RESUMO
The neural mechanisms underlying paternal care in biparental mammals are not well understood. The California mouse (Peromyscus californicus) is a biparental rodent in which virtually all fathers are attracted to pups, while virgin males vary widely in their behavior toward unrelated infants, ranging from attacking to avoiding to huddling and grooming pups. We previously showed that pharmacologically inhibiting the synthesis of the neurotransmitter norepinephrine (NE) with the dopamine ß-hydroxylase inhibitor nepicastat reduced the propensity of virgin male and female California mice to interact with pups. The current study tested the hypothesis that nepicastat would reduce pup-induced c-Fos immunoreactivity, a cellular marker of neural activity, in the medial preoptic area (MPOA), medial amygdala (MeA), basolateral amygdala (BLA), and bed nucleus of the stria terminalis (BNST), brain regions implicated in the control of parental behavior and/or anxiety. Virgin males were injected with nepicastat (75â¯mg/kg, i.p.) or vehicle 2â¯hours prior to exposure to either an unrelated pup or novel object for 60â¯minutes (n = 4-6 mice per group). Immediately following the 60-minute stimulus exposure, mice were euthanized and their brains were collected for c-Fos immunohistochemistry. Nepicastat reduced c-Fos expression in the MeA and MPOA of pup-exposed virgin males compared to vehicle-injected controls. In contrast, nepicastat did not alter c-Fos expression in any of the above brain regions following exposure to a novel object. Overall, these results suggest that the noradrenergic system might influence MeA and MPOA function to promote behavioral interactions with pups in virgin males.
Assuntos
Dopamina beta-Hidroxilase , Comportamento Paterno , Peromyscus , Área Pré-Óptica , Núcleos Septais , Animais , Masculino , Dopamina beta-Hidroxilase/metabolismo , Dopamina beta-Hidroxilase/antagonistas & inibidores , Comportamento Paterno/fisiologia , Comportamento Paterno/efeitos dos fármacos , Núcleos Septais/efeitos dos fármacos , Núcleos Septais/metabolismo , Área Pré-Óptica/metabolismo , Área Pré-Óptica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Feminino , Inibidores Enzimáticos/farmacologia , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Corticomedial/efeitos dos fármacos , Complexo Nuclear Corticomedial/metabolismo , Norepinefrina/metabolismo , Imidazóis , TionasRESUMO
Psychosocial stress negatively impacts reproductive function by inhibiting pulsatile luteinizing hormone (LH) secretion. The posterodorsal medial amygdala (MePD) is responsible in part for processing stress and modulating the reproductive axis. Activation of the neurokinin 3 receptor (NK3R) suppresses the gonadotropin-releasing hormone (GnRH) pulse generator, under hypoestrogenic conditions, and NK3R activity in the amygdala has been documented to play a role in stress and anxiety. We investigate whether NK3R activation in the MePD is involved in mediating the inhibitory effect of psychosocial stress on LH pulsatility in ovariectomised female mice. First, we administered senktide, an NK3R agonist, into the MePD and monitored the effect on pulsatile LH secretion. We then delivered SB222200, a selective NK3R antagonist, intra-MePD in the presence of predator odour, 2,4,5-trimethylthiazole (TMT) and examined the effect on LH pulses. Senktide administration into the MePD dose-dependently suppresses pulsatile LH secretion. Moreover, NK3R signalling in the MePD mediates TMT-induced suppression of the GnRH pulse generator, which we verified using a mathematical model. The model verifies our experimental findings: (i) predator odour exposure inhibits LH pulses, (ii) activation of NK3R in the MePD inhibits LH pulses and (iii) NK3R antagonism in the MePD blocks stressor-induced inhibition of LH pulse frequency in the absence of ovarian steroids. These results demonstrate for the first time that NK3R neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator.
