Active and passive coping strategies: the periaqueductal grey to cerebellar link

Lead Research Organisation: University of Bristol
Department Name: Physiology and Pharmacology


From the perspective of survival, if a threatening, painful or fearful event arises it is imperative that an animal generates the appropriate behavioural response. The midbrain periaqueductal grey (PAG) plays a key role in mediating suitable 'coping strategies', involving an integrated array of cardiovascular adjustments, sensory regulation and motor output. Active coping (eg.confrontational behaviours with increased responsiveness to external stimuli) is associated with activation of a column of cells in the dorsolateral/lateral (dl/l) PAG, whilst passive coping (eg. quiescence with reduced responsiveness to external stimuli) is associated with activation of a column of cells in the ventrolateral (vl) PAG. A major gap in our understanding concerns how these different columns of the PAG are connected to the motor system to elicit these distinct defensive responses. It is also unknown if the functional columns of the PAG differ in their regulation of sensory signals that feed into (and can modify) motor circuits. The proposed plan of work will build on experiments in which we have shown that vlPAG projects to pre-cerebellar structures, can evoke activity in the cerebellum, and can also powerfully control access of sensory signals to this major brain centre critically involved in movement control. The cerebellum is a highly modular structure so there is ample scope for different pathways to be involved in the range of behaviours associated with active and passive coping. We will therefore focus attention on PAG links to cerebellar circuits. Our key aims are to: 1) chart the chain of neural connections that link the different functional columns of the PAG to the cerebellum and pre-cerebellar structures; 2) test directly for a causal link between cerebellar function and PAG-related motor output; and 3) study the role of individual functional columns of the PAG in controlling access of sensory information to different cerebellar modules. Choice of techniques To understand how distinct behaviours are underpinned by neuronal networks in the intact animal we will use the combined power of anatomical, pharmacological, electrophysiological and behavioural techniques at the systems level of analysis. Linking these different methods should greatly improve our understanding of the way (i) different functional columns of the PAG regulate transmission of sensory signals of different behavioural significance (non-noxious versus noxious) in pathways important for movement control and (ii) the structure and function of neural circuits through which PAG elicits different motor responses associated with active versus passive coping. In particular, if specific modules of the cerebellum are an essential part of the neural circuitry by which individual functional columns of the PAG elicit particular motor responses, then inactivation of these modules should lead to an altered motor response. Choice of experimental model The defensive behaviours elicited by different functional columns of the PAG are very similar in rat and cat, and our pilot work in rats suggests that a link between the PAG and modules in the cerebellar vermis may be an important component of this circuitry. Cerebellar architecture and patterns of connectivity, especially of the vermis are highly conserved across mammalian species. Our results using rats as an experimental model should therefore have general applicability. Since regulation of sensory signals by the PAG is a dynamic process dependent on behavioural state our programme of experiments will also include study of the changes in such control during development of two well characterized behavioural situations in which the PAG is involved: (i) the acquisition of a chronic pain state; and (ii) the acquisition of an aversive (fear) response. Overall, these experiments will therefore reveal the structure and dynamic function of the basic neural circuitry underlying behavioural responses critical to survival.

Technical Summary

The periaqueductal grey (PAG) plays a pivotal role in CNS circuitry by mediating defensive behaviours in response to stressful, painful or threatening situations. Active and passive coping strategies arise from different functional columns within the PAG. However, there is a conspicuous lack of data on how the PAG interacts with supraspinal motor circuits to elicit these distinct behavioural responses critical for survival. The current study will address this important gap in our understanding, building on our recent BBSRC funded work and highly novel preliminary findings that demonstrate a potent link between the PAG and the cerebellum (the largest sensorimotor structure in the brain). We will test the related hypotheses that: 1) distinct PAG-cerebellar connections are involved in active versus passive coping, and 2) PAG regulation of sensory inputs to the cerebellum are dynamic. To test these hypotheses three in vivo experimental approaches will be used in rats: (i) neuroanatomical/physiological mapping; ii) intervention experiments in naive and age-matched animals in which a chronic pain state has been induced, and iii) behavioural studies in which sensory inputs to the cerebellum will be studied during aversive conditioning. The mapping studies will determine the spatial pattern of PAG efferents to cerebellar-related structures. The complementary electrophysiological and behavioural studies will characterize and provide direct evidence for: PAG-cerebellar functional links; the role of the cerebellum in mediating motor output elicited by the different functional columns within PAG; and how sensory inputs to the cerebellum are controlled by the PAG in an experience-dependent manner. Overall, these experiments will provide new insights into the way the PAG interacts with the motor system to elicit behavioural responses essential to animal welfare and survival.


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Description -Strong physiological link between the dorsolateral/lateral periaqueductal grey (dl/lPAG) and olivocerebellar system. -A reduction in conditioned freezing behaviour resulting from targeted olivocerebellar lesion is accompanied by a reduction in C-Fos e
Exploitation Route The findings will be of use to other researchers, including pharma, with an interest in neural mechanisms of fear, anxiety and pain
Sectors Pharmaceuticals and Medical Biotechnology

Description Optogenetic control of cerebellar operation during coping behaviours in a Cre transgenic rat 
Organisation Helmholtz Association of German Research Centres
Department The Max Delbrück Center for Molecular Medicine (MDC)
Country Germany 
Sector Academic/University 
PI Contribution We have developed a collaboration with a research group based in MDC Research Institute in Berlin, Germany. The overall aim of this collaboration is to identify the feasibility of using the sophistication of optogenetic methods, in a Cre recombinase transgenic rat (developed by our collaborators in MDC), to study the contributions that the mammalian cerebellum makes to the control of behaviours (motor and cognitive) associated with coping strategies (i.e. fear behaviour). The results from this collaboration will allow the function of key components of brain pathways to be studied with high levels of precision and in addition will shed light on fundamental brain processes that underly our ability to perform coordinated movements under threatening circumstances, which fits very well with the remit of our ongoing project grant.
Start Year 2012