Functional Ontogeny of Hypothalamic Agrp Neurons in Neonatal Mouse Behaviors.

Hypothalamic Agrp neurons regulate food ingestion in adult mice. Whether these neurons are functional before animals start to ingest food is unknown. Here, we studied the functional ontogeny of Agrp neurons during breastfeeding using postnatal day 10 mice. In contrast to adult mice, we show that isolation from the nursing nest, not milk deprivation or ingestion, activated Agrp neurons. Non-nutritive suckling and warm temperatures blunted this effect. Using in vivo fiber photometry, neonatal Agrp neurons showed a rapid increase in activity upon isolation from the nest, an effect rapidly diminished following reunion with littermates. Neonates unable to release GABA from Agrp neurons expressed blunted emission of isolation-induced ultrasonic vocalizations. Chemogenetic overactivation of these neurons further increased emission of these ultrasonic vocalizations, but not milk ingestion. We uncovered important functional properties of hypothalamic Agrp neurons during mouse development, suggesting these neurons facilitate offspring-to-caregiver bonding.

Preparatory neurons for building a nest.

Mothers build nests in anticipation of the delivery of their offspring. How the brain coordinates this behavior is unknown. Topilko et al. (2022) demonstrate that nest building in pregnant females relies on the activity of peptidergic neurons in the Edinger-Westphal nucleus.

Development of "Hunger Neurons" and the Unanticipated Relationship Between Energy Metabolism and Mother-Infant Interactions.

Over the course of a lifetime, the perinatal period plays an outsized role in the function of physiological systems. Here, we discuss how neurons that regulate energy metabolism contribute to the infant's relationship with the mother. We focus our discussion on Agrp neurons, which are located in the arcuate nucleus of the hypothalamus. These neurons heavily regulate energy metabolism. Because offspring transition from a period of dependence on the caregiver to independence, we discuss the importance of the caregiver-offspring relationship for the function of Agrp neurons. We present evidence that in the adult, Agrp neurons motivate the animal to eat, while in the neonate, they motivate the offspring to seek the proximity of the caregiver. We specifically highlight the peculiarities in the development of Agrp neurons and how they relate to the regulation of metabolism and behavior over the course of a lifetime. In sum, this review considers the unique insights that ontogenetic studies can offer toward our understanding of complex biological systems, such as the regulation of energy metabolism and mother-infant attachment.

AgRP neurons control compulsive exercise and survival in an activity-based anorexia model.

Hypothalamic agouti-related peptide (AgRP) and neuropeptide Y-expressing neurons have a critical role in driving food intake, but also in modulating complex, non-feeding behaviours1. We interrogated whether AgRP neurons are relevant to the emergence of anorexia nervosa symptomatology in a mouse model. Here we show, using in vivo fibre photometry, a rapid inhibition of AgRP neuronal activity following voluntary cessation of running. All AgRP neuron-ablated, food-restricted mice die within 72 h of compulsive running, while daily activation of AgRP neurons using a chemogenetic tool increases voluntary running with no lethality of food-restricted animals. Animals with impaired AgRP neuronal circuits are unable to properly mobilize fuels during food-restriction-associated exercise; however, when provided with elevated fat content through diet, their death is completely prevented. Elevated fat content in the diet also prevents the long-term behavioural impact of food-restricted fit mice with elevated exercise volume. These observations elucidate a previously unsuspected organizational role of AgRP neurons, via the mediation of the periphery, in the regulation of compulsive exercise and its related lethality with possible implications for psychiatric conditions, such as anorexia nervosa.

Medial Preoptic Regulation of the Ventral Tegmental Area Related to the Control of Sociosexual Behaviors.

