Intercalated cells of the amygdala

The Intercalated cells of the amygdala (ITC or ICCs) are GABAergic neurons situated between the basolateral and central nuclei of the amygdala that play a significant role in inhibitory control over the amygdala.[1] They regulate amygdala-dependent emotional processing like fear memory and social behavior. Their function has been best studied with selective ITC ablation which impairs fear extinction, fear generalization, and social behavior.[2][3] Studies have begun to recognize that ITC clusters may be implicated in reward, addiction, and withdrawal circuits given their heavy expression of dopamine and opioid receptors.[4]

In rodents, ITCs are organized into distinct clusters that wrap the basolateral amygdala (BLA).[5] Each cluster is unique in connectivity, intrinsic properties, and function.[5][6][7] These clusters are named by their location relative to the BLA with medial ITC clusters towards the central amygdala.

Function

ITC cells are thought to play a role as the "off" switch for the amygdala, inhibiting the amygdala's central nucleus output neurons and its basolateral nucleus neurons.[1] The ITC clusters work together to activate either "fear promoting" or "fear extinction" pathways within the amygdala.[6] Some researchers speculate that ITC cells could serve as a substrate for the expression and storage of extinction memory via their extensive local inhibition within the amygdala.[1]

Connectivity

ITCs have complex connections from both thalamic and cortical nuclei. In the rodent model, each ITC cluster has its own connection and projection patterns. Furthermore, ITC neurons within each cluster are often connected to each other and distinct clusters appear to be connected to each other[8][6][9]

The best clusters studied to date are the ITCdm and ITCvm clusters which are reciprocally connected to each other.[6][9] These clusters work collaborately to activate populations of neurons within the basal amygdala (BA) that project to the medial prefrontal cortex (mPFC). The opposing action of these two clusters has been shown to modulate fear vs extinction states.[6]

There is also some evidence that ITCs receive some inputs from the mPFC and was originally thought that the infralimbic prefrontal cortex directly innervates the ITCs.[1] However, recent optogenetic studies have shown that in the rodent model, ITCs do not receive direct inputs from the IL prefrontal cortex.[10]

See also

References
  1. Quirk GJ, Mueller D (January 2008). "Neural mechanisms of extinction learning and retrieval". Neuropsychopharmacology. 33 (1): 56–72. doi:10.1038/sj.npp.1301555. PMC 2668714. PMID 17882236.
  2. Likhtik E, Popa D, Apergis-Schoute J, Fidacaro GA, Paré D (July 2008). "Amygdala intercalated neurons are required for expression of fear extinction". Nature. 454 (7204): 642–645. Bibcode:2008Natur.454..642L. doi:10.1038/nature07167. PMC 2528060. PMID 18615014.
  3. Kuerbitz J, Arnett M, Ehrman S, Williams MT, Vorhees CV, Fisher SE, et al. (January 2018). "Loss of Intercalated Cells (ITCs) in the Mouse Amygdala of Tshz1 Mutants Correlates with Fear, Depression, and Social Interaction Phenotypes". The Journal of Neuroscience. 38 (5): 1160–1177. doi:10.1523/JNEUROSCI.1412-17.2017. PMC 5792476. PMID 29255003.
  4. Gregoriou, Gabrielle C.; Patel, Sahil D.; Pyne, Sebastian; Winters, Bryony L.; Bagley, Elena E. (2021-12-23). "Opioid withdrawal abruptly disrupts amygdala circuit function by reducing peptide actions". dx.doi.org. Retrieved 2023-03-11.
  5. Busti D, Geracitano R, Whittle N, Dalezios Y, Mańko M, Kaufmann W, et al. (March 2011). "Different fear states engage distinct networks within the intercalated cell clusters of the amygdala". The Journal of Neuroscience. 31 (13): 5131–5144. doi:10.1523/JNEUROSCI.6100-10.2011. PMC 6622967. PMID 21451049.
  6. Hagihara KM, Bukalo O, Zeller M, Aksoy-Aksel A, Karalis N, Limoges A, et al. (June 2021). "Intercalated amygdala clusters orchestrate a switch in fear state". Nature. 594 (7863): 403–407. Bibcode:2021Natur.594..403H. doi:10.1038/s41586-021-03593-1. PMC 8402941. PMID 34040259.
  7. Asede D, Doddapaneni D, Chavez A, Okoh J, Ali S, Von-Walter C, Bolton MM (May 2021). "Apical intercalated cell cluster: A distinct sensory regulator in the amygdala". Cell Reports. 35 (7): 109151. doi:10.1016/j.celrep.2021.109151. PMID 34010641. S2CID 234792714.
  8. Aksoy-Aksel, Ayla; Gall, Andrea; Seewald, Anna; Ferraguti, Francesco; Ehrlich, Ingrid (2021-05-24). Shansky, Rebecca; Huguenard, John R; Likhtik, Ekaterina (eds.). "Midbrain dopaminergic inputs gate amygdala intercalated cell clusters by distinct and cooperative mechanisms in male mice". eLife. 10: e63708. doi:10.7554/eLife.63708. ISSN 2050-084X. PMC 8143799.
  9. Asede, Douglas; Doddapaneni, Divyesh; Bolton, M. McLean (2022-12-07). "Amygdala Intercalated Cells: Gate Keepers and Conveyors of Internal State to the Circuits of Emotion". Journal of Neuroscience. 42 (49): 9098–9109. doi:10.1523/JNEUROSCI.1176-22.2022. ISSN 0270-6474. PMC 9761677. PMID 36639901.
  10. Adhikari A, Lerner TN, Finkelstein J, Pak S, Jennings JH, Davidson TJ, et al. (November 2015). "Basomedial amygdala mediates top-down control of anxiety and fear". Nature. 527 (7577): 179–185. Bibcode:2015Natur.527..179A. doi:10.1038/nature15698. PMC 4780260. PMID 26536109.
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