Parental brain through time: The origin and development of the neural circuit of mammalian parenting.

This review consolidates current knowledge on mammalian parental care, focusing on its neural mechanisms, evolutionary origins, and derivatives. Neurobiological studies have identified specific neurons in the medial preoptic area as crucial for parental care. Unexpectedly, these neurons are characterized by the expression of molecules signaling satiety, such as calcitonin receptor and BRS3, and overlap with neurons involved in the reproductive behaviors of males but not females. A synthesis of comparative ecology and paleontology suggests an evolutionary scenario for mammalian parental care, possibly stemming from male-biased guarding of offspring in basal vertebrates. The terrestrial transition of tetrapods led to prolonged egg retention in females and the emergence of amniotes, skewing care toward females. The nocturnal adaptation of Mesozoic mammalian ancestors reinforced maternal care for lactation and thermal regulation via endothermy, potentially introducing metabolic gate control in parenting neurons. The established maternal care may have served as the precursor for paternal and cooperative care in mammals and also fostered the development of group living, which may have further contributed to the emergence of empathy and altruism. These evolution-informed working hypotheses require empirical validation, yet they offer promising avenues to investigate the neural underpinnings of mammalian social behaviors.

Behavioral and histochemical characterization of sexually dimorphic responses to acute social isolation and reunion in mice.

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.

[Neurobiology of Loneliness, Social Isolation, and Affiliative Social Behavior].

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.

Role of Calcr expressing neurons in the medial amygdala in social contact among females.

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.

Amylin-Calcitonin receptor signaling in the medial preoptic area mediates affiliative social behaviors in female mice.

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.

Calcitonin receptor signaling in the medial preoptic area enables risk-taking maternal care.

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.

Thyroid Hormone Induces PGC-1α during Dendritic Outgrowth in Mouse Cerebellar Purkinje Cells.

Thyroid hormone 3,3',5-Triiodo-L-thyronine (T3) is essential for proper brain development. Perinatal loss of T3 causes severe growth defects in neurons and glia, including strong inhibition of dendrite formation in Purkinje cells in the cerebellar cortex. Here we show that T3 promotes dendritic outgrowth of Purkinje cells through induction of peroxisome proliferator-activated receptor gamma (PPARγ) co-activator 1α (PGC-1α), a master regulator of mitochondrial biogenesis. PGC-1α expression in Purkinje cells is upregulated during dendritic outgrowth in normal mice, while it is significantly retarded in hypothyroid mice or in cultures depleted of T3. In cultured Purkinje cells, PGC-1α knockdown or molecular perturbation of PGC-1α signaling inhibits enhanced dendritic outgrowth and mitochondrial generation and activation caused by T3 treatment. In contrast, PGC-1α overexpression promotes dendrite extension even in the absence of T3. PGC-1α knockdown also downregulates dendrite formation in Purkinje cells in vivo. Our findings suggest that the growth-promoting activity of T3 is partly mediated by PGC-1α signaling in developing Purkinje cells.

Mitochondrial fission protein Drp1 regulates mitochondrial transport and dendritic arborization in cerebellar Purkinje cells.

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.

Synergistic action of dendritic mitochondria and creatine kinase maintains ATP homeostasis and actin dynamics in growing neuronal dendrites.

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.