Role of the cerebellum in survival circuits activated by fear.

Our understanding of how disturbances in neural networks in the brain result in emotional disorders is limited, and many patients (animal and human) don't respond well to existing treatments. Fundamental research into the neural networks that underlie 'survival circuits' in animals will provide essential information that will inform the development of new therapeutic strategies.

There are two types of survival circuits that produce defensive responses to aversive or fearful events. One generates an UNCONDITIONED response, innate and hard wired, the other a CONDITIONED response, the result of activity in survival circuits modified by experience. Both co-ordinate adjustments to emotional state, cardiovascular activity and generate appropriate actions such as fight, flight or freezing. The sum of these activities constitutes a defensive response.

The neural networks involved can be likened to a postal service that 'knows' what's being posted and where it needs to go in order that the appropriate information informs the necessary outcome. A major gap in our understanding concerns how this postal service engages with motor systems of the brain to elicit distinct and behaviourally appropriate unconditioned and conditioned defensive responses to fearful events. It is also unknown if the motor system can feed back and modify activity in survival circuits.

We aim to provide new insights into the ANATOMY - which defines the 'postal address'; the PHYSIOLOGY - which determines the nature of the 'message' being transmitted; and the BEHAVIOUR- the effect the message has. The cerebellum is the largest motor controller in the brain and an emerging concept is that it plays a key role in this postal system. Recently we have shown that defensive freezing behaviour in rats, evoked by unconditioned and conditioned fearful events, is dependent on intact cerebellar circuitry. The cerebellum is a highly modular structure, so there is ample scope for different pathways to be involved in the range of defensive responses essential for survival.

We will focus on cerebellar interactions with key components of central survival circuits, namely the midbrain periaqueductal grey and the amygdala. Our key objectives are to:
(i) chart the chain of neural connections that link the cerebellum with the brain survival network;
(ii) test directly for a causal link between cerebellar function and survival circuit-related unconditioned and conditioned defensive responses.

We will use the combined power of anatomical, electrophysiological and behavioural techniques at the systems level of analysis to improve understanding of the structure and function of brain circuits involved in animal survival. If specific regions of the cerebellum (modules) are an essential part of the neural network by which survival circuits elicit particular aspects of a defensive response, then experimental inactivation of these different regions should lead to an altered emotional, motor and/or cardiovascular response.

Choice of experimental model: cerebellar and survival network architecture and patterns of connectivity are highly conserved across mammalian species, including human. However, rats are the experimental animal of choice because our understanding of the basic neuroanatomy and physiology is most complete in this species. Importantly, our experiments will include study of neural network interactions during behavioural situations that have been most thoroughly characterized in rats, namely: unconditioned and conditioned behaviours in response to exposure to an aversive or fearful stimulus e.g. predator (cat) odour and aversive footshock.

Our results should reveal general rules as to how brain circuit structure and information coding give rise to the well-defined behavioural responses that are so critical to animal welfare and survival.

Understanding the anatomy and physiology of central survival circuits is an essential prerequisite to determining the neurobiological basis of emotional disorders. The neural network underpinning survival behaviours includes the amygdala and midbrain periaqueductal grey (PAG) which generate defensive responses to aversive or fearful stimuli. Different circuits within the network generate innate and conditioned responses. But how these survival circuits interact with supraspinal motor/cognitive systems to elicit appropriate behavioural responses remains poorly understood.

Building on preliminary data that demonstrate a potent link between the cerebellum and the PAG, we will test the hypothesis that cerebellar interaction with survival circuits is dependent on its modular organization. More specifically, that different parts of the cerebellar A module located in individual vermal lobules, are associated with cognitive, motor and/or autonomic aspects of defensive behaviours.

Three systems level approaches will be used in adult rats:
(i) anatomical/electrophysiological mapping, including use of transneuronal axonal tracers; ii) intervention experiments; and iii) behavioural studies in which cerebellar neuronal interactions with survival circuits will be studied during innate and associative fear conditioning.

The mapping studies will determine the spatial pattern of cerebellar efferents to survival circuits. The physiological and behavioural studies will characterize cerebellar-survival circuit functional links (with a focus on connections with PAG), and will provide direct evidence of a causal link between network interactions and function.

Overall, the project will provide new insights into the structure and function of survival circuits with the overarching goal of providing the foundations for understanding the neural mechanisms that underlie emotional disorders.

The research will be of benefit to:
(i) Companion and farmed animals with anxiety-related behavioural disturbances.
(ii) Patients suffering from anxiety disorders; and their families, charities and organizations seeking to support patients with such disorders.
(iii) The research staff employed on the grant.
(iv) Members of the general public with an interest in anxiety disorders.
(v) Academia.

How will they benefit from this research?
(i) Companion and farmed animals with anxiety-related behavioural disturbances. These are common problems and can lead to behavioural (e.g. stereotypy, aggression), reproductive (e.g. infertility) and other issues. A greater understanding of the neural circuitry underpinning emotional behaviour could, in the longer term, lead to identification of novel brain targets for drug treatment without producing sedation. This would be hugely advantageous in a range of common veterinary problems such as managing fear aggression and separation anxiety in pet dogs. In the longer term our research hopes to improve treatment of such animals by identifying novel brain targets for drug treatment. Progress in understanding network dysfunction that leads to anxiety disorders requires a global perspective on brain function i.e. it is not sufficient to study one brain region in isolation. The network analysis we seek to provide will offer a more accurate picture of the neurobiology involved.

(ii) Patients suffering from anxiety-related disorders. At present there is no satisfactory treatment for mood related psychiatric diseases (e.g. anxiety disorders including post traumatic stress disorder and phobias). In large part this is because the underlying neurobiology of these disorders is unknown. The impact of the research on patient groups and their families will be in terms of identifying potential new targets for therapies and being able to provide a better understanding of the brain circuitry that underpins these distressing conditions. These types of disorder can also be very damaging to an individual's social life and well being, leading to a negative impact on carers, friends and family. By providing insights into normal and aberrant brain circuit function associated with anxiety disorders, the research will enable charities which support patients with such disorders to realize their mission of providing education and help to patients and their carers.

(iii) The named staff employed on the grant will develop expertise in highly novel and state-of-the-art research techniques that will aid their future careers. As indicated in the Academic Beneficiaries section, there is a worldwide skills shortage of researchers with experimental animal in vivo research expertise. By taking a lead role in the research programme (see work plan) the named postdoc will also develop her time/project management, communication, team working and other transferable skills.

(iv) Members of the general public. The findings from this project are applicable to understanding human anxiety disorders. Such knowledge is of wide interest to the general public. The findings will therefore be appropriate to disseminate through public engagement activities.

(v) Academia. International academia in the fields of preclinical and clinical psychiatry, as well as basic scientists in the fields of motor, cognitive and behavioural neuroscience are likely to benefit from the scientific progress made by this research (see 'Academic Beneficiaries').