Model Article: A pathway from midcingulate cortex to posterior insula gates nociceptive hypersensitivity (Tan et al 2017)
This is a beautiful and insightful paper from Rohini Kuner’s lab. I’m using this as an exemplary model of how to causally implicate a brain region in some kind of pain behavior. The general approach is to take a region of interest, push and pull it (manipulate) using some kind of selective manipulative method like optogenetics, and then look at various aspects of the output of interest (in this case pain hypersensitivity due to capsaicin).
That’s the general approach to many circuit papers these days. Of course, each biological question will necessitate lots of idiosyncratic variations in how to address the question. But overall, there is a general model of:
Region of interest -> Silence/Activate (Manipulate) Neurons in Region -> Look for Effect on Behavioral Output -> Iteratively Apply the Manipulation to Find Additional Information about the Circuit
OK. So let’s break this down. I’m going to focus less on the actual results and more on the rationale, approach and question that each part of this paper addresses.
Human Clinical Observation about Role of Some Structure in a Behavioral Phenomenon:
Notably, the contributions of the MCC in pain have not been specifically interrogated, despite its consistent and marked activation in human subjects and patients demonstrating clinical deviations from normal pain sensitivity.
Correlate to the role of the human structure to a relevant animal model
Ex vivo electrophysiological recordings in rodent models of pain have demon- strated synaptic potentiation in the anterior cingulate cortex (ACC), suggesting the ACC is involved in pain memories.
State the Gap in Knowledge
However, the distinct cingulate subdivisions that can be delineated on the basis of cytoarchitecture, neurochemistry and connectivity, as well as differential activity patterns, have not been considered in most functional studies
Central Question and Main Approach
Here we address the specific contributions of the MCC to nociception, acute pain and subacute plasticity of nociceptive processing using optogenetic manipulations, circuit mapping and functional interrogation in awake mice.
More generally, this can framed as:
Test causal role of neurons in a brain structure by manipulating with some kind of selective manipulative methods (e.g. Optogenetics, Chemogenetics, Ablation)
Fig 1. Silence Neurons in the region of interest (i.e. MCC, S1) in naive state and look at various output variables:
- Manipulation: +/- Optogenetic Silencing
- Output Assays: Von Frey, Extracellular Electrophysiology, Activity-Labeling
Fig 2. Silence Neurons in the region of interest (i.e. MCC, S1) after intervention and look for differential effects
- Intervention: Capsaicin-induced hypersensitivity
- Manipulation: +/- Optogenetic Silencing
- Output Assays: Von Frey, Extracellular Electrophysiology
- Variables: Region of Manipulation (MCC or S1), Time after Intervention, Mode of Silence (Continuous vs. Constant)
Fig 3. Apply same silencing paradigm in different models of chronic pain