Sex-specific neuromodulation in adaptive instinctive behaviours

• Applicant: Elena Kutsarova, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515465001

Instinctive behaviours, such as hunting, mating and escape require no prior learning and are critical for the survival of the individual and the species. The neural circuits underlying these behaviours are highly conserved, and are often considered to be ‘hard-wired’ to support stereotyped behavioural outputs. Mounting evidence however suggests that there is substantial flexibility in instinctive behaviours. Action selection and execution of these behaviours can vary as a result of the internal state (e.g. hunger, stress, oestrous) and prior experience of the animal. A neural hub crucial for the execution of most instinctive behaviours is the midbrain periaqueductal gray (PAG). Here, a columnarly organised network of glutamatergic and GABAergic neurons provides the neural substrate for executing appropriate behaviours. The PAG expresses a very high density of neuromodulatory receptors, such as opioid receptors. Despite being well-positioned to bestow the PAG with flexibility, the role of neuromodulation in PAG function is poorly explored. This is largely because little is known about the cytoarchitecture, synaptic properties and network topology of the PAG. In this project, I will focus on the role of neuromodulation in the PAG in the emergence of flexibility in instinctive behaviours in mice. I will take advantage of naturally occurring changes in opioid neuromodulation between males and females, and across the oestrous cycle in females, to reveal plasticity mechanisms in individual neurons and the resulting changes in circuit computations. I have obtained preliminary data confirming that there are indeed sex- and oestrous specific changes in the density of opioid receptors and further extending the previous literature to suggest that the excitation-to-inhibtion balance in the PAG may be shifted in a sex- (and oestrous) specific manner. This shift may have profound effects on the selection and execution of instinctive behaviours. The successful completion of this study will result in the first systematic characterisation of PAG microcircuits. Further, identifying the neural basis for sex-specific differences in instinctive behaviours will be paramount in supporting a societal shift towards better understanding the dramatically overlooked specifics of female physiology.

• DFG Programme: WBP Position