RESUMO
In many mammalian species, females exhibit higher sociability and gregariousness than males, presumably due to the benefit of group living for maternal care. We have previously reported that adult female mice exhibit contact-seeking behaviors upon acute social isolation via amylin-calcitonin receptor (Calcr) signaling in the medial preoptic area (MPOA). In this study, we examined the sex differences in the behavioral responses to acute social isolation and reunion, and the levels of amylin and Calcr expression in the MPOA. We found that male mice exhibited significantly less contact-seeking upon social isolation. Upon reunion, male mice contacted each other to a similar extent as females, but their interactions were more aggressive and less affiliative compared with females. While Calcr-expressing neurons were activated during social contacts in males as in females, the amylin and Calcr expression were significantly lower in males than in females. Together with our previous findings, these findings suggested that the lower expression of both amylin and Calcr may explain the lower contact-seeking and social affiliation of male mice.
Assuntos
Polipeptídeo Amiloide das Ilhotas Pancreáticas , Área Pré-Óptica , Camundongos , Animais , Feminino , Masculino , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Área Pré-Óptica/metabolismo , Isolamento Social , Caracteres Sexuais , MamíferosRESUMO
Prolonged social isolation has been reported to be one of the risk factors for human health, equivalent to smoking cigarettes. Therefore, some developed countries have recognized prolonged social isolation as a social problem and have started to address this problem. Studies on rodent models are essential to fundamentally clarify the impacts of social isolation on human health mentally and physically. In this review, we conduct an overview of the neuromolecular mechanisms of loneliness, perceived social isolation, and the effects of prolonged social isolation. Finally, we consider the evolutionary development of neural bases of loneliness.
Assuntos
Solidão , Isolamento Social , Humanos , Comportamento Social , Fatores de RiscoRESUMO
Social animals become stressed upon social isolation, proactively engaging in affiliative contacts among conspecifics after resocialization. We have previously reported that calcitonin receptor (Calcr) expressing neurons in the central part of the medial preoptic area (cMPOA) mediate contact-seeking behaviors in female mice. Calcr neurons in the posterodorsal part of the medial amygdala (MeApd) are also activated by resocialization, however their role in social affiliation is still unclear. Here we first investigated the functional characteristics of MeApd Calcr + cells; these neurons are GABAergic and show female-biased Calcr expression. Next, using an adeno-associated virus vector expressing a short hairpin RNA targeting Calcr we aimed to identify its molecular role in the MeApd. Inhibiting Calcr expression in the MeApd increased social contacts during resocialization without affecting locomotor activity, suggesting that the endogenous Calcr signaling in the MeApd suppresses social contacts. These results demonstrate the distinct roles of Calcr in the cMPOA and MeApd for regulating social affiliation.
Assuntos
Complexo Nuclear Corticomedial , Receptores da Calcitonina , Feminino , Animais , Camundongos , Receptores da Calcitonina/metabolismo , Tonsila do Cerebelo/metabolismo , Neurônios/metabolismo , Área Pré-Óptica/metabolismoRESUMO
Social animals actively engage in contact with conspecifics and experience stress upon isolation. However, the neural mechanisms coordinating the sensing and seeking of social contacts are unclear. Here we report that amylin-calcitonin receptor (Calcr) signaling in the medial preoptic area (MPOA) mediates affiliative social contacts among adult female mice. Isolation of females from free social interactions first induces active contact-seeking, then depressive-like behavior, concurrent with a loss of Amylin mRNA expression in the MPOA. Reunion with peers induces physical contacts, activates both amylin- and Calcr-expressing neurons, and leads to a recovery of Amylin mRNA expression. Chemogenetic activation of amylin neurons increases and molecular knockdown of either amylin or Calcr attenuates contact-seeking behavior, respectively. Our data provide evidence in support of a previously postulated origin of social affiliation in mammals.