Assuntos
Hormônio Luteinizante , Quinolinas , Receptores da Neurocinina-3 , Transdução de Sinais , Estresse Psicológico , Substância P/análogos & derivados , Animais , Feminino , Receptores da Neurocinina-3/metabolismo , Receptores da Neurocinina-3/antagonistas & inibidores , Receptores da Neurocinina-3/agonistas , Hormônio Luteinizante/metabolismo , Estresse Psicológico/metabolismo , Camundongos , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos dos fármacos , Complexo Nuclear Corticomedial/metabolismo , Complexo Nuclear Corticomedial/efeitos dos fármacos , Complexo Nuclear Corticomedial/fisiologia , Fragmentos de Peptídeos/farmacologia , Hormônio Liberador de Gonadotropina/metabolismo , Camundongos Endogâmicos C57BL , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/efeitos dos fármacosRESUMO
We investigated the role of angiotensin II type 1 (AT1 receptor) and type 2 (AT2 receptor) and MAS receptors present in the medial amygdaloid nucleus (MeA) in behavioral changes in the forced swimming test (FST) evoked by acute restraint stress in male rats. For this, rats received bilateral microinjection of either the selective AT1 receptor antagonist losartan, the selective AT2 receptor antagonist PD123319, the selective MAS receptor antagonist A-779, or vehicle 10 min before a 60 min restraint session. Then, behavior in the FST was evaluated immediately after the restraint (15 min session) and 24 h later (5 min session). The behavior in the FST of a non-stressed group was also evaluated. We observed that acute restraint stress decreased immobility during both sessions of the FST in animals treated with vehicle in the MeA. The decreased immobility during the first session was inhibited by intra-MeA administration of PD123319, whereas the effect during the second session was not identified in animals treated with A-779 into the MeA. Microinjection of PD123319 into the MeA also affected the pattern of active behaviors (i.e., swimming and climbing) during the second session of the FST. Taken together, these results indicate an involvement of angiotensinergic neurotransmissions within the MeA in behavioral changes in the FST evoked by stress.
Assuntos
Angiotensinas/metabolismo , Comportamento Animal , Complexo Nuclear Corticomedial/metabolismo , Atividade Motora , Sistema Renina-Angiotensina , Estresse Psicológico/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Complexo Nuclear Corticomedial/efeitos dos fármacos , Complexo Nuclear Corticomedial/fisiopatologia , Modelos Animais de Doenças , Masculino , Atividade Motora/efeitos dos fármacos , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Ratos Wistar , Tempo de Reação , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Restrição Física , Transdução de Sinais , Estresse Psicológico/etiologia , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Natação , Fatores de TempoRESUMO
The medial amygdala (MeA) is a sexually dimorphic brain region that integrates sensory information and hormonal signaling, and is involved in the regulation of social behaviors. Lesion studies have shown a role for the MeA in copulation, most prominently in the promotion of ejaculation. The role of the MeA in sexual motivation, but also in temporal patterning of copulation, has not been extensively studied in rats. Here, we investigated the effect of chemogenetic inhibition and stimulation of the MeA on sexual incentive motivation and copulation in sexually experienced male rats. AAV5-CaMKIIa viral vectors coding for Gi, Gq, or no DREADDs (sham) were bilaterally infused into the MeA. Rats were assessed in the sexual incentive motivation test and copulation test upon systemic clozapine N-oxide (CNO) or vehicle administration. We report that MeA stimulation and inhibition did not affect sexual incentive motivation. Moreover, both stimulation and inhibition of the MeA decreased the number of ejaculations in a 30 min copulation test and increased ejaculation latency and the number of mounts and intromissions preceding ejaculation, while leaving the temporal pattern of copulation intact. These results indicate that the MeA may be involved in the processing of sensory feedback required to reach ejaculation threshold. The convergence of the behavioral effects of stimulating as well as inhibiting the MeA may reflect opposing behavioral control of specific neuronal populations within the MeA.
Assuntos
Copulação/fisiologia , Complexo Nuclear Corticomedial/fisiologia , Ejaculação/fisiologia , Retroalimentação Sensorial/fisiologia , Motivação/fisiologia , Comportamento Sexual Animal/fisiologia , Animais , Complexo Nuclear Corticomedial/efeitos dos fármacos , Vetores Genéticos , Masculino , Ratos , Ratos WistarRESUMO
The brain renin-angiotensin system (RAS) has been implicated in anxiety and depression disorders, but the specific brain sites involved are poorly understood. The medial amygdaloid nucleus (MeA) is involved in expression of behavioral responses. However, despite evidence of the presence of all angiotensinergic receptors in this amygdaloid nucleus, regulation of anxiety- and depressive-like behaviors by angiotensinergic neurotransmissions within the MeA has never been reported. Thus, the present study aimed to investigate the role angiotensin II (AT1 and AT2 receptors) and angiotensin-(1-7) (Mas receptor) receptors present within the MeA in behavioral responses in the elevated plus-maze (EPM) and forced swimming test (FST). For this, male Wistar rats had cannula-guide bilaterally implanted into the MeA, and independent sets of animals received bilateral microinjections of either the selective AT1 receptor antagonist losartan, the selective AT2 receptor antagonist PD123319, the selective Mas receptor antagonist A-779 or vehicle into the MeA before the EPM and FST. Treatment of the MeA with either PD123319 or A-779 decreased the EPM open arms exploration, while losartan did not affect behavioral responses in this apparatus. However, intra-MeA microinjection of losartan decreased immobility in the FST. Administration of either PD123319 or A-779 into the MeA did not affect the immobility during the FST, but changed the pattern of the active behaviors swimming and climbing. Altogether, these results indicate the presence of different angiotensinergic mechanisms within the MeA controlling behavioral responses in the FST and EPM.
