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Despite significant advances in the study of fear and fear memory formation, little is known about fear learning and expression in females. This omission has been proven surprising, as normal and pathological behaviors are highly influenced by ovarian hormones, particularly estradiol and progesterone. In the current study, we investigated the joint influence of serotonin (5-HT) neurotransmission and estrous cycle phases (low or high levels of estradiol and progesterone) on the expression of conditioned fear in a group of female rats that were previously divided according to their response to stressful stimuli into low or high anxiety-like subjects. The baseline amplitude of the unconditioned acoustic startle responses was high in high-anxiety female rats, with no effect on the estrous cycle observed. Data collected during the proestrus-estrus phase revealed that low-anxiety rats had startle amplitudes similar to those of high-anxiety rats. It is supposed that high-anxiety female rats benefit from increased estradiol and progesterone levels to achieve comparable potentiated startle amplitudes. In contrast, female rats experienced a significant decrease in hormone levels during the Diestrus phase. This decrease is believed to play a role in preventing them from displaying a heightened startle response when faced with strongly aversive stimuli. Data collected after 5-HT and 8-OH-DPAT were administered into the basolateral nuclei and dorsal periaqueductal gray suggest that 5-HT neurotransmission works with progesterone and estrogen to reduce startle potentiation, most likely by activating the serotonin-1A receptor subtype.
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Complexo Nuclear Basolateral da Amígdala , Estradiol , Medo , Substância Cinzenta Periaquedutal , Progesterona , Receptor 5-HT1A de Serotonina , Reflexo de Sobressalto , Animais , Feminino , Ratos , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Estradiol/farmacologia , Estradiol/metabolismo , Ciclo Estral/fisiologia , Medo/fisiologia , Medo/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Progesterona/farmacologia , Progesterona/metabolismo , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Reflexo de Sobressalto/fisiologia , Reflexo de Sobressalto/efeitos dos fármacos , Serotonina/metabolismoRESUMO
The sensorimotor gating is a nervous system function that modulates the acoustic startle response (ASR). Prepulse inhibition (PPI) phenomenon is an operational measure of sensorimotor gating, defined as the reduction of ASR when a high intensity sound (pulse) is preceded in milliseconds by a weaker stimulus (prepulse). Brainstem nuclei are associated with the mediation of ASR and PPI, whereas cortical and subcortical regions are associated with their modulation. However, it is still unclear how the modulatory units can influence PPI. In the present work, we developed a computational model of a neural circuit involved in the mediation (brainstem units) and modulation (cortical and subcortical units) of ASR and PPI. The activities of all units were modeled by the leaky-integrator formalism for neural population. The model reproduces basic features of PPI observed in experiments, such as the effects of changes in interstimulus interval, prepulse intensity, and habituation of ASR. The simulation of GABAergic and dopaminergic drugs impaired PPI by their effects over subcortical units activity. The results show that subcortical units constitute a central hub for PPI modulation. The presented computational model offers a valuable tool to investigate the neurobiology associated with disorder-related impairments in PPI.
