Title: State-dependent Neural Processing
Funder: The Francis Crick Institute

Abstract: The brain is typically thought of as a system that receives sensory inputs, processes this information and then generates appropriate behavioural outputs. In recent years, dramatic progress has been made by systems neuroscience towards understanding the form and function of the brain circuits underlying this transformation. One common observation, however, is that identical sensory inputs can result in vastly different behavioural outputs, depending on an animal’s physiological (internal) state. Such internal states are often mediated by modulators such as hormones, but we know little about how these molecules act on the brain to alter behaviour. Our overarching goal is to understand the mechanisms underlying such state-dependent neural processing. Pregnancy will be a central paradigm for this purpose, since (1) it is a well-defined change in reproductive state, which (2) is associated with drastic behavioural adaptations, and (3) for which key hormones and receptors have been identified. I therefore propose to investigate, in a mouse model, how the hormonal milieu of pregnancy alters information processing in the brain. Recent methodological advances now offer an exciting opportunity to link behavioural phenomena with their underlying molecular, cellular and circuit-level mechanisms. Genetically specified neuronal populations were recently identified which mediate specific instinctive behaviours such as parenting, feeding and aggression, and genetic the circuits within which these neurons operate have been anatomically and functionally dissected. However, it has become clear that the function of these circuits is not static, but rather depends on the animal’s physiological (internal) state. For instance, my own work has shown that reproductive state profoundly modulates the function of circuits for parental behaviour. Since changes in reproductive state are also associated with striking changes in food intake and aggressivity, hormonal changes very likely act on feeding and aggression circuits. Despite existing behavioural data from rats the exact time course, location, and cellular and circuit-level mechanisms of pregnancy hormone action remain unclear. Our goal is to uncover the underlying mechanisms using a combination of state-of-the-art approaches, including automated behavioural profiling, functional imaging, in vitro and in vivo electrophysiology, in vivo optical recordings, optogenetics and chemogenetics, viral circuit tracing and single-neuron expression profiling. Understanding the molecular, cellular and circuit-level mechanisms by which physiological states affect neural information processing will advance our knowledge of brain function in health and disease. In the case of pregnancy, understanding hormonal effects on the brain is critical not only from a biological, but also from a clinical perspective, since this period is associated with an increased risk of developing mental health problems such as postnatal depression. More general, addressing the effects of hormones on neurons in their native context – in vivo – might critically contribute to the development of novel therapeutic agents for the treatment of neuropsychiatric disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL