves the anticipation of social acceptance or rejection and mental state attribution, mediated by networks of reward, punishment, and mentalizing. Third, self-enhancement entails the excessive representation of positive self-related information and suppression of negative self-related information, ingroup favoritism and/or outgroup derogation, and elaborated mentalizing processes to the ingroup, supported by brain systems of reward, punishment, and mentalizing. Therefore, recent brain imaging studies have provided important insights into the fundamental motivations of social conformity in terms of component processes and brain mechanisms.

Brain Circuits Involved in the Development of Chronic Musculoskeletal Pain: Evidence From Non-invasive Brain Stimulation.

It has been well-documented that the brain changes in states of chronic pain. Less is known about changes in the brain that predict the transition from acute to chronic pain. Evidence from neuroimaging studies suggests a shift from brain regions involved in nociceptive processing to corticostriatal brain regions that are instrumental in the processing of reward and emotional learning in the transition to the chronic state. In addition, dysfunction in descending pain modulatory circuits encompassing the periaqueductal gray and the rostral anterior cingulate cortex may also be a key risk factor for pain chronicity. Although longitudinal imaging studies have revealed potential predictors of pain chronicity, their causal role has not yet been determined. Here we review evidence from studies that involve non-invasive brain stimulation to elucidate to what extent they may help to elucidate the brain circuits involved in pain chronicity. Especially, we focus on studies using non-invasive brain stimulation techniques [e.g., transcranial magnetic stimulation (TMS), particularly its repetitive form (rTMS), transcranial alternating current stimulation (tACS), and transcranial direct current stimulation (tDCS)] in the context of musculoskeletal pain chronicity. We focus on the role of the motor cortex because of its known contribution to sensory components of pain via thalamic inhibition, and the role of the dorsolateral prefrontal cortex because of its role on cognitive and affective processing of pain. We will also discuss findings from studies using experimentally induced prolonged pain and studies implicating the DLPFC, which may shed light on the earliest transition phase to chronicity. We propose that combined brain stimulation and imaging studies might further advance mechanistic models of the chronicity process and involved brain circuits. Implications and challenges for translating the research on mechanistic models of the development of chronic pain to clinical practice will also be addressed.

Brain Mechanisms of COVID-19-Sleep Disorders.

2020 and 2021 have been unprecedented years due to the rapid spread of the modified severe acute respiratory syndrome coronavirus around the world. The coronavirus disease 2019 (COVID-19) causes atypical infiltrated pneumonia with many neurological symptoms, and major sleep changes. The exposure of people to stress, such as social confinement and changes in daily routines, is accompanied by various sleep disturbances, known as 'coronasomnia' phenomenon. Sleep disorders induce neuroinflammation, which promotes the blood-brain barrier (BBB) disruption and entry of antigens and inflammatory factors into the brain. Here, we review findings and trends in sleep research in 2020-2021, demonstrating how COVID-19 and sleep disorders can induce BBB leakage via neuroinflammation, which might contribute to the 'coronasomnia' phenomenon. The new studies suggest that the control of sleep hygiene and quality should be incorporated into the rehabilitation of COVID-19 patients. We also discuss perspective strategies for the prevention of COVID-19-related BBB disorders. We demonstrate that sleep might be a novel biomarker of BBB leakage, and the analysis of sleep EEG patterns can be a breakthrough non-invasive technology for diagnosis of the COVID-19-caused BBB disruption.

Supramodal Mechanisms of the Cognitive Control Network in Uncertainty Processing.

Information processing under conditions of uncertainty requires the involvement of cognitive control. Despite behavioral evidence of the supramodal function (i.e., independent of sensory modality) of cognitive control, the underlying neural mechanism needs to be directly tested. This study used functional magnetic imaging together with visual and auditory perceptual decision-making tasks to examine brain activation as a function of uncertainty in the two stimulus modalities. The results revealed a monotonic increase in activation in the cortical regions of the cognitive control network (CCN) as a function of uncertainty in the visual and auditory modalities. The intrinsic connectivity between the CCN and sensory regions was similar for the visual and auditory modalities. Furthermore, multivariate patterns of activation in the CCN predicted the level of uncertainty within and across stimulus modalities. These findings suggest that the CCN implements cognitive control by processing uncertainty as abstract information independent of stimulus modality.

