Modulation of neuronal activity by reward identity in the monkey subthalamic nucleus

International audienceThe subthalamic nucleus (STN) has been argued to be an important component of reward-sensitive basal ganglia circuitry. This view is especially supported by the behavioral changes observed after STN inactivation which could reflect impairments in the motivational control of action. However, it is still unclear how the STN integrates reward information and to what extent such integration correlates with behavior. In this study, we investigated the response properties of STN neurons in monkeys performing reaching movements with a cue predicting the identity of an upcoming liquid reward (juice or water). Although the timing of movements reliably indicated that monkeys had greater motivation for juice than water, rarely did task-related changes in neuronal activity depend on the nature of the expected reward. Conversely, when presented with a choice of selecting a response that leads to juice or water delivery, animals showed a clear preference for juice and more than half of the neurons were differentially modulated dependent on the reward obtained, mostly after the monkeys’s overt choice of action. Under such circumstances, an increase in activity specifically followed the action outcomes across the population of neurons when monkeys failed to choose the juice reward. These results indicate that STN neurons encode whether or not a preferred reward had been received when a choice between response alternatives is required. This differential neuronal activity might reflect the participation of the STN in evaluating the reward value of chosen actions thus highlighting its contribution to decision-making processes

High frequency stimulation of the subthalamic nucleus has beneficial antiparkinsonian effects on motor functions in rats, but less efficiency in a choice reaction time task

International audienceno abstrac

Implications fonctionnelles du noyau subthalamique chez l'animal sain et dans un modèle animal analogue expérimental de la maladie de Parkinson chez le rat (Approche électrophysiologique, pharmacologique et stimulation cérébrale profonde chez le rat intact et rendu parkinsonien. Approche électrophysiologique chez le primate sain)

AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats

E-52862 is a selective σ(1)R antagonist currently undergoing phase II clinical trials for neuropathic pain and represents a potential first-in-class analgesic. Here, we investigated the effect of single and repeated administration of E-52862 on different pain-related behaviours in several neuropathic pain models in rats: mechanical allodynia in cephalic (trigeminal) neuropathic pain following chronic constriction injury of the infraorbital nerve (IoN), mechanical hyperalgesia in streptozotocin (STZ)-induced diabetic polyneuropathy, and cold allodynia in oxaliplatin (OX)-induced polyneuropathy. Mechanical hypersensitivity induced after IoN surgery or STZ administration was reduced by acute treatment with E-52862 and morphine, but not by pregabalin. In the OX model, single administration of E-52862 reversed the hypersensitivity to cold stimuli similarly to 100 mg/kg of gabapentin. Interestingly, repeated E-52862 administration twice daily over 7 days did not induce pharmacodynamic tolerance but an increased antinociceptive effect in all three models. Additionally, as shown in the STZ and OX models, repeated daily treatment with E-52862 attenuated baseline pain behaviours, which supports a sustained modifying effect on underlying pain-generating mechanisms. These preclinical findings support a role for σ(1)R in neuropathic pain and extend the potential for the use of selective σ(1)R antagonists (e.g., E-52862) to the chronic treatment of cephalic and extra-cephalic neuropathic pain

Oral probiotic treatment of Lactobacillus rhamnosus Lcr35 ® prevents visceral hypersensitivity to a colonic inflammation and an acute psychological stress

International audienceAims: This study evaluated the efficacy of a repeated oral treatment with two active pharmaceutical ingredients (Lcr Lenio (R) and Lcr Restituo (R)) derivated from the probiotic bacterial strain Lactobacillus rhamnosus Lcr35 (R) in two animal models mimicking different features of irritable bowel syndrome (IBS). IBS is characterized by visceral pain associated with alteration of bowel transit. IBS patients present visceral hypersensitivity with peripheral and central origins.Methods and Results: The injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS) into the proximal colon as well as an acute partial restraint stress (PRS) produces colonic hypersensitivity measured in conscious rats by a decrease in pain threshold in response to distal colonic distension. Visceral hypersensitivity was produced by injection of TNBS 7 days before colonic distension or by acute PRS on testing day. Treatments were performed once a day during eight consecutive days.Conclusions: This study indicates that an 8-day probiotic treatment (Lcr Lenio and Lcr Restituo) produces an antihypersensitivity activity in both TNBS and PRS visceral pain models. As this probiotic strain attenuates peripherally and centrally induced visceral hypersensitivity in rats, it may be active in treatment of IBS symptoms. An immunomodulatory effect of the probiotics was highlighted in the TNBS model on the IL-23 secretion, suggesting a mechanism of action involving a regulation of the local IL-23/Th17 immune activation.Significance and Impact of the Study: Two formulas of Lcr35 (R) probiotic strain show very encouraging results for the treatment of IBS patients. Further studies are needed to better understand the role and mechanisms of probiotics on the pathogenesis of IBS

Comparison of 6-hydroxydopamine lesions of the substantia nigra and the medial forebrain bundle on a lateralised choice reaction time task in mice

Parkinson's disease is most commonly modelled via unilateral infusion of the neurotoxin 6-hydroxydopamine (6-OHDA) in the rat, but recent work has been aimed to translate the reproducibility and reliability of the model to the mouse. Here we present the effects of unilateral 6-OHDA lesions to either the medial forebrain bundle or the substantia nigra (SN) in mice, which were trained on a lateralised choice reaction time (RT) task. This task measures response accuracy as well as RT and movement time latencies, and offers the opportunity for a more fine-grained analysis of the precise nature of the movement deficit, motor learning and functional recovery than can be achieved using classical tests of simple motor asymmetry. Both lesion types caused impaired response accuracy, which was more pronounced when responses had to be directed contralateral to the lesion. Furthermore, movement times were increased for both lesion groups, whereas only the bundle lesion group displayed a RT deficit. The lesions were stable over three consecutive weeks of testing, therefore lesion-type and behavioural assessment on the operant task are suitable to investigate the dopaminergic system in parkinsonian mice. Both lesions were stable over time, and were more pronounced when responses were directed in contralateral space; the mice with more complete bundle lesions displayed a greater deficit than mice that received lesions to the SN. The translation of this choice RT task will be beneficial for the assessment of therapeutics in mouse models of the disease