Assuntos
Angiotensina II , Angiotensina I , Antagonistas de Receptores de Angiotensina/farmacologia , Comportamento Animal/efeitos dos fármacos , Complexo Nuclear Corticomedial/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Fragmentos de Peptídeos , Angiotensina II/análogos & derivados , Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina/administração & dosagem , Animais , Imidazóis/farmacologia , Losartan/farmacologia , Masculino , Fragmentos de Peptídeos/farmacologia , Piridinas/farmacologia , Ratos , Ratos Wistar , NataçãoRESUMO
Phytoestrogens comprise biologically active constituents of human and animal diet that can impact on systemic and local estrogen functions in the brain. Here we report on the importance of dietary phytoestrogens for maintaining activity in a brain circuit controlling aggressive and social behavior of male mice. After six weeks of low-phytoestrogen chronic diet (diadzein plus genistein <20 µg/g) a reduction of intermale aggression and altered territorial marking behavior could be observed, compared to littermates on a standard soy-bean based diet (300 µg/g). Further, mice on low-phyto diet displayed a decrease in sociability and a reduced preference for social odors, indicating a general disturbance of social behavior. Underlying circuits were investigated by analysing the induction of the activity marker c-Fos upon social encounter. Low-phyto diet led to a markedly reduced c-Fos induction in the medial as well as the cortical amygdala, the lateral septum, medial preoptic area and bed nucleus of the stria terminalis. No difference between groups was observed in the olfactory bulb. Together our data suggest that dietary phytoestrogens critically modulate social behavior circuits in the male mouse brain.
Assuntos
Agressão/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Fitoestrógenos/farmacologia , Comportamento Social , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Complexo Nuclear Corticomedial/citologia , Complexo Nuclear Corticomedial/efeitos dos fármacos , Complexo Nuclear Corticomedial/metabolismo , Dieta , Isoflavonas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/fisiologia , Área Pré-Óptica/citologia , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , TerritorialidadeRESUMO
The medial amygdaloid nucleus (MeA) is a limbic structure that has been demonstrated to be part of the central circuitry regulating baroreflex function. However, the local neurochemical mechanisms involved in baroreflex control by this forebrain structure is poorly understood. Thus, in the present study, we investigated the specific role of AT1, AT2, and MAS angiotensinergic receptors within the MeA in baroreflex responses in unanesthetized rats. For this, the baroreflex function was assessed using both the pharmacological approach via intravenous infusion of vasoactive agents and the sequence analysis technique. Using the pharmacological approach, we observed that bilateral microinjection of the selective AT2 receptor antagonist PD123319 into the MeA increased the tachycardia evoked by blood pressure decrease, but without affecting the reflex bradycardia caused by blood pressure increase. Besides, bilateral microinjection of the selective MAS receptor antagonist A-779 decreased both tachycardic and bradycardic responses of the baroreflex. The sequence analysis technique indicated that PD123319 into the MeA increased baroreflex effectiveness index while A-779 had an opposite effect. Treatment of the MeA with the selective AT1 receptor antagonist losartan did not affect baroreflex function assessed by either the pharmacological approach or sequence analysis technique. Overall, these findings provide evidence that MAS receptor within the MeA plays a facilitatory role in baroreflex function, whereas local AT2 receptor inhibits cardiac baroreflex responses. Results also indicate that AT1 receptor within the MeA is not involved in the control of baroreflex function.
Assuntos
Barorreflexo/fisiologia , Complexo Nuclear Corticomedial/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Complexo Nuclear Corticomedial/efeitos dos fármacos , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Imidazóis/farmacologia , Losartan/farmacologia , Masculino , Proto-Oncogene Mas , Piridinas/farmacologia , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismoRESUMO
Tonic immobility (TI) is a temporary state of profound motor inhibition associated with great danger as the attack of a predator. Previous studies carried out in our laboratory evidenced high Fos-IR in the posteroventral region of the medial nucleus of the amygdala (MEA) after induction of the TI response. Here, we investigated the effects of GABAA and GABAB of the MEA on TI duration. Intra-MEA injections of the GABAA agonist muscimol and GABAB agonist baclofen reduced TI response, while intra-MEA injections of the GABAA antagonist bicuculline and GABAB antagonist phaclofen increased the TI response. Moreover, the effects observed with muscimol and baclofen administrations into MEA were blocked by pretreatment with bicuculline and phaclofen (at ineffective doses per se). Finally, the activation of GABAA and GABAB receptors in the MEA did not alter the spontaneous motor activity in the open field test. These data support the role of the GABAergic system of the MEA in the modulation of innate fear.
