Anatomical, behavioral, and imaging data for a study on neural circuits for stress modulation of pain

Stress is a potent modulator of pain. Specifically, acute stress due to
physical restraint induces stress-induced analgesia (SIA). However, where
and how acute stress and pain pathways interface in the brain are poorly
understood. Here, we describe how the dorsal lateral septum (dLS), a
forebrain limbic nucleus, facilitates SIA through its downstream targets
in the lateral hypothalamic area (LHA) of mice. Taking advantage of
transsynaptic viral-genetic, optogenetic, and chemogenetic techniques, we
show that the dLS→LHA circuitry is sufficient to drive analgesia and is
required for SIA. Further, our results reveal that the dLS→LHA pathway is
opioid-dependent and modulates pain through the pro-nociceptive neurons in
the rostral ventromedial medulla (RVM). Remarkably, we found that the
inhibitory dLS neurons are recruited specifically when the mice struggle
to escape under restraint and, in turn, inhibit excitatory LHA neurons. As
a result, the RVM neurons downstream of LHA are disengaged, thus
suppressing nociception. Together, we delineate a poly-synaptic pathway
that can transform escape behavior in mice under restraint to acute stress
into analgesia.