Assuntos
Comportamento Animal/fisiologia , Área Pré-Óptica/fisiologia , Receptores da Calcitonina/metabolismo , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo , Comportamento Social , Animais , Feminino , Técnicas de Inativação de Genes , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Camundongos , RNA Mensageiro/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Maternal mammals exhibit heightened motivation to care for offspring, but the underlying neuromolecular mechanisms have yet to be clarified. Here, we report that the calcitonin receptor (Calcr) and its ligand amylin are expressed in distinct neuronal populations in the medial preoptic area (MPOA) and are upregulated in mothers. Calcr+ MPOA neurons activated by parental care project to somatomotor and monoaminergic brainstem nuclei. Retrograde monosynaptic tracing reveals that significant modification of afferents to Calcr+ neurons occurs in mothers. Knockdown of either Calcr or amylin gene expression hampers risk-taking maternal care, and specific silencing of Calcr+ MPOA neurons inhibits nurturing behaviors, while pharmacogenetic activation prevents infanticide in virgin males. These data indicate that Calcr+ MPOA neurons are required for both maternal and allomaternal nurturing behaviors and that upregulation of amylin-Calcr signaling in the MPOA at least partially mediates risk-taking maternal care, possibly via modified connectomics of Calcr+ neurons postpartum.
Assuntos
Comportamento Animal/fisiologia , Comportamento Materno/fisiologia , Área Pré-Óptica/metabolismo , Receptores da Calcitonina/metabolismo , Assunção de Riscos , Transdução de Sinais , Animais , Estrogênios/metabolismo , Feminino , Inativação Gênica , Marcação de Genes , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Lactação , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Período Pós-Parto , Prolactina/metabolismo , Sinapses/metabolismo , Regulação para CimaRESUMO
Mitochondria dynamically change their shape by repeated fission and fusion in response to physiological and pathological conditions. Recent studies have uncovered significant roles of mitochondrial fission and fusion in neuronal functions, such as neurotransmission and spine formation. However, the contribution of mitochondrial fission to the development of dendrites remains controversial. We analyzed the function of the mitochondrial fission GTPase Drp1 in dendritic arborization in cerebellar Purkinje cells. Overexpression of a dominant-negative mutant of Drp1 in postmitotic Purkinje cells enlarged and clustered mitochondria, which failed to exit from the soma into the dendrites. The emerging dendrites lacking mitochondrial transport remained short and unstable in culture and in vivo. The dominant-negative Drp1 affected neither the basal respiratory function of mitochondria nor the survival of Purkinje cells. Enhanced ATP supply by creatine treatment, but not reduced ROS production by antioxidant treatment, restored the hypomorphic dendrites caused by inhibition of Drp1 function. Collectively, our results suggest that Drp1 is required for dendritic distribution of mitochondria and thereby regulates energy supply in growing dendritic branches in developing Purkinje cells.
Assuntos
Dinaminas/metabolismo , Mitocôndrias/metabolismo , Neurogênese , Células de Purkinje/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Transporte Biológico , Células Cultivadas , Dendritos/metabolismo , Dinaminas/genética , Camundongos , Camundongos Endogâmicos ICR , Células de Purkinje/citologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
The distribution of mitochondria within mature, differentiated neurons is clearly adapted to their regional physiological needs and can be perturbed under various pathological conditions, but the function of mitochondria in developing neurons has been less well studied. We have studied mitochondrial distribution within developing mouse cerebellar Purkinje cells and have found that active delivery of mitochondria into their dendrites is a prerequisite for proper dendritic outgrowth. Even when mitochondria in the Purkinje cell bodies are functioning normally, interrupting the transport of mitochondria into their dendrites severely disturbs dendritic growth. Additionally, we find that the growth of atrophic dendrites lacking mitochondria can be rescued by activating ATP-phosphocreatine exchange mediated by creatine kinase (CK). Conversely, inhibiting cytosolic CKs decreases dendritic ATP levels and also disrupts dendrite development. Mechanistically, this energy depletion appears to perturb normal actin dynamics and enhance the aggregation of cofilin within growing dendrites, reminiscent of what occurs in neurons overexpressing the dephosphorylated form of cofilin. These results suggest that local ATP synthesis by dendritic mitochondria and ATP-phosphocreatine exchange act synergistically to sustain the cytoskeletal dynamics necessary for dendritic development.