Cocaine Triggers Glial-Mediated Synaptogenesis

Synaptogenesis is essential in forming new neurocircuits during development, and this is mediated in part by astrocyte-released thrombospondins (TSPs) and activation of their neuronal receptor, α2δ-1. Here, we show that this developmental synaptogenic mechanism is utilized during cocaine experience to induce spinogenesis and the generation of AMPA receptor-silent glutamatergic synapses in the adult nucleus accumbens (NAc). Specifically, cocaine administration activates NAc astrocytes, and preventing this activation blocks cocaine-induced generation of silent synapses. Furthermore, knockout of TSP2, or pharmacological inhibition or viral-mediated knockdown of α2δ-1, prevents cocaine-induced generation of silent synapses. Moreover, disrupting TSP2-α2δ-1-mediated spinogenesis and silent synapse generation in the NAc occludes cue-induced cocaine seeking after withdrawal from cocaine self-administration and cue-induced reinstatement of cocaine seeking after drug extinction. These results establish that silent synapses are generated by an astrocyte-mediated synaptogenic mechanism in response to cocaine experience and embed critical cue-associated memory traces that promote cocaine relapse.

Inter-Species Differences in Regulation of the Progranulin–Sortilin Axis in TDP-43 Cell Models of Neurodegeneration

Cytoplasmic aggregates and nuclear depletion of the ubiquitous RNA-binding protein TDP-43 have been described in the autoptic brain tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD) patients and both TDP-43 loss-of-function and gain-of-function mechanisms seem to contribute to the neurodegenerative process. Among the wide array of RNA targets, TDP-43 regulates progranulin (GRN) mRNA stability and sortilin (SORT1) splicing. Progranulin is a secreted neurotrophic and neuro-immunomodulatory factor whose endocytosis and delivery to the lysosomes are regulated by the neuronal receptor sortilin. Moreover, GRN loss-of-function mutations are causative of a subset of FTLD cases showing TDP-43 pathological aggregates. Here we show that TDP-43 loss-of-function differently affects the progranulin–sortilin axis in murine and human neuronal cell models. We demonstrated that although TDP-43 binding to GRN mRNA occurs similarly in human and murine cells, upon TDP-43 depletion, a different control of sortilin splicing and protein content may determine changes in extracellular progranulin uptake that account for increased or unchanged secreted protein in murine and human cells, respectively. As targeting the progranulin–sortilin axis has been proposed as a therapeutic approach for GRN-FTLD patients, the inter-species differences in TDP-43-mediated regulation of this pathway must be considered when translating studies from animal models to patients.

972. A Mycobacterium tuberculosis Secreted Lipid Triggers Cough Through a Neuronal Cough Receptor

Background A hallmark symptom of active pulmonary tuberculosis vital for disease transmission is cough. The current paradigm for tuberculosis-related cough is that it results from airway damage or irritation. However, there is limited experimental data to support this theory, and whether Mycobacterium tuberculosis (Mtb) induces cough to facilitate its own transmission has not been explored. The cough reflex is a complex and coordinated event involving both the nervous and musculoskeletal systems initiated by particulate or chemical molecules activating nociceptive neurons, which sense pain or irritation. This activation induces a signaling cascade ultimately resulting in a cough. Respiratory nociceptive neurons innervate the airway of humans and most mammals and thus are poised to respond to noxious molecules to help protect the lung from damage. Because Mtb is a lung pathogen, cough is a primary mechanism of Mtb transmission, and respiratory nociceptive neurons activate cough, we hypothesized that Mtb produces molecules that stimulate cough thereby facilitating its spread from infected to uninfected individuals. We previously identified a cough molecule produced by Mtb, and in this work characterize its neuronal receptor using genetics, biochemistry, and pharmacology. Methods We used an in vitro neuronal activation bioassay to study Mtb cough-inducing molecules. We also used a biochemical assay to identify the cough receptor. Finally, we used gene silencing, biochemistry, and pharmacologic inhibition to validate and characterize the activity of the newly discovered cough receptor. Results We isolated a complex lipid produced by Mtb that activates nociceptive neurons. Both an organic Mtb extract and the purified molecule alone were sufficient to induce cough in a conscious guinea pig cough model and guinea pigs infected with wild-type Mtb cough much more frequently than guinea pigs infected with Mtb strains unable to produce nociceptive molecules. Using genetics, biochemistry, and pharmacology techniques, we identified and validated a cough receptor for the Mtb lipid expressed on nociceptive neurons. Conclusion We conclude that Mtb produces a molecule that activates nociceptive neurons and induces cough through a specific neuronal receptor. These findings have significant implications for our understanding of Mtb transmission. Disclosures All Authors: No reported Disclosures.

5-methoxy-N,N-dimethyltryptamine: An ego-dissolving endogenous neurochemical catalyst of creativity

Abstract5-Methoxy-N,N-dimethyltryptamine (acronymized as 5-MeO-DMT) is sui generis among the numerous naturally-occurring psychoactive substances due to its unparalleled ego-dissolving effects which can culminate in a state of nondual consciousness (which is phenomenologically similar to transformative peak experiences described in various ancient contemplative traditions, e.g., Advaita Vedānta, Mahāyāna Buddhism). The enigmatic molecule is endogenous to the human brain and has profound psychological effects which are hitherto only very poorly understood due to the absence of scientifically controlled human experimental trials. Its exact neuronal receptor binding profile is a matter of ongoing scientific research, however, its remarkable psychoactivity is presumably mediated via agonism of the 5-HT2A (serotonin) receptor subtype. Anthropological/ethnopharmacological evidence indicates that various cultures utilized 5-MeO-DMT containing plants for medicinal, psychological, and spiritual purposes for millennia. In this paper we argue that this naturally occurring serotonergic compound could be fruitfully utilized as a neurochemical research tool which has the potential to significantly advance our understanding of the cognitive and neuronal processes which underpin cognition and creativity (downregulation of the default-mode network, increased neuronal functional connectivity, etc.). An eclectic interdisciplinary perspective is adopted, and we present converging evidence from a plurality of sources in support of this conjecture. Specifically, we suggest that 5-MeO-DMT has great potential in this respect due to its incommensurable capacity to completely disintegrate self-referential cognitive/neuronal processes (viz., “ego death”). The importance of unbiased systematic scientific research on naturally occurring endogenous psychoactive compounds is discussed from a Jamesian radical empiricism perspective and potential scenarios of abuse are discussed (particularly in the context of military torture).