Selective optogenetic inhibition of medial prefrontal glutamatergic neurons reverses working memory deficits induced by neuropathic pain

• Published in: Pain (Amsterdam) Vol. 160; no. 4; pp. 805 - 823
• Main Authors: Cardoso-Cruz, Helder, Paiva, Pedro, Monteiro, Clara, Galhardo, Vasco
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer 01-04-2019
• Subjects: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Choice Behavior - physiology; Disease Models, Animal; Evoked Potentials - physiology; Glutamates - metabolism; Humans; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Male; Memory Disorders - etiology; Memory Disorders - therapy; Memory, Short-Term - physiology; Neural Inhibition - drug effects; Neural Inhibition - physiology; Neuralgia - complications; Neurons - metabolism; Optogenetics - methods; Prefrontal Cortex - cytology; Prefrontal Cortex - metabolism; Rats; Rats, Sprague-Dawley; Reaction Time - physiology; Transduction, Genetic
• ISSN: 0304-3959; 1872-6623
• DOI: 10.1097/j.pain.0000000000001457

Stability of local medial prefrontal cortex (mPFC) network activity is believed to be critical for sustaining cognitive processes such as working memory (WM) and decision making. Dysfunction of the mPFC has been identified as a leading cause to WM deficits in several chronic pain conditions; however, the underlying mechanisms remain largely undetermined. Here, to address this issue, we implanted multichannel arrays of electrodes in the prelimbic region of the mPFC and recorded the neuronal activity during a food-reinforced delayed nonmatch to sample (DNMS) task of spatial WM. In addition, we used an optogenetic technique to selectively suppress the activity of excitatory pyramidal neurons that are considered the neuronal substrate for memory retention during the delay period of the behavioral task. Within-subject behavioral performance and pattern of neuronal activity were assessed after the onset of persistent pain using the spared nerve injury model of peripheral neuropathy. Our results show that the nerve lesion caused a disruption in WM and prelimbic spike activity and that this disruption was reversed by the selective inhibition of prelimbic glutamatergic pyramidal neurons during the delay period of the WM task. In spared nerve injury animals, photoinhibition of excitatory neurons improved the performance level and restored neural activity to a similar profile observed in the control animals. In addition, we found that selective inhibition of excitatory neurons does not produce antinociceptive effects. Together, our findings suggest that disruption of balance in local prelimbic networks may be crucial for the neurological and cognitive deficits observed during painful syndromes.