When interacting with the environment, we experience many different states simultaneously, like hunger, thirst, tiredness or fear, all underlined by fluctuating states such as hormone cycles or circadian rhythms. And the brain has to integrate all this information and decide on the most appropriate behaviour. 

Investigating how we integrate multiple states by looking at the human isn’t currently possible, so researchers like Jonny Kohl aim to explore this phenomenon in mice.  

“Brain architecture and hormones are very similar between mice and humans,” says Jonny. “So how the brain integrates incoming signals and responds appropriately might also be relatively similar.”

Hunger cues

In a new study published in Nature, Jonny and his team investigated how virgin female mice interact with pups when sated or hungry. Normally, virgin females ignore pups or are spontaneously parental, but after just a few hours after food is removed, a substantial number became aggressive towards pups, an effect that was diminished when the mice were fed. 

“These mice were only aggressive towards pups, and continued to act normally in other contexts, such as towards other adult mice,” says Jonny. “This suggested to us that hunger and parenting circuits in the brain somehow interact.” 

Finding the control centre in the brain

Mingran Cao, former PhD student at the Crick, who conducted the experiments, describes how the team identified the neurons behind this behavioural switch. 

“Neurons in the hypothalamus, called AgRP neurons, are responsible for regulating appetite, but we saw that they also mediate the effect of food deprivation on behaviour towards pups,” she explains. “Experimentally switching on AgRP neurons increased pup-directed aggression in satiated mice, and silencing them diminished pup-directed aggression in hungry mice.”

By tracing and manipulating projections from AgRP neurons, the researchers found that a region called the medial preoptic area (MPOA), important for parental behaviour, was a key downstream region for the effect of hunger on parental behaviour. 

Coordinating hunger and reproductive state

Still, a question remained. Why did only about 60% of females show aggressive behaviours? 

“Hunger levels were the same between aggressive and non-aggressive mice, so we considered that reproductive state might influence whether or not a mouse becomes aggressive,” Jonny considers. 

The team found that mice in certain stages of the reproductive ‘estrous’ cycle were more likely to become aggressive towards pups. Specifically, they observed that the ratio of the ovarian hormones oestradiol and progesterone, which fluctuate across the cycle, sets the baseline responsiveness of MPOA neurons.

The team then showed that hunger information carried by AgRP neurons dampens neuronal activity in the MPOA, stimulating the switch from caring behaviour to pup-directed aggression. 

They believe that these behavioural changes during the estrous cycle reflect a change in priorities as the mouse’s internal states fluctuate. 

“Female mice have to decide how to behave towards pups based on their current internal states, as parental interactions are usually very energetically costly,” Mingran concludes. “We’ve shown that their brains integrate physiological state (hunger) and reproductive state in the same region to elicit a state-dependent response.Our work focuses on mouse behaviour, and we know that humans don’t experience the same simple behavioural switches, but these findings stress the importance of understanding hormones when looking at how different physical states interact in the brain.”

One of the next steps in this line of research will be to look at how this integrated signal brings about behavioural changes downstream of the MPOA, shedding more light on how complex internal states shape behaviour.