Peripheral sensory neurons regenerate their axon after nerve injury to enable functional recovery. Intrinsic mechanisms operating in sensory neurons are known to regulate nerve repair, but whether satellite glial cells (SGC), which completely envelop the neuronal soma, contribute to nerve regeneration remains unexplored. Using a single cell RNAseq approach, we reveal that SGC are distinct from Schwann cells and share similarities with astrocytes. Nerve injury elicits changes in the expression of genes related to fatty acid synthesis and peroxisome proliferator-activated receptor (PPARα) signaling. Conditional deletion of fatty acid synthase (Fasn) in SGC impairs axon regeneration. The PPARα agonist fenofibrate rescues the impaired axon regeneration in mice lacking Fasn in SGC. These results indicate that PPARα activity downstream of FASN in SGC contributes to promote axon regeneration in adult peripheral nerves and highlight that the sensory neuron and its surrounding glial coat form a functional unit that orchestrates nerve repair.

Peripheral sensory neurons switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Whether satellite glial cells (SGC), which completely surround the neuronal soma, contribute to the regenerative responses remains unexplored. Here we defined the transcriptional profile of SGC and identified Fabp7/BLBP as a novel marker of SGC. We report that nerve injury changes gene expression in SGC, which is mostly related to lipid metabolism, specifically fatty acid synthesis and PPARa signaling. Conditional deletion of Fatty acid synthase (Fasn), the committed enzyme in de novo fatty acid synthesis in SGC impairs axon regeneration. Treatment with the PPARa agonist fenofibrate rescues axon regeneration in mice lacking Fasn in SGC. This results indicates that PPARa functions downstream of fatty acid synthesis in SGC to promote axon regeneration. These results identify fatty acid synthesis in SGC as a fundamental novel mechanism mediating axon regeneration in adult peripheral nerves.

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Objectives People with schizophrenia have challenges in their self-assessments of everyday functioning and those who report no sadness also tend to overestimate their everyday functional abilities. While previous studies were cross-sectional, this study related longitudinal assessments of sadness to self-reports of abilities in domains of everyday functioning and cognitive abilities. Methods 71 people with bipolar illness (BPI) were compared to 102 people with schizophrenia (SCZ). Participants were sampled 3 times per day for 30 days with a smartphone-based Ecological Momentary Assessment (EMA) survey. Each survey asked where they were, with whom they were, what they were doing, and if they were sad. Performance based assessments of executive functioning, social competence, and everyday activities were collected after the EMA period, at which time the participants and observers were asked to provide ratings of three different domains of everyday functioning and neurocognitive ability. Results 18% of participants with SCZ reported that they were never sad on any one of the 90 EMA surveys. Reports of never being sad were associated with overestimated functioning compared to observers and SCZ participants who reported that they were never sad were more commonly home and alone than both SCZ participants who reported occasional sadness and participants with BPI. These participants reported being significantly happier than all people in the study. Implications Reporting that you were never sad was associated with overestimation of everyday functioning and cognitive abilities. Although participants who were never sad did not perform more poorly on objective measures than those were occasionally sad, their self-assessed functioning was significantly elevated. These data suggest that negative symptoms constructs such as reduced emotional experience need to consider reduced ability to subjectively evaluate emotional experience as a feature of negative symptoms.

Cognitive impairment is a predictor of disability across different neuropsychiatric conditions, and cognitive abilities are also strongly related to educational attainment and indices of life success in the general population. Previous attempts at drug development for cognitive enhancement have commonly attempted to remedy defects in transmitters systems putatively associated with the conditions of interest such as the glutamate system in schizophrenia. Recent studies of the genomics of cognitive performance have suggested influences that are common in the general population and in different neuropsychiatric conditions. Thus, it seems possible that transmitter systems that are implicated for cognition across neuropsychiatric conditions and the general population would be a viable treatment target. We review the scientific data on cognition and the muscarinic cholinergic receptor system (M1 and M4) across different diagnoses, in aging, and in the general population. We suggest that there is evidence suggesting potential beneficial impacts of stimulation of critical muscarinic receptors for the enhancement of cognition in a broad manner, as well as the treatment of psychotic symptoms. Recent developments make stimulation of the M1 receptor more tolerable, and we identify the potential benefits of M1 and M4 receptor stimulation as a trans-diagnostic treatment model.