A major goal of modern neuroscience is uncovering the circuit mechanisms that control naturalistic behaviors, including foraging, nesting, and social behaviors such as mating, aggression, and parenting. These behaviors are highly conserved across species and extremely relevant for human physiology and pathophysiology. However, they are also influenced by factors such as age, sex, and physiological state, revealing a complex neural control of these behaviors.
Dr. Catherine Dulac’s lab has been focused on parental behavior, a set of naturalistic social behaviors involving interactions between infants and adults to support the survival of young. Recent discoveries have made significant progress in defining the neural mechanisms governing pro-parental interactions. Studies in Dr. Dulac’s lab have made the seminal discovery that galanin-expressing neurons of the medial preoptic area (MPOA) are essential for pro-parental behavior in male and female mice (Wu et al., Nature, 2014), that the MPOA galanin neurons have many projections and inputs that coordinate specific components of parental behavior (Kohl et al., Nature, 2018), and that specific subsets of galanin neurons in the MPOA respond to pups under different physiological conditions (Moffit, Bambah-Mukku, Science, 2018).
However, less is known about the circuit mechanisms controlling anti-parental interactions with offspring. Infanticide became a flashpoint in ethological studies when Sarah Hrdy first observed this behavior in male langurs in the 1970s as part of her Ph.D. work at Harvard. This research was initially met with criticism that the behavior was either pathological or incorrectly documented. However, since then, infanticide has been observed in a range of species, including mice: attack of infants by foreign males is thought to correspond to an evolutionarily conserved behavior to eliminate the progeny of rivals and sire their own, while in females, attack and neglect of infants is often associated with stress.
While the evolutionary and ecological pressures on this behavior are still a subject of active study in the wild, laboratory studies have focused on developing animal models in which to dissect the neurobiological mechanisms controlling infanticide. In many strains of laboratory mice, males show infanticidal behavior toward pups prior to mating and switch to parenting after mating. A recent study in the Dulac lab has defined some of the vomeronasal receptors that respond to pup cues in mice (Isogai et al., Cell, 2018), confirming a critical role for non-volatile odorants in infant-directed aggression behavior.
The current study (Autry et al., eLife, 2021) sought to follow up on these key observations by studying associated brain areas active during infanticidal behavior. First, several brain regions were identified by immediate early gene expression to be differentially active during infanticide including the lateral septum, the perifornical area of hypothalamus, and the medial amygdala. A majority of infanticide-activated neurons in the perifornical area of hypothalamus (PeFA) expressed the neuropeptide urocortin-3 (Ucn3). Intriguingly, this neural population has previously been implicated in the physiological stress response (Venihaki et al., Journal of Neuroendocrinology, 2004), but not for infant-directed behavior. Using this genetic handle, the authors were able to manipulate PeFA Ucn3-positive neurons in males and females as well as trace associated input and output components of the neural circuit.
The authors showed that optogenetic or chemogenetic activation of PeFA Ucn3-positive neurons in female mice reduced parental behavior and uncovered aspects of infant-directed aggression behavior while optogenetic inhibition in male mice blocked expression of infanticide. The authors next determined that the PeFA Ucn3 –positive neurons receive input from brain regions relevant for social behavior, parenting, and stress, further implicating this circuit node in control of infant-directed behavior. Subsequently, the authors showed that projections from the PeFA Ucn3-positive neurons connect to brain areas established to be essential for aggression and anxiety-related behaviors. Finally, the authors demonstrate that optogenetic activation of each major projection target elicits specific aspects of infant-directed aggression in female mice ranging from avoidance to attack.
Altogether, these data illustrate a novel role for a genetically-identified circuit node, the Ucn3-positive cells of the PeFA, in the control of infant-directed aggression in both male and female mice. This work offers tantalizing insights into the circuit-logic for infanticide, demonstrating that both sexes are capable of expressing this behavior, that stress may impact this circuit, and that this circuit node may be critical for integrating pup-cues with interoceptive cues into an aggressive response. Importantly, the PeFA Ucn3 circuit has been documented in primates (Battagello et al., Frontier Neuroanatomy, 2017) and might be conserved in humans as well. Thus, these data hold significant translational importance across many fields of research including neuroscience, ethology, and medicine.
by Anita Autry and Catherine Dulac
