Estrus-Cycle Regulation of Cortical activity

The brain of mammalian females is exposed to periodic fluctuations of hormones known as the menstrual (in humans) or estrus (in rodents) cycle, during the reproductive period. Sex hormone fluctuations are known to modulate social, sexual and reproductive behaviors, as well as drug craving and appetite control. These hormonal fluctuations are also associated with female-specific risks for neuropsychiatric disorders, such as anxiety and depression, premenstrual dysphoric disorder, menstrual migraine attacks, cyclic aggravation of psychotic symptoms in women with schizophrenia and the cyclic occurrence of epileptic crisis in catamenial epilepsy.

Unfortunately, while cyclical changes have been investigated in subcortical structures such as hypothalamus and basolateral amygdala, the female cortex and, in particular, its inherent dynamics remain so far largely unexplored. As a consequence, the neuronal mechanisms underlying estrus-related changes in cortical functions are unknown. The lack of previous studies is partly due to the fact that methods for recording large populations of neurons during several consecutive days (such as the 5 days of a rodent's estrus cycle) have only been developed in recent years.

In addition, studies focusing on the female brain have been historically rare compared to studies including exclusively males.

Rodents represent a good model to study the effects of naturally occurring sex-hormone fluctuations on brain activity since the human follicular and luteal phases are mimicked by the rodent proestrus (high oestrogen-low progesterone) and early diestrus (low oestrogen-high progesterone) phases, respectively. The aim of this project is to test whether estrus modulates cortical activity, using the mouse visual cortex as a model of cortical circuits.

We will use, the recently developed high density silicon probes (Neuropixels probes) that offer the advantage of high-throughput and standardized recordings of both excitatory and inhibitory neuronal activity across all cortical layers simultaneously, and throughout a complete mouse estrus cycle (5 days). The cycle stage will be determined based on daily vaginal smears and visual inspection of vagina. Specifically, we will test whether:

Estrus modulates the activity of cortical excitatory and inhibitory neurons across cortical layers Estrus-cycle dependent activity differs across cortical areas

This project would strongly benefit from a Pioneer award since it is hard to obtain funding for such study without preliminary data. The acquisition of such preliminary data, however, requires substantial funding since these experiments require a highly skilled post-doctoral researcher as well as costly consumables (chronic recording probes).

These results will be critical to investigate the neuronal mechanisms underlying sex hormone-dependent behaviours and brain functions. More generally, it will open a new field of research investigating the impact of hormones on cortical functions in both males and females, in the young and ageing mammalian brain. Noteworthy, both a negative (no estrus-dependent changes) and a positive (estrus-dependent changes) outcome of this project will be highly valuable.

A negative result will indicate that cyclic brain changes in activity are restricted to subcortical areas, which is important to understand the origin of sex-hormone dependent disorders. In addition, one of the major reasons for excluding females from studies is that female neuronal activity and behavior are thought to be intrinsically more variable than males.

A negative result, i.e. no variation of cortical activity during estrus cycle, will show that this assumption is wrong. A positive result, showing that the variability occurs as a function of sex hormone levels, will be critical to create a foundation for future studies investigating sex-specific and sex-hormone-dependent cortical activities in health and disease, throughout the lifespan of the mammalian brain.