Glass-Blowing-Inspired Upcycling of Thermosetting Polymer to Neuron-Like Hierarchical Carbon for Microwave Absorption and Conversion.

Upgrading thermosetting polymer waste and harvesting unwanted electromagnetic energy are of great significance in solving environmental pollution and energy shortage problems. Herein, inspired by the glass-blowing art, a spontaneous, controllable, and scalable strategy is proposed to prepare hollow carbon materials by inner blowing and outside blocking. Specifically, hierarchically neuron-like hollow carbon materials (HCMSs) with various sizes are fabricated from melamine-formaldehyde sponge (MS) waste. Benefiting from the synergistic of the hollow "cell body" and the connected "protrusions" networks, HCMSs reveal superior electromagnetic absorption performance with a strong reflection loss of -54.9 dB, electromagnetic-heat conversion ability with a high conversion efficiency of 34.4%, and efficient energy storage performance in supercapacitor. Furthermore, a multifunctional device integrating electromagnetic-heat-electrical energy conversion is designed, and its feasibility is proved by experiments and theoretical calculations. The integrated device reveals an output voltage of 34.5 mV and a maximum output power of 0.89 µW with electromagnetic radiation for 60 s. This work provides a novel solution to recycle polymer waste, electromagnetic energy, and unwanted thermal energy.

Dissociable dorsal medial prefrontal cortex ensembles are necessary for cocaine seeking and fear conditioning in mice.

The dmPFC plays a dual role in modulating drug seeking and fear-related behaviors. Learned associations between cues and drug seeking are encoded by a specific ensemble of neurons. This study explored the stability of a dmPFC cocaine seeking ensemble over two weeks and its influence on persistent cocaine seeking and fear memory retrieval. In the first series of experiments, we trained TetTag mice in cocaine self-administration and tagged strongly activated neurons with EGFP during the initial day 7 cocaine seeking session. Subsequently, a follow-up seeking test was conducted two weeks later to examine ensemble reactivation between two seeking sessions via c-Fos immunostaining. In the second series of experiments, we co-injected viruses expressing TRE-cre and a cre-dependent inhibitory PSAM-GlyR into the dmPFC of male and female c-fos -tTA mice to enable "tagging" of cocaine seeking ensemble or cued fear ensemble neurons with an inhibitory chemogenetic receptors. Then we investigated their contribution to subsequent cocaine seeking and fear recall during inhibition of the tagged ensemble by administering uPSEM792s (0.3 mg/kg), a selective ligand for PSAM-GlyR. In both sexes, there was a positive association between the persistence of cocaine seeking and the proportion of reactivated EGFP+ neurons within the dmPFC. More importantly, inhibition of the cocaine seeking ensemble suppressed cocaine seeking, but not recall of fear memory, while inhibition of the fear ensemble reduced conditioned freezing but not cocaine seeking. The results demonstrate that cocaine and fear recall ensembles in the dmPFC are stable, but largely exclusive from one another.

Nano-Interfacial Supramolecular Adhesion of Metal-Organic Framework-Based Separator Enables High-Safety and Wide-Temperature-Range Lithium Batteries.

Polyolefin separators are the most commonly used separators for lithium batteries; however, they tend to shrink when heated, and their Li+ transference number (t Li +) is low. Metal-organic frameworks (MOFs) are expected to solve the above problems due to their high thermal stability, abundant pore structure, and open metal sites. However, it is difficult to prepare high-porosity MOF-based membranes by conventional membrane preparation methods. In this study, a high-porosity free-standing MOF-based safety separator, denoted the BCM separator, is prepared through a nano-interfacial supramolecular adhesion strategy. The BCM separator has a large specific surface area (450.22 m2 g-1) and porosity (62.0%), a high electrolyte uptake (475 wt%), and can maintain its morphology at 200 °C. The ionic conductivity and t Li + of the BCM separator are 1.97 and 0.72 mS cm-1, respectively. Li//LiFePO4 cells with BCM separators have a capacity retention rate of 95.07% after 1100 cycles at 5  C, a stable high-temperature cycling performance of 300 cycles at 80 °C, and good capacity retention at -40 °C. Li//NCM811 cells with BCM separators exhibit significantly improved rate performance and cycling performance. Pouch cells with BCM separators can work at 120 °C and have good safety at high temperature.

