Harvard University - Department of Molecular & Cellular Biology

Key Regulatory Node for Parental Behavior Identified

by Anita Autry, Zheng Wu and Catherine Dulac

May 15th, 2014

(l to r) Zheng Wu, Anita Autry, Catherine Dulac, Joseph Bergan, and Mitsuko Watabe-Uchida

The discovery of neural circuits underlying social behavior is among the most fascinating goals in modern neuroscience: the specific brains areas and neuronal subsets in which social cues are detected and encoded by the brain in order to lead to distinct behavioral responses, and the mechanisms by which social responses are modulated by animal’s physiological and reproductive status are still very poorly understood. Parental behavior, a set of interactions aimed at the care and protection of the young, serves as a prime example of social behavior. Laboratory mice exhibit dramatic behavioral sexual dimorphism toward pups. Virgin males typically attack pups, while virgin females and moms exhibit spontaneous, stereotyped displays of maternal care. Remarkably, males stop attacking and become paternal toward pups in a transient period after mating with a female, starting at the approximate time of birth until the weaning of pups. The switch between the two opposing behaviors raises an important and fascinating question in the study of parental interactions. Using cell-type specific gain- and loss-of-function manipulations, a recent study by Wu et al. started a dissection of the behavior circuit underlying parental behavior, from brain regions to genetically-defined cell populations.

The vomeronasal organ (VNO) is an organ that primarily detects non-volatile pheromones representing information about social and sexual status of individuals. Previous studies in the Dulac lab using mice deficient in TRPC2, an ion channel specifically expressed in VNO receptor neurons and essential for VNO sensory transduction, showed that the vomeronasal pathway is critical for social interactions including inter-male aggression and sexual behavior. Utilizing the same line, this study found that Trpc2 knockout virgin males do not attack pups and are parental, suggesting a key role of the vomeronasal system in controlling pup-directed aggression.

Furthermore, this study has identified a genetically defined population in the medial preoptic area (MPOA) governing parental behavior. The MPOA of the anterior hypothalamus has previously been implicated in the control of maternal behavior in rats, as well as in many other brain functions such as thermoregulation and reproduction. However, the MPOA is a highly heterogeneous structure, which receives inputs from and projects to many brain areas. What is the molecular identity of the neural population involved in control of parental behavior?

Using in situ hybridization between c-fos, an immediate early gene transiently induced by neural activity, and a number of cell markers in the MPOA, they identified the neuropeptide gene galanin (Gal) as a marker for the active neurons. Cell-type specific ablation of the MPOA Gal cells leads to parental defects in virgin females, mothers and fathers, whereas optogenetic activation of these neurons in virgin males suppressed pup-directed aggression and induces pup grooming. These results thus establish the MPOA Gal neurons as an essential regulatory node of parenting behavior in both males and females.

Interestingly, a separate subset of Gal neurons was found activated in mating behavior, medial to those that are activated by parenting, as revealed by cellular compartment analysis of temporal activity by fluorescent in situ hybridization (catFISH) which allows direct comparison of cells activated by the two behaviors. Accordingly, the ablation of the MPOA Gal neurons also leads to deficits in mating behavior but not in inter-male aggression. However, optogenetic activation of these cells abolishes aggression but does not affect mating behavior. These results, while still perplexing, imply further functional heterogeneity within the Gal cells or an intricate interaction between various types of social behaviors.

These findings represent the first genetic characterization of command-like neurons for parental responses in vertebrates and illustrate how the activation of a single cell population is able to switch on/off a social behavior. Furthermore, these results provide a precious entry point for further dissection of neural circuits underlying parental care and pup-directed aggression. Future studies will require more refined characterization of the Gal cells, the identification of other circuit components and their coordination with Gal cells, and ultimately their modulation by sensory inputs and the animal’s physiological and reproductive states.

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