Acute aerobic exercise enhances pleasant compared to unpleasant visual scene processing.

Although acute aerobic exercise benefits different aspects of emotional functioning, it is unclear how exercise influences the processing of emotional stimuli and which brain mechanisms support this relationship. We assessed the influence of acute aerobic exercise on valence biases (preferential processing of negative/positive pictures) by performing source reconstructions of participants' brain activity after they viewed emotional scenes. Twenty-four healthy participants (12 women) were tested in a randomized and counterbalanced design that consisted of three experimental protocols, each lasting 30 min: low-intensity exercise (Low-Int); moderate-intensity exercise (Mod-Int); and a seated rest condition (REST). After each of the protocols, participants viewed negative and positive pictures, during which event-related magnetic fields were recorded. Analyses revealed that exercise strongly impacted the valence processing of emotional scenes within a widely distributed left hemispheric spatio-temporal cluster between 190 and 310 ms after picture onset. Brain activity in this cluster showed that a negativity bias at REST (negative > positive picture processing) diminished after the Low-Int condition (positive = negative) and even reversed to a positivity bias after the Mod-Int condition (positive > negative). Thus, acute aerobic exercise of low and moderate intensities induces a positivity bias which is reflected in early, automatic processes.

TMS reveals inhibitory extrastriate cortico-cortical feedback modulation of V1 activity in humans.

The interaction between the primary visual cortex (V1) and extrastriate visual areas provides the first building blocks in our perception of the world. V2, in particular, seems to play a crucial role in shaping contextual modulation information through feedback projections to V1. However, whether this feedback is inhibitory or excitatory is still unclear. In order to test the nature of V2 feedback to V1, we used neuronavigation-guided offline inhibitory transcranial magnetic stimulation (TMS) on V2 before testing participants on collinear facilitation, a contrast detection task with lateral masking. This contextual modulation task is thought to rely on horizontal connections in V1 and possibly extrastriate feedback. Results showed that when inhibitory TMS was delivered over V2, contrast thresholds decreased for targets presented in the contralateral hemifield, consistent with the retinotopic mapping of this area, while having no effect for targets presented in the ipsilateral hemifield or after control (CZ) stimulation. These results suggest that feedback from V2 to V1 during contextual modulation is mostly inhibitory, corroborating recent observations in monkey electrophysiology and extending this mechanism to human visual system. Moreover, we provide for the first time direct evidence of the involvement of extrastriate visual areas in collinear facilitation.

Inferior parietal lobule and early visual areas support elicitation of individualized meanings during narrative listening.

INTRODUCTION: When listening to a narrative, the verbal expressions translate into meanings and flow of mental imagery. However, the same narrative can be heard quite differently based on differences in listeners' previous experiences and knowledge. We capitalized on such differences to disclose brain regions that support transformation of narrative into individualized propositional meanings and associated mental imagery by analyzing brain activity associated with behaviorally assessed individual meanings elicited by a narrative. METHODS: Sixteen right-handed female subjects were instructed to list words that best described what had come to their minds while listening to an eight-minute narrative during functional magnetic resonance imaging (fMRI). The fMRI data were analyzed by calculating voxel-wise intersubject correlation (ISC) values. We used latent semantic analysis (LSA) enhanced with Wordnet knowledge to measure semantic similarity of the produced words between subjects. Finally, we predicted the ISC with the semantic similarity using representational similarity analysis. RESULTS: We found that semantic similarity in these word listings between subjects, estimated using LSA combined with WordNet knowledge, predicting similarities in brain hemodynamic activity. Subject pairs whose individual semantics were similar also exhibited similar brain activity in the bilateral supramarginal and angular gyrus of the inferior parietal lobe, and in the occipital pole. CONCLUSIONS: Our results demonstrate, using a novel method to measure interindividual differences in semantics, brain mechanisms giving rise to semantics and associated imagery during narrative listening. During listening to a captivating narrative, the inferior parietal lobe and early visual cortical areas seem, thus, to support elicitation of individual meanings and flow of mental imagery.

Route of placebo administration: Robust placebo effects in laboratory and clinical settings.

