Remembering immunity: Neuronal ensembles in the insular cortex encode and retrieve specific immune responses

Tamar Koren, Maria Krot, Nadia T. Boshnak, Mariam Amer, Tamar Ben-Shaanan, Hilla Azulay-Debby, Haitham Hajjo, Eden Avishai, Maya Schiller, Hedva Haykin, Ben Korin, Dorit Cohen-Farfara, Fahed Hakim, Kobi Rosenblum, Asya Rolls

Preprint posted on 4 December 2020

Rolls´s lab makes it again! In a fascinating new study they go beyond the prevailing dogma of immunological memory and elegantly demonstrate that insular neuronal ensembles do both store and recover highly specific representations of immunity.

Selected by Javier M. Peralta Ramos

Categories: immunology, neuroscience


Over the last years, several reports have provided evidence that the brain can exert a top-down control of peripheral immunity1–3. Activation of the ventral tegmental area, a key component of the dopaminergic reward system, has been shown to enhance the response of both the innate and adaptive arms of the immune system upon a bacterial infection1. Most importantly, it has been found to modulate anti-tumor immunity and attenuate cancer progression2.

For the field of neuroscience, the concept of memory has been strongly linked to the expression of a fear response upon the recall of an aversive stimulus, in an experimental setting called fear-conditioning4. Likewise, in immunology, the terms “trained immunity” and “immune memory” refer to the process by which the innate and adaptive immune system, respectively, deploy a heightened response to a subsequent inflammatory event5.

The posterior insular cortex (InsCtx) is a region considered to be the primary cortical site for sensing the body´s physiological state. Now, making a smart use of a toolbox combining the best of neuroscience and immunology, Koren et al. elegantly demonstrate that neuronal ensembles located in the InsCtx, store and recover highly specific peripheral immune-related information in two mouse models of colitis and peritonitis, unveiling a novel aspect of the concept of immune memory.

Key findings

  • Capture of neuronal ensembles located in the posterior InsCtx using activity-dependent cell labeling in FosTRAP transgenic mice during colitis, and subsequent chemogenetic-mediated reactivation 4 weeks after cessation of the treatment, resembles most of the immunological features of the prior immune inflammatory event specifically in the colon.
  • Reactivation of these neuronal ensembles captured across distinct stages of the colitis, result in a different magnitude of the immune response.
  • Unspecific reactivation of the InsCtx does not exert any evident peripheral immune response in the colon.
  • Reactivation of neuronal ensembles following capture, in a mouse model of peritonitis, recapitulates traits of the prior immune inflammatory event specifically in the peritoneum but not in the colon.

What I like about the preprint & why I think this new work is important

Much of what we know about brain-immune communication has been previously demonstrated by manipulating the peripheral immune system, and subsequently studying the impact of this intervention in the brain. By approaching this in the opposite direction, this preprint nicely supports the notion of the brain´s top-down regulation of peripheral immunity. Their findings demonstrate a previously unexplored aspect of the concept of immune memory.

Future directions & questions to the authors

  • Foxp3+ T regulatory cells (Tregs) have been shown to suppress inflammation during colitis6. Do you believe the striking increase in activated CD4+ T cells following reactivation might be driven by an increase in suppressive Tregs?
  • It has been demonstrated that immunological imprinting upon peripheral inflammation induces either training or tolerance in immune cells5. Following reactivation of insular neuronal ensembles, does retrieval of the information encoded in the brain, and therefore the magnitude of the peripheral immune response, correlate with the magnitude of the prior immunological imprinting?
  • Following this rationale, does any immune cell population induce an improved immunological imprinting of the information to be acquired in the InsCtx?
  • Would you expect this neuronal representation of immunity to be successfully retrieved in a Parkinson´s disease model, where both the gut and brain are affected?


  1. Ben-Shaanan, T. L. et al. Activation of the reward system boosts innate and adaptive immunity. Nat. Med. 22, 940–944 (2016).
  2. Ben-Shaanan, T. L. et al. Modulation of anti-tumor immunity by the brain’s reward system. Nat. Commun. 9, 2723 (2018).
  3. Zhang, X. et al. Brain control of humoral immune responses amenable to behavioural modulation. Nature 581, 204–208 (2020).
  4. Liu, X. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484, 381–385 (2012).
  5. Wendeln, A.-C. et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature 556, 332–338 (2018).
  6. Chaudhry, A. et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 34, 566–578 (2011).

Tags: gut-brain-axis, inflammatory bowel disease, neurodegeneration

Posted on: 7 May 2021


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