Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice

ABSTRACTObjectiveMetformin exhibits therapeutic potential in behavioural deficits induced by methamphetamine (METH) in rats. Emerging studies suggest gut microbiota may impact psychiatric symptoms, but there is no direct evidence supporting metformin’s participation in the pathophysiology of withdrawal symptoms via modulation of gut microbiota.MehodsIn order to define the functional contributions by gut microbiota and metformin to the behavioural deficits during METH withdrawal, we utilized a combination of fecal microbiota transplantation (FMT), high-throughput sequencing, and untargeted metabolomics technologies.ResultsFirst, METH addicts exhibited higher α diversity and distinct microbial structures compared to heathy controls. In particular, the relative abundance of Rikenellaceae was positively correlated with the severity of anxiety and depression. Second, both human-to-mouse and mouse-to-mouse FMTs confirmed that METH-altered-microbiota transplantation is sufficient to promote anxiety and depression-like behaviours in recipient germ-free mice, and these behavioural disturbances could be ameliorated by metformin. In-depth analysis revealed that METH significantly altered the bacterial composition and structure as well as relative abundance of several bacterial taxa and metabolites, including Rikenellaceae and inosine, respectively, whereas add-on metformin could remodel these alterations. Finally, the inosine complementation successfully restored METH-induced anxiety and depression-like behaviours in mice.DiscussionThis study demonstrates that METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model. The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota-derived metabolites, highlighting the role of the gut microbiota in substance use disorders and the pathophysiology of withdrawal symptoms.Study HighlightsWhat is known?There are no targeted therapies for substance withdrawal syndrome, but there is considerable evidence that withdrawal-associated psychiatric manifestations contribute to the poor adherence to rehabilitation treatment as well as the relapse rates.Metformin has shown its therapeutic potential against METH-induced neurobehavioural changes and neurodegeneration in rats through CREB/BDNF and Akt/GSK3 signaling pathways in the anxiety-related brain nuclei.What is new here?METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model.The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota derived metabolites.Inosine complementation could restore METH withdrawal-induced anxiety and depression-like behaviours.

Oxytocin neurons mediates the effect of social isolation via the VTA circuits

Social interaction during adolescence strongly influences brain function and behaviour, and the recent pandemic has emphasized the devastating effect of social distancing on mental health. While accumulating evidences have shown the importance of the reward system in encoding specific aspects of social interaction, the consequences of social isolation on the reward system and the development of social skills later in adulthood are still largely unknown. Here, we found that one week of social isolation during adolescence in mice increased social interaction at the expense of social habituation and social novelty preference. Behavioural changes were accompanied by the acute hyperexcitability of dopamine (DA) neurons in the ventral segmental area (VTA) and long-lasting expression of GluA2-lacking AMPARs at excitatory inputs onto DA neurons that project to the prefrontal cortex (PFC). Social isolation-dependent behavioural deficits and changes in neural activity and synaptic plasticity were reversed by chemogenetic inhibition of oxytocin neurons in the paraventricular nucleus (PVN) of the hypothalamus. These results demonstrate that social isolation has acute and long-lasting effects on social interaction and suggest that these effects are mediated by homeostatic adaptations within the reward circuit.

Neonatal administration of a subanaesthetic dose of JM-1232(−) in mice results in no behavioural deficits in adulthood

In animal models, neonatal exposure of general anaesthetics significantly increases apoptosis in the brain, resulting in persistent behavioural deficits later in adulthood. Consequently, there is growing concern about the use of general anaesthetics in obstetric and paediatric practice. JM-1232(−) has been developed as a novel intravenous anaesthetic, but the effects of JM-1232(−) on the developing brain are not understood. Here we show that neonatal administration of JM-1232(−) does not lead to detectable behavioural deficits in adulthood, contrarily to other widely-used intravenous anaesthetics. At postnatal day 6 (P6), mice were injected intraperitoneally with a sedative-equivalent dose of JM-1232(−), propofol, or midazolam. Western blot analysis of forebrain extracts using cleaved poly-(adenosine diphosphate-ribose) polymerase antibody showed that JM-1232(−) is accompanied by slight but measurable apoptosis 6 h after administration, but it was relatively small compared to those of propofol and midazolam. Behavioural studies were performed in adulthood, long after the neonatal anaesthesia, to evaluate the long-term effects on cognitive, social, and affective functions. P6 administration to JM-1232(−) was not accompanied by detectable long-term behavioural deficits in adulthood. However, animals receiving propofol or midazolam had impaired social and/or cognitive functions. These data suggest that JM-1232(−) has prospects for use in obstetric and paediatric practice.

Cocoa supplementation reduces amyloid-beta1–42 (Aβ1–42) induced deficits in a transgenic C. elegans

BACKGROUND: Cocoa, a significant contributor of polyphenols to the western diet has been shown to be effective against Aβ induced toxicity in vitro. However, the effects of long-term cocoa supplementation on Aβ induced behavioural deficits, particularly on the short-term memory loss observed in human AD are not well defined. OBJECTIVE: This study characterized the phenotype of a pan-neuronal Aβ expressing C. elegans strain and investigated the effects of long-term cocoa supplementation on Aβ induced behavioural deficits including short-term memory loss and lifespan. METHODS: Cocoa powder was supplemented to the E. coli OP50 diet of C. elegans starting from L1 stage until they die. Neuronally controlled processes including locomotion, learning and memory were studied at different stages of the lifespan. In addition, lifespan was evaluated with different cocoa doses. Aβ fibril levels were determined with Thioflavin T. RESULTS: Aβ expressing worms showed a reduced growth, a reduced maximum speed at old age, short-term memory deficits at middle age and a reduced lifespan. Cocoa-supplementation reversed the deficits in growth, maximum speed, short-term memory loss and lifespan to reach similar levels to control counterparts while reducing the Aβ fibril levels. CONCLUSIONS: Long-term cocoa supplementation seemed to improve Aβ induced deficits in C. elegans.

The role of noradrenaline in cognition and cognitive disorders

Many aspects of cognition and behaviour are regulated by noradrenergic projections to the forebrain originating from the locus coeruleus, acting through alpha and beta adrenoreceptors. Loss of these projections is common in neurodegenerative diseases and contributes to their cognitive and behavioural deficits. We review the evidence for a noradrenergic modulation of cognition in its contribution to Alzheimer’s disease, Parkinson’s disease and other cognitive disorders. We discuss the advances in human imaging and computational methods that quantify the locus coeruleus and its function in humans, and highlight the potential for new noradrenergic treatment strategies.