Recent advances in laboratory and clinical research have greatly enhanced our understanding of placebo effects. However, little progress has been made in translational research that can well integrate these findings. This article examines pivotal role of placebo administration in subsequent placebo responses, providing a unified framework that accounts for robust placebo effects in both laboratory and clinical settings.

A Principle for Describing and Verifying Brain Mechanisms Using Ongoing Activity.

Not even the most informed scientist can setup a theory that takes all brain signals into account. A neuron not only receives neuronal short range and long range input from all over the brain but a neuron also receives input from the extracellular space, astrocytes and vasculature. Given this complexity, how does one describe and verify a typical brain mechanism in vivo? Common to most described mechanisms is that one focuses on how one specific input signal gives rise to the activity in a population of neurons. This can be an input from a brain area, a population of neurons or a specific cell type. All remaining inputs originating from all over the brain are lumped together into one background input. The division into two inputs is attractive since it can be used to quantify the relative importance of either input. Here we have chosen to extract the specific and the background input by means of recording and inhibiting the specific input. We summarize what it takes to estimate the two inputs on a single trial level. The inhibition should not only be strong but also fast and the specific input measurement has to be tailor-made to the inhibition. In essence, we suggest ways to control electrophysiological experiments in vivo. By applying those controls it may become possible to describe and verify many brain mechanisms, and it may also allow the study of the integration of spontaneous and ongoing activity, which in turn governs cognition and behavior.

Social Cognition in Williams Syndrome: Face Tuning.

Many neurological, neurodevelopmental, neuropsychiatric, and psychosomatic disorders are characterized by impairments in visual social cognition, body language reading, and facial assessment of a social counterpart. Yet a wealth of research indicates that individuals with Williams syndrome exhibit remarkable concern for social stimuli and face fascination. Here individuals with Williams syndrome were presented with a set of Face-n-Food images composed of food ingredients and in different degree resembling a face (slightly bordering on the Giuseppe Arcimboldo style). The primary advantage of these images is that single components do not explicitly trigger face-specific processing, whereas in face images commonly used for investigating face perception (such as photographs or depictions), the mere occurrence of typical cues already implicates face presence. In a spontaneous recognition task, participants were shown a set of images in a predetermined order from the least to most resembling a face. Strikingly, individuals with Williams syndrome exhibited profound deficits in recognition of the Face-n-Food images as a face: they did not report seeing a face on the images, which typically developing controls effortlessly recognized as a face, and gave overall fewer face responses. This suggests atypical face tuning in Williams syndrome. The outcome is discussed in the light of a general pattern of social cognition in Williams syndrome and brain mechanisms underpinning face processing.

Brain Oscillations, Hypnosis, and Hypnotizability.

In this article, we summarize the state-of-science knowledge regarding the associations between hypnosis and brain oscillations. Brain oscillations represent the combined electrical activity of neuronal assemblies, and are usually measured as specific frequencies representing slower (delta, theta, alpha) and faster (beta, gamma) oscillations. Hypnosis has been most closely linked to power in the theta band and changes in gamma activity. These oscillations are thought to play a critical role in both the recording and recall of declarative memory and emotional limbic circuits. Here we propose that it is this role that may be the mechanistic link between theta (and perhaps gamma) oscillations and hypnosis; specifically that theta oscillations may facilitate, and that changes in gamma activity observed with hypnosis may underlie, some hypnotic responses. If these hypotheses are supported, they have important implications for both understanding the effects of hypnosis, and for enhancing response to hypnotic treatments.

Meditation and Yoga can Modulate Brain Mechanisms that affect Behavior and Anxiety-A Modern Scientific Perspective.

Meditation and Yoga techniques are receiving increased attention throughout the world, due to the accumulation of evidence based research that proves the direct and indirect benefits of such practices. Based on studies conducted so far, it has been found that the practice of meditation triggers neurotransmitters that modulate psychological disorders such as anxiety. This paper will review the psychological effects of the practice of meditation, the role of neurotransmitters, and studies using EEG and fMRI.

Brain mechanisms for prepulse inhibition in adults with Tourette syndrome: initial findings.