Synaptic and mitochondrial mechanisms behind alcohol-induced imbalance of excitatory/inhibitory synaptic activity and associated cognitive and behavioral abnormalities.

Alcohol consumption during pregnancy can significantly impact the brain development of the fetus, leading to long-term cognitive and behavioral problems. However, the underlying mechanisms are not well understood. In this study, we investigated the acute and chronic effects of binge-like alcohol exposure during the third trimester equivalent in postnatal day 7 (P7) mice on brain cell viability, synapse activity, cognitive and behavioral performance, and gene expression profiles at P60. Our results showed that alcohol exposure caused neuroapoptosis in P7 mouse brains immediately after a 6-hour exposure. In addition, P60 mice exposed to alcohol during P7 displayed impaired learning and memory abilities and anxiety-like behaviors. Electrophysiological analysis of hippocampal neurons revealed an excitatory/inhibitory imbalance in alcohol-treated P60 mice compared to controls, with decreased excitation and increased inhibition. Furthermore, our bioinformatic analysis of 376 dysregulated genes in P60 mouse brains following alcohol exposure identified 50 synapse-related and 23 mitochondria-related genes. These genes encoded proteins located in various parts of the synapse, synaptic cleft, extra-synaptic space, synaptic membranes, or mitochondria, and were associated with different biological processes and functions, including the regulation of synaptic transmission, transport, synaptic vesicle cycle, metabolism, synaptogenesis, mitochondrial activity, cognition, and behavior. The dysregulated synapse and mitochondrial genes were predicted to interact in overlapping networks. Our findings suggest that altered synaptic activities and signaling networks may contribute to alcohol-induced long-term cognitive and behavioral impairments in mice, providing new insights into the underlying synaptic and mitochondrial molecular mechanisms and potential neuroprotective strategies.

Descending mechanism by which medial prefrontal cortex endocannabinoid signaling controls the development of neuropathic pain and neuronal activity of dorsal root ganglion.

ABSTRACT: Although regulation of nociceptive processes in the dorsal horn by deep brain structures has long been established, the role of cortical networks in pain regulation is minimally explored. The medial prefrontal cortex (mPFC) is a key brain area in pain processing that receives ascending nociceptive input and exerts top-down control of pain sensation. We have shown critical changes in mPFC synaptic function during neuropathic pain, controlled by endocannabinoid (eCB) signaling. This study tests whether mPFC eCB signaling modulates neuropathic pain through descending control. Intra-mPFC injection of cannabinoid receptor type 1 (CB1R) agonist WIN-55,212-2 (WIN) in the chronic phase transiently alleviates the pain-like behaviors in spared nerve injury (SNI) rats. By contrast, intra-mPFC injection of CB1R antagonist AM4113 in the early phase of neuropathic pain reduces the development of pain-like behaviors in the chronic phase. Spared nerve injury reduced the mechanical threshold to induce action potential firing of dorsal horn wide-dynamic-range neurons, but this was reversed in rats by WIN in the chronic phase of SNI and by mPFC injection of AM4113 in the early phase of SNI. Elevated dorsal root ganglion neuronal activity after injury was also diminished in rats by mPFC injection of AM4113, potentially by reducing antidromic activity and subsequent neuronal inflammation. These findings suggest that depending on the phase of the pain condition, both blocking and activating CB1 receptors in the mPFC can regulate descending control of pain and affect both dorsal horn neurons and peripheral sensory neurons, contributing to changes in pain sensitivity.