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Reaction time is accelerated if a loud (startling) sound accompanies the cue-the "StartReact" effect. Animal studies revealed a reticulospinal substrate for the startle reflex; StartReact may similarly involve the reticulospinal tract, but this is currently uncertain. Here we trained two female macaque monkeys to perform elbow flexion/extension movements following a visual cue. The cue was sometimes accompanied by a loud sound, generating a StartReact effect in electromyogram response latency, as seen in humans. Extracellular recordings were made from antidromically identified corticospinal neurons in primary motor cortex (M1), from the reticular formation (RF), and from the spinal cord (SC; C5-C8 segments). After loud sound, task-related activity was suppressed in M1 (latency, 70-200 ms after cue), but was initially enhanced (70-80 ms) and then suppressed (140-210 ms) in RF. SC activity was unchanged. In a computational model, we simulated a motoneuron pool receiving input from different proportions of the average M1 and RF activity recorded experimentally. Motoneuron firing generated simulated electromyogram, allowing reaction time measurements. Only if ≥60% of motoneuron drive came from RF (≤40% from M1) did loud sound shorten reaction time. The extent of shortening increased as more drive came from RF. If RF provided <60% of drive, loud sound lengthened the reaction time-the opposite of experimental findings. The majority of the drive for voluntary movements is thus likely to originate from the brainstem, not the cortex; changes in the magnitude of the StartReact effect can measure a shift in the relative importance of descending systems.SIGNIFICANCE STATEMENT Our results reveal that a loud sound has opposite effects on neural spiking in corticospinal cells from primary motor cortex, and in the reticular formation. We show that this fortuitously allows changes in reaction time produced by a loud sound to be used to assess the relative importance of reticulospinal versus corticospinal control of movement, validating previous noninvasive measurements in humans. Our findings suggest that the majority of the descending drive to motoneurons producing voluntary movement in primates comes from the reticulospinal tract, not the corticospinal tract.
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Neurônios Motores , Tratos Piramidais , Humanos , Animais , Feminino , Tratos Piramidais/fisiologia , Eletromiografia , Tempo de Reação/fisiologia , Movimento , Macaca , Reflexo de Sobressalto/fisiologiaRESUMO
The ability to detect threatening stimuli and initiate an escape response is essential for survival and under stringent evolutionary pressure. In diverse fish species, acoustic stimuli activate Mauthner neurons, which initiate a C-start escape response. This reflexive behavior is highly conserved across aquatic species and provides a model for investigating the neural mechanism underlying the evolution of escape behavior. Here, we characterize evolved differences in the C-start response between populations of the Mexican cavefish, Astyanax mexicanus. Cave populations of A. mexicanus inhabit an environment devoid of light and macroscopic predators, resulting in evolved differences in various morphological and behavioral traits. We find that the C-start is present in river-dwelling surface fish and multiple populations of cavefish, but that response kinematics and probability differ between populations. The Pachón population of cavefish exhibits an increased response probability, a slower response latency and speed, and reduction of the maximum bend angle, revealing evolved differences between surface and cave populations. Analysis of the responses of two other independently evolved populations of cavefish, revealed the repeated evolution of reduced angular speed. Investigation of surface-cave hybrids reveals a correlation between angular speed and peak angle, suggesting these two kinematic characteristics are related at the genetic or functional levels. Together, these findings provide support for the use of A. mexicanus as a model to investigate the evolution of escape behavior.
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Characidae/fisiologia , Reflexo de Sobressalto , Estimulação Acústica , Animais , Evolução Biológica , Fenômenos Biomecânicos , Cavernas , Escuridão , Reação de Fuga/fisiologia , Modelos Animais , Reflexo de Sobressalto/fisiologiaRESUMO
Behavioral arrest is an essential feature of an animal's survival. Acoustic startle reflex (ASR) is an involuntary whole-body contraction of the skeletal musculature to an unexpected auditory stimulus. This strong reaction can be decreased by prepulse inhibition (PPI) phenomenon; which, for example, is important in reducing distraction during the processing of sensory input. Several brainstem regions are involved in the PPI and startle reflex, but a previous study from our laboratory showed that the main input structure of Basal Ganglia (BG) - the striatum - modulates PPI. The pallidum and nigra are connected with striatum and these brainstem structures. Here, we investigated the role of these striatum outputs in the brain regions on startle amplitude, PPI regulation, and exploratory behavior in Wistar rats. The temporary bilateral inhibition of the globus pallidus (GP) by muscimol lead to motor impairment, without disturbing startle amplitude or PPI. Similarly, inhibition of the entopeduncular nucleus (EPN) specifically disrupted the exploratory behavior. On the other hand, the substantia nigra reticulata (SNr) inhibition interfered in all measured behaviors: decreased the PPI percentage, increased ASR and impaired the locomotor activity. The nigra is a key BG output structure which projects to the thalamus and brainstem. These findings extend our previous study showing that the striatum neurons expressing D1 receptors involvement in PPI occurs via the direct pathway to SNr, but not to the pallidum which more likely occurs by its connection with the caudal pontine nucleus, superior colliculus and/or pedunculopontine nucleus pivotal structures for startle reflex modulation.