Prepulse inhibition (PPI) of the startle reflex is disrupted in a number of developmental neuropsychiatric disorders, including Tourette syndrome (TS). This disruption is hypothesized to reflect abnormalities in sensorimotor gating. We applied whole-brain functional magnetic resonance imaging (fMRI) to elucidate the neural correlates of PPI in adult TS subjects using airpuff stimuli to the throat to elicit a tactile startle response. We used a cross-sectional, case-control study design and a blocked-design fMRI paradigm. There were 33 participants: 17 with TS and 16 healthy individuals. As a measure of PPI-related brain activity, we looked for differential cerebral activation to prepulse-plus-pulse stimuli versus activation to pulse-alone stimuli. In healthy subjects, PPI was associated with increased activity in multiple brain regions, of which activation in the left middle frontal gyrus in the healthy controls showed a significant linear correlation with the degree of PPI measured outside of the magnet. Group comparisons identified nine regions where brain activity during PPI differed significantly between TS and healthy subjects. Among the TS subjects, activation in the left caudate was significantly correlated with current tic severity as measured by the total score on the Yale Global Tic Severity Scale. Differential activation of the caudate nucleus associated with current tic severity is consistent with neuropathological data and suggests that portions of cortical-striatal circuits may modulate the severity of tic symptoms in adulthood.

Towards a neuroscience of empathy: ontogeny, phylogeny, brain mechanisms, context and psychopathology.

Empathy allows individuals to share the affective states of others, predict others' actions, and stimulate prosocial behavior. Whilst the proximate mechanisms of empathy, modulated in part by neuropeptides such as oxytocin, control the ways we interact with our social environment, the ultimate causes seem to have arisen along with the mechanisms involved in mammalian parental care. The conceptual boundaries of empathy, however, have been blurred by definitional inaccuracies of mechanisms that can be regarded as phylogenetic precursors or physiological prerequisites for empathy, including mimicry and emotion contagion. Contextual factors such as early experiences with primary care-givers (attachment), current mood states and other environmental contingencies are capable of modulating empathy. Moreover, evidence suggests that there is also a "dark side" of empathy, namely envy and schadenfreude (gloating) that are elicited by social comparison, competition and ingroup-outgroup distinction. This review aims at clarifying some of the open definitional questions related to empathy, and emphasizing the need for considering contextual factors in the study of empathy in both normal and abnormal psychology.

Influence of the estrous cycle on some non reproductive behaviors and on brain mechanisms in the female rat

Sex hormone fluctuations in females are involved in some behavioral states such as mood, anxiety, aggression and stress response, due to functional changes in the central nervous system (CNS) activity induced by the cyclic sex hormone fluctuation. This review includes three sections. 1.- A description of the three major hormone fluctuations in the estrous cycle: estrogens (E2), progesterone (P4) and prolactine (PRL). E2 achieves the maximum circulation levels during P.E2 is mainly excitatory and has been considered to have an antidepressive action. The highest plasma levels of P4 and its metabolite allopregnenolone(ALLO) occur in P. Ovulation takes place in the night of P, and the resulting corpora lutea produces a secondary increase in P4 (and ALLO) on D. The P4 peak level occurring in D1 and in the evening of P was shown to exert benzodiazepine-like effects, including sedation. It has been proposed that ALLO, rather than P4 is the one acting on GABA systems. Circulating levels of ALLO parallel those of P4 across the estrous cycle and is known to have anxiolytic properties. PRL is produced mainly in the adenohypophysis, though synthesis in other sites of the brain also occurs. Its regulation is mostly inhibitory and is exerted by dopamine (DA) released in the hypothalamus. A surge in PRL secretion occurs during P. PRL would be a modulator of the HPA-axis, and is considered as a stress hormone. 2.- Some behavioral and neural changes occur at each stage of the cycle. Lower anxiety level in P females was described. This has been correlated with increased circulating levels of endogenous ALLO in P. PRL is another hormone that may cause the lower scores of anxiety observed at P, since the peak of plasma PRL is observed at this stage. A novel peptide, the Prolactin Releasing Peptide (PrRP), which is sensitive to E2 fluctuation, has also been linked to the lower activity of the HPA axis. Stress-induced activation of PrRP neurons is significantly decreased in E compared with P and D, suggesting that E2 suppresses the activation of PrRP neurons. The late luteal phase (D) correlates with the premenstrual phase in women, commonly associated with psychological disturbances, including mood disorders and increased aggression. Consistently, increased levels of anxiety and aggression have been detected in rats during D. 3.- Findings about cyclic hormone influences on the CNS neurotransmitters and on the stress mediator, prolactine-releasing peptide (PrRP) were described. GABA is the main inhibitory system in the brain. Estrous-cycle-dependent increases in -GABA A receptors were reported; this subtype underlying a tonic inhibitory current, is the most sensitive target of P4 and ALLO. E2 causes a reduction in GABAergic inhibition, leading to an increase in the excitatory tone. It also acts on hippocampus causing a transient lowering of GABA synthesis in the interneuron. These findings suggest an excitatory role for E2 through inhibition of the GABA system. The serotonin system, involved in behavioral responses such as stress, anxiety and depression, also exhibits variations along the estrous cycle, in part dependant of GABA-receptor changes. Gender differences were described for DA function in the brain, due to E2 and P4 modulation. DA release and reuptake fluctuate with changes in circulating steroid levels. E2 enhances DA release and DA-mediated behaviors, such as general activity stimulation, food seeking behavior and sexual motivation. PrRP is produced in hypothalamic and extra hypothalamic structures. It has been proposed as a mediator of stress responses. Though gender differences have been shown, distribution of PrRP does not change during the estrous cycle. We hope this review may contribute to understand the mechanism of female behavioral variations and their pharmacological and diagnostic implications.(AU)

