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The release of neuropeptides from dense core vesicles (DCVs) modulates neuronal activity and plays a critical role in cognitive function and emotion. The granin family is considered a master regulator of DCV biogenesis and the release of DCV cargo molecules. The expression of the VGF protein (nonacronymic), a secreted neuropeptide precursor that also belongs to the extended granin family, has been previously shown to be induced in the brain by hippocampus-dependent learning, and its downregulation is mechanistically linked to neurodegenerative diseases such as Alzheimer’s disease and other mood disorders. Currently, whether changes in translational efficiency of Vgf and other granin mRNAs may be associated and regulated with learning associated neural activity remains largely unknown. Here, we show that either contextual fear memory training or the administration of TLQP-62, a peptide derived from the C-terminal region of the VGF precursor, acutely increases the translation of VGF and other granin proteins, such as CgB and Scg2, via an mTOR-dependent signaling pathway in the absence of measurable increases in mRNA expression. Luciferase-based reporter assays confirmed that the 3′-untranslated region (3′UTR) of the Vgf mRNA represses VGF translation. Consistently, the truncation of the endogenous Vgf mRNA 3′UTR results in substantial increases in VGF protein expression both in cultured primary neurons and in brain tissues from knock in mice expressing a 3′UTR-truncation mutant encoded by the modified Vgf gene. Importantly, Vgf 3′UTR-truncated mice exhibit enhanced memory performance and reduced anxiety- and depression-like behaviors. Our results therefore reveal a rapid, transcription-independent induction of VGF and other granin proteins after learning that are triggered by the VGF-derived peptide TLQP-62. Our findings suggest that the rapid, positive feedforward increase in the synthesis of granin family proteins might be a general mechanism to replenish DCV cargo molecules that have been released in response to neuronal activation and is crucial for memory function and mood stability.

Hedgehog-interacting protein (HHIP) sequesters Hedgehog ligands to repress Smoothened (SMO)-mediated recruitment of the GLI family of transcription factors. Allelic variation in HHIP confers risk of chronic obstructive pulmonary disease and other smoking-related lung diseases, but underlying mechanisms are unclear. Using single-cell and cell-type-specific translational profiling, we show that HHIP expression is highly enriched in medial habenula (MHb) neurons, particularly MHb cholinergic neurons that regulate aversive behavioral responses to nicotine. HHIP deficiency dysregulated the expression of genes involved in cholinergic signaling in the MHb and disrupted the function of nicotinic acetylcholine receptors (nAChRs) through a PTCH-1/cholesteroldependent mechanism. Further, CRISPR/Cas9-mediated genomic cleavage of the Hhip gene in MHb neurons enhanced the motivational properties of nicotine in mice. These findings suggest that HHIP influences vulnerability to smoking-related lung diseases in part by regulating the actions of nicotine on habenular aversion circuits.

The authors implicate the transcriptional repressor methyl CpG–binding protein MeCP2 in cocaine addiction. They report that MeCP2 regulates cocaine intake through microRNA-212 to control cocaine's effects on strital BDNF levels. The X-linked transcriptional repressor methyl CpG binding protein 2 (MeCP2), known for its role in the neurodevelopmental disorder Rett syndrome, is emerging as an important regulator of neuroplasticity in postmitotic neurons. Cocaine addiction is commonly viewed as a disorder of neuroplasticity, but the potential involvement of MeCP2 has not been explored. Here we identify a key role for MeCP2 in the dorsal striatum in the escalating cocaine intake seen in rats with extended access to the drug, a process that mimics the increasingly uncontrolled cocaine use seen in addicted humans. MeCP2 regulates cocaine intake through homeostatic interactions with microRNA-212 (miR-212) to control the effects of cocaine on striatal brain-derived neurotrophic factor (BDNF) levels. These data suggest that homeostatic interactions between MeCP2 and miR-212 in dorsal striatum may be important in regulating vulnerability to cocaine addiction.

Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula–pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions. The transcription factor TCF7L2 mediates two important responses to nicotine in the medial habenula region of the rodent brain: aversion to nicotine, and regulation of blood sugar levels through a polysynaptic habenula–pancreas circuit.

Cocaine addiction is characterized by a gradual loss of control over drug use, but the molecular mechanisms regulating vulnerability to this process remain unclear. Here we report that microRNA-212 (miR-212) is upregulated in the dorsal striatum of rats with a history of extended access to cocaine. Striatal miR-212 decreases responsiveness to the motivational properties of cocaine by markedly amplifying the stimulatory effects of the drug on cAMP response element binding protein (CREB) signalling. This action occurs through miR-212-enhanced Raf1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential CREB co-activator TORC (transducer of regulated CREB; also known as CRTC). Our findings indicate that striatal miR-212 signalling has a key role in determining vulnerability to cocaine addiction, reveal new molecular regulators that control the complex actions of cocaine in brain reward circuitries and provide an entirely new direction for the development of anti-addiction therapeutics based on the modulation of noncoding RNAs. Anti-addictive microRNA Extended cocaine-taking triggers a number of structural and functional changes in the brain that may lead to compulsive drug seeking, but the mechanisms that regulate the process are unclear. Experiments in rats now reveal a fundamental role for microRNAs in the striatum in governing the development of compulsive cocaine-seeking behaviour. The microRNA miR-212 decreases cocaine seeking, but only in rats that have taken the drug for an extended amount of time, and not in non-drug-dependent rats. miR-212 appears to act by amplifying the activity of the transcription factor CREB, a known regulator of the rewarding effects of cocaine. This work raises the possibility that agents that modulate the action of noncoding RNAs might be effective in reversing drug addiction. Extended cocaine taking triggers several structural and functional changes in the brain that may lead to compulsive drug seeking, but the mechanisms that regulate the process are unclear. Here, a microRNA — miR-212 — is identified that is upregulated in the striatum of rats with a history of extended access to cocaine. The authors suggest that miR-212 protects against the development of compulsive drug taking, and that it may act through the CREB protein, a known regulator of the rewarding effects of cocaine.

Addiction can be defined as compulsive drug use despite negative consequences. The negative health and economic consequence on society associated with cocaine abuse remains a key concern and currently there is no FDA-approved pharmacological intervention for the treatment of cocaine dependence. Chronic use of drugs of abuse like cocaine can perturb the reward pathways in the brain and cause changes in neuronal plasticity and function. MicroRNAs (miRNAs) are small noncoding RNA transcripts that regulate gene expression at the post-transcriptional level. Cocaine and other drugs of abuse modulate expression of miRNAs in addiction-relevant brain sites, including the striatum, which in turn influences their motivational properties by controlling expression of targeted genes. Previous studies from our group have shown that levels of miR-212, and the closely related miR-132, are increased in the striatum of rats with a history of extended access to intravenous cocaine self-administration that demonstrates compulsive-like consumption of the drug. Here we show that these cocaine-responsive miRNAs differentially modulate cocaine -associated behaviors. In our attempt to investigate the molecular signaling cascades impacted by these miRNAs to help us understand how they influence drug-taking behavior we found that they regulate TNF-α signaling, an important pathway recently shown to control cocaine-induced striatal neuroplasticity. Interestingly, even though miR-212 and miR-132 share common seed sequences and share a similar target profile, we found that miR-212 and miR-132 exert markedly different effects on TNF-α signaling through a mechanism that involves differential targeting of gene transcripts. Our data identifies one of these differentially targeted genes as CYLD (cylindromatosis), a key regulator of TNF-α signaling. CYLD is a K63 deubiquitinase that regulates non-proteolytic ubiquitin signaling, and is highly enriched in striatum. We find that miR-132 and miR-212 signaling play a critical role in regulating AMPA receptor signaling in primary striatal neurons, providing a potential mechanism by which miR-132 and miR-212 can differentially influence cocaine-induced plasticity. Finally, our in vivo studies suggest that this miR-212/132-TNF signaling axis in striatum could be important in regulating vulnerability to drug relapse.