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Agonistas de Receptores de GABA-A/farmacologia , Globo Pálido/fisiologia , Locomoção/fisiologia , Muscimol/farmacologia , Parte Reticular da Substância Negra/fisiologia , Inibição Pré-Pulso/fisiologia , Reflexo de Sobressalto/fisiologia , Animais , Globo Pálido/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Microinjeções , Parte Reticular da Substância Negra/efeitos dos fármacos , Inibição Pré-Pulso/efeitos dos fármacos , Ratos , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacosRESUMO
Prepulse inhibition (PPI) is a sensorimotor gating mechanism that reduces interfering influences to the neural processing of incoming stimuli, and is associated with several neurodevelopmental disorders. To date, research on PPI and neurodevelopmental disorders has primarily been in cross-sectional, clinical settings. In this prospective, epidemiologic study, we used a data-driven prediction model to identify socio-demographic predictors of PPI in children and adolescents from Mexico City to inform future etiologic studies evaluating PPI. We conducted variable selection and validation using a modified version of the multiple imputation random lasso (MIRL) variable selection algorithm. MIRL identified six predictors of PPI at a stimulus onset asynchrony of 120 ms or 240 ms. Of those six predictors, maternal education, birthweight, and total breastfeeding months were highlighted as previously unstudied variables associated with enhanced PPI. Our findings highlight the potential value of PPI as an adjunct screening tool for identifying children at risk for neurodevelopmental disorders and underscore the relevance for validation research on this topic.
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Transtornos do Neurodesenvolvimento/epidemiologia , Inibição Pré-Pulso , Adolescente , Algoritmos , Criança , Demografia , Feminino , Humanos , Masculino , México/epidemiologia , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Filtro SensorialRESUMO
BACKGROUND AND AIMS: We sought a robust behavioural test that evoked increased anxiety-like behaviour during the late dioestrus phase of the oestrous cycle (similar to the premenstrual period in women) and tested whether this could be prevented by acute low-dose fluoxetine (FLX). METHODS: Female Wistar rats in different stages of their cycle were exposed to four different tests of anxiety-like behaviour. RESULTS: No oestrous cycle differences were detected in fear potentiated startle or conditioned freezing to an aversive context. In a light switch-off test where rats move from one compartment of a shuttle-box to the other to turn off an aversive light, females displayed enhanced responding in late dioestrus. During isolation restraint stress females in late dioestrus emitted three times more 22 kHz ultrasound vocalisations (USV) than at other cycle stages. Using the USV test, short-term administration of low-dose FLX (1.75 mg kg-1, i.p.) designed to blunt the sharp fall in brain allopregnanolone concentration during late dioestrus but without affecting 5-HT systems, prevented the increase in isolation stress-evoked USVs. CONCLUSIONS: The light switch-off and isolation restraint-induced USV tests evoke unconditioned adverse emotional responses that are ethologically relevant and sensitive to oestrous cycle stage. The USV test fulfils many criteria required of a model for premenstrual syndrome in women. Using the USV test, short-term administration of FLX to increase brain allopregnanolone concentration without affecting 5-HT systems prevented the increased USV responding in late dioestrus. Short-term low-dose FLX treatment may have potential to alleviate development of adverse premenstrual symptoms in women.