During sociosexual encounters, different brain mechanisms interact to orchestrate information about the salience of external stimuli along with the current physiological and environmental conditions in order to process these in an optimal manner. One candidate neural system involves the potential interplay between the medial preoptic nucleus (POM) and mesolimbic reward circuitry. We present here evidence indicating that projections originating from the POM play a modulatory role on the mesolimbic reward circuitry related to male sexual behavior in Japanese quail (Coturnix japonica). First, we used an asymmetrical inactivation strategy where POM and ventral tegmental area (VTA) were unilaterally inactivated via the GABAA agonist muscimol, either in an ipsilateral or contralateral fashion. Ipsilateral injections of muscimol had negligible effects on both appetitive and consummatory sexual behaviors. In contrast, contralateral injections significantly impaired appetitive sexual behaviors but had no clear effect on consummatory sexual behaviors. Next, we labeled cells projecting from the POM to the VTA by stereotaxic injection into VTA of the retrograde tracer biotinylated dextran amine (BDA). Two weeks later, brains from males who had been allowed to interact freely with a female (15 min) or kept as controls were collected and fixed for double immunohistochemical labeling of BDA and the immediate early gene Fos. More retrogradely labeled BDA cells in POM expressed Fos after sociosexual interactions than in control conditions. Overall, these findings provide novel evidence for the interplay between POM and VTA in the modulation of appetitive but not consummatory sexual behaviors. Schematic representation of the putative role of the projection from the medial POM to the VTA in the regulation of appetitive and consummatory sexual behaviors. Unilateral inactivation of POM and VTA on (1) ipsilateral sides has negligible effects on both aspects of sexual behaviors, whereas (2) contralateral inactivation disrupts appetitive sexual behaviors.

Fos expression in monoaminergic cell groups in response to sociosexual interactions in male and female Japanese quail.

Monoaminergic neurotransmitters regulate different components of sexual behaviors, but how the different monoaminergic cell groups selectively regulate these behaviors is not well understood. We examined the potential contribution of these different cell groups in the control of different aspects of sexual behaviors in male and female quail. We used double-label immunohistochemistry, labeling the protein product of the immediate early gene, Fos, along with tyrosine hydroxylase (TH) or tryptophan hydroxylase (TPH), markers for catecholaminergic or indolaminergic cells, respectively. Rhythmic Cloacal Sphincter Movements (RCSM) were recorded as a measure of male appetitive sexual behavior. Consummatory sexual behaviors were evaluated based on the species-typical copulation sequence. Enhanced Fos expression in the medial preoptic nucleus and bed nucleus of the stria terminalis was observed in association with both physical and visual contact to the opposite sex for males, but not for females. Fos induction associated with physical contact was observed in the ventral tegmental area and anterior periaqueductal gray in both sexes. In males only, the number of Fos-immunoreactive (ir) cells increased in the visual contact condition in these 2 dopaminergic cell groups, however no significant effect was observed for double-labeled TH-Fos-ir cells. In addition, consummatory but not appetitive sexual behavior increased Fos expression in TPH-ir cells in the raphe pallidus of males. This increase following physical but not visual contact agrees with the notion that activation of the serotoninergic system is implicated in the development of sexual satiation but not activated by simply viewing a female, in contrast to the dopaminergic system.

Blue but not red light stimulation in the dark has antidepressant effect in behavioral despair.

The present study investigated potential antidepressant effect of light exposure in the dark phase of a 12:12 L/D cycle on behavioral despair. In Exp.1, male Wistar rats were administered a single, 10 min broadband light pulse (1300lx) either 3h (ZT15) or 9h (ZT21) after dark onset (ZT12) and tested in two consecutive swim tests separated by 24 h. Photic stimulation at ZT21 but not ZT15 significantly reduced immobility in the second swim test relative to the first test compared to controls that were treated similarly except for light pulse administration (p<0.05). In Exp.2, groups were exposed to a single 10-min light pulse (1300lx) either in the blue or red end of the spectrum at ZT21 or were treated similarly except for photic exposure (controls). Exposure to blue light resulted in significantly reduced duration of immobility in the second swim test relative to that of the first test compared to the red light and control groups (p<0.05). The present findings suggest a critical role in the antidepressant effect of blue light stimulation for the melanopsin-containing ganglion cells in the retina that are sensitive to wavelengths in the blue but not red end of the visible spectrum.