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

Cardoso-Cruz, Heldera,b,*; Paiva, Pedroa,b,c; Monteiro, Claraa,b; Galhardo, Vascoa,b

doi: 10.1097/j.pain.0000000000001457
Research Paper

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.

Selective optogenetic inhibition of the prelimbic medial prefrontal cortex glutamatergic neurons during the delay period reverses pain-related working memory deficits but has no antinociceptive effects.

aDepartamento de Biomedicina - Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Porto, Portugal

bi3S/IBMC, Instituto de Investigação e Inovação em Saúde e Instituto de Biologia Molecular e Celular - “Pain Research Group”, Universidade do Porto, Porto, Portugal

cFCUP/ICBAS, Faculdade de Ciências e Instituto de Ciências Biomédicas Abel Salazar - Mestrado em Bioquímica, Universidade do Porto, Porto, Portugal

Corresponding author. Address: Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Unidade de Biologia Experimental, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal. Tel.: +351 225 513 600; fax: +351 225 513 601. E-mail address: (H. Cardoso-Cruz).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received February 21, 2018

Received in revised form October 28, 2018

Accepted November 29, 2018

© 2019 International Association for the Study of Pain
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