The silk gland proteome of Stenopsyche angustata provides insights into the underwater silk secretion.

Caddisworms (Trichoptera) spin adhesive silks to construct a variety of underwater composite structures. Many studies have focused on the fibroin heavy chain of caddisworm silk and found that it contains heavy phosphorylation to maintain a stable secondary structure. Besides fibroins, recent studies have also identified some new silk proteins within caddisworm silk. To better understand the silk composition and its secretion process, this study reports the silk gland proteome of a retreat-building caddisworm, Stenopsyche angustata Martynov (Trichoptera, Stenopsychidae). Using liquid chromatography tandem mass spectrometry (LC-MS/MS), 2389 proteins were identified in the silk gland of S. angustata, among which 192 were predicted as secreted silk proteins. Twenty-nine proteins were found to be enriched in the front silk gland, whereas 109 proteins were enriched in the caudal silk gland. The fibroin heavy chain and nine uncharacterized silk proteins were identified as phosphorylated proteins. By analysing the sequence of the fibroin heavy chain, we found that it contains 13 Gly/Thr/Pro-rich regions, 12 Val/Ser/Arg-rich regions and a Gly/Arg/Thr-rich region. Three uncharacterized proteins were identified as sericin-like proteins due to their larger molecular weights, signal peptides and repetitive motifs rich in serine. This study provides valuable information for further clarifying the secretion and adhesion of underwater caddisworm silk.

Psilocybin analog 4-OH-DiPT enhances fear extinction and GABAergic inhibition of principal neurons in the basolateral amygdala.

Psychedelics such as psilocybin show great promise for the treatment of depression and PTSD, but their long duration of action poses practical limitations for patient access. 4-OH-DiPT is a fast-acting and shorter-lasting derivative of psilocybin. Here we characterized the pharmacological profile of 4-OH-DiPT and examined its impact on fear extinction learning as well as a potential mechanism of action. First, we profiled 4-OH-DiPT at all 12 human 5-HT GPCRs. 4-OH-DiPT showed strongest agonist activity at all three 5-HT2A/2B/2C receptors with near full agonist activity at 5-HT2A. Notably, 4-OH-DiPT had comparable activity at mouse and human 5-HT2A/2B/2C receptors. In a fear extinction paradigm, 4-OH-DiPT significantly reduced freezing responses to conditioned cues in a dose-dependent manner with a greater potency in female mice than male mice. Female mice that received 4-OH-DiPT before extinction training had reduced avoidance behaviors several days later in the light dark box, elevated plus maze and novelty-suppressed feeding test compared to controls, while male mice did not show significant differences. 4-OH-DiPT produced robust increases in spontaneous inhibitory postsynaptic currents (sIPSCs) in basolateral amygdala (BLA) principal neurons and action potential firing in BLA interneurons in a 5-HT2A-dependent manner. RNAscope demonstrates that Htr2a mRNA is expressed predominantly in BLA GABA interneurons, Htr2c mRNA is expressed in both GABA interneurons and principal neurons, while Htr2b mRNA is absent in the BLA. Our findings suggest that 4-OH-DiPT activates BLA interneurons via the 5-HT2A receptor to enhance GABAergic inhibition of BLA principal neurons, which provides a potential mechanism for suppressing learned fear.

cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement.

