Layer- and subregion-specific electrophysiological and morphological changes of the medial prefrontal cortex in a mouse model of neuropathic pain

Abstract

Chronic neuropathic pain constitutes a serious public health problem, but the disease mechanisms are only partially understood. The involvement of different brain regions like the medial prefrontal cortex has already been established, but the comparison of the role of different subregions and layers is still inconclusive. In the current study, we performed patch-clamp recordings followed by anatomical reconstruction of pyramidal cells from different layers of the prelimbic and infralimbic subregions of the medial prefrontal cortex in neuropathic (spared nerve injury, SNI) and control mice. We found that in the prelimbic cortex, layer 2/3 pyramidal cells from SNI mice exhibited increased excitability compared to sham controls, whereas prelimbic layer 5 pyramidal neurons showed reduced excitability. Pyramidal cells in both layer 2/3 and layer 5 of the infralimbic subregion did not change their excitability, but layer 2/3 pyramidal cells displayed increased dendritic length and branching. Our findings support the view that chronic pain is associated with subregion- and layer-specific changes in the medial prefrontal cortex. They therefore provide new insights into the mechanisms underlying the chronification of pain.

Sex-Specific Disruption of Distinct mPFC Inhibitory Neurons in Spared-Nerve Injury Model of Neuropathic Pain

“…Our results showing that SNI does not alter the excitability of PVINs or SOM neurons in the IL region of the mPFC are consistent with studies showing that IL pyramidal neurons are unchanged in chronic pain models (Cheriyan and Sheets, 2018;Mitrić et al, 2019). However, this result is also intriguing given previous findings in other pain models.…”

“…Given their sparse expression in the cortex (~20%-30%), minor alterations to their function are believed to drive significant changes to circuit activity. Numerous pain studies report structural and functional alterations to the medial prefrontal cortex (mPFC), a region implicated in affective and cognitive disturbances associated with chronic pain (Cardoso-Cruz et al, 2013;Cheriyan and Sheets, 2018;Huang et al, 2019;Ji et al, 2010;Kelly et al, 2016;Lee et al, 2015;Metz et al, 2009;Millecamps et al, 2007;Mitrić et al, 2019;Shiers et al, 2018;Zhang et al, 2015). Aspects of cellular and circuit mechanisms underlying these disturbances have emerged.…”

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats

“…Pre-clinical findings suggest that loss of mPFC – PAG functional communication is explained by both local and inter-regional network alterations. In neuropathic rodents, at 7-10 days post-nerve injury, there is a decline in spontaneous and evoked PrL layer 5 pyramidal cell activity including those that project to the PAG (Cheriyan and Sheets, 2018; Mitrić et al , 2019). This reduction in PrL projection neurones excitability is produced by enhanced feedforward inhibition from local GABAergic interneurons, and driven by inputs from the basolateral amygdala (Zhang et al , 2015; Cheriyan et al , 2016; Kiritoshi, Ji and Neugebauer, 2016; Cheriyan and Sheets, 2018; Huang et al , 2019).…”

Elevated O-GlcNAcylation induces an antidepressant-like phenotype and decreased inhibitory transmission in medial prefrontal cortex

“…Moreover, it is also intriguing that the reduction in sIPSC frequency was only observed in PrL layer II/III neurons, but not in PrL layer V, IL layer II/III, and IL layer V of the mPFC. This difference presumably results from the structurally and functionally distinct nature of neurons in the PrL and IL subregions [45][46][47] , and the functional significance of PrL layer II/III neurons in regulating depressive-like phenotypes has been reported previously 15,17,19 . In particular, pyramidal neurons exhibited distinct electrophysiological and/or morphological properties, and a different susceptibility to spared nerve injury across different subregions of the mPFC 47 .…”

“…This difference presumably results from the structurally and functionally distinct nature of neurons in the PrL and IL subregions [45][46][47] , and the functional significance of PrL layer II/III neurons in regulating depressive-like phenotypes has been reported previously 15,17,19 . In particular, pyramidal neurons exhibited distinct electrophysiological and/or morphological properties, and a different susceptibility to spared nerve injury across different subregions of the mPFC 47 . A potential difference in the subpopulation of GABAergic inhibitory neurons as well as local inhibitory circuits across the mPFC subregions may also contribute to the specific changes in PrL layer II/III neurons 48 .…”