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Ansiedade/metabolismo , Ansiedade/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Ciclo Estral/metabolismo , Fluoxetina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Modelos Animais de Doenças , Medo/efeitos dos fármacos , Feminino , Fluoxetina/administração & dosagem , Ratos , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Vocalização Animal/efeitos dos fármacosRESUMO
Schizophrenia is a severe psychiatric disorder that involves positive, negative and cognitive symptoms. Prepulse inhibition of startle reflex (PPI) is a paradigm that assesses the sensorimotor gating functioning and is impaired in schizophrenia patients as well as in animal models of this disorder. Recent data point to the participation of the endocannabinoid system in the pathophysiology and pharmacotherapy of schizophrenia. Here, we focus on the effects of cannabinoid drugs on the PPI deficit of animal models of schizophrenia, with greater focus on the SHR (Spontaneously Hypertensive Rats) strain, and on the future prospects resulting from these findings.
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INTRODUCTION: Dimensional models of psychopathology describe mental illness in terms of natural variance along certain phenotypic dimensions that are continuous with normal. Vulnerability to psychopathology might arise when certain adaptive psychophysiological processes, conserved between humans and non-human animals, function outside of their "normal" range. Therefore, an in-depth understanding of the neurobiology and neurochemistry underlying these processes could identify possible novel drug targets. AREAS COVERED: Psychophysiological processes that might be related to anxiety disorders and depression are proposed and discussed. Those processes relevant to depressive disorders include: hedonic responsiveness, biases in the processing of stimuli, and sleep architecture. Those relevant to anxiety disorders include: startle reactivity, CO2 sensitivity, and fear generalization. Rodent behavioral tests for assessing the function of these processes and investigating their neurobiology are described. A psychophysiological process strategy for translational research is proposed, which focusses on understanding the neurobiology and neurochemistry underlying key psychophysiological processes that, when their activity deviates from normal, are associated with neuropsychiatric symptoms. This strategy emphasizes the use of analogous tests and measures in both preclinical and clinical studies, while de-emphasizing the use of preclinical animal models that attempt to replicate features of the neuropsychiatric disorder through experimental manipulations. EXPERT OPINION: Investigating the neurobiology of key psychophysiological processes in rodents should enhance our understanding of the pathophysiology of neuropsychiatric disorders. New drug development could be directed toward developing pharmacological strategies that would normalize the function of these psychophysiological processes.
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Comportamento Animal/efeitos dos fármacos , Descoberta de Drogas/métodos , Transtornos Mentais/tratamento farmacológico , Animais , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/fisiopatologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Transtornos Mentais/fisiopatologia , RoedoresRESUMO
Neurophysiological measurements of the response to pre-pulse and startle stimuli have been suggested to represent an important endophenotype for both substance dependence and other select psychiatric disorders. We have previously shown, in young adult Mexican Americans (MA), that presentation of a short delay acoustic pre-pulse, prior to the startle stimuli can elicit a late negative component at about 400 msec (N4S), in the event-related potential (ERP), recorded from frontal cortical areas. In the present study, we investigated whether genetic factors associated with this endophenotype could be identified. The study included 420 (age 18-30 years) MA men (n = 170), and women (n = 250). DNA was genotyped using an Affymetrix Axiom Exome1A chip. An association analysis revealed that the CCKAR and CCKBR (cholecystokinin A and B receptor) genes each had a nearby variant that showed suggestive significance with the amplitude of the N4S component to pre-pulse stimuli. The neurotransmitter cholecystokinin (CCK), along with its receptors, CCKAR and CCKBR, have been previously associated with psychiatric disorders, suggesting that variants near these genes may play a role in the pre-pulse/startle response in this cohort.
