Fear balance is maintained by bodily feedback to the insular cortex in mice

Abstract

How the body regulates fear Although fear is important for survival, it is maladaptive if it is either too strong, as in anxiety disorders, or too weak, as in exaggerated risk taking. Working in mice, Klein et al . observed that the insular cortex has an unparalleled dual role in either enhancing or weakening the extinction of fear, depending on the internal fear state of the animal (see the Perspective by Christianson). This insula function helps to maintain fear within a homeostatic range and depends on bodily feedback signals: Fear-induced freezing behavior is associated with a slowed heart rate, which in turn dampens fear-evoked activity of the insular cortex. Two opposite signals, prediction of threat by fear-associated cues and negative feedback signals from the body, are thus integrated within the insular cortex. —PRS

Insular cortex corticotropin-releasing factor integrates stress signaling with social affective behavior

“…Not surprisingly, insula is associated with many cognitive functions and, in human neuroimaging studies, insula activity correlates with emotion recognition, pain, drug craving and anticipatory fear [ 5 – 8 ]. Specifically, the posterior insular cortex in rodents integrates external sensory cues with internal states and is interconnected with a number of subcortical regions to modulate behavior in response to these cues in a top-down fashion [ 4 , 9 , 10 ]. Aberrant activity and functional connectivity of the posterior insula and associated network structures leads to hypervigilance, increased interoception and poor emotion regulation—hallmark symptoms of many neuropsychiatric disorders including autism spectrum disorders, schizophrenia, and posttraumatic stress disorder [ 11 ].…”

Brain-wide screen of prelimbic cortex inputs reveals a functional shift during early fear memory consolidation

“…Out of the regions projecting to PL engrams, we selected six brain areas with consistent input tracing for further investigation, because of their previously documented implication in various aspects of fear memory: The EC, for its role in memory formation (Roy et al, 2017) and its known projection to the mPFC necessary at encoding (Kitamura et al, 2017) and retrieval (Pilkiw et al, 2022); the RSP for its necessity for recent (Cowansage et al, 2014) and remote fear memory recall (Todd et al, 2016); the INS for its requirement during the consolidation and expression of contextual fear memories (Alves et al, 2013), as well as for its regulation of fear expression (Gehrlach et al, 2019; Klein et al, 2021); vCA1 for its importance for CFC encoding (Kim & Cho, 2020) and recent recall (Jimenez et al, 2020); the BLA for the role of BLA to PL projections in memory encoding (Kitamura et al, 2017; Klavir et al, 2017) and PL to BLA projections in memory recall (Do-Monte et al, 2015; Kitamura et al, 2017); and the CLA as CLA to EC projections are necessary during memory encoding (Kitanishi & Matsuo, 2017) and for its involvement in attention (Atlan et al, 2018).…”

“…In line with the notion of an overall shift in PL circuits during early memory consolidation, we report that the INS → PL projection is necessary at recent, but not at remote memory recall. The INS as a whole has classically been involved in taste learning (Yiannakas & Rosenblum, 2017) and the encoding of conditioned taste aversion (Sano et al, 2014), but has also been been implicated in recent CFC recall (Alves et al, 2013) as well as in auditory fear memory extinction (Klein et al, 2021). The INS to mPFC reciprocal connectivity has only been investigated in the context of taste learning, where it was recently found necessary for the expression of novel taste aversion (Kayyal et al, 2021).…”

Sex Hormone-Specific Neuroanatomy of Takotsubo Syndrome: Is the Insular Cortex a Moderator?

“…When an individual confronts danger, a combination of autonomic, behavioral, and cognitive responses occurs for self-preservation. These features are shown to be merged at the Ic, which fine-tunes behavioral responses to match the level of expected danger [ 124 , 125 ]. In light of these findings, it is possible that altered amygdalo-insular connectivity might also play a pivotal role as a TTS trigger, linked to increased sympathetic nervous system activity ( Figure 9 ).…”