Assuntos
Complexo Nuclear Corticomedial/fisiologia , Agonistas de Receptores de GABA-A/fisiologia , Agonistas dos Receptores de GABA-B/fisiologia , Resposta de Imobilidade Tônica/fisiologia , Animais , Baclofeno/administração & dosagem , Baclofeno/análogos & derivados , Baclofeno/antagonistas & inibidores , Baclofeno/farmacologia , Bicuculina/administração & dosagem , Bicuculina/farmacologia , Complexo Nuclear Corticomedial/efeitos dos fármacos , Agonistas de Receptores de GABA-A/administração & dosagem , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/administração & dosagem , Antagonistas de Receptores de GABA-A/farmacologia , Agonistas dos Receptores de GABA-B/administração & dosagem , Agonistas dos Receptores de GABA-B/farmacologia , Antagonistas de Receptores de GABA-B/administração & dosagem , Antagonistas de Receptores de GABA-B/farmacologia , Cobaias , Resposta de Imobilidade Tônica/efeitos dos fármacos , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Muscimol/administração & dosagem , Muscimol/antagonistas & inibidores , Muscimol/farmacologiaRESUMO
Taste neophobia is a feeding system defense mechanism that limits consumption of an unknown, and therefore potentially dangerous, edible until the post-ingestive consequences are experienced. We found that transient pharmacological inhibition (induced with the GABA agonists baclofen and muscimol) of the gustatory thalamus (GT; Experiment 1), but not medial amygdala (MeA; Experiment 2), during exposure to a novel saccharin solution attenuated taste neophobia. In Experiment 3 we found that inhibition of MeA neurons (induced with the chemogenetic receptor hM4DGi) enhanced the expression of taste neophobia whereas excitation of MeA neurons (with hM3DGq) had no influence of taste neophobia. Overall, these results refine the temporal involvement of the GT in the occurrence of taste neophobia and support the hypothesis that neuronal excitation in the GT is necessary for taste neophobia. Conversely, we show that chemogenetically, but not pharmacologically, inhibiting MeA neurons is sufficient to exaggerate the expression of taste neophobia.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Complexo Nuclear Corticomedial/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Percepção Gustatória/efeitos dos fármacos , Núcleos Ventrais do Tálamo/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Técnicas Genéticas , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Perinatal exposure to bisphenol A (BPA) causes several alterations in brain function and behavior. In previous studies, we showed that prenatal treatment with low-level BPA impaired gender-specific behavior, enhanced depression-like behavior, and augmented behavioral responses to predator odor in rats. On this premise, we hypothesized that BPA-treated rats were more susceptible to predator odor stress. To test the potential neural mechanism underlying this effect, we conducted an electrophysiological study of neurons in the medial amygdala-a regional component of the olfactory pathway with high estrogen and androgen receptor expression, and thus a potential target of BPA-in rats exposed to BPA. Extracellular recordings were obtained during the presentation of 3 plant odors and 3 predator odorants. Odor-responsive neurons in BPA-exposed rats showed greater activity in response to fox odor than did those in control rats. This finding complements the results of our previous behavioral study in which BPA-exposed rats exhibited enhanced avoidance behavior in response to fox odor. Given the close relationship between olfactory signaling and the stress response system, we suspect that BPA modifies the olfactory pathway at the level of the medial amygdala and thus modulates the corresponding stress response.
