Brainstem circuits for defensive states
The encounter of a threat evokes a multitude of systemic adjustments in order to avoid or reduce harm. ‘Defensive states’ are thus an important evolutionary adaptation, which has evolved in many animals and humans. However, a dysfunctional neuronal network that underlies those defensive states can lead to a variety of anxiety disorders in humans. The consequences are exaggerated reactions towards a (putative) threatening stimulus. A better understanding of the neuronal mechanisms that underlie defensive states is a fundamental prerequisite for new translational research approaches and find efficient and targeted therapies for anxiety disorder patients. Defensive states encompass for example changes in the behavior or cardiovascular adaptations. We aim at capturing dynamic state interactions by measuring a variety of different parameters simultaneously. Using novel analytical approaches, we define stereotypic combinations of those parameters building a distinct defensive state.
Our research focuses on the neural brain circuitries underlying those short-lasting microstates and long-lasting macrostates defensive states. Specifically, we concentrate onto brainstem circuits that exert control over and integrate behavioral and cardiac functions during the fear reaction. For this, we are using modern neuroscience techniques like anatomical tracings, optogenetics, in vivo calcium imaging, and in vitro electrophysiological recordings of identified neuronal circuit elements. The systems neuroscience approach allows us to observe and perturb certain neuronal populations not only defined by their molecular identity, but also by their connectivity with other specific circuit elements.
Cardiac interoception processes
Mental and cardiac health are intricately linked, as exemplified by a number of clinical studies showing increased risk of heart disease in patients suffering from depression or anxiety-related disorders. The autonomic nervous system links brain and heart, and serves as a crucial network element for bidirectional information flow. Yet, little is known about the circuit mechanisms underlying heart-brain communication and how cardiac feedback to the brain, a process termed interoception, influences affective behavioral states.
In the DCL we are developing state-of-the-art methods to modulate heart rate in freely moving mice by optical activation of cardiac-innervating neurons. By combining cardiac optogenetics, heart rate and neuronal activity measurements with classic and semi-naturalistic behavioral fear and anxiety tests in rodents we investigate the network mechanisms underlying internal states and their corresponding bodily functions. Together with the cardiology department at the University Hospital Würzburg we aim to develop a technology for general application in cardiology and neurobiology research to study pathophysiological processes in inter-organ systems disease mechanisms.
Cerebellar contribution to defensive states
The cerebellum has long been known for its function in sensorimotor control. Nevertheless, there is increasing evidence that the cerebellum is also involved in the regulation of aversive emotional states. While the cerebellar algorithm has been extensively characterized, the essential characteristics and biological substrate of its involvement in emotions, and its clinical implications remain unknown. This project aims to investigate and characterize the functional connections between the deep cerebellar nuclei, the output region of the cerebellum, and the midbrain periaqueductal grey. It is hypothesized that cerebellar-PAG circuits form a crucial network element that modulates aversive emotions via somatosensory integration of behavioural and autonomic responses. Anatomical tracings as well as deep brain imaging techniques and optogenetics are used to characterize functional pathways between those two brain regions.
This project is part of the Marie Skłodowska-Curie Innovative Training Network "Cerebellum and Emotional Networks" (CEN), funded by the European Union's Horizon 2020 Framework Program for Research and Innovation under Marie Skłodowska-Curie Agreement.
Defensive state mechanisms in Parkinson’s disease
Freezing of gait (FoG) is a severely debilitating motor symptom of Parkinson’s disease (PD) that currently lacks optimal treatment options. Anxiety has been associated with severity of FoG in PD, which is further affected by stress and emotional situations. In rodents, fear-induced freezing involves disinhibitory circuit mechanisms in the periaqueductal gray (PAG, Tovote et al. 2016), a midbrain structure where emotional and (pre-)motor circuits converge. As part of the Collaborative Research Centre TRR 295 ReTune, we investigate how the loss of monoaminergic neuromodulation during PD alters PAG activity, thereby contributing to locomotor dysfunction during fear and anxiety states.
Using a mouse model of synucleinopathy in combination with optogenetic, electrophysiological, and imaging techniques, we characterize the neuroarchitecture and function of brainstem circuits throughout the pathophysiology of PD to understand its effects on motor- and anxiety-related behavior. Ultimately, we aim at combining neuronal activity and kinematic parameters with behavioral and cardiac measurements to get an integrated understanding of the PD pathostate.