Neuron: How do you perceive cold environments? Scientists reveal spinal nerve circuits for cold sensitivity

The maintenance of body temperature homeostasis is essential
for the survival of thermostatic animals.
Spinal cord neural circuits encode cold messages and are delivered to the brain
by projecting neurons.
Single-cell sequencing technology found the presence of 21 excitatory neurons and 43 inhibitory neuron subtypes
in the spinal cord.

Kcnip2 encodes a voltage-gated potassium channel interaction protein whose role in cardiac physiology has been extensively studied
.
Kcnip2 is a molecular marker of a class of inhibitory interneurons located in the dorsal horn of the spinal cord
.
Kcnip2-positive neurons in the retinal ganglia are used to detect looming objects and participate in subsequent escape and freezing behavior
.

Ciguatera toxin poisoning is most characterized by cold abnormal pain with inverted temperature sensation, specifically manifested as a pain disorder that causes a burning sensation when exposed to cold objects, which is also present in
neuropathic pain.

In November 2022, the research team of Hendrik Wildne at the University of Zurich in Switzerland published an article revealing that Kcnip2-positive neurons play an important role
in regulating the perception of cold environments.

1

Kcnip2-positive neurons in the spinal cord are involved in cold sensitivity

The researchers constructed Kcnip2-cre tool mice and found that Kcnip2-positive neurons were mainly expressed in the dorsal horns of the spinal cord II and III, the vast majority were suppressor neurons (92.
6%), and a small amount was expressed in the somatic sensory and auditory systems
of the brain.
The sensitivity of mice to cold sensation increased after virus-specific induction of apoptosis of Kcnip2-positive neurons in the spinal cord, and this enhancement
did not occur in nociceptive stimuli.

In the temperature-preference behavioral experiment, normal mice stayed in the cold region (between 13 degrees Celsius and 22 degrees Celsius) for about 521 seconds, while mice with inactivated spinal cord Kcnip2-positive neurons stayed in this region for 227 seconds, showing a reduction
in cold environment response.
Chemogenetics chronically activated spinal cord Kcnip2-positive neurons in mice had a prolonged response time to cold sensation, further indicating reduced sensitivity to cold perception
.

Figure 1: Distribution of Kcnip2-positive neurons in the spinal cord

2

Spinal cord Kcnip2-positive neurons output, input neurons

Mechanical stimulation, hot water (52 degrees) and ice water (-20 degrees) can activate Kcnip2-positive neurons in the spinal cord, among which ice water activates the largest
number of Kcnip2-positive neurons.
TRPM8, a member of the transient receptor potential channel family, is a cold receptor, and experiments have shown that TRPM8 agonists can promote the increase
in excitatory postsynaptic current in cold-sensitive Kcnip2-positive neurons in the spinal cord.
It was shown that Kcnip2-positive neurons could receive input
from TRPM8-positive fibers.

Further viral tracing experiments were used to find that most of the neurons (about 80%) output by Kcnip2-positive neurons in the spinal cord were located in the superficial layers I and II of the spinal cord, and there were nociceptive output neurons
in this area.
Photoactivation of Kcnip2-positive neurons in the spinal cord can cause superficial layer I inhibitory postsynaptic current, which can be blocked
by the poached peonine.

Experiments on rodents have shown that hypothermia exerts partial analgesic effects
.
The researchers found that chronic activation of Kcnip2-positive neurons in the spinal cord reduced the response of mice to nociceptive stimuli and exerted analgesic effects
.
It can also reduce cold abnormal pain caused by chronic coarctative injury of the sciatic nerve, but has little effect
on mechanical stimulation.

summary

In this paper, it was found that there is a class of inhibitory neurons in the spinal cord, Kcnip2-positive neurons, which regulate the body's sensitivity to the external cold environment, and this type of neuron participates in cold analgesia when the function is normal, and causes cold abnormal pain
when it is abnormal.

Original source:

Albisetti et al.
， Inhibitory Kcnip2 neurons of the spinal dorsal horn control behavioral sensitivity to environmental cold.
Neuron (2022).