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Review
. 2021 Nov 17;109(22):3576-3593.
doi: 10.1016/j.neuron.2021.08.036. Epub 2021 Sep 27.

Cellular activity in insular cortex across seconds to hours: Sensations and predictions of bodily states

Yoav Livneh  1 , Mark L Andermann  2
Affiliations
Review

Cellular activity in insular cortex across seconds to hours: Sensations and predictions of bodily states

Yoav Livneh et al. Neuron. .

Abstract

Our wellness relies on continuous interactions between our brain and body: different organs relay their current state to the brain and are regulated, in turn, by descending visceromotor commands from our brain and by actions such as eating, drinking, thermotaxis, and predator escape. Human neuroimaging and theoretical studies suggest a key role for predictive processing by insular cortex in guiding these efforts to maintain bodily homeostasis. Here, we review recent studies recording and manipulating cellular activity in rodent insular cortex at timescales from seconds to hours. We argue that consideration of these findings in the context of predictive processing of future bodily states may reconcile several apparent discrepancies and offer a unifying, heuristic model for guiding future work.

Keywords: cellular level; circuit level; gustatory; homeostasis; human; hunger; insula; insular cortex; interoception; motivation; mouse; need states; prediction; predictive coding; rat; salient cues; thirst; visceral.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

Figure 1:
Figure 1:. InsCtx as a Sensory Cortex – Function and Connectivity
A. Illustration of some of the different organs and systems that are thought to provide direct or indirect sensory information to InsCtx (highlighted in red): mouth and tongue, stomach, intestines, liver, pancreas, blood, kidneys, heart, and lungs. Note that several additional relevant organs, such as the urinary bladder, esophagus, and genitals, are not shown. B. Schematic side-view of the rodent brain, highlighting the different cytoarchitectural subdivisions of InsCtx (purple), and their neighboring cortical regions. A: anterior, P: posterior, D: dorsal, V: ventral. C. Spatial organization of some of the prominent inputs to InsCtx. Purple and grey regions receive or lack these inputs, respectively. D. Summary of the brain-wide connectivity of posterior, mid, and anterior InsCtx. Note increasing sensory cortical input and decreasing motor output from anterior to posterior regions. Modified with permission from Gehrlach et al., 2020. E. Schematic view of the primate InsCtx and the general organization of its inputs. Based on Evrard, 2019. Connectivity in human InsCtx is considered to be very similar.
Figure 2:
Figure 2:. InsCtx Activity on Short and Long Time-Scales
A-B. Examples of InsCtx activity on short time-scales. A. Single-trial responses of a single InsCtx neuron (spike rasters) to intra-oral infusion of different tastants, and to an air-puff to the whisker region. Modified with permission from Vincis et al., 2016. B. Top: Single-trial responses of 3 different InsCtx neurons (Ca2+ imaging of fluorescence changes) to a visual food cue (gray bar at bottom), lick bout onsets (white ticks) and liquid food reward (Ensure; pink ticks). Heatmaps sorted by lick bout onset. Bottom: average response. Modified with permission from Livneh et al., 2017. C-D. Examples of InsCtx activity on long time-scales. C. Ongoing activity of a population of simultaneously imaged InsCtx neurons (calcium imaging of fluorescence changes in a subset of inter-trial intervals, see Livneh et al., 2020 for details) during gradual quenching of thirst. After a quenched state was reached, the hypothalamic thirst system was stimulated to induce an artificial motivational drive. Note that despite restoration of behavior (e.g., resumed water consumption), InsCtx ongoing activity maintains a faithful representation of the true (isosmotic, euvolemic) hydration state. Modified with permission from Livneh et al., 2020. D. Calcium activity of a population of simultaneously imaged InsCtx neurons. Left: activity after initial fear conditioning and then following extinction, potentially reflecting anxiety levels. Right: activity before and after induction of visceral malaise by systemic injection of LiCl. Modified with permission from Gehrlach et al., 2019. E. Schematic model suggesting that the activity of InsCtx in different