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Americanos Mexicanos/genética , Receptor de Colecistocinina A/genética , Receptor de Colecistocinina B/genética , Reflexo de Sobressalto/genética , Adolescente , Adulto , Estudos de Coortes , Fenômenos Eletrofisiológicos , Feminino , Humanos , Masculino , Medição de Risco , Adulto JovemRESUMO
Environmental conditions during early development in ectothermic vertebrates can lead to variation in vertebral number among individuals of the same species. It is often seen that individuals of a species raised at cooler temperatures have more vertebrae than individuals raised at warmer temperatures, although the functional consequences of this variation in vertebral number on swimming performance are relatively unclear. To investigate this relationship, we tested how vertebral number in axolotls (Ambystoma mexicanum) affected performance of aquatic escape responses (C-starts). Axolotls were reared at four temperatures (12-24°C) encompassing their natural thermal range and then transitioned to a mean temperature (18°C) three months before C-starts were recorded. Our results showed variation in vertebral number, but that variation was not significantly affected by developmental temperature. C-start performance among axolotls was significantly correlated with caudal vertebral number, and individuals with more caudal vertebrae were able to achieve greater curvature more quickly during their responses than individuals with fewer vertebrae. However, our results show that these individuals did not achieve greater displacements or velocities, and that developmental temperature did not have any effect on C-start performance. We highlight that the most important aspects of escape swim performance (i.e., how far individuals get from a threat and how quickly they move the most important parts of the body away from that threat) are consistent across individuals regardless of developmental temperature and morphological variation.
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Ambystoma mexicanum/anatomia & histologia , Reação de Fuga/fisiologia , Coluna Vertebral/anatomia & histologia , Natação/fisiologia , Animais , TemperaturaRESUMO
El objetivo de esta investigación fue comprobar el fenómeno de priming motivacional, observado a través de la modulación del reflejo de sobresalto en población colombiana. Participaron 73 estudiantes universitarios (38 hombres y 35 mujeres), los cuales fueron expuestos a 21 imágenes del Sistema Internacional de Imágenes Afectivas y a un estímulo sonoro de sobresalto de 105 dB. Se midió la electromiografía del músculo orbicular del ojo para evaluar la magnitud del reflejo de sobresalto. A través de un ANOVA de medidas repetidas, se encontró que la valencia de las imágenes modula la magnitud del reflejo de sobresalto (p < 0.0001, η² = 0.41) independientemente del sexo de los participantes. Se concluye que el fenómeno de priming motivacional también se presenta en esta población y que la metodología de la modulación del reflejo de sobresalto puede ser utilizada de forma confiable en ella.
The objective of this research was to test the phenomenon of motivational priming observed through the modulation of the startle reflex in Colombian population, involved 73 university students (38 men and 35 women) who were exposed to 21 pictures of the International Affective Pictures System and a sound startle stimulus of 105 dB. Electromyography of the orbicularis oculi of the eye was measured to assess the magnitude of the startle reflex. Through repeated measures ANOVA we found that the pictures valence modulates the magnitude of the startle reflex (p < 0.0001, η² = 0.41) and that modulation does not depend on the sex of the participants. It is concluded that motivational priming phenomenon occurs also in this population and this methodology can be used reliably in this population.
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Emoções , MotivaçãoRESUMO
The forced swim test (FST) is widely used to evaluate the antidepressant-like activity of compounds and is sensitive to stimuli that cause depression-like behaviors in rodents. The immobility behavior observed during the test has been considered to represent behavioral despair. In addition, some studies suggest that the FST impairs rats' performance on cognitive tests, but these findings have rarely been explored. Thus, we investigated the effects of the FST on behavioral tests related to neuropsychiatric diseases that involve different cognitive components: novel object recognition (NOR), the object location test (OLT) and prepulse inhibition (PPI). Brain-derived neurotrophic factor (BDNF) levels in the frontal cortex and hippocampus were evaluated. The rats were forced to swim twice (15-min session followed by a 5-min session 24h later) and underwent cognitive tests 24h after the last swimming exposure. The FST impaired the rats' performance on the OLT and reduced the PPI and acoustic startle responses, whereas the NOR was not affected. The cognitive impairments were not correlated with an immobility behavior profile, but a significant negative correlation between the frontal BDNF levels and immobility behavior was identified. These findings suggest a protective role of BDNF against behavioral despair and demonstrate a deleterious effect of the FST on spatial memory and pre-attentive processes, which point to the FST as a tool to induce cognitive impairments analogous to those observed in depression and in other neuropsychiatric disorders.
