Science - USA (2021-10-29)

548 29 OCTOBER 2021 • VOL 374 ISSUE 6567 science.org SCIENCE

PHOTOS: (TOP TO BOTTOM HAPPY HOUR HEADSHOTS; MIKE NICHOLS/MEDICAL PORTRAIT STUDIO; FLUSSREIF

mice and are highly active during food depri-
vation ( 5 , 6 ). We therefore hypothesized that
activity in this neuron population may under-
lie the interaction between hunger and pain.
Optogenetic activation of AgRP neurons
recapitulated the effects of hunger by selec-
tively inhibiting long-term inflammatory
pain caused by injection of a noxious chem-
ical into the mouse paw. To identify the
neural circuit that mediates this behavioral
interaction, we performed a systematic
functional analysis of distinct AgRP neu-
ron subpopulations that project to different
brain regions. These experiments revealed
a population of only ~300 AgRP neurons
that project to the hindbrain parabrachial
nucleus (PBN), which eliminates behaviors
associated with inflammatory pain. These
findings demonstrate the notable specific-
ity through which a hypothalamic-to-hind-
brain circuit suppresses competing survival
behaviors during hunger.
We further refined our understanding of
this circuit by demonstrating that neuro-
peptide Y (NPY) released from AgRP neu-
rons inhibits pain. We also restored pain re-
sponses in hungry mice by blocking NPY Y1
receptor signaling in the PBN, highlighting
the physiological relevance of this analgesic
mechanism ( 3 ).
These findings place hunger circuits in a
neural hierarchy that filters and processes
sensory information to prioritize behavior.
We are optimistic about the prospect of
using hunger circuits as a starting point
for the development of safe and effective
pain therapeutics. Determining the precise
mechanisms through which central hunger
circuits inhibit ascending sensory informa-
tion has the potential to revolutionize our
ability to treat chronic pain.

GUT-BRAIN SIGNALING AND FOOD INTAKE
Hunger circuits can clearly have profound ef-
fects on an organism’s responses to sensory
stimuli, but how do sensory stimuli affect
neural activity in hunger circuits? We next
monitored AgRP neuron activity in awake,
behaving mice to determine how sensory in-
formation in the gastrointestinal tract affects
activity in hypothalamic neurons.
There are multiple qualities of food
that influence neural activity and behav-
ior ( 7 – 9 ), including external sensory cues
(e.g., visual, olfactory, and taste) and the
nutritive content of food. We sought to
determine the aspects of food intake that
are most important for the regulation of
AgRP neurons. By examining the effects of
caloric and noncaloric foods on neural ac-
tivity, we showed that calories are required
for sustained reductions in AgRP neuron
activity ( 10 ). Direct nutrient infusion into
the stomach was sufficient to suppress

AgRP neuron activity, further suggesting

a key role for calories in mediating these

changes. Indeed, we showed that calories

train sensory cues to inhibit AgRP neuron

activity in a single trial ( 10 ).

What are the gut-brain pathways through

which nutritive signals ultimately inhibit

AgRP neurons? We performed a series of ex-

periments to manipulate different gut-brain

pathways while monitoring in vivo AgRP

neuron activity and found that whereas

fat engages vagal signaling to inhibit AgRP

neuron activity, the vagus nerve is not re-

quired for the inhibition of AgRP neuron

activity by glucose ( 11 , 12 ). Rather, sugar

engages spinal afferent signaling pathways

that communicate with hypothalamic hun-

ger neurons ( 12 ). These unexpected findings

highlight the role of an understudied gut-

brain pathway—spinal afferents—in nutri-

ent sensing and provide insight into how

different nutrients affect our brains and

therefore our behavior.

Determining the pathways through

which gut signals influence key feeding

centers in the brain has important implica-

tions for diseases related to weight control.

For example, a better understanding of how

gut-brain pathways are engaged by particu-

lar nutrients may provide insight into why

some foods, such as those that are high in

fat and sugar, are more rewarding than

others. Because AgRP neurons drive food

intake by transmitting a negative valence

signal ( 13 ), understanding the pathways for

AgRP neuron inhibition may help ease the

negative feelings associated with hunger,

and therefore improve weight-loss efforts.

BRIDGING THE BRAIN-PERIPHERY DIVIDE

Research has begun to unravel the mecha-

nisms through which the brain interacts with

the rest of the body, and vice versa, but our

understanding of this complex and multifac-

eted communication is incomplete. Moving

forward, research in my laboratory will focus

on understanding these interactions. Ulti-

mately, disentangling these mechanisms will

aid in the development of targeted therapies

for a broad range of human diseases that in-

volve pain and weight control. j

REFERENCES AND NOTES

1. S. M. Sternson, A. K. Eiselt, Annu. Rev. Physiol. 79 , 401
   (2017).


2. A. K. Sutton, M. J. Krashes, Trends Endocrinol. Metab. 31 ,
   495 (2020).


3. A. L. Alhadeff et al., Cell 173 , 140 (2018).


4. A. L. Alhadeff, O. Park, E. Hernandez, J. N. Betley,
   Neuroscience 450 , 126 (2020).


5. S. Luquet, F. A. Perez, T. S. Hnasko, R. D. Palmiter, Science
   310 , 683 (2005).


6. K. A. Takahashi, R. D. Cone, Endocrinology 146 , 1043
   (2005).


7. J. N. Betley et al., Nature 521 , 180 (2015).


8. Y. Mandelblat-Cerf et al., eLife 4 , e07122 (2015).


9. Y. Chen, Y. C. Lin, T. W. Kuo, Z. A. Knight, Cell 160 , 829
   (2015).


10. Z. Su, A. L. Alhadeff, J. N. Betley, Cell Rep. 21 , 2724
    (2017).


11. A. L. Alhadeff et al., Neuron 103 , 891 (2019).


12. N. Goldstein et al., Cell Metab. 33 , 676 (2021).


13. J. N. Betley et al., Nature 521 , 180 (2015).

10.1126/science.abl7121

WINNER

Amber L. Alhade

Amber L. Alhadeff

received her under-

graduate degree and

PhD from the Univer-

sity of Pennsylvania.

After also completing her postdoc-

toral fellowship there, Amber started

her laboratory at the Monell Chemical

Senses Center and the Department

of Neuroscience at the University of

Pennsylvania in 2020. Her research

investigates gut-brain signaling and

its contributions to feeding and other

motivated behaviors.

FINALIST

Justin

Rustenhoven

Justin Rustenhoven

received an under-

graduate degree and

PhD in pharmacol-

ogy from the University of Auckland

in New Zealand. He performed his

postdoctoral training in the labora-

tory of Professor Jonathan Kipnis at

Washington University in St. Louis,

where he continues to work as a

research fellow. His research explores

the mechanisms underlying immune

surveillance of the central nervous

system from the brain’s borders.

science.org/doi/10.1126/science.abl7122

FINALIST

Andreas J. Keller

Andreas Keller

received his un-

dergraduate and

graduate degrees in

physics from ETH

Zürich. His PhD work, completed

under Dr. Kevan Martin, focused on

rapid network state transitions in the

visual cortex. He joined the labora-

tory of Dr. Massimo Scanziani at

the University of San Francisco for

his postdoctoral training. Andreas

started his laboratory at the Institute

of Molecular and Clinical Ophthalmol-

ogy Basel in 2021, where his research

focuses on mechanisms of cortical

plasticity in feedforward and feedback

circuits. science.org/doi/10.1126/

science.abl7124

INSIGHTS | PRIZE ESSAY