Nature - USA (2020-05-14)

208 | Nature | Vol 581 | 14 May 2020

Article

here, even though our T-cell ablation study does not directly prove that
such T cells relay noradrenergic signals to B cells.
Our surgical ablation of the splenic nerve, instead of catecholamin-
ergic denervation by neurotoxins, allowed us to demonstrate that
an efferent pathway that descends into the spleen is the mechanism
responsible for the immunostimulatory effects of CRH neurons. These
effects do not appear to involve acute reflexes, but rather hinge on
tonic and provoked activities in CeA and PVN CRH neurons, which are
intrinsically rhythmic^16 and may be modulated by inputs from other
brain areas^17. The CRH-controlled HPA axis can also potently suppresses
immune responses by releasing glucocorticoids. It is likely that, above
a certain threshold of activation intensity, secretion of the HPA-driving
hormone and consequent immunosuppression would dominate over
the immunostimulatory effects of CRH neurons; below such a thresh-
old, immunostimulation by neuronal signals descending into the spleen
are more dominant.
In summary, our findings demonstrate brain control of adaptive
immunity via direct neural connection. We speculate that bodily

behaviours and psychological conditioning could be used to induce

stress of an appropriate strength and form, eventually to be defined

in qualitative and quantitative terms of neuron activation in specific

brain areas, in order to enhance host adaptive immunity.

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a b d f

0

1

2

3

2 –10 2 –5 20

P = 0.1 P = 0.2 P = 0.9

Untreated

c eg

P (1.73-fold)< 0.0001

Ablation control

CRH ablation

Sham-operated

Spleen-denervated μMT: Chrna9–/–

0

1

2

3

0

1

2

3

0

1

2

3

0

1

2

3

0

1

2

3

1

2

3

2 –10 2 –5 20 2 –10 2 –5 20 2 –10^2 –5 20 2 –10^2 –5^20

2 –10 2 –5 20 2 –10 2 –5 20

EPS

P (1.41-fold)= 0.003 P (1.36-fold)= 0.01 P (1.43-fold)= 0.004

μMT: Chrna9+/+

Dilution factor Dilution factor Dilution factor Dilution factor

Dilution factor Dilution factor Dilution factor

Optical density Optical density Optical density Optical density

Optical density Optical density Optical density

Fig. 5 | EPS enhances the antigen-specif ic antibody response via the PVN/
CeA–splenic nerve axis. NP-specific IgG titres of NP-KLH-immunized control
or EPS-experienced mice following manipulations of the CeA/PVN–splenic
nerve axis. a, B6 mice that were untreated (n = 17) or subjected to EPS (n = 16).
b, c, Control (b) or CeA/PVN CRH neuron-ablated (c) mice; untreated control
(n = 14), EPS control (n = 13), untreated ablation (n = 14), EPS ablation (n = 1 1).
d, e, Sham-operated (d) or spleen-denervated (e) mice; untreated
sham-operated (n = 5), EPS sham-operated (n = 6), untreated denervated (n = 6),
EPS denervated (n = 6). f, g, μMT Chrna9+/+ (d) or μMT Chrna9−/− (e) chimaeric
mice; untreated μMT Chrna9+/+ (n = 16), EPS μMT Chrna9+/+ (n = 15), untreated
μMT Chrna9−/− (n = 16), EPS μMT Chrna9−/− (n = 14). On x-axis (dilution factor), 2^0
corresponds to 1:800 of the original serum. Mean ± s.e.m. of all animals at each
dilution overlaid with dose–response regression curves (goodness of fit
R^2  > 0.9 in all cases). For each untreated-versus-EPS comparison, fold changes in
IgG titres were calculated by EC 50 of the respective curves, with between-group
P values by extra sum-of-squares F-test.