Chronic cocaine exposure induces enduring neuroadaptations that facilitate motivated drug taking. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to modulate neuronal firing and pacemaker activity in ventral tegmental area (VTA) dopamine neurons. However, it remained unknown whether cocaine self-administration affects HCN channel function and whether HCN channel activity modulates motivated drug taking. We report that rat VTA dopamine neurons predominantly express Hcn3-4 mRNA, while VTA GABA neurons express Hcn1-4 mRNA. Both neuronal types display similar hyperpolarization-activated currents (Ih), which are facilitated by acute increases in cAMP. Acute cocaine application decreases voltage-dependent activation of Ih in VTA dopamine neurons, but not in GABA neurons. Unexpectedly, chronic cocaine self-administration results in enhanced Ih selectively in VTA dopamine neurons. This differential modulation of Ih currents is likely mediated by a D2 autoreceptor-induced decrease in cAMP as D2 (Drd2) mRNA is predominantly expressed in dopamine neurons, whereas D1 (Drd1) mRNA is barely detectable in the VTA. Moreover, chronically decreased cAMP via Gi-DREADD stimulation leads to an increase in Ih in VTA dopamine neurons and enhanced binding of HCN3/HCN4 with tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), an auxiliary subunit that is known to facilitate HCN channel surface trafficking. Finally, we show that systemic injection and intra-VTA infusion of the HCN blocker ivabradine reduces cocaine self-administration under a progressive ratio schedule and produces a downward shift of the cocaine dose-response curve. Our results suggest that cocaine self-administration induces an upregulation of Ih in VTA dopamine neurons, while HCN inhibition reduces the motivation for cocaine intake.

Non-flammable solvent-free liquid polymer electrolyte for lithium metal batteries.

As a replacement for highly flammable and volatile organic liquid electrolyte, solid polymer electrolyte shows attractive practical prospect in high-energy lithium metal batteries. However, unsatisfied interface performance and ionic conductivities are two critical challenges. A common strategy involves introducing organic solvents or plasticizers, but this violates the original intention of security design. Here, an electrolyte concept called liquid polymer electrolyte without any small molecular solvents is proposed for safe and high-performance batteries, based on the design of a room-temperature liquid-state brush-like polymer as the sole solvent of lithium salts. This liquid polymer electrolyte is non-flammable and exhibits high ionic conductivity (1.09 [Formula: see text] 10-4 S cm-1 at 25 °C), significant lithium dendrite suppression, and stable long-term cycling over a wide operating temperature range ( ≥ 1000 cycles at 60 °C and 90 °C). Moreover, the pouch cell can resist thermal abuse, vacuum environment, and mechanical abuse. This electrolyte and design strategy are expected to provide enlightening ideas for the development of safe and high-performance polymer electrolytes.

Correction to: Effective transport network driven by tortuosity gradient enables high-electrochem-active solid-state batteries.

[This corrects the article DOI: 10.1093/nsr/nwac272.].

How autophagy, a potential therapeutic target, regulates intestinal inflammation.

Inflammatory bowel disease (IBD) is a group of disorders that cause chronic inflammation in the intestines, with the primary types including ulcerative colitis and Crohn's disease. The link between autophagy, a catabolic mechanism in which cells clear protein aggregates and damaged organelles, and intestinal health has been widely studied. Experimental animal studies and human clinical studies have revealed that autophagy is pivotal for intestinal homeostasis maintenance, gut ecology regulation and other aspects. However, few articles have summarized and discussed the pathways by which autophagy improves or exacerbates IBD. Here, we review how autophagy alleviates IBD through the specific genes (e.g., ATG16L1, IRGM, NOD2 and LRRK2), crosstalk of multiple phenotypes with autophagy (e.g., Interaction of autophagy with endoplasmic reticulum stress, intestinal antimicrobial defense and apoptosis) and autophagy-associated signaling pathways. Moreover, we briefly discuss the role of autophagy in colorectal cancer and current status of autophagy-based drug research for IBD. It should be emphasized that autophagy has cell-specific and environment-specific effects on the gut. One of the problems of IBD research is to understand how autophagy plays a role in intestinal tract under specific environmental factors. A better understanding of the mechanism of autophagy in the occurrence and progression of IBD will provide references for the development of therapeutic drugs and disease management for IBD in the future.

Effective transport network driven by tortuosity gradient enables high-electrochem-active solid-state batteries.

