Caffeine appears to have limited efficacy for maintaining alertness and wakefulness across 5 days of sleep restriction. Perhaps more importantly, there may be recovery costs associated with caffeine use following conditions of prolonged sleep loss.

Survival motor neuron (SMN) protein deficiency results in loss of alpha motor neurons and subsequent muscle atrophy in patients with spinal muscular atrophy (SMA). Reactive microglia have been reported in SMA mice and depleting microglia rescues the number of proprioceptive synapses, suggesting a role in SMA pathology. Here, we explore the contribution of lymphocytes on microglia reactivity in SMA mice and investigate how SMN deficiency alters the reactive profile of human induced pluripotent stem cell (iPSC)‐derived microglia. We show that microglia adopt a reactive morphology in spinal cords of SMA mice. Ablating lymphocytes did not alter the reactive morphology of SMA microglia and did not improve the survival or motor function of SMA mice, indicating limited impact of peripheral immune cells on the SMA phenotype. We found iPSC‐derived SMA microglia adopted an amoeboid morphology and displayed a reactive transcriptome profile, increased cell migration, and enhanced phagocytic activity. Importantly, cell morphology and electrophysiological properties of motor neurons were altered when they were incubated with conditioned media from SMA microglia. Together, these data reveal that SMN‐deficient microglia adopt a reactive profile and exhibit an exaggerated inflammatory response with potential impact on SMA neuropathology.

No abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by reduced expression of the survival motor neuron (SMN) protein. Current disease-modifying therapies increase SMN levels and dramatically improve survival and motor function of SMA patients. Nevertheless, current treatments are not cures and autopsy data suggest that SMN induction is variable. Our group and others have shown that combinatorial approaches that target different modalities can improve outcomes in rodent models of SMA. Here we explore if slowing SMN protein degradation and correcting SMN splicing defects could synergistically increase SMN production and improve the SMA phenotype in model mice. We show that co-administering ML372, which inhibits SMN ubiquitination, with an SMN modifying antisense oligonucleotide (ASO) increases SMN production in SMA cells and model mice. In addition, we observed improved spinal cord, neuromuscular junction, and muscle pathology when ML372 and the ASO were administered in combination. Importantly, the combinatorial approach resulted in increased motor function and extended survival of SMA mice. Our results demonstrate that a combination of treatment modalities synergistically increases SMN levels and improves pathophysiology of SMA model mice over individual treatment.

Posttraumatic stress disorder (PTSD) is a chronic mental health disorder that impairs daily functioning and reduces overall quality of life. Current treatments are effective only in some patient populations and do not adequately address all aspects of PTSD’s complex symptomatology. This is largely attributable to current gaps in knowledge about the pathophysiology of the disorder. Animal models of PTSD are a critical part of the drug discovery process. Animal models of PTSD use intense stressors to model trauma exposure and careful outcome measures translatable to PTSD symptoms to probe the central mechanisms underpinning the disorder. This review highlights common animal models of PTSD and their strengths and weaknesses in modeling the disorder. Outcome measures of translational value and the utility of these models for making further discoveries to inform the treatment of PTSD are also discussed.