Both Cardiovascular and Behavioral Threat Responses Contribute to Defensive States
Post by Lincoln Tracy
The takeaway
A new framework developed in mice involving microstates, macrostates, specific behaviors, and heart rate dynamics has proven beneficial in learning more about the complex neural states and associated systemic functions in response to an external threat.
What's the science?
The typical defensive reaction to an external threat, a key part of fear or anxiety, involves multiple behavioral and physiological responses that are controlled by our neural circuitry. There have been attempts to propose a unified and species-preserved concept describing defensive responses, or ‘states’, but such attempts have largely focused on behavioral mechanisms and ignored autonomic responses. This week in Nature Neuroscience, Signoret-Genest and colleagues provide a novel framework for characterizing integrated cardiovascular and behavioral defensive states using behavioral, heart rate, and thermal imaging data from freely moving mice across several experimental paradigms. They show how this allows linking of specific defensive states to key brain circuitry such as the periaqueductal gray (PAG).
How did they do it?
The authors implanted electrocardiogram electrodes in mice, which allowed them to record changes in heart rate while the mice were exposed to a series of environments that varied in threat intensity and acuteness, each eliciting a different emotional state. The environments included low-threat situations (i.e., their home cage) to high-threat, fear and anxiety-evoking experiments such as a conditioned fear (or ‘flight’) paradigm, the open field test, and the elevated plus maze. The authors were interested in comparing the association between immobility, or ‘freezing’ behaviors, and decreases in heart rate when the mice were exposed to different threat environments. Finally, they used optogenetics to manipulate the activity of glutamatergic neurons as well as subtypes of this population (vesicular glutamate transporter 2 [Vglut2] and Chx10) in the PAG in an attempt to identify the specific neural circuits involved in the control of these defensive states.
What did they find?
First, the authors identified threat ‘microstates’, involving immobility and bradycardia (a decrease in heart rate) during the conditioned flight paradigm. They noticed that the immobility-associated bradycardia increased as the conditioning session went on, and hypothesized there were other underlying processes interfering with the heart rate changes at both a global level and in the defensive microstates. They called the dynamic changes operating at an extended timescale ‘macrostates’. This suggests that rather than simply following changes in behavioral activity (rearing or immobility), threat-induced changes in heart rate reflect integrated defensive microstates involving both behavioral and autonomic components. The authors also found the changes in heart rate were strongly influenced by the pre-existing state of the animal. Furthermore, they identified that the integrated defensive response was context-dependent, with higher contextual threat levels resulting in more constrained heart rate changes. Finally, they found stimulating Vglut2+ neurons evoked intensity-depended behavioral and cardiovascular responses (low intensity stimulation led to immobility and bradycardia, while high intensity stimulation led to a mixture of flight responses and immobility accompanied by bradycardia) but stimulating Chx10+ neurons led to robust immobility and bradycardia. This suggests Chx10+ neurons in the midbrain periaqueductal gray mediate a particular defensive microstate associated with both immobility and bradycardia.
What's the impact?
The findings from this study act as a starting point for a more complete understanding of the neuronal mechanisms underlying emotions such as fear and anxiety. The novel framework teases the possibility of returning to a translational research pathway (from mice to humans) and the potential ability to explore maladapted fear and anxiety responses across species.
