State-dependent Neural Processing

Lead Research Organisation: The Francis Crick Institute

Abstract

We are investigating how the state of the body shapes information processing in the brain. The brain coordinates behaviour through evolutionarily sculpted neural circuits. These circuits do not work in isolation. Instead how they work profoundly depends on an animal’s current physiological state, such as sleep or hunger. Little is known about the molecular, cellular and circuit-level mechanisms by which such internal states alter neural processing in the brain. We aim to address these questions by using the mouse as a model. Mice have very robust and elaborate behaviours, and we can study their brains using a wide range of recently developed genetic tools. We use a multidisciplinary approach, combining cutting-edge methods in circuit neuroscience, molecular and cellular biology, and behavioural analysis to investigate how signals from the rest of the body affect the brain. Studying these mechanisms will provide us with exciting insights into brain function in both health and disease.

Technical Summary

This work was supported by the Francis Crick Institute which receives its core funding from the UK Medical Research Council (FC001000), the Wellcome Trust (FC001000),and Cancer Research UK (FC001000)

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.

Publications

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