Assuntos
Comportamento Agonístico/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Compostos Benzidrílicos/efeitos adversos , Complexo Nuclear Corticomedial/efeitos dos fármacos , Complexo Nuclear Corticomedial/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Odorantes , Condutos Olfatórios/efeitos dos fármacos , Fenóis/efeitos adversos , Comportamento Predatório/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Caracteres Sexuais , Estresse Psicológico/etiologia , Animais , Feminino , Masculino , Condutos Olfatórios/metabolismo , Condutos Olfatórios/fisiopatologia , Gravidez , Ratos Wistar , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/metabolismoRESUMO
Methamphetamine (Meth) is a psychomotor stimulant associated with increased sexual drive and risky sexual behaviors in both men and women. Females are comparatively understudied, despite the fact that are just as likely as men to use methamphetamine. Importantly, Meth-associated sexual behaviors put female-users at a greater risk for unplanned pregnancies, and increase the risk of psychiatric co-morbidities such as depression. Our work in a rodent model has demonstrated that in the presence of the ovarian steroids, estradiol (EB) and progesterone (P), methamphetamine facilitates the activation of neurons of in the Medial Amygdala (MePD) and Ventromedial Nucleus of the Hypothalamus (VMN), nuclei that are integral to female sexual behavior. As methamphetamine has been previously associated with epigenetic changes in males, we hypothesized that methamphetamine may facilitate sexual motivation in females by modulating the amount of epigenetic enzymatic activity in the VMN and MePD. To test this hypothesis, histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activity was quantitated in both the VMN and MePD in the presence and absence of methamphetamine in femalerats who were ovariectomized (OVX), or OVXed and hormone replaced with EBâ¯+â¯P. DMNT1 and DNMT3B protein levels were also assessed. Our results show that methamphetamine alters DNMT and HDAC activity in the MePD in an ovarian steroid-dependent fashion. Both methamphetamine alone and EBâ¯+â¯P alone significantly reduce DNMT enzymatic activity in an OVX female, but do not further decrease activity when both are given in combination. In contrast, no changes in HDAC or DNMT activity were seen in the VMN regardless of treatment, but the amount of DNMT3b after methamphetamine was significantly altered depending on the presence or absence of ovarian steroids. Taken together, these results support the hypothesis that methamphetamine induces change on an epigenetic level in female rats in both a hormone and nucleus dependent manner, and suggests epigenetic changes may play a role in methamphetamine's mechanism to facilitate the sexual motivation.
Assuntos
Complexo Nuclear Corticomedial/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Histona Desacetilases/metabolismo , Metanfetamina/farmacologia , Ovário/metabolismo , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Complexo Nuclear Corticomedial/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Estradiol/análogos & derivados , Estradiol/farmacologia , Feminino , Ovário/efeitos dos fármacos , Progesterona/farmacologia , Ratos , Ratos Sprague-Dawley , Comportamento Sexual Animal/efeitos dos fármacos , Comportamento Sexual Animal/fisiologia , DNA Metiltransferase 3BRESUMO
Declining estradiol (E2), as occurs during menopause, increases risk for obesity and psychopathology (i.e., depression, anxiety). E2 modulates mood and energy homeostasis via binding to estrogen receptors (ER) in the brain. The often comorbid and bidirectional relationship between mood and metabolic disorders suggests shared hormonal and/or brain networks. The medial amygdala (MeA) is abundant in ERs and regulates mood, endocrine, and metabolic stress responses; therefore we tested the hypothesis that E2 in the MeA mitigates emotional and metabolic dysfunction in a rodent model of surgical menopause. Adult female rats were ovariectomized (OVX) and received bilateral implants of E2 or cholesterol micropellets aimed at the MeA. E2-MeA decreased anxiety-like (center entries, center time) and depression-like (immobility) behaviors in the open field and forced swim tests (FST), respectively in ovariectomized rats. E2-MeA also prevented hyperphagia, body weight gain, increased visceral adiposity, and glucose intolerance in ovariectomized rats. E2-MeA decreased caloric efficiency, suggestive of increased energy expenditure. E2-MeA also modulated c-Fos neural activity in amygdalar (central and medial) and hypothalamic (paraventricular and arcuate) brain regions that regulate mood and energy homeostasis in response to the FST, a physically demanding task. Given the shared neural circuitry between mood and body weight regulation, c-Fos expression in discrete brain regions in response to the FST may be due to the psychologically stressful and/or metabolic demands of the task. Together, these findings suggest that the MeA is a critical node for mediating estrogenic effects on mood and energy homeostasis.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Estradiol/farmacologia , Obesidade/psicologia , Estresse Psicológico , Tonsila do Cerebelo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Complexo Nuclear Corticomedial/efeitos dos fármacos , Complexo Nuclear Corticomedial/metabolismo , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Ovariectomia , Ratos , Ratos Long-Evans , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/fisiologia , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
