RESUMO
The nucleus reuniens has been shown to support the acquisition, consolidation, maintenance, destabilization upon retrieval, and extinction of aversive memories. However, the direct participation of this thalamic subregion in memory reconsolidation is yet to be examined. The present study addressed this question in contextually fear-conditioned rats. Post-reactivation infusion of the GABAA receptor agonist muscimol, the glutamate N2A-containing NMDA receptor antagonist TCN-201, or the protein synthesis inhibitor anisomycin into the NR induced significant impairments in memory reconsolidation. Administering muscimol or TCN-201 and anisomycin locally, or associating locally infused muscimol or TCN-201 with systemically administered clonidine, an α2-receptor adrenergic agonist that attenuates the noradrenergic tonus associated with memory reconsolidation, produced no further reduction in freezing times when compared with the muscimol-vehicle, TCN-201-vehicle, vehicle-anisomycin, and vehicle-clonidine groups. This pattern of results indicates that such treatment combinations produced no additive/synergistic effects on reconsolidation. It is plausible that NR inactivation and antagonism of glutamate N2A-containing NMDA receptors weakened/prevented the subsequent action of anisomycin and clonidine because they disrupted the early stages of signal transduction pathways involved in memory reconsolidation. It is noteworthy that these pharmacological interventions, either alone or combined, induced no contextual memory specificity changes, as assessed in a later test in a novel and unpaired context. Besides, omitting memory reactivation precluded the impairing effects of muscimol, TCN-201, anisomycin, and clonidine on reconsolidation. Together, the present findings demonstrate interacting mechanisms through which the NR can regulate contextual fear memory restabilization.
Assuntos
Medo/fisiologia , Consolidação da Memória/fisiologia , Núcleos da Linha Média do Tálamo/fisiologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Anisomicina/farmacologia , Clonidina/farmacologia , Medo/psicologia , Agonistas de Receptores de GABA-A/farmacologia , Masculino , Consolidação da Memória/efeitos dos fármacos , Núcleos da Linha Média do Tálamo/efeitos dos fármacos , Núcleos da Linha Média do Tálamo/metabolismo , Muscimol/farmacologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/fisiologia , Sulfonamidas/farmacologiaRESUMO
The neural circuit supporting aversive memory destabilization after retrieval includes the hippocampus, amygdala, and medial prefrontal cortex. The nucleus reuniens (NR) contributes to the functional interaction of these brain regions relevant to cognitive processing. However, the direct participation of this thalamic subregion in memory destabilization is yet to be investigated. The present study addressed this question in contextually fear-conditioned rats. Pre-reactivation infusion of the GABAA receptor agonist muscimol, the protein degradation inhibitor clasto-lactacystin ß-lactone (ß-lac), or the glutamate N2B-containing NMDA receptors antagonist ifenprodil into the NR prevented the post-reactivation amnestic effects of both locally infused anisomycin and systemically administered clonidine. In either case, the results suggest a significant disruption in memory destabilization. It is noteworthy that these pharmacological interventions induced no changes in expression or contextual specificity of the memory. Moreover, omitting memory reactivation precluded the muscimol, ß-lac, and ifenprodil effects on destabilization and the anisomycin and clonidine effects on reconsolidation. We also quantified the Egr1/Zif268-expressing neurons to investigate the effects of muscimol-induced NR inactivation on the activity-related plasticity locally, and in other brain regions supporting fear memory destabilization-reconsolidation. Relative to controls, there were reduced values in the NR, the dorsal CA1 hippocampus, the prelimbic cortex, and the infralimbic cortex. In contrast, increases happened in the ventral CA1 hippocampus and the basolateral amygdala. These results suggest that NR has a circuit-level influence on this process. Together, present findings demonstrate how the NR can regulate contextual fear memory destabilization upon retrieval.