behavioral contexts could be explained by its interoceptive sensory function. A salient stimulus (bitter taste, appetitive/aversive predictive cue) first activates a small subset of InsCtx neurons. The salient stimulus then induces autonomic changes (heart rate, anticipatory gastric motility, etc.), which in turn activate a larger population of InsCtx neurons. From the experimenter’s perspective, interpretation of InsCtx activity is challenging in the absence of concurrent recording of other bodily signals. F. Schematic model summarizing the pathways by which information from the body, as well as salient information from the outside world, affect InsCtx activity. MnPO: median preoptic area, POA: preoptic area, VMH: ventromedial hypothalamus.
Figure 3:
Figure 3:. Short Time-Scale Activity as a Prediction of Long Time-Scale Activity in InsCtx
A. InsCtx population activity patterns are multi-dimensional. Within this multi-dimensional activity space, activity can move along many different axes of deficit/surfeit (e.g. axes in panel ‘E’, below). We first consider only 2 axes of activity in the multi-dimensional activity space: caloric and fluid deficit. B. Similar to ‘A’, but for short time-scale activity. During caloric or fluid deficit, cue-driven consumption of a very small food/water reward (0.1–1% of the amount needed for satiety) transiently drives activity patterns along the relevant deficit axis towards the sated state. This potentially reflects a transient prediction of the future satiety state that will be reached in 1–2 hrs following repeated consumption of such rewards. C. Experimental data supporting the model in ‘A’ and ‘B’. Modified with permission from Livneh et al., 2020. Note that artificial activation of hypothalamic “hunger neurons” in sated animals drives cue-driven consumption, but does not affect InsCtx ongoing activity. During AgRP activation, cue driven consumption drives activity patterns along the caloric deficit axis beyond the pattern associated with satiety. This potentially reflects a transient prediction of the future state associated with over-consumption. D. Similar to ‘B’, but now showing the results of activation of hypothalamic “hunger neurons” and “thirst neurons” (which evoked no change in activity pattern on their own) and of the dynamics of InsCtx activity patterns following food or water cue presentation (purple trajectory; cf. panel C). E. Schematic of InsCtx multi-dimensional population activity space, illustrated along three axes for simplicity. Activity can move within this space along different axes, simultaneously representing the broad range of visceral physiological states. F. Example states caused by two physiological perturbations (gray circles) that each induced varying levels of both caloric and fluid deficiency. A cue predicting the availability of both food and water, and thus a return to the homeostatic ‘set point’, will have a general reward value that is proportional to its net distance from the ‘set point’. Additionally, this cue will have specific reward values along the two deficiency axes. Note that consumption of dry, salty food might have negative general reward values in these example states, as it pushes activity further away from the eucaloric/euhydrated state.
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References

    1. Accolla R, Bathellier B, Petersen CC, and Carleton A (2007). Differential spatial representation of taste modalities in the rat gustatory cortex. J Neurosci 27, 1396–1404. - PMC - PubMed
    1. Accolla R, and Carleton A (2008). Internal body state influences topographical plasticity of sensory representations in the rat gustatory cortex. Proc Natl Acad Sci U S A 105, 4010–4015. - PMC - PubMed
    1. Aguilar-Rivera M, Kim S, Coleman TP, Maldonado PE, and Torrealba F (2020). Interoceptive insular cortex participates in sensory processing of gastrointestinal malaise and associated behaviors. Sci Rep 10, 21642. - PMC - PubMed
    1. Aleksandrov VG, Bagaev VA, Nozdrachev AD, and Panteleev SS (1996). Identification of gastric related neurones in the rat insular cortex. Neurosci Lett 216, 5–8. - PubMed
    1. Alhadeff AL, Su Z, Hernandez E, Klima ML, Phillips SZ, Holland RA, Guo C, Hantman AW, De Jonghe BC, and Betley JN (2018). A Neural Circuit for the Suppression of Pain by a Competing Need State. Cell 173, 140–152 e115. - PMC - PubMed

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