Alcohol exposure in adolescence is an important risk factor for the development of alcoholism in adulthood. Epigenetic processes are implicated in the persistence of adolescent alcohol exposure-related changes, specifically in the amygdala. We investigated the role of histone methylation mechanisms in the persistent effects of adolescent intermittent ethanol (AIE) exposure in adulthood. Adolescent rats were exposed to 2 g/kg ethanol (2 days on/off) or intermittent n-saline (AIS) during postnatal days (PND) 28-41 and used for behavioral and epigenetic studies. We found that AIE exposure caused a long-lasting decrease in mRNA and protein levels of lysine demethylase 1(Lsd1) and mRNA levels of Lsd1 + 8a (a neuron-specific splice variant) in specific amygdaloid structures compared with AIS-exposed rats when measured at adulthood. Interestingly, AIE increased histone H3 lysine 9 dimethylation (H3K9me2) levels in the central nucleus of the amygdala (CeA) and medial nucleus of the amygdala (MeA) in adulthood without producing any change in H3K4me2 protein levels. Acute ethanol challenge (2 g/kg) in adulthood attenuated anxiety-like behaviors and the decrease in Lsd1 + 8a mRNA levels in the amygdala induced by AIE. AIE caused an increase in H3K9me2 occupancy at the brain-derived neurotrophic factor exon IV promoter in the amygdala that returned to baseline after acute ethanol challenge in adulthood. These results indicate that AIE specifically modulates epizymes involved in H3K9 dimethylation in the amygdala in adulthood, which are possibly responsible for AIE-induced chromatin remodeling and adult psychopathology such as anxiety.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Código das Histonas/efeitos dos fármacos , Histona Desmetilases/efeitos dos fármacos , Metilação/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , Fatores Etários , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade , Fator Neurotrófico Derivado do Encéfalo/genética , Núcleo Central da Amígdala/efeitos dos fármacos , Núcleo Central da Amígdala/metabolismo , Complexo Nuclear Corticomedial/efeitos dos fármacos , Complexo Nuclear Corticomedial/metabolismo , Epigênese Genética/efeitos dos fármacos , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histonas/efeitos dos fármacos , Histonas/metabolismo , Masculino , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
The medial amygdala (MeA) is crucial for sexual behavior; kisspeptin (Kiss1) also plays a role in sexual function. Kisspeptin receptor (Kiss1r) knockout mice display no sexual behavior. Recently Kiss1 and Kiss1r have been discovered in the posterodorsal subnucleus of the medial amygdala (MePD). We hypothesised that Kiss1 in the MePD may have an influence on male sexual behavior. To test this we bilaterally cannulated the MePD and infused kisspeptin-10 in male rats. This caused the rats to have multiple erections, an effect specific to Kiss1 receptor activation, because Kiss1r antagonism blocked the erectile response. When Kiss1 was infused into the lateral cerebroventricle, there were no observed erections. We also measured the plasma levels of LH when Kiss1 is infused into the MePD or lateral cerebroventricle; Kiss1 increased plasma LH to comparable levels when infused into both sites. We conclude that Kiss1 has a role in male sexual behavior, which is specific to the MePD.
Assuntos
Complexo Nuclear Corticomedial/efeitos dos fármacos , Complexo Nuclear Corticomedial/fisiologia , Kisspeptinas/administração & dosagem , Receptores Acoplados a Proteínas G/fisiologia , Comportamento Sexual Animal/fisiologia , Animais , Hormônio Liberador de Gonadotropina/sangue , Hormônio Luteinizante/sangue , Masculino , Ereção Peniana/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Kisspeptina-1RESUMO
Our previous study in male rats demonstrated that bilateral administration of flutamide, an androgen receptor (AR) antagonist, into the posterodorsal medial amygdala (MePD) increased the time sniffing male odors to as high as that sniffing estrous odors, eliminating the preference for estrous odors over male odors. This made us speculate that under blockade of AR in the MePD, testosterone-derived estrogen acting on the same brain region arouses interest in male odors which is otherwise suppressed by concomitant action of androgen. In cyclic female rats, endogenous androgen has been thought to be involved in inhibitory regulation of estrogen-activated sexual behavior. Thus, in the present study, we investigated the possibility that in female rats the arousal of interest in male odors is also normally regulated by both estrogen and androgen acting on