Increased fronto-hippocampal connectivity in the Prrxl1 knockout mouse model of congenital hypoalgesia

Abstract

Despite the large number of studies addressing how prolonged painful stimulation affects brain functioning, there are only a handful of studies aimed at uncovering if persistent conditions of reduced pain perception would also result in brain plasticity. Permanent hypoalgesia induced by neonatal injection of capsaicin or carrageenan has already been shown to affect learning and memory and to induce alterations in brain gene expression. In this study, we used the Prrxl1 model of congenital mild hypoalgesia to conduct a detailed study of the neurophysiological and behavioral consequences of reduced pain experience. Prrxl1 knockout animals are characterized by selective depletion of small diameter primary afferents and abnormal development of the superficial dorsal laminae of the spinal cord, resulting in diminished pain perception but normal tactile and motor behaviour. Behavioral testing of Prrxl1 mice revealed that these animals have reduced anxiety levels, enhanced memory performance, and improved fear extinction. Neurophysiological recordings from awake behaving Prrxl1 mice show enhanced altered fronto-hippocampal connectivity in the theta- and gamma-bands. Importantly, although inflammatory pain by Complete Freund Adjuvant injection caused a decrease in fronto-hippocampal connectivity in the wild-type animals, Prrxl1 mice maintained the baseline levels. The onset of inflammatory pain also reverted the differences in forebrain expression of stress- and monoamine-related genes in Prrxl1 mice. Altogether our results suggest that congenital hypoalgesia may have an effect on brain plasticity that is the inverse of what is usually observed in animal models of chronic pain.

Dorsal Root Ganglia Homeobox downregulation in primary sensory neurons contributes to neuropathic pain in rats

“…To explore pain-relevant target genes of the homeobox transcription factor DRGX, we assessed genes whose expression was reportedly changed in the forebrain of DRGX-knockout mice. 22 Among them, we focused on MMP-9 and EP 2 , both of which were increased in DRGX-null forebrain and is involved in neuropathic pain. 23,25,26 Expression levels of MMP-9 and EP 2 were increased in L5 DRG after SNL (Figure 4(a) and (b)).…”

“…However, in the medial prefrontal cortex, amygdala, or hippocampus of DRGX-null mice, mRNA levels of dozens of genes were reportedly changed. 22 Therefore, DRGX downregulation-induced pain was most likely mediated by transcriptional regulation of pain-related genes. Consistent with this idea, DRGX downregulation induced upregulation of MMP-9 and EP 2 in the DRG, as well as hyperalgesia.…”

“…26 However, impact of DRGX downregulation on neuronal activity remains unknown, although functional connectivity between medial prefrontal cortex and dorsal hippocampus during behavioral tasks were increased in DRGX knockout mice. 22 Overall, DRGX likely Figure 5. MMP-9 inhibitor alleviated mechanical allodynia and thermal hyperalgesia induced by DRGX knockdown.…”

Bidirectional optogenetic modulation of prefrontal-hippocampal connectivity in pain-related working memory deficits

“…The oscillatory interactions across different brain circuits reflect a global state of the system, and are suggested to act as an alert mechanism to identify functional perturbations 37 . In the scope of nociceptive information processing, these perturbations have been reported in the cortico-hippocampal 29,31,44 and cortico-thalamic 30,39,45 circuits in chronic pain patients and in animal models of chronic pain. In this study, an important aspect was the effects of bidirectional optogenetic manipulations of PL-mPFC CaMKIIα-expressing neurons activity in spectral properties.…”

Blockade of dopamine D2 receptors disrupts intrahippocampal connectivity and enhances pain‐related working memory deficits in neuropathic pain rats

“…Hippocampal theta ‐oscillations are positively correlated with cognitive and mnemonic processes (Klimesch, ; Tesche and Karhu, ; Royer et al., ; Schmidt et al., ). These theta power oscillations have been also associated to fronto‐hippocampal interactions that facilitate decision‐making processes (Jones and Wilson, ; Onton et al., ; Hyman et al., ), that are disturbed during neuropathic pain (Cardoso‐Cruz et al., ; Monteiro et al., ) and anxiety conditions (Adhikari et al., ). We found that D2r blockade disrupts global theta power oscillations in SNI‐treated animals.…”