El rol de las hormonas sexuales sobre el comportamiento reproductivo ha sido extensamente documentado. La fluctuación periódica de hormonas sexuales en hembras de numerosas especies ha sido relacionada con cambios comportamentales no sexuales tales como humor, ansiedad, agresión y respuesta a estrés. El sustrato biológico-neural de estos cambios se basa en los cambios que estas hormonas inducen en el Sistema Nervioso Central. Este trabajo resume algunos cambios que afectan a receptores y neurotrasmisores de los sistemas GABAérgico, serotoninérgico, dopaminérgico y péptido liberador de prolactina del SNC de la rata. La rata hembra posee un ciclo sexual de 4 días de duración, denominado ciclo estrual. La presente revisión se informa en tres secciones. (1) Se presenta una breve descripción de la variación de tres hormonas sexuales principales con acción directa sobre el SNC: estrógenos (E2), progesterona (P4) y prolactina (PRL). Se han descripto propiedades ansiolíticas para P4 y anti-estrés para PRL; para E2, la bibliografía es controvertida, describiéndose acciones excitatorias y anti-estrés. (2) Se informan algunos cambios cerebrales y comportamentales que tienen lugar en cada estadio del ciclo estrual. Las fluctuaciones hormonales se consideran básicas para la interpretación de tales cambios. (3) Se mencionan algunos hallazgos acerca de la influencia hormonal cíclica sobre los sistemas de neurotransmisión del SNC y sobre un nuevo péptido propuesto como mediador de la respuesta a estrés, el péptido liberador de prolactina (PrRP). Esperamos que este trabajo contribuya a un mejor entendimiento de los mecanismos del comportamiento de las hembras y sus variaciones, y sus implicancias farmacológicas y diagnósticas.(AU)

Influence of the estrous cycle on some non reproductive behaviors and on brain mechanisms in the female rat

