The amygdala instructs insular feedback for affective learning

Abstract

Affective responses depend on assigning value to environmental predictors of threat or reward. Neuroanatomically, this affective value is encoded at both cortical and subcortical levels. However, the purpose of this distributed representation across functional hierarchies remains unclear. Using fMRI in mice, we mapped a discrete cortico-limbic loop between insular cortex (IC), central amygdala (CE), and nucleus basalis of Meynert (NBM), which decomposes the affective value of a conditioned stimulus (CS) into its salience and valence components. In IC, learning integrated unconditioned stimulus (US)-evoked bodily states into CS valence. In turn, CS salience in the CE recruited these CS representations bottom-up via the cholinergic NBM. This way, the CE incorporated interoceptive feedback from IC to improve discrimination of CS valence. Consequently, opto-/chemogenetic uncoupling of hierarchical information flow disrupted affective learning and conditioned responding. Dysfunctional interactions in the IC↔CE/NBM network may underlie intolerance to uncertainty, observed in autism and related psychiatric conditions.

Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction

“…The CeA promotes aversive affective states, including fear-like responses ( 140 ) and anxiety-like responses ( 141 ). The CeA has been implicated in affective learning, and recently, a reciprocal insular cortex–CeA circuit was shown to link conditioned stimuli valence with interoceptive states to drive conditioned responding ( 142 ).…”

“…The CeA also reciprocally interacts with the BNST (136,137) and sensitizes to glucocorticoid feedback following chronic stimulation of the HPA axis (138,139) (141). The CeA has been implicated in affective learning, and recently, a reciprocal insular cortex-CeA circuit was shown to link conditioned stimuli valence with interoceptive states to drive conditioned responding (142).…”

Dorsal Bed Nucleus of the Stria Terminalis-Subcortical Output Circuits Encode Positive Bias in Pavlovian Fear and Reward

“…Such BNST dysregulation may, in fact, underly increased reward-seeking in rodent models of drug abuse (Erb et al, 2001 ; Shaham et al, 2003 ), as increased BNST anxiety may evolve into drug-seeking. Using a combined Pavlovian reward and fear conditioning paradigm (Shabel and Janak, 2009 ; Kargl et al, 2020 ) and circuit physiology, we examined how dBNST and its key outputs to PVH and PAG differentially encode and control fear and reward stimuli and behaviors.…”

Central amygdala circuitry modulates nociceptive processing through differential hierarchical interaction with affective network dynamics

“…This nociceptive information flow is antagonized by PKCδ + activity, which inhibits CEm outputs and suppresses aversive states in cortical networks bottom-up by uncoupling primary sensory and cingulate cortex from subcortical nociceptive states via direct synaptic projections to the basal forebrain. We note that PKCδ + projections to the basal forebrain gate the affective value of environmental stimuli in cortical areas 17 . Thus, PKCδ + activity may antagonize aversive brain states (pain) by uncoupling the cortical affective experience from the subcortical primary sensory component of pain.…”

“…A straightforward interpretation would be that the molecular makeup promotes neuronal activation in SST + cells, whereas it attenuates activation of PKCδ + neurons, in response to (the same) incoming nociceptive signals. In turn, this increases the inhibition of SST + onto PKCδ + neurons, potentially disinhibiting CE output to the brainstem, while suppressing PKCδ + -mediated bottom-up modulation of cortical pain states via the basal forebrain 17 .…”