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Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/etiologia , Reação de Congelamento Cataléptica/fisiologia , Lobo Frontal/metabolismo , Estresse Fisiológico , Natação/psicologia , Estimulação Acústica , Acústica , Análise de Variância , Animais , Comportamento Exploratório/fisiologia , Masculino , Inibição Pré-Pulso/fisiologia , Ratos , Ratos Wistar , Reconhecimento Psicológico , Estatística como Assunto , Fatores de TempoRESUMO
Chlorpyrifos (CPF) is an organophosphorus cholinesterase inhibitor widely used as an insecticide. Neuro and genotoxicity of this agent were evaluated following daily subcutaneous injections at 0.1, 1 and 10mg/kg or its vehicle to laboratory rats during one week, at the end of which somatosensory evoked potentials (SEP) and power spectrum of the electroencephalogram (EEGp) were recorded under urethane anesthesia. In another group of conscious animals, auditory startle reflex (ASR) was evaluated followed, after euthanasia, with measurements of plasma B-esterases, and genotoxicity with the alkaline comet assay (ACA) at the same CPF doses. The results indicated a CPF dose related inhibition of B-esterases. Enhanced inhibition of the ASR by a subthreshold pre-pulse was observed at all doses and ACA showed a significant higher DNA damage than vehicle controls in animals exposed to 10mg/kg CPF. A trend to higher frequencies of EEGp and an increase in amplitude of the first negative wave of the SEP were found at all doses. The first positive wave of the SEP decreased at the CPF dose of 10mg/kg. In summary, a shift to higher EEG frequencies and alterations of somatosensory and auditory input to the central nervous system were sensitive manifestations of CPF toxicity, associated with depression of B-esterases. The changes in electrical activity of the cerebral cortex and DNA damage observed at doses that do not elicit overt toxicity may be useful in the detection of CPF exposure before clinical signs appear.
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Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Clorpirifos/toxicidade , Inibidores da Colinesterase/toxicidade , Dano ao DNA/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Acetilcolinesterase/sangue , Estimulação Acústica , Animais , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Butirilcolinesterase/sangue , Carboxilesterase/sangue , Relação Dose-Resposta a Droga , Eletroencefalografia , Esterases/sangue , Esterases/efeitos dos fármacos , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Masculino , Testes de Mutagenicidade , Inibição Pré-Pulso/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
The emotional response to socially affective stimuli is an important variable to understand aggression. Research is lacking on the psychophysiological basis of verbal aggressiveness that would allow the identification of these emotional responses. The aim of the present study was to investigate modulation of the startle response in verbal aggressors during the presentation of visual stimuli with different affective social content. Acoustic startle probes were administered to 29 verbal aggressors and 28 non-verbal aggressors while viewing slides from the International Affective Picture System, which contains sexual, filial, neutral, unpleasant, and suffering of others pictures. Verbal aggressors showed a low startle response to sexual pictures compared with non-verbal aggressors and a potentiated startle response to neutral pictures compared with unpleasant, filial, and suffering of others pictures. These differences were observed among women. Based on previous studies, the present results may be explained by high testosterone levels, low cortisol levels, and moral disengagement exhibited by verbally aggressive women...