Assuntos
Tonsila do Cerebelo/fisiologia , Região CA1 Hipocampal/fisiologia , Medo , Memória/fisiologia , Núcleos da Linha Média do Tálamo/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Anisomicina/farmacologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Clonidina/farmacologia , Cognição , Inibidores de Cisteína Proteinase/farmacologia , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Lactonas/farmacologia , Memória/efeitos dos fármacos , Núcleos da Linha Média do Tálamo/efeitos dos fármacos , Núcleos da Linha Média do Tálamo/metabolismo , Muscimol/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Piperidinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Kisspeptin, encoded by Kiss1, stimulates reproduction and is synthesized in the hypothalamic anteroventral periventricular and arcuate nuclei. Kiss1 is also expressed at lower levels in the medial amygdala (MeA) and bed nucleus of the stria terminalis (BNST), but the regulation and function of Kiss1 there is poorly understood. γ-Aminobutyric acid (GABA) also regulates reproduction, and female GABAB1 receptor knockout (KO) mice have compromised fertility. However, the interaction between GABAB receptors and Kiss1 neurons is unknown. Here, using double-label in situ hybridization, we first demonstrated that a majority of hypothalamic Kiss1 neurons coexpress GABAB1 subunit, a finding also confirmed for most MeA Kiss1 neurons. Yet, despite known reproductive impairments in GABAB1KO mice, Kiss1 expression in the anteroventral periventricular and arcuate nuclei, assessed by both in situ hybridization and real-time PCR, was identical between adult wild-type and GABAB1KO mice. Surprisingly, however, Kiss1 levels in the BNST and MeA, as well as the lateral septum (a region normally lacking Kiss1 expression), were dramatically increased in both GABAB1KO males and females. The increased Kiss1 levels in extrahypothalamic regions were not caused by elevated sex steroids (which can increase Kiss1 expression), because circulating estradiol and testosterone were equivalent between genotypes. Interestingly, increased Kiss1 expression was not detected in the MeA or BNST in prepubertal KO mice of either sex, indicating that the enhancements in extrahypothalamic Kiss1 levels initiate during/after puberty. These findings suggest that GABAB signaling may normally directly or indirectly inhibit Kiss1 expression, particularly in the BNST and MeA, and highlight the importance of studying kisspeptin populations outside the hypothalamus.
Assuntos
Regulação da Expressão Gênica , Kisspeptinas/metabolismo , Receptores de GABA-B/metabolismo , Transdução de Sinais , Tonsila do Cerebelo/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Mapeamento Encefálico , Estradiol/metabolismo , Feminino , Genótipo , Hipotálamo/metabolismo , Imuno-Histoquímica , Kisspeptinas/genética , Masculino , Camundongos , Camundongos Knockout , Núcleos da Linha Média do Tálamo/metabolismo , Neurônios/metabolismo , Fenótipo , Receptores de GABA-B/genética , Núcleos Septais/metabolismo , Testosterona/metabolismo , Fatores de Tempo , Regulação para Cima , Ácido gama-Aminobutírico/metabolismoRESUMO
The anteroventral periventricular nucleus (AVPV) is sexually dimorphic, presenting a higher neuronal density in females. The AVPV contains a dense collection of oestrogen and progesterone receptors and has been related to the modulation of gonadotrophin-releasing hormone (GnRH) secretion and gene expression in response to circulating hormonal levels. It has been suggested that cocaine- and amphetamine-regulated transcript (CART) is also related to reproductive control because CART immunoreactive fibres are in close apposition with GnRH neurones. A portion of these fibres originate in the AVPV but its role in mediating hormonal action needs to be better explored. We hypothesised that CART expression in the AVPV would be influenced by the reproductive state and, consequently, by hormonal levels. To test this hypothesis, we analysed CART expression in the AVPV of female rats in different reproductive states (pro-oestrous, pregnancy and lactation). We found that, on the 19th day of pregnancy, female rats presented increased CART expression. Our findings indicate that AVPV CART expression is influenced by the reproductive state and that CART neurones in the AVPV may play a role in the hormonal mechanisms involved in the induction of maternal behaviour.