Drug-associated reward memories are conducive to intense craving and often trigger relapse. Simvastatin has been shown to regulate lipids that are involved in memory formation but its influence on other cognitive processes is elusive. Here, we used a mass spectrometry-based lipidomic method to evaluate the impact of simvastatin on the mouse brain in a cocaine-induced reinstatement paradigm. We found that simvastatin blocked the reinstatement of cocaine-induced conditioned place preference (CPP) without affecting CPP acquisition. Specifically, only simvastatin administered during extinction prevented cocaine-primed reinstatement. Global lipidome analysis showed that the nucleus accumbens was the region with the greatest degree of change caused by simvastatin. The metabolism of fatty-acids, phospholipids, and triacylglycerol was profoundly affected. Simvastatin reversed most of the effects on phospholipids induced by cocaine. The correlation matrix showed that cocaine and simvastatin significantly reshaped the lipid metabolic pathways in specific brain regions. Furthermore, simvastatin almost reversed all changes in the fatty acyl profile and unsaturation caused by cocaine. In summary, pre-extinction treatment with simvastatin facilitates cocaine extinction and prevents cocaine relapse with brain lipidome remodeling.
Animals ; Brain ; Cocaine ; Conditioning, Operant ; Extinction, Psychological ; Lipidomics ; Male ; Mice ; Simvastatin/therapeutic use*

The basolateral amygdala (BLA) receives dense projections from cholinergic neurons of the basal forebrain. Acetylcholine can contributes to amygdala-dependent behaviors: formation and extinction of fear memory and appetitive instrumental learning. However, the cholinergic mechanism at the circuit level has not been defined yet. We demonstrated that cholinergic-induced di-synaptic inhibition of BLA pyramidal neurons exhibits a retrograde form of short-term synaptic inhibition, depolarization-induced suppression of inhibition (DSI). Activation of nicotinic receptors was sufficient to evoke action potentials in cholecystokinin (CCK)-positive inhibitory neurons, which strongly inhibit pyramidal neurons through their perisomatic synapses. Our cell type-specific monosynaptic retrograde tracing also revealed that CCK neurons are innervated by basal forebrain cholinergic neurons. Therefore, our data indicated that CCK inhibitory neurons mediate the cholinergic-induced di-synaptic inhibition of BLA pyramidal neurons.
Acetylcholine ; Action Potentials ; Basal Forebrain ; Basolateral Nuclear Complex ; Cholecystokinin ; Cholinergic Neurons ; Conditioning, Operant ; Iontophoresis ; Memory ; Neurons ; Pyramidal Cells ; Receptors, Nicotinic ; Synapses

OBJECTIVE: Brain activity is known to be voluntarily controllable by neurofeedback, a kind of electroencephalographic (EEG) operant conditioning. Although its efficacy in clinical effects has been reported, it is yet to be uncovered whether or how a specific band activity is controllable. Here, we examined EEG spectral profiles along with conditioning training of a specific brain activity, theta band (4–8 Hz) amplitude, in rats. METHODS: During training, the experimental group received electrical stimulation to the medial forebrain bundle contingent to suppression of theta activity, while the control group received stimulation non-contingent to its own band activity. RESULTS: In the experimental group, theta activity gradually decreased within the training session, while there was an increase of theta activity in the control group. There was a significant difference in theta activity during the sessions between the two groups. The spectral theta peak, originally located at 7 Hz, shifted further towards higher frequencies in the experimental group. CONCLUSION: Our results showed that an operant conditioning technique could train rats to control their specific EEG activity indirectly, and it may be used as an animal model for studying how neuronal systems work in human neurofeedback.
Animals ; Brain ; Conditioning, Operant ; Electric Stimulation ; Electroencephalography ; Humans ; Medial Forebrain Bundle ; Models, Animal ; Neurofeedback ; Neurons ; Rats

OBJECTIVE: To assess the effectiveness of Internet of Things (IoT)-based behavioral intervention for reducing depressive symptom of older adults with major depressive disorder. METHODS: A 12-week randomized cross-over controlled study was conducted at community mental health center. We recruited 39 participants with major depressive disorder aged 60 years or older. As a multidomain intervention, four evidence-based therapeutic factors (physical activity, healthy diet, social activity, and emotional regulation) were approached. To maintain motivation of participants, we applied contingency management using IoT device based on operant conditioning theory. RESULTS: The primary outcome was change of depressive symptom measured by Montgomery-Asberg Depression Rating Scale (MADRS). Mixed-effect model compared the effectiveness of intervention and usual care management (intervention by time and period interaction, p=0.017). And during the study period consisting of a total of visit 8, significant group difference was shown in post hoc test at visit 4 (MADRS score of intervention group : MADRS score of control group=7.7±3.4 : 21.1±11.5, p=0.008). CONCLUSION: Community-implementable IoT-based behavioral intervention resulted in greater reduction of depressive symptom of elderly with major depressive disorder.
Adult ; Aged ; Conditioning, Operant ; Depression ; Depressive Disorder, Major ; Diet ; Humans ; Internet ; Mental Health ; Motivation

Animals always seek rewards and the related neural basis has been well studied. However, what happens when animals fail to get a reward is largely unknown, although this is commonly seen in behaviors such as predation. Here, we set up a behavioral model of repeated failure in reward pursuit (RFRP) in Drosophila larvae. In this model, the larvae were repeatedly prevented from reaching attractants such as yeast and butyl acetate, before finally abandoning further attempts. After giving up, they usually showed a decreased locomotor speed and impaired performance in light avoidance and sugar preference, which were named as phenotypes of RFRP states. In larvae that had developed RFRP phenotypes, the octopamine concentration was greatly elevated, while tβh mutants devoid of octopamine were less likely to develop RFRP phenotypes, and octopamine feeding efficiently restored such defects. By down-regulating tβh in different groups of neurons and imaging neuronal activity, neurons that regulated the development of RFRP states and the behavioral exhibition of RFRP phenotypes were mapped to a small subgroup of non-glutamatergic and glutamatergic octopaminergic neurons in the central larval brain. Our results establish a model for investigating the effect of depriving an expected reward in Drosophila and provide a simplified framework for the associated neural basis.
Acetates ; pharmacology ; Animals ; Animals, Genetically Modified ; Avoidance Learning ; physiology ; Biogenic Amines ; metabolism ; Conditioning, Operant ; physiology ; Drosophila ; physiology ; Drosophila Proteins ; genetics ; metabolism ; Feeding Behavior ; drug effects ; physiology ; Instinct ; Larva ; physiology ; Locomotion ; drug effects ; genetics ; Nervous System ; cytology ; Neurons ; physiology ; Octopamine ; metabolism ; RNA Interference ; physiology ; Reward ; Statistics, Nonparametric ; Transcription Factors ; genetics ; metabolism

OBJECTIVE: Prior functional magnetic resonance imaging (fMRI) