Hypothalamic circuits for the selection of defensive and mating behavior in females

Project Information

YinYang

Grant agreement ID: 772827

DOI

10.3030/772827

Project closed

EC signature date 13 February 2018

Start date 1 March 2018

End date 29 February 2024

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 952 188,00

EU contribution

€ 1 952 188,00

Coordinated by

FUNDACAO D. ANNA DE SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Portugal

Periodic Reporting for period 4 - YinYang (Hypothalamic circuits for the selection of defensive and mating behavior in females)

Reporting period: 2022-09-01 to 2024-02-29

Summary of the context and overall objectives of the project

Sex is fundamental for species preservation and evolution. But sex can also pose danger to animals, as it increases the risk of predation or infection. Therefore, it is not surprising that in most species the willingness to engage in sexual behavior is restricted to periods when fertilization can occur and inhibited otherwise. In females this regulation is usually under the control of the reproductive cycle and sex hormones, whose fluctuating levels modulate the activity of neural circuits coordinating female sexual receptivity with reproductive capacity.
The close coordination between sexual receptivity and reproductive capacity is clearly demonstrated in rodents, as females only accept copulation attempts by the male and engage in sexual behavior during the receptive/fertile phase of the reproductive cycle. Outside the fertile period, sex never happens, not only because the female does not engage in receptive postures that allow for copulation, but also because they actively reject any attempt of copulation. Sadly, while a lot of attention has been dedicated to the study of the neural underpinnings of sexual receptivity and its modulation by the reproductive cycle, very little attention has been given to the study of rejection behavior.

The ventrolateral region of the ventromedial hypothalamus (VMHvl) is long known for controlling female sexual receptivity. This brain region not only receives male olfactory information, but its electrical stimulation increases receptivity, while its lesion has the opposite effect. Moreover, neurons within the VMHvl express receptors for the sex hormones progesterone and estrogen and given the fluctuating levels of these hormones across the cycle, it is not surprising that neural activity in this hypothalamic structure is in flux as well, biasing the outcome of socio-sexual interactions to match the reproductive state of the female.

While receptivity has been associated with plasticity in the VMHvl, nothing was known regarding the neural control of the rejection behavior displayed by non-sexually receptive females. Using the house mouse as model system, during the period of this grant we have studied the involvement of progesterone receptor expressing neurons of the VMHvl (PR+.VMHvl) in the regulation of rejection behavior across the reproductive cycle.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

While the VMHvl is unequivocally linked to female sexual receptivity, recent studies have uncovered an unappreciated complexity and multifunctional nature of this region, especially across its anterior posterior axis. In fact, it has been shown that receptivity is controlled by its most posterior region, as well as maternal aggression, in a hormone dependent manner. The rejection of sexual attempts should however not be mistaken for aggression but rather as a form of self-defense to avoid unwanted social interactions. Interestingly, rejection behavior displayed in the sexual context by female mice resembles the behavior of submissive males when faced with dominant intruders. Importantly, in males this self-defense behavior is controlled by the most anterior part of the VMHvl and as such we hypothesized if the anterior region of the VMHvl in females, in particular its PR+.VMHvl population, could be involved in rejection behavior when non-sexually receptive.

During the duration of this project, we gathered evidence supporting this hypothesis. In particular we have shown that:

- Anterior PR+VMHvl neurons are more active when non-receptive females interact with a male, an interaction dominated by rejection behavior, when compared with the same population in receptive females.
- Using calcium sensors to monitor the activity of PR+.VMHvl neurons in real time in behaving females, we found spatial segregation in the response profile of this population: while receptivity-related activity was observed in the posterior region, the anterior subpopulation is active when the female rejects.
- We have found a possible mechanism linking the reproductive cycle and the changing properties of anterior PR+.VMHvl neurons. With in vitro recordings we have found that the amount of inhibition received by anterior PR+.VMHvl neurons changes across the cycle, with these cells receiving less inhibition when females are non-fertile/non-receptive. This change in the amount of inhibition suggests that these cells might be more active when a non-receptive female interacts with a male and rejects him.
- To causally relate the changes in the electrophysiological properties of the anterior PR+.VMHvl population and rejection behavior, we performed optogenetic stimulation of anterior PR+.VMHvl neurons in receptive females which usually exhibit very low levels of rejection. As expected, the artificial stimulation increased rejection behavior in sexually receptive females and disrupted sexual behavior. Importantly, the behavior exhibited by manipulated females closely resembles the behavior of non-receptive females, supporting the idea that our manipulation impinged on the population that normally controls this behavior when females are not fertile.
- We have uncovered the output connectivity of the anterior and posterior PR+.VMHvl subpopulations to the midbrain, showing that anterior and posterior neurons have different connectivity, which might underlie the control of disparate behaviors, such as receptive posture and rejection.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

By carefully examining the in vitro and in vivo properties of spatially segregated populations of progesterone receptor expressing neurons within the VMHvl, in combination with detailed analysis of female sexual behavior and optogenetic manipulations of neuronal activity, we have identified a new hypothalamic subregion which controls female rejection behavior across the reproductive cycle. With our new results we would like to propose that the female’s response to copulation attempts across the reproductive cycle is the outcome of two parallel processes, receptivity and rejection, both controlled by distinct and spatially segregated subpopulations of PR+.VMHvl neurons, whose activity is modulated by sex hormones in a bidirectional and opposing manner.

Behavioral switch across the reproductive cycle