Simultaneously achieving high electrochemical activity and high loading for solid-state batteries has been hindered by slow ion transport within solid electrodes, in particular with an increase in electrode thickness. Ion transport governed by 'point-to-point' diffusion inside a solid-state electrode is challenging, but still remains elusive. Herein, synchronized electrochemical analysis using X-ray tomography and ptychography reveals new insights into the nature of slow ion transport in solid-state electrodes. Thickness-dependent delithiation kinetics are spatially probed to identify that low-delithiation kinetics originate from the high tortuous and slow longitudinal transport pathways. By fabricating a tortuosity-gradient electrode to create an effective ion-percolation network, the tortuosity-gradient electrode architecture promotes fast charge transport, migrates the heterogeneous solid-state reaction, enhances electrochemical activity and extends cycle life in thick solid-state electrodes. These findings establish effective transport pathways as key design principles for realizing the promise of solid-state high-loading cathodes.

Concentration Scaling on Linear Viscoelastic Properties of Cellular Suspensions and Effects of Equilibrium Phase Behavior.

Concentration scaling on linear viscoelastic properties of cellular suspensions has been studied by rheometric characterisation of Phormidium suspensions and human blood in a wide range of volume fraction under small amplitude oscillatory shear experiments. The rheometric characterisation results are analysed by the time-concentration superposition (TCS) principle and show a power law scaling of characteristic relaxation time, plateau modulus and the zero-shear viscosity over the concentration ranges studied. The results show that the concentration effect of Phormidium suspensions on their elasticity is much stronger than that of human blood due to its strong cellular interactions and a high aspect ratio. For human blood, no obvious phase transition could be observed over the range of hematocrits studied here and with respect to a high-frequency dynamic regime, only one concentration scaling exponent could be identified. For Phormidium suspensions with respect to a low-frequency dynamic regime, three concentration scaling exponents in the volume fraction Region I (0.36≤ϕ/ϕref≤0.46), Region II (0.59≤ϕ/ϕref≤2.89) and Region III (3.11≤ϕ/ϕref≤3.44) are identified. The image observation shows that the network formation of Phormidium suspensions occurs as the volume fraction is increased from Region I to Region II; the sol-gel transition takes place from Region II to Region III. In combination with analysis of other nanoscale suspensions and liquid crystalline polymer solutions reported in the literature, it is revealed that such a power law concentration scaling exponent depends on colloidal or molecular interactions mediated with solvent and is sensitive to the equilibrium phase behaviour of complex fluids. The TCS principle is an unambiguous tool to give a quantitative estimation.

Genetic Disruption of System xc-Mediated Glutamate Release from Astrocytes Increases Negative-Outcome Behaviors While Preserving Basic Brain Function in Rat.

The importance of neuronal glutamate to synaptic transmission throughout the brain illustrates the immense therapeutic potential and safety risks of targeting this system. Astrocytes also release glutamate, the clinical relevance of which is unknown as the range of brain functions reliant on signaling from these cells hasn't been fully established. Here, we investigated system xc- (Sxc), which is a glutamate release mechanism with an in vivo rodent expression pattern that is restricted to astrocytes. As most animals do not express Sxc, we first compared the expression and sequence of the obligatory Sxc subunit xCT among major classes of vertebrate species. We found xCT to be ubiquitously expressed and under significant negative selective pressure. Hence, Sxc likely confers important advantages to vertebrate brain function that may promote biological fitness. Next, we assessed brain function in male genetically modified rats (MSxc) created to eliminate Sxc activity. Unlike other glutamatergic mechanisms, eliminating Sxc activity was not lethal and didn't alter growth patterns, telemetry measures of basic health, locomotor activity, or behaviors reliant on simple learning. However, MSxc rats exhibited deficits in tasks used to assess cognitive behavioral control. In a pavlovian conditioned approach, MSxc rats approached a food-predicted cue more frequently than WT rats, even when this response was punished. In attentional set shifting, MSxc rats displayed cognitive inflexibility because of an increased frequency of perseverative errors. MSxc rats also displayed heightened cocaine-primed drug seeking. Hence, a loss of Sxc-activity appears to weaken control over nonreinforced or negative-outcome behaviors without altering basic brain function.SIGNIFICANCE STATEMENT Glutamate is essential to synaptic activity throughout the brain, which illustrates immense therapeutic potential and risk. Notably, glutamatergic mechanisms are expressed by most types of brain cells. Hence, glutamate likely encodes multiple forms of intercellular signaling. Here, we hypothesized that the selective manipulation of astrocyte to neuron signaling would alter cognition without producing widespread brain impairments. First, we eliminated activity of the astrocytic glutamate release mechanism, Sxc, in rat. This impaired cognitive flexibility and increased expression of perseverative, maladaptive behaviors. Notably, eliminating Sxc activity did not alter metrics of health or noncognitive brain function. These data add to recent evidence that the brain expresses cognition-specific molecular mechanisms that could lead to highly precise, safe medications for impaired cognition.

Synthesis of Quercetin-Acid Esters and Its Reduction of H2 O2 -Triggered PC12 Cells Damage by Down-Regulating ROS.

Quercetin is a kind of polyphenolic flavonoid compounds which has perfect antioxidant properties. However, quercetin is not available in many situations due to its poor bioavailability. In this work, the QAEs with better solubility and even stronger antioxidant properties were synthesized, through the esterification between quercetin and the chlorinated cinnamic acid or its derivatives, whose chlorination were achieved by using SOCl2 . The protective effects of the QAEs were evaluated by the H2 O2 -induced apoptosis experiment in rat adrenal pheochromocytoma cells (PC12 cells) and its ability to remove ROS generated by oxidative stress. Compared with the original quercetin group, the QAEs groups showed much improved cell viability and capability of removing ROS, which means their higher bioavailability than the parent.

Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1.

Necroptosis is a form of regulated necrosis involved in various pathological diseases. The process of necroptosis is controlled by receptor-interacting kinase 1 (RIPK1), RIPK3, and pseudokinase mixed lineage kinase domain-like protein (MLKL), and pharmacological inhibition of these kinases has been shown to have therapeutic potentials in a variety of diseases. In this study, using drug repurposing strategy combined with high-throughput screening (HTS), we discovered that AZD4547, a previously reported FGFR inhibitor, is able to interfere with necroptosis through direct targeting of RIPK1 kinase. In both human and mouse cell models, AZD4547 blocked RIPK1-dependent necroptosis. In addition, AZD4547 rescued animals from TNF-induced lethal shock and inflammatory responses. Together, our study demonstrates that AZD4547 is a potent and selective inhibitor of RIPK1 with therapeutic potential for the treatment of inflammatory disorders that involve necroptosis.

Palladium-Catalyzed C-H Activation/Cyclization for the Synthesis of [60]Fullerene-Fused Phosphinolactones.

A novel and efficient palladium-catalyzed C-H activation reaction of [60]fullerene with arylphosphinic acids has been developed for the synthesis of [60]fullerene-fused phosphinolactones. A possible reaction mechanism is proposed to explain the generation of the obtained products. A representative product can be further electrochemically transformed into bis-benzylated 1,2- and 1,4-adducts of [60]fullerene. In addition, a [60]fullerene-fused phosphinolactone with a 12-membered ring can also be synthesized from the electrochemical ring expansion of the employed phosphinolactone with a 6-memebered ring with 1,2-bis(bromomethyl)benzene.

Treadmill Exercise Reduces Neuroinflammation, Glial Cell Activation and Improves Synaptic Transmission in the Prefrontal Cortex in 3 × Tg-AD Mice.

