How do we learn to stay away from potential harm?
A nervous system circuit that transmits the emotional component of pain and that leads to avoiding threats in the environment has been discovered. The findings from the University of Washington-led study are published online July 16 by the journal Cell.
The brain circuit that is created from experience to help avoid future harm
Their report advances the understanding of how we learn from experiences and could lead to new, more effective treatments for pain, particularly those often associated with significant emotional or psychological component such as migraine, post traumatic stress disorder and chronic arthritis pain. Sung Han, a research associate in Richard Palmiter’s lab in the UW Department of Biochemistry, was the paper’s lead author.
Pain signals travel via two main pathways. One, the sensory discriminative pain pathway, travels from the spinal cord to the brain and helps us sense the pain and locate its source. The other, the affective motivational pain pathway, colors the pain with emotion so that we perceive it as unpleasant, and motivates us to avoid the source of the discomfort.
It has been hypothesized that affective motivational or emotional pain pathway involved a structure in the midbrain called the parabrachial nucleus (PBN), but this had never been proved. Han, Palmiter and their colleagues suspected it was. They were particularly interested cells in this structure that produced a neurotransmitter, called calcitonin gene-related peptide (CGRP), that extended axons to cells in the amygdala that have receptors for the CGRP.
The questions for the researchers were whether these CGRP-expressing neurons in the PBN were indeed responsible for relaying the affective motivational pain signals to the CCRP-receptor cells in amygdala and whether this circuit helped create threat memory. The amygdala is a tear-shaped collection of cells deep in the brain. It is believed to process emotions, including fear and pleasure.
The researchers used techniques to selectively switch the CGRP cells "on" or "off" and see if that changed how mice responded to a mild electric pulse to their feet or affected the ability to associate the mild annoyance of the pulse with the place where it happened — an indication that they had acquired a threat memory.
Sung Han Richard Palmiter
The researchers first looked to see what effect the switching “off” the CGRP cells in the PBN had on the mice’s response to the electronic pulse. They found mice still had the reflexive withdrawl responses to the electric pulse but did not try to escape, as normal mice would. “It was as though they felt the pulse, but did not care,” Han said.
This behavior of the CGRP-silenced mice suggested that the PBN cells transmit the emotional component of pain to the amygdala. The fact that the mice also did not freeze to a standstill when they were returned to the tray — a sign they associated the tray with the pulses — suggesting that the affective component was needed to create a threat memory.
To tease out what was going on, Han used a technique called optogenetics to directly activate the CGRP cells without administering any stimulus to the mouse’s foot. He found that when he activated the CGRP neurons in the PBN alone, the mice froze and developed a threat memory as normal mice would to such an experience. This suggested the PBN cells generate the affective component of a signal needed for the mouse to show an immediate defensive response as well as generate a threat memory.
The second set of cells in the circuit, the cells in the amygdala that also appear to be essential in forming threat memory. After these cells were blocked, the mice did not try to escape to a pulse as normal mice would. They also failed to acquire a threat memory. But activating the cells caused the mice to do both. “What this means,” Han explains, “is that by activating just these amygdala cells alone, it is possible to create a false memory of an experience that never happened,” Han said.
“The findings,” said Palmiter, “indicate that the PBN-amygdala circuit is the affective — the emotional — pain pathway required to create the memories we need to avoid the same situations in the future. The discovery of this circuit suggests that it maybe possible to treat painful conditions, particularly those that often have a significant emotional component, with drugs that alter the function of the CGRP neuron signaling.”
This work was supported by the Howard Hughes Medical Institute.