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State-dependent regulation of fear extinction learning by the interoceptive insular cortex
State-dependent regulation of fear extinction learning by the interoceptive insular cortex
Fear is an adaptive behavioral response to avoid or reduce harm and thus ensure survival. However, fear is maladaptive when it persists in the absence of direct threat or when it prevents an organism to attend to its homeostatic needs. The interoceptive, posterior insular cortex (pIC) is the major cortical recipient for signals from inside the body and is at the same time increasingly recognized as an intricate part of a wider neuronal network regulating fear and anxiety. However, the neuronal underpinnings of an insular role in fear regulation remain elusive. In my thesis, I demonstrated that the pIC regulates the extinction of learned fear in a state dependent manner. Using fiber photometry recordings of excitatory neuron activity and electrophysiological single-unit recordings in the mouse pIC, I found that the pIC processes state-dependently fear-eliciting cues and painful stimuli. Further, I revealed that specific subpopulations of pIC neurons encoded sustained affective states. I next conducted optogenetic silencing experiments to decipher the involvement of the pIC in extinction learning and revealed surprising, bidirectional effects: while pIC inhibition facilitated extinction learning in animals displaying a low internal fear state, the same circuit manipulation impaired fear extinction learning in animals displaying a high internal fear state. Additionally, in an attempt to unravel how internal states can influence pIC activity, I developed a vagus nerve stimulation (VNS) protocol to manipulate interoceptive processes during extinction. I found that stimulation of the vagus nerve, that carries bodily signals to the brain, elicited insula activity and regulated extinction learning in the same, bidirectional and state-dependent manner. Taken together, my data suggest that the pIC maintains optimal fear extinction learning despite differences in internal fear states, a process that may be modulated by vagal afferents transmitting interoceptive signals to the brain.
Insula Interoception, Vagus nerve, State-dependency fear, fear extinction
Klein, Alexandra
2020
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Klein, Alexandra (2020): State-dependent regulation of fear extinction learning by the interoceptive insular cortex. Dissertation, LMU München: Faculty of Biology
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Abstract

Fear is an adaptive behavioral response to avoid or reduce harm and thus ensure survival. However, fear is maladaptive when it persists in the absence of direct threat or when it prevents an organism to attend to its homeostatic needs. The interoceptive, posterior insular cortex (pIC) is the major cortical recipient for signals from inside the body and is at the same time increasingly recognized as an intricate part of a wider neuronal network regulating fear and anxiety. However, the neuronal underpinnings of an insular role in fear regulation remain elusive. In my thesis, I demonstrated that the pIC regulates the extinction of learned fear in a state dependent manner. Using fiber photometry recordings of excitatory neuron activity and electrophysiological single-unit recordings in the mouse pIC, I found that the pIC processes state-dependently fear-eliciting cues and painful stimuli. Further, I revealed that specific subpopulations of pIC neurons encoded sustained affective states. I next conducted optogenetic silencing experiments to decipher the involvement of the pIC in extinction learning and revealed surprising, bidirectional effects: while pIC inhibition facilitated extinction learning in animals displaying a low internal fear state, the same circuit manipulation impaired fear extinction learning in animals displaying a high internal fear state. Additionally, in an attempt to unravel how internal states can influence pIC activity, I developed a vagus nerve stimulation (VNS) protocol to manipulate interoceptive processes during extinction. I found that stimulation of the vagus nerve, that carries bodily signals to the brain, elicited insula activity and regulated extinction learning in the same, bidirectional and state-dependent manner. Taken together, my data suggest that the pIC maintains optimal fear extinction learning despite differences in internal fear states, a process that may be modulated by vagal afferents transmitting interoceptive signals to the brain.