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Humanos , Masculino , Feminino , Adulto , Agressão , Emoções , Estimulação Luminosa , Reflexo de Sobressalto , PsicofisiologiaRESUMO
The emotional response to socially affective stimuli is an important variable to understand aggression. Research is lacking on the psychophysiological basis of verbal aggressiveness that would allow the identification of these emotional responses. The aim of the present study was to investigate modulation of the startle response in verbal aggressors during the presentation of visual stimuli with different affective social content. Acoustic startle probes were administered to 29 verbal aggressors and 28 non-verbal aggressors while viewing slides from the International Affective Picture System, which contains sexual, filial, neutral, unpleasant, and suffering of others pictures. Verbal aggressors showed a low startle response to sexual pictures compared with non-verbal aggressors and a potentiated startle response to neutral pictures compared with unpleasant, filial, and suffering of others pictures. These differences were observed among women. Based on previous studies, the present results may be explained by high testosterone levels, low cortisol levels, and moral disengagement exhibited by verbally aggressive women.(AU)
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Humanos , Masculino , Feminino , Adulto , Reflexo de Sobressalto , Agressão , Estimulação Luminosa , Emoções , PsicofisiologiaRESUMO
Interactions between the prelimbic cortex and the basolateral amygdala underlie fear memory processing, mostly through acquiring and consolidating the learning of a conditioned fear. More recently, studies highlighted the role of the dorsal periaqueductal gray (DPAG) in the modulation of learning fear responses. In addition, extensive data in the literature have signaled the importance of serotonin (5-HT) on fear and anxiety. In the present study, the role of 5-HT neurotransmission of the prelimbic cortex, basolateral amygdala or the DPAG on the unconditioned and conditioned fear responses in rats previously selected as low- (LA) or high-anxious (HA) were assessed through local infusions of 5-HT itself (10nmol/0.2µl) or the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT - 0.3µg/0.2µl). Behavioral analysis was conducted using the fear-potentiated startle (FPS) procedure. Dependent variables recorded were the latency and amplitude of the unconditioned startle response and FPS. Our findings suggest that, on the prelimbic cortex, 5-HT modulates the expression of conditioned fear response in HA rats and this modulation is dependent on 5-HT1A receptors. This is not true, however, for the basolateral amygdala or the DPAG. In these regions LA but not HA rats were susceptible to the anxiolytic-like effect of 5-HT1A receptor activation. It is thought that the expression of conditioned fear in HA subjects may be dependent on other 5-HT receptors, as the 5-HT1B subtype, and/or changes in other systems such as the GABA and glutamate neurotransmitters. These results increase our understanding of the rostrocaudal influence of 5-HT on the unconditioned and conditioned fear responses in LA and HA subjects and, to some extent, are in disagreement with the theoretical current that emphasizes the role of 5-HT on anxiety, mainly at the subcortical and midbrain levels.
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Ansiedade/fisiopatologia , Encéfalo/fisiopatologia , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Receptor 5-HT1A de Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Ansiedade/tratamento farmacológico , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Encéfalo/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Individualidade , Masculino , Testes Neuropsicológicos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/fisiopatologia , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
Chemical and electrical stimulation of the inferior colliculus (IC) causes defensive behavior. Electrical stimulation of the IC at the escape threshold enhances dopamine (DA) release in the prefrontal cortex. Intra-ventral tegmental area injections of quinpirole at doses that act presynaptically reduce the release of DA in the terminal fields of the mesolimbic system and clearly reduce conditioned fear in several animal models of anxiety. However, little is known about the involvement of DA in the mediation of unconditioned fear, such as the reactivity to acute stressors. The present study investigated the neural substrates mediated by DA transmission associated with emotional changes triggered by the activation or inhibition of D2 receptors during conditioned and unconditioned fear. We examined the effects of systemic or local injections of the DA-receptor antagonist and agonist haloperidol and quinpirole, respectively, into the IC in rats subjected to fear-potentiated startle, a Pavlovian paradigm that uses loud sounds as the unconditioned stimulus and light previously paired with footshock as the conditioned stimulus. We also assessed auditory-evoked potentials (AEPs) recorded from electrodes implanted in the IC. Intraperitoneal haloperidol administration dose-dependently enhanced AEPs induced by loud tones and inhibited fear-potentiated startle. Intra-IC injections of quinpirole left AEPs unchanged, suggesting that an optimal level of postsynaptic D2 receptors in the IC may regulate the transmission of aversive information through the midbrain tectum. These findings provide evidence of opposing DA-mediated mechanisms in fear/anxiety processes that depend on the area under study. The activity of the neural substrates of conditioned fear was attenuated by haloperidol, whereas midbrain neural substrates of unconditioned fear were enhanced. Thus, DA appears to regulate unconditioned fear at the midbrain level, likely by reducing the sensory gating of aversive events and reducing conditioned fear by acting at more rostral levels of the brain.