the MePD, as predicted by our previous study in male rats. Implantation of either the estrogen receptor blocker tamoxifen (TX) or a non-aromatizable androgen 5α-dihydrotestosterone (DHT) into the MePD of ovariectomized, estrogen-primed female rats eliminated preference for male odors over estrous odors by significantly decreasing the time sniffing male odors to as low as that sniffing estrous odors. The subsequent odor discrimination tests confirmed that the DHT and TX administration did not impair the ability to discriminate between male and estrous odors. These results suggest that in estrous female rats estrogen action in the MePD plays critical roles in the expression of the preference for male odors while androgen action in the same brain region interferes with the estrogen action.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Estrogênios/farmacologia , Casamento , Odorantes , Comportamento Sexual Animal/efeitos dos fármacos , Testosterona/farmacologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiologia , Animais , Complexo Nuclear Corticomedial/efeitos dos fármacos , Complexo Nuclear Corticomedial/metabolismo , Di-Hidrotestosterona/farmacologia , Estro/efeitos dos fármacos , Feminino , Flutamida/farmacologia , Masculino , Casamento/psicologia , Ratos , Ratos Long-Evans , Receptores Androgênicos/metabolismo , Comportamento Sexual/efeitos dos fármacos , Comportamento Sexual Animal/fisiologiaRESUMO
The tonic immobility (TI) response is an innate fear behavior associated with intensely dangerous situations, exhibited by many species of invertebrate and vertebrate animals. In humans, it is possible that TI predicts the severity of posttraumatic stress disorder symptoms. This behavioral response is initiated and sustained by the stimulation of various groups of neurons distributed in the telencephalon, diencephalon and brainstem. Previous research has found the highest Fos-IR in the posteroventral part of the medial nucleus of the amygdala (MEA) during TI behavior; however, the neurotransmission of this amygdaloid region involved in the modulation of this innate fear behavior still needs to be clarified. Considering that a major drug class used for the treatment of psychopathology is based on serotonin (5-HT) neurotransmission, we investigated the effects of serotonergic receptor activation in the MEA on the duration of TI. The results indicate that the activation of the 5HT1A receptors or the blocking of the 5HT2 receptors of the MEA can promote a reduction in fear and/or anxiety, consequently decreasing TI duration in guinea pigs. In contrast, blocking the 5HT1A receptors or activating the 5HT2 receptors in this amygdalar region increased the TI duration, suggesting an increase in fear and/or anxiety. These alterations do not appear to be due to a modification of spontaneous motor activity, which might non-specifically affect TI duration. Thus, these results suggest a distinct role of the 5HT receptors in the MEA in innate fear modulation.
Assuntos
Complexo Nuclear Corticomedial/fisiologia , Medo/fisiologia , Resposta de Imobilidade Tônica , Receptor 5-HT1A de Serotonina/fisiologia , Receptor 5-HT2A de Serotonina/fisiologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Animais , Ansiedade/fisiopatologia , Complexo Nuclear Corticomedial/efeitos dos fármacos , Medo/efeitos dos fármacos , Cobaias , Resposta de Imobilidade Tônica/efeitos dos fármacos , Ketanserina/administração & dosagem , Masculino , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagemRESUMO
Testosterone, after being converted to estradiol in the brain, acts on estrogen receptors (ERα and ERß) and controls the expression of male-type social behavior. Previous studies in male mice have revealed that ERα expressed in the medial preoptic area (MPOA) and medial amygdala (MeA) are differently involved in the regulation of sexual and aggressive behaviors by testosterone action at the time of testing in adult and/or on brain masculinization process during pubertal period. However, a role played by ERß in these brain regions still remains unclear. Here we examined the effects of site-specific knockdown of ERß (ßERKD) in the MPOA and MeA on male social behaviors with the use of adeno-associated viral mediated RNA interference methods in ICR/Jcl mice. Prepubertal ßERKD in the MPOA revealed that continuous suppression of ERß gene expression throughout the pubertal period and adulthood decreased aggressive but not sexual behavior tested as adults. Because ßERKD in the MPOA only in adulthood did not affect either sexual or aggressive behaviors, it was concluded that pubertal ERß in the MPOA might have an essential role for the full expression of aggressive behavior in adulthood. On the other hand, although neither prepubertal nor adult ßERKD in the MeA had any effects on sexual and aggressive behavior, ßERKD in adulthood disrupted sexual preference of receptive females over nonreceptive females. Collectively, these results suggest that ERß in the MPOA and MeA are involved in the regulation of male sexual and aggressive behavior in a manner substantially different from that of ERα.
