Differential Role of Anterior Cingulate Cortical Glutamatergic Neurons in Pain-Related Aversion Learning and Nociceptive Behaviors in Male and Female Rats

Abstract

Pain is comprised of both sensory and affective components. The anterior cingulate cortex (ACC) is a key brain region involved in the emotional processing of pain. Specifically, glutamatergic transmission within the ACC has been shown to modulate pain-related aversion. In the present study, we use in vivo optogenetics to activate or silence, using channelrhodopsin (ChR2) and archaerhodopsin (ArchT) respectively, calmodulin-kinase IIα (CaMKIIα)-expressing excitatory glutamatergic neurons of the ACC during a formalin-induced conditioned place aversion (F-CPA) behavioral paradigm in both female and male adult Sprague-Dawley rats. Expression of c-Fos, a marker of neuronal activity, was assessed within the ACC using immunohistochemistry. Optogenetic inhibition of glutamatergic neurons of the ACC abolished F-CPA without affecting formalin-induced nociceptive behavior during conditioning. In male rats, optogenetic activation of ACC glutamatergic neurons decreased formalin-induced nociceptive behavior during conditioning without affecting F-CPA. Interestingly, the opposite effect was seen in females, where optogenetic activation of glutamatergic neurons of the ACC increased formalin-induced nociceptive behavior during conditioning. The abolition of F-CPA following optogenetic inhibition of glutamatergic neurons of the ACC was associated with a reduction in c-Fos immunoreactivity in the ACC in male rats, but not female rats. These results suggest that excitatory glutamatergic neurons of the ACC play differential and sex-dependent roles in the aversion learning and acute sensory components of pain.

Monoamine Neurotransmitters Control Basic Emotions and Affect Major Depressive Disorders

“…We can use GABA as one example to introduce the interactions between monoamine and other chemicals. The specific neurotransmitters include glutamatergic excitatory neurons and GABAergic inhibitory interneurons, which are the main executive systems regulating neural circuit connections in emotional brain regions and between brain regions [ 152 ]. The structure and function of glutamatergic and GABAergic neurons in the prefrontal cortex and hippocampus of brain regions and the imbalance of their local loop activity are also the monoaminergic targets for the antidepressant drug treatments [ 153 ].…”

Dissecting the Neural Circuitry for Pain Modulation and Chronic Pain: Insights from Optogenetics

“…On the other hand, accumulating evidence suggests that the ACC is also involved in pain modulation. Selective activation of inhibitory neurons in the ACC inhibits pain and the responses of pyramidal neurons to painful stimuli [81,82], while activation of glutamatergic neurons facilitates nociception [82,83]. In addition, inhibition of ACC excitatory neurons is able to reduce cancer pain [84].…”

In Utero Electroporation for Manipulation of Specific Neuronal Populations

“…By expressing light-gated ion channels and pumps in distinct neuronal populations, researchers can precisely control the activity of specific neurons [ 2 , 5 , 6 , 7 ]. Optogenetic approaches have enabled the exploration of a variety of neuronal populations, revealing a series of neuronal circuits associated with sensory processing, memory, and learning [ 8 , 9 , 10 , 11 , 12 , 13 ].…”