Female socio-sexual behavior: role of hypothalamic neuronal activity across the reproductive cycle

Social encounters are often initiated with mutual investigation, but can develop into different outcomes depending on the internal state of the intervenients. For example, a non-sexually receptive female mouse will vigorously reject the mount attempts of a male. In contrast, during the receptive phase of the cycle, she will gladly mate with him. This adaptive switching in social decisions endows individuals with the capacity of exhibiting different behavioral strategies to maximize benefits and minimize costs. In the case of rodent reproduction, for example, can minimize the costs inherently associated with mating risk of predation and exposure to parasites. This capacity is fundamental for the well-being and survival of the individual and ultimately the species.

The ventrolateral region of the ventromedial hypothalamus VMHvl is essential for female sexual behavior: it has access to sensory stimuli from conspecifics and expresses receptors for sex hormones. Several studies have shown the VMHvl has a facilitatory role in female sexual behavior, since its activation electrical or with sex hormones increases the probability of exhibiting lordosis, a mating posture that aids copulation. Still, very little is known about the activity of the VMHvl in intact behaving females or how it underlies behavioral decisions in an adaptive manner across the reproductive cycle, in particular, prior to copulation.

Previously, using conventional extracellular electrophysiological recordings, our lab has discovered that the activity of female VMHvl neurons during social investigation is modulated by the reproductive cycle, so that the neural representation of male stimuli is enhanced during the sexually receptive state Nomoto and Lima, Current Biology 2015, in press. This gender-specific and state-dependent modulation of neuronal activity during investigatory behavior lead us to hypothesize that the enhancement in male representation may be necessary to drive the normal progression from social investigation appetitive phase to copulation consummatory phase, which usually occurs when a sexually receptive female interacts with a male.

To test this hypothesis, and taking advantage of state of the art tools available in mice, we propose three aims:

Aim 1: Identify populations of neurons within the VMHvl that are male responsive and which have the capacity of being modulated across the reproductive cycle. This neuronal populations should in principle fit three requirements: 1 Be activated in the presence of males; 2 Express receptors for sex hormones; 3 Project to other brain areas involved in the control of sexual behavior. We propose to use immediate early genes as read-out of neuronal activity in combination with immunohistochemistry and pathway specific viral tracers to identify this populations.

Aim 2: Monitor the activity of delineated populations of neurons in naturally cycling females engaged in interactions with males In collaboration with Rui M Costa at the Champalimaud Foundation. We will express genetically driven indicators of neuronal activity calcium indicators in the populations identified in Aim1 and test if their activity is indeed modulated by the reproductive cycle when females interact with males.

Aim 3: Establish a causal link between the activity of neurons whose firing rate is modulated across the cycle and the progression from social investigation to sexual interaction. This will be done by performing optogenetic manipulation of the neuronal populations identified in Aims 1/2. Briefly, we will use channelrhodopsin-2 and archaerhodopsin to activate and inhibit, respectively, the activity of neurons whose activity is modulated during the social investigation. We will test if manipulating the activity of these neurons will affect the subsequent sexual interaction.

Since investigatory behavior is crucial to all social behaviors, this proposal and our results may have implications not only for female sexual behavior, but also for other social behaviors such as aggression, social fear and maternal behavior, where the contributions of the VMHvl has recently been reported. By identifying the neuronal populations that are specifically involved in socio-sexual behavior, we will open the possibility of designing new drugs that can have an influence on female sexual behavior. And because the VMHvl is also present in primates, with similar connectivity and properties to the rodent counterpart, our findings might also be important for future research in human sexuality and social behavior in general.