Assuntos
Condicionamento Clássico/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Medo/efeitos dos fármacos , Haloperidol/farmacologia , Colículos Inferiores/efeitos dos fármacos , Animais , Catalepsia/induzido quimicamente , Condicionamento Clássico/fisiologia , Agonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Potenciais Evocados Auditivos/efeitos dos fármacos , Potenciais Evocados Auditivos/fisiologia , Medo/fisiologia , Colículos Inferiores/fisiologia , Masculino , Quimpirol/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/fisiologiaRESUMO
Recently, our group described the ether-à-go-go1(Eag1) voltage-gated potassium (K(+)) channel (Kv10.1) expression in the dopaminergic cells indicating that these channels are part of the diversified group of ion channels related to dopaminergic neurons function. The increase of dopamine neurotransmission induces a reduction in the prepulse inhibition (PPI) of the acoustic startle reflex in rodents, which is a reliable index of sensorimotor gating deficits. The PPI response has been reported to be abnormally reduced in schizophrenia patients. The role of Eag1 K(+) channels in the PPI reaction had not been revealed until now, albeit the singular distribution of Eag1 in the dentate gyrus of the hippocampus and the hippocampal regulation of the startle reflex and PPI. The aim of this work was to investigate if Eag1 blockade on hippocampus modifies the PPI-disruptive effects of apomorphine in Wistar rats. Bilateral injection of anti-Eag1 single-chain antibody into the dentate gyrus of hippocampus did not modify apomorphine-disruptive effects in the PPI response. However, Eag1 antibody completely restored the startle amplitude decrease revealed after dentate gyrus surgery. These potentially biological important phenomenon merits further investigation regarding the role of Eag1 K(+) channels, mainly, on startle reflex modulation, since the physiological role of these channels remain obscure.
Assuntos
Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/fisiologia , Hipocampo/fisiologia , Inibição Neural/fisiologia , Filtro Sensorial/fisiologia , Estimulação Acústica/métodos , Animais , Anticorpos Anti-Idiotípicos/farmacologia , Apomorfina/farmacologia , Agonistas de Dopamina/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Inibição Neural/efeitos dos fármacos , Ratos , Ratos Wistar , Filtro Sensorial/efeitos dos fármacosRESUMO
Startle epilepsy is a syndrome of reflex epilepsy in which the seizures are precipitated by a sudden and surprising, usually auditory, stimulus. We describe herein a girl who had been suffering with startle-induced seizures since 2 years of age. She had focal, tonic and tonic-clonic seizures, refractory to antiepileptic treatment. Daily tonic seizures led to very frequent falls and morbidity. Neurologically, she had no deficit. Interictal EEG showed slow waves and epileptiform discharges in central and fronto-central regions. Video-polygraphic recordings of seizures, triggered by stimuli, showed generalised symmetric tonic posturing with ictal EEG, characterised by an abrupt and diffuse electrodecremental pattern of fast activity, followed by alpha-theta rhythm superimposed by epileptic discharges predominantly over the vertex and anterior regions. Magnetic resonance imaging showed no abnormalities. Corpus callosotomy was performed when the patient was 17. Since surgery, the patient (one year follow-up) has remained seizure-free. Corpus callosotomy may be considered in patients with startle epilepsy and tonic seizures, in the absence of focal lesions amenable to surgery. [Published with video sequences].