Structural and functional alterations in the retrosplenial cortex following neuropathic pain

Human and animal imaging studies demonstrated that chronic pain profoundly alters the structure and the functionality of several brain regions. In this article, we conducted a longitudinal and multimodal study to assess how chronic pain affects the brain. Using the spared nerve injury model which promotes both long-lasting mechanical and thermal allodynia/hyperalgesia but also pain-associated comorbidities, we showed that neuropathic pain deeply modified the intrinsic organization of the brain functional network 1 and 2 months after injury. We found that both functional metrics and connectivity of the part A of the retrosplenial granular cortex (RSgA) were significantly correlated with the development of neuropathic pain behaviours. In addition, we found that the functional RSgA connectivity to the subiculum and the prelimbic system are significantly increased in spared nerve injury animals and correlated with peripheral pain thresholds. These brain regions were previously linked to the development of comorbidities associated with neuropathic pain. Using a voxel-based morphometry approach, we showed that neuropathic pain induced a significant increase of the gray matter concentration within the RSgA, associated with a significant activation of both astrocytes and microglial cells. Together, functional and morphological imaging metrics of the RSgA could be used as a predictive biomarker of neuropathic pain.This work was supported by Inserm, Clermont Auvergne University, grants from Agence Nationale de la Recherche (ANR13-BSV1-0006-03), the Société Française d’Étude et de Traitement de la Douleur

Acid-Sensing Ion Channel 1a in the amygdala is involved in pain and anxiety-related behaviours associated with arthritis

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Long-term effects of interference on short-term memory performance in the rat

<div><p>A distinction has always been made between long-term and short-term memory (also now called working memory, WM). The obvious difference between these two kinds of memory concerns the duration of information storage: information is supposedly transiently stored in WM while it is considered durably consolidated into long-term memory. It is well acknowledged that the content of WM is erased and reset after a short time, to prevent irrelevant information from proactively interfering with newly stored information. In the present study, we used typical WM radial maze tasks to question the brief lifespan of spatial WM content in rodents. Groups of rats were submitted to one of two different WM tasks in a radial maze: a WM task involving the repetitive presentation of a same pair of arms expected to induce a high level of proactive interference (PI) (HIWM task), or a task using a different pair in each trial expected to induce a low level of PI (LIWM task). Performance was effectively lower in the HIWM group than in LIWM in the final trial of each training session, indicative of a “within-session/short-term” PI effect. However, we also observed a different “between-session/long-term” PI effect between the two groups: while performance of LIWM trained rats remained stable over days, the performance of HIWM rats dropped after 10 days of training, and this impairment was visible from the very first trial of the day, hence not attributable to within-session PI. We also showed that a 24 hour-gap across training sessions known to allow consolidation processes to unfold, was a necessary and sufficient condition for the long-term PI effect to occur. These findings suggest that in the HIWM task, WM content was not entirely reset between training sessions and that, in specific conditions, WM content can outlast its purpose by being stored more permanently, generating a long-term deleterious effect of PI. The alternative explanation is that WM content could be transferred and stored more permanently in an intermediary form or memory between WM and long-term memory.</p></div

Behavioral protocols used in Experiments 1 to 3.

<p>(A) Drawing code used to represent the radial maze. (B) Classic LIWM and HIWM training (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0173834#sec002" target="_blank">Materials and methods</a>) performed in Experiment 1, illustrated with one session (four trials). The pair of arms used for each trial is different for the LIWM training while it is identical for HIWM training. Training was spaced, meaning that two sessions were separated by 24h with a total of 10 sessions. The sequence of arms presentation shown in (B) is only informative and does not represent the sequence used each day. This sequence is different every day and pseudo-randomly determined by the experimenter. (C) In Experiment 2, the two tasks used were the same as in A), except that training was massed (mLIWM and mHIWM): each session was separated by 10 min, with 10 sessions on day 1 and 10 other sessions on day 2. (D) In Experiment 3, we used a spaced training as in A), but the arms used during the choice phase were no longer adjacent but formed a 90° angle (LIWM90 and HIWM90), as illustrated in the example.</p

Massed training prevents performance drop in the HIWM group but long-term proactive interference appears after a 24 hour-interruption that allows consolidation of the content of WM into a more durable form of memory.

<p>Percentage of correct choices across blocks of two sessions with a massed training of 10 sessions by day during two days. ANOVA revealed a significant Group effect only on day 2 (*** p < 0.001) due to lower performance in the HIWM group. A <i>split-by</i> Group analysis of performance on day 2 showed a significant improvement in HIWM trained animals leading to similar level of performance between the two groups on final block 10.</p

Early 5‐HT6 receptor blockade prevents symptom onset in a model of adolescent cannabis abuse

[Image: see text

Reducing the need for pattern separation prevents performance drop in the HIWM group.

<p>Percentage of correct choices across blocks of two sessions with a spaced training in the two tasks during which the angle between two choice arms was 90° to reduce the need for pattern separation relative to the same tasks with 45° spaced-arms as used in experiment 1. ANOVA revealed no Group effect (NS: non-significant).</p

Performance drop in the final sessions of HIWM training reveals accumulation of PI across days, and hence long-lasting WM.

<p>(A) Evolution of the percentage of correct choices across blocks of two sessions, for rats trained in the LIWM or the HIWM task. ANOVA revealed a significant Group effect (*** p < 0.001), due to the drop of performance in the HIWM group across days revealed by the <i>split-by</i> Group analysis. (B) Percentage of correct choices made by trial for the first and the last 5 days of training, for the two groups. For Days 1 to 5 ANOVA revealed no Group effect but a significant Trial effect with a drop of performance on trial 4 for the HIWM group (Sidak's <i>post-hoc</i> test, * p < 0.05), indicative of short-term PI. On the contrary for days 6 to 10 there was a significant Group effect, due to lower performance in the HIWM group from the very first trial (Sidak's <i>post-hoc</i> test, ** p < 0.01). This reduction of performance in the HIWM task could not be attributable to short-term PI, but to accumulation of PI across days indicating that WM was not entirely reset at the end of each training and could partly last at least 24h.</p

Early 5-HT6 receptor blockade prevents symptom onset in a model of adolescent cannabis abuse

Cannabis abuse during adolescence confers an increased risk for developing later in life cognitive deficits reminiscent of those observed in schizophrenia, suggesting common pathological mechanisms that remain poorly characterized. In line with previous findings that revealed a role of 5-HT6 receptor-operated mTOR activation in cognitive deficits of rodent developmental models of schizophrenia, we show that chronic administration of ∆9-tetrahydrocannabinol (THC) to mice during adolescence induces a long-lasting activation of mTOR in prefrontal cortex (PFC), alterations of excitatory/inhibitory balance, intrinsic properties of layer V pyramidal neurons, and long-term depression, as well as cognitive deficits in adulthood. All are prevented by administrating a 5-HT6 receptor antagonist or rapamycin, during adolescence. In contrast, they are still present 2 weeks after the same treatments delivered at the adult stage. Collectively, these findings suggest a role of 5-HT6 receptor-operated mTOR signaling in abnormalities of cortical network wiring elicited by THC at a critical period of PFC maturation and highlight the potential of 5-HT6 receptor antagonists as early therapy to prevent cognitive symptom onset in adolescent cannabis abusers