Assuntos
Complexo Nuclear Corticomedial/metabolismo , Receptor beta de Estrogênio/deficiência , Área Pré-Óptica/metabolismo , Comportamento Social , Fatores Etários , Agressão/efeitos dos fármacos , Análise de Variância , Animais , Animais Recém-Nascidos , Complexo Nuclear Corticomedial/efeitos dos fármacos , Dependovirus/genética , Estradiol/farmacologia , Receptor beta de Estrogênio/genética , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ovariectomia , Área Pré-Óptica/efeitos dos fármacos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Comportamento Sexual Animal/efeitos dos fármacos , Transdução GenéticaRESUMO
Previous results show that the activation of CRF type 1 (CRFR1) receptors of the medial amygdala (MeA) induces anxiogenic-like effects. The present study investigates the role played by medial amygdala CRF type 2 receptors (CRFR2) in the modulation of anxiety and panic-related responses. Male Wistar rats were administered into the MeA with the CRFR2 agonist urocortin 2 (0.5 e 1.0µg/0.2µl, experiment 1) or with the CRFR2 antagonist astressin 2-B (60ng/0.2µl, experiment 2) and 10min later tested in the elevated T-maze (ETM) for inhibitory avoidance and escape measurements. In clinical terms, these responses have been respectively related to generalized anxiety and panic disorder. In a third experiment, the effects of the combined treatment with urocortin 2 (1.0µg/0.2µl) and a sub-effective dose of astressin 2-B (30ng/0.2µl) were also investigated. All animals were tested in an open field, immediately after the ETM, for locomotor activity assessment. Results showed that urocortin 2, in the highest dose administered (1.0µg/0.2µl), facilitated ETM avoidance, an anxiogenic-like effect. Astressin 2-B, also in the highest dose (60ng/0.2µl), significantly decreased avoidance latencies, an anxiolytic-like effect. The lower dose of astressin 2-B (30ng/0.2µl) did not induce anxiolytic-like effects but was able to counteract the anxiogenic-like effects of urocortin 2. None of the compounds administered altered escape responses or locomotor activity measurements. These results suggest that CRFR2 in the medial amygdala, as CRFR1, selectively modulate an anxiety-related response.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Complexo Nuclear Corticomedial/fisiologia , Inibição Psicológica , Aprendizagem em Labirinto/fisiologia , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Análise de Variância , Animais , Ansiolíticos/farmacologia , Complexo Nuclear Corticomedial/efeitos dos fármacos , Hormônio Liberador da Corticotropina/farmacologia , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microinjeções , Fragmentos de Peptídeos/farmacologia , Ratos , Tempo de Reação/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/agonistas , Urocortinas/farmacologiaRESUMO
Comfort eating during periods of stress is a common phenomenon observed in both animals and humans. However, the underlying mechanisms of stress-induced food intake remain elusive. The amygdala plays a central role in higher-order emotional processing and the posterodorsal subnucleus of the medial amygdala (MePD), in particular, is involved in food intake. Extra-hypothalamic corticotrophin-releasing factor (CRF) is well recognised for mediating behavioural responses to stress. To explore the possible role of amygdala CRF receptor activation in stress-induced food intake, we evaluated whether a stressor such as tail-pinch, which reliably induces food intake, would fail to do so in animals bearing bilateral neurotoxic lesions of the MePD. Our results showed that ibotenic acid induced lesions of the MePD markedly reduced tail-pinch induced food intake in ovariectomised, 17ß-oestradiol replaced rats. In addition, intra-MePD (right side only) administration of CRF (0.002 or 0.02 ng) via chronically implanted cannulae resulted in a dose-dependent increase in food intake, although higher doses of 0.2 and 2 ng CRF had less effect, producing a bell shaped curve. Furthermore, intra-MePD (bilateral) administration of the CRF receptor antagonist, astressin (0.3 µg per side) effectively blocked tail-pinch induced food intake. These data suggest that the MePD is involved in stress-induced food intake and that the amygdala CRF system may be a mediator of comfort eating.
Assuntos
Complexo Nuclear Corticomedial/fisiopatologia , Ingestão de Alimentos , Estresse Psicológico/fisiopatologia , Animais , Complexo Nuclear Corticomedial/efeitos dos fármacos , Hormônio Liberador da Corticotropina/administração & dosagem , Ingestão de Alimentos/efeitos dos fármacos , Estradiol/administração & dosagem , Feminino , Ovariectomia , Fragmentos de Peptídeos/administração & dosagem , Estimulação Física , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidoresRESUMO
During puberty, attention turns away from same-sex socialization to focus on the opposite sex. How the brain mediates this change in perception and motivation is unknown. Polysialylated neural cell adhesion molecule (PSA-NCAM) virtually disappears from most of the central nervous system after embryogenesis, but it remains elevated in discrete regions of the adult brain. One such brain area is the posterodorsal subnucleus of the medial amygdala (MePD). The MePD has been implicated in male sexual attraction, measured here as the preference to investigate female odors. We hypothesize that PSA-NCAM gates hormone-dependent plasticity necessary for the emergence of males' attraction to females. To evaluate this idea, we first measured PSA-NCAM levels across puberty in several brain regions, and identified when female odor preference normally emerges in male Syrian hamsters. We found that MePD PSA-NCAM staining peaks shortly before the surge of pubertal androgen and the emergence of preference. To test the necessity of PSA-NCAM for female odor preference, we infused endo-neuraminidase-N into the MePD to deplete it of PSAs before female odor preference normally appears. This blocked female odor preference, which suggests that PSA-NCAM facilitates behaviorally relevant, hormone-driven plasticity.