Physical exercise improves memory and cognition in physiological aging and Alzheimer's disease (AD), but the mechanisms remain poorly understood. Here, we test the hypothesis that Aß oligomer accumulation, neuroinflammation, and glial cell activation may lead to disruption of synaptic transmission in the prefrontal cortex of 3 × Tg-AD Mice, resulting in impairment of learning and memory. On the other hand, treadmill exercise could prevent the pathogenesis and exert neuroprotective effects. Here, we used immunohistochemistry, western blotting, enzyme-linked immunosorbent assay, and slice electrophysiology to analyze the levels of GSK3ß, Aß oligomers (Aß dimers and trimers), pro-inflammatory cytokines (IL-1ß, IL-6, and TNFα), the phosphorylation of CRMP2 at Thr514, and synaptic currents in pyramidal neurons in the prefrontal cortex. We show that 12-week treadmill exercise beginning in three-month-old mice led to the inhibition of GSK3ß kinase activity, decreases in the levels of Aß oligomers, pro-inflammatory cytokines (IL-1ß, IL-6, and TNFα), and the phosphorylation of CRMP2 at Thr514, reduction of microglial and astrocyte activation, and improvement of excitatory and inhibitory synaptic transmission of pyramidal neurons in the prefrontal cortex of 3 × Tg-AD Mice. Thus, treadmill exercise reduces neuroinflammation, glial cell activation and improves synaptic transmission in the prefrontal cortex in 3 × Tg-AD mice, possibly related to the inhibition of GSK3ß kinase activity.

A red nucleus-VTA glutamate pathway underlies exercise reward and the therapeutic effect of exercise on cocaine use.

Physical exercise is rewarding and protective against drug abuse and addiction. However, the neural mechanisms underlying these actions remain unclear. Here, we report that long-term wheel-running produced a more robust increase in c-fos expression in the red nucleus (RN) than in other brain regions. Anatomic and functional assays demonstrated that most RN magnocellular portion (RNm) neurons are glutamatergic. Wheel-running activates a subset of RNm glutamate neurons that project to ventral tegmental area (VTA) dopamine neurons. Optogenetic stimulation of this pathway was rewarding, as assessed by intracranial self-stimulation and conditioned place preference, whereas optical inhibition blocked wheel-running behavior. Running wheel access decreased cocaine self-administration and cocaine seeking during extinction. Last, optogenetic stimulation of the RNm-to-VTA glutamate pathway inhibited responding to cocaine. Together, these findings indicate that physical exercise activates a specific RNm-to-VTA glutamatergic pathway, producing exercise reward and reducing cocaine intake.

Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via enhancement of dopamine release.

Repeated exposure to drugs of abuse results in an upregulation of cAMP signaling in the mesolimbic dopamine system, a molecular adaptation thought to be critically involved in the development of drug dependence. Exchange protein directly activated by cAMP (Epac2) is a major cAMP effector abundantly expressed in the brain. However, it remains unknown whether Epac2 contributes to cocaine reinforcement. Here, we report that Epac2 in the mesolimbic dopamine system promotes cocaine reinforcement via enhancement of dopamine release. Conditional knockout of Epac2 from midbrain dopamine neurons (Epac2-cKO) and the selective Epac2 inhibitor ESI-05 decreased cocaine self-administration in mice under both fixed-ratio and progressive-ratio reinforcement schedules and across a broad range of cocaine doses. In addition, Epac2-cKO led to reduced evoked dopamine release, whereas Epac2 agonism robustly enhanced dopamine release in the nucleus accumbens in vitro. This mechanism is central to the behavioral effects of Epac2 disruption, as chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons via deschloroclozapine (DCZ)-induced activation of Gs-DREADD increased dopamine release and reversed the impairment of cocaine self-administration in Epac2-cKO mice. Conversely, chemogenetic inhibition of VTA dopamine neurons with Gi-DREADD reduced dopamine release and cocaine self-administration in wild-type mice. Epac2-mediated enhancement of dopamine release may therefore represent a novel and powerful mechanism that contributes to cocaine reinforcement.