Differential co-expression networks of the gut microbiota are associated with depression and anxiety treatment resistance among psychiatric inpatients.

BACKGROUND: Comorbid anxiety and depression are common and are associated with greater disease burden than either alone. Our recent efforts have identified an association between gut microbiota dysfunction and severity of anxiety and depression. In this follow-up, we applied Differential Co-Expression Analysis (DiffCoEx) to identify potential gut microbiota biomarker(s) candidates of treatment resistance among psychiatric inpatients. METHODS: In a sample of convenience, 100 psychiatric inpatients provided clinical data at admission and discharge; fecal samples were collected early during the hospitalization. Whole genome shotgun sequencing methods were used to process samples. DiffCoEx was used to identify clusters of microbial features significantly different based on treatment resistance status. Once overlapping features were identified, a knowledge-mining tool was used to review the literature using a list of microbial species/pathways and a select number of medical subject headlines (MeSH) terms relevant for depression, anxiety, and brain-gut-axis dysregulation. Network analysis used overlapping features to identify microbial interactions that could impact treatment resistance. RESULTS: DiffCoEx analyzed 10,403 bacterial features: 43/44 microbial features associated with depression treatment resistance overlapped with 43/114 microbial features associated with anxiety treatment resistance. Network analysis resulted in 8 biological interactions between 16 bacterial species. Clostridium perfringens evidenced the highest connection strength (0.95). Erysipelotrichaceae bacterium 6_1_45 has been most widely examined, is associated with inflammation and dysbiosis, but has not been associated with depression or anxiety. CONCLUSION: DiffCoEx potentially identified gut bacteria biomarker candidates of depression and anxiety treatment-resistance. Future efforts in psychiatric microbiology should examine the mechanistic relationship of identified pro-inflammatory species, potentially contributing to a biomarker-based algorithm for treatment resistance.

Persistent pain after spinal cord injury is maintained by primary afferent activity.

Chronic pain caused by insults to the CNS (central neuropathic pain) is widely assumed to be maintained exclusively by central mechanisms. However, chronic hyperexcitablility occurs in primary nociceptors after spinal cord injury (SCI), suggesting that SCI pain also depends upon continuing activity of peripheral sensory neurons. The present study in rats (Rattus norvegicus) found persistent upregulation after SCI of protein, but not mRNA, for a voltage-gated Na(+) channel, Nav1.8, that is expressed almost exclusively in primary afferent neurons. Selectively knocking down Nav1.8 after SCI suppressed spontaneous activity in dissociated dorsal root ganglion neurons, reversed hypersensitivity of hindlimb withdrawal reflexes, and reduced ongoing pain assessed by a conditioned place preference test. These results show that activity in primary afferent neurons contributes to ongoing SCI pain.

Action of octopamine and tyramine on muscles of Drosophila melanogaster larvae.

Octopamine (OA) and tyramine (TA) play important roles in homeostatic mechanisms, behavior, and modulation of neuromuscular junctions in arthropods. However, direct actions of these amines on muscle force production that are distinct from effects at the neuromuscular synapse have not been well studied. We utilize the technical benefits of the Drosophila larval preparation to distinguish the effects of OA and TA on the neuromuscular synapse from their effects on contractility of muscle cells. In contrast to the slight and often insignificant effects of TA, the action of OA was profound across all metrics assessed. We demonstrate that exogenous OA application decreases the input resistance of larval muscle fibers, increases the amplitude of excitatory junction potentials (EJPs), augments contraction force and duration, and at higher concentrations (10(-5) and 10(-4) M) affects muscle cells 12 and 13 more than muscle cells 6 and 7. Similarly, OA increases the force of synaptically driven contractions in a cell-specific manner. Moreover, such augmentation of contractile force persisted during direct muscle depolarization concurrent with synaptic block. OA elicited an even more profound effect on basal tonus. Application of 10(-5) M OA increased synaptically driven contractions by ≈ 1.1 mN but gave rise to a 28-mN increase in basal tonus in the absence of synaptic activation. Augmentation of basal tonus exceeded any physiological stimulation paradigm and can potentially be explained by changes in intramuscular protein mechanics. Thus we provide evidence for independent but complementary effects of OA on chemical synapses and muscle contractility.