Sex hormone fluctuations in females are involved in some behavioral states such as mood, anxiety, aggression and stress response, due to functional changes in the central nervous system (CNS) activity induced by the cyclic sex hormone fluctuation. This review includes three sections. 1.- A description of the three major hormone fluctuations in the estrous cycle: estrogens (E2), progesterone (P4) and prolactine (PRL). E2 achieves the maximum circulation levels during P.E2 is mainly excitatory and has been considered to have an antidepressive action. The highest plasma levels of P4 and its metabolite allopregnenolone(ALLO) occur in P. Ovulation takes place in the night of P, and the resulting corpora lutea produces a secondary increase in P4 (and ALLO) on D. The P4 peak level occurring in D1 and in the evening of P was shown to exert benzodiazepine-like effects, including sedation. It has been proposed that ALLO, rather than P4 is the one acting on GABA systems. Circulating levels of ALLO parallel those of P4 across the estrous cycle and is known to have anxiolytic properties. PRL is produced mainly in the adenohypophysis, though synthesis in other sites of the brain also occurs. Its regulation is mostly inhibitory and is exerted by dopamine (DA) released in the hypothalamus. A surge in PRL secretion occurs during P. PRL would be a modulator of the HPA-axis, and is considered as a stress hormone. 2.- Some behavioral and neural changes occur at each stage of the cycle. Lower anxiety level in P females was described. This has been correlated with increased circulating levels of endogenous ALLO in P. PRL is another hormone that may cause the lower scores of anxiety observed at P, since the peak of plasma PRL is observed at this stage. A novel peptide, the Prolactin Releasing Peptide (PrRP), which is sensitive to E2 fluctuation, has also been linked to the lower activity of the HPA axis. Stress-induced activation of PrRP neurons is significantly decreased in E compared with P and D, suggesting that E2 suppresses the activation of PrRP neurons. The late luteal phase (D) correlates with the premenstrual phase in women, commonly associated with psychological disturbances, including mood disorders and increased aggression. Consistently, increased levels of anxiety and aggression have been detected in rats during D. 3.- Findings about cyclic hormone influences on the CNS neurotransmitters and on the stress mediator, prolactine-releasing peptide (PrRP) were described. GABA is the main inhibitory system in the brain. Estrous-cycle-dependent increases in -GABA A receptors were reported; this subtype underlying a tonic inhibitory current, is the most sensitive target of P4 and ALLO. E2 causes a reduction in GABAergic inhibition, leading to an increase in the excitatory tone. It also acts on hippocampus causing a transient lowering of GABA synthesis in the interneuron. These findings suggest an excitatory role for E2 through inhibition of the GABA system. The serotonin system, involved in behavioral responses such as stress, anxiety and depression, also exhibits variations along the estrous cycle, in part dependant of GABA-receptor changes. Gender differences were described for DA function in the brain, due to E2 and P4 modulation. DA release and reuptake fluctuate with changes in circulating steroid levels. E2 enhances DA release and DA-mediated behaviors, such as general activity stimulation, food seeking behavior and sexual motivation. PrRP is produced in hypothalamic and extra hypothalamic structures. It has been proposed as a mediator of stress responses. Though gender differences have been shown, distribution of PrRP does not change during the estrous cycle. We hope this review may contribute to understand the mechanism of female behavioral variations and their pharmacological and diagnostic implications.

El rol de las hormonas sexuales sobre el comportamiento reproductivo ha sido extensamente documentado. La fluctuación periódica de hormonas sexuales en hembras de numerosas especies ha sido relacionada con cambios comportamentales no sexuales tales como humor, ansiedad, agresión y respuesta a estrés. El sustrato biológico-neural de estos cambios se basa en los cambios que estas hormonas inducen en el Sistema Nervioso Central. Este trabajo resume algunos cambios que afectan a receptores y neurotrasmisores de los sistemas GABAérgico, serotoninérgico, dopaminérgico y péptido liberador de prolactina del SNC de la rata. La rata hembra posee un ciclo sexual de 4 días de duración, denominado ciclo estrual. La presente revisión se informa en tres secciones. (1) Se presenta una breve descripción de la variación de tres hormonas sexuales principales con acción directa sobre el SNC: estrógenos (E2), progesterona (P4) y prolactina (PRL). Se han descripto propiedades ansiolíticas para P4 y anti-estrés para PRL; para E2, la bibliografía es controvertida, describiéndose acciones excitatorias y anti-estrés. (2) Se informan algunos cambios cerebrales y comportamentales que tienen lugar en cada estadio del ciclo estrual. Las fluctuaciones hormonales se consideran básicas para la interpretación de tales cambios. (3) Se mencionan algunos hallazgos acerca de la influencia hormonal cíclica sobre los sistemas de neurotransmisión del SNC y sobre un nuevo péptido propuesto como mediador de la respuesta a estrés, el péptido liberador de prolactina (PrRP). Esperamos que este trabajo contribuya a un mejor entendimiento de los mecanismos del comportamiento de las hembras y sus variaciones, y sus implicancias farmacológicas y diagnósticas.