Brain control of humoral immune responses amenable to behavioural modulation

Nature. 2020 May;581(7807):204-208. doi: 10.1038/s41586-020-2235-7. Epub 2020 Apr 29.


It has been speculated that brain activities might directly control adaptive immune responses in lymphoid organs, although there is little evidence for this. Here we show that splenic denervation in mice specifically compromises the formation of plasma cells during a T cell-dependent but not T cell-independent immune response. Splenic nerve activity enhances plasma cell production in a manner that requires B-cell responsiveness to acetylcholine mediated by the α9 nicotinic receptor, and T cells that express choline acetyl transferase1,2 probably act as a relay between the noradrenergic nerve and acetylcholine-responding B cells. We show that neurons in the central nucleus of the amygdala (CeA) and the paraventricular nucleus (PVN) that express corticotropin-releasing hormone (CRH) are connected to the splenic nerve; ablation or pharmacogenetic inhibition of these neurons reduces plasma cell formation, whereas pharmacogenetic activation of these neurons increases plasma cell abundance after immunization. In a newly developed behaviour regimen, mice are made to stand on an elevated platform, leading to activation of CeA and PVN CRH neurons and increased plasma cell formation. In immunized mice, the elevated platform regimen induces an increase in antigen-specific IgG antibodies in a manner that depends on CRH neurons in the CeA and PVN, an intact splenic nerve, and B cell expression of the α9 acetylcholine receptor. By identifying a specific brain-spleen neural connection that autonomically enhances humoral responses and demonstrating immune stimulation by a bodily behaviour, our study reveals brain control of adaptive immunity and suggests the possibility to enhance immunocompetency by behavioural intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Acetylcholine / pharmacology
  • Adrenergic Neurons / metabolism
  • Amygdala / cytology
  • Amygdala / drug effects
  • Amygdala / metabolism
  • Animals
  • Behavior, Animal / physiology*
  • Brain / cytology
  • Brain / drug effects
  • Brain / physiology*
  • Choline O-Acetyltransferase / metabolism
  • Corticotropin-Releasing Hormone / metabolism
  • Hemocyanins / immunology
  • Immunity, Humoral / immunology*
  • Immunoglobulin G / immunology
  • Lymphocyte Activation
  • Male
  • Mice
  • Paraventricular Hypothalamic Nucleus / cytology
  • Paraventricular Hypothalamic Nucleus / drug effects
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Plasma Cells / cytology
  • Plasma Cells / drug effects
  • Plasma Cells / immunology
  • Receptors, Nicotinic / deficiency
  • Receptors, Nicotinic / metabolism
  • Spleen / cytology
  • Spleen / drug effects
  • Spleen / immunology*
  • Spleen / innervation*
  • Stress, Psychological / immunology
  • Stress, Psychological / metabolism
  • T-Lymphocytes / immunology


  • Immunoglobulin G
  • Receptors, Nicotinic
  • Hemocyanins
  • Corticotropin-Releasing Hormone
  • Choline O-Acetyltransferase
  • keyhole-limpet hemocyanin
  • Acetylcholine