Serotonin reuptake inhibitors improve muscle stem cell function and muscle regeneration in male mice.

Serotonin reuptake inhibitor antidepressants such as fluoxetine are widely used to treat mood disorders. The mechanisms of action include an increase in extracellular level of serotonin, neurogenesis, and growth of vessels in the brain. We investigated whether fluoxetine could have broader peripheral regenerative properties. Following prolonged administration of fluoxetine in male mice, we showed that fluoxetine increases the number of muscle stem cells and muscle angiogenesis, associated with positive changes in skeletal muscle function. Fluoxetine also improved skeletal muscle regeneration after single and multiples injuries with an increased muscle stem cells pool and vessel density associated with reduced fibrotic lesions and inflammation. Mice devoid of peripheral serotonin treated with fluoxetine did not exhibit beneficial effects during muscle regeneration. Specifically, pharmacological, and genetic inactivation of the 5-HT1B subtype serotonin receptor also abolished the enhanced regenerative process induced by fluoxetine. We highlight here a regenerative property of serotonin on skeletal muscle.

Autism spectrum disorder in young patients with congenital central hypoventilation syndrome: role of the autonomic nervous system dysfunction.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare condition characterized by alveolar hypoventilation and autonomic nervous system (ANS) dysfunction requiring long-term ventilation. CCHS could constitute a risk factor of autism spectrum disorder (ASD) due to birth injury related to respiratory failure, which remains to be determined. ANS dysfunction has also been described in ASD and there are indications for altered contribution of ANS-central nervous system interaction in processing of social information; thus, CCHS could be a risk factor for ASD based on pathophysiological background also. Our study aimed to determine the prevalence of ASD among CCHS patients, identify risk factors, and explore the relationship between the ANS, evaluated by heart rate variability indices, and adaptative functioning. RESULTS: Our retrospective study, based on the analysis of records of a French national center of patients with CCHS under 20 years of age, determined that the prevalence of ASD (diagnosed by a psychiatrist, following the criteria of DSM-4 or DSM-5) was 6/69 patients, 8.7% (95% confidence interval: 3.3-18.0%). In a case (CCHS with ASD, n = 6) - control (CCHS without ASD, n = 12) study with matching on sex, longer neonatal hospitalization stay and glycemic dysfunction were associated with ASD. Adaptative functioning was assessed using Vineland Adaptative behavioral scales (VABS) and heart rate variability indices (including daytime RMSSD as an index of parasympathetic modulation) were obtained from ECG Holter performed the same day. In 19 young subjects with CCHS who had both ECG Holter and VABS, significant positive correlations were observed between RMSSD and three of four sub-domains of the VABS (communication: R = 0.50, p = 0.028; daily living skills: R = 0.60, p = 0.006; socialization: R = 0.52, p = 0.021). CONCLUSION: Our study suggests a high prevalence of ASD in patients with CCHS. Glycemic dysfunction and longer initial hospitalization stays were associated with ASD development. A defect in parasympathetic modulation was associated with worse adaptative functioning.

Increased Semantic Memorization in Children with ADHD during a Paradigm of Motor Priming: Exploratory Findings.

AIM: The aim was to evaluate the effect of body actions on learning process, particularly semantic memory capabilities in drug-naïve children with attention deficit hyperactivity disorder (ADHD). METHOD: Thirty children had to listen to a story which was repeated three times in a row and then a fourth time five minutes later. After each listen, the child was asked what she/he remembered from the story. The whole sample was split randomly into three subgroups of equal IQ (mean 102.2 ± 12.7), age (mean age 8 ± 0.6 years), sex (ratio female to male 1:5) and severity of ADHD symptoms (34.2 ± 7.4); a G1 "Freeze" subgroup, which implied listening to the story while sitting on a chair without moving; a G2 "Minimal" subgroup, which implied listening to the story while sitting on a chair but free movement was allowed; a G3 "Prescribed movement" subgroup, which implied listening to the story standing up, while copying the experimenter movements that mimicked the actions told in the story. RESULTS: Although our sample was limited in size, interestingly, children in the G3 subgroup showed the highest short-term semantic memory retention compared to G1. In all subgroups, repetition allowed an increase in performance. CONCLUSIONS: Our exploratory findings stress the positive role of movement in children with ADHD to increase semantic memorization. Hyperactivity may counteract the deficit of memorization related to attention impairment in children with ADHD. Our results may encourage parents or teachers to allow children with ADHD to move around during short-term memory-retention tasks.

Elevated Effort Cost Identified by Computational Modeling as a Distinctive Feature Explaining Multiple Behaviors in Patients With Depression.

BACKGROUND: Motivational deficit is a core clinical manifestation of depression and a strong predictor of treatment failure. However, the underlying mechanisms, which cannot be accessed through conventional questionnaire-based scoring, remain largely unknown. According to decision theory, apathy could result either from biased subjective estimates (of action costs or outcomes) or from dysfunctional processes (in making decisions or allocating resources). METHODS: Here, we combined a series of behavioral tasks with computational modeling to elucidate the motivational deficits of 35 patients with unipolar or bipolar depression under various treatments compared with 35 matched healthy control subjects. RESULTS: The most striking feature, which was observed independent of medication across preference tasks (likeability ratings and binary decisions), performance tasks (physical and mental effort exertion), and instrumental learning tasks (updating choices to maximize outcomes), was an elevated sensitivity to effort cost. By contrast, sensitivity to action outcomes (reward and punishment) and task-specific processes were relatively spared. CONCLUSIONS: These results highlight effort cost as a critical dimension that might explain multiple behavioral changes in patients with depression. More generally, they validate a test battery for computational phenotyping of motivational states, which could orientate toward specific medication or rehabilitation therapy, and thereby help pave the way for more personalized medicine in psychiatry.

Defective angiogenesis in CXCL12 mutant mice impairs skeletal muscle regeneration.

BACKGROUND: During muscle regeneration, the chemokine CXCL12 (SDF-1) and the synthesis of some specific heparan sulfates (HS) have been shown to be critical. CXCL12 activity has been shown to be heavily influenced by its binding to extracellular glycosaminoglycans (GAG) by modulating its presentation to its receptors and by generating haptotactic gradients. Although CXCL12 has been implicated in several phases of tissue repair, the influence of GAG binding under HS influencing conditions such as acute tissue destruction remains understudied. METHODS: To investigate the role of the CXCL12/HS proteoglycan interactions in the pathophysiology of muscle regeneration, we performed two models of muscle injuries (notexin and freeze injury) in mutant CXCL12Gagtm/Gagtm mice, where the CXCL12 gene having been selectively mutated in critical binding sites of CXCL12 to interact with HS. Histological, cytometric, functional transcriptomic, and ultrastructure analysis focusing on the satellite cell behavior and the vessels were conducted on muscles before and after injuries. Unless specified, statistical analysis was performed with the Mann-Whitney test. RESULTS: We showed that despite normal histology of the resting muscle and normal muscle stem cell behavior in the mutant mice, endothelial cells displayed an increase in the angiogenic response in resting muscle despite the downregulated transcriptomic changes induced by the CXCL12 mutation. The regenerative capacity of the CXCL12-mutated mice was only delayed after a notexin injury, but a severe damage by freeze injury revealed a persistent defect in the muscle regeneration of CXCL12 mutant mice associated with vascular defect and fibroadipose deposition with persistent immune cell infiltration. CONCLUSION: The present study shows that CXCL12 is crucial for proper muscle regeneration. We highlight that this homing molecule could play an important role in drastic muscle injuries and that the regeneration defect could be due to an impairment of angiogenesis, associated with a long-lasting fibro-adipogenic scar.

One-year mirror-image study of the impact of olanzapine long-acting injection on healthcare resource utilization and costs in severe schizophrenia.

Olanzapine long-acting injections (OLAIs) are often prescribed to patients with severe schizophrenia who are typically excluded from randomized clinical trials. To date, no mirror-image study has examined the impact of OLAIs on healthcare resource utilizations in these patients. We conducted a retrospective, one-year mirror-image study of OLAIs on 40 patients with severe schizophrenic disorder. Illness severity was defined by failure to respond to two sequential antipsychotics. Outcomes included: (i) healthcare resource utilizations via hospitalization admissions, bed days, outpatient visits, and inpatient service costs computations (ii) clinical efficacy through changes in the Brief Psychiatric Rating Scale (BPRS) and in the Clinical Global Impression-Schizophrenia Scale (CGI-SCH), and (iii) adverse effects. After one year, OLAIs were associated with significant decreases of 65.7%, 86.2% and 86.2% in hospitalization admissions, bed days, and inpatient service costs respectively. A significant mean change of -0.47 and -0.63 was determined the BPRS and the CGI-SCH scores, respectively. There were no significant differences in the number of outpatient visits and adverse effects, except for post-injection sedation/delirium syndrome whose incidence was 0.30% per injection. This mirror-image study provides the first evidence that prescribing OLAIs reduces in a cost-effective manner average bed days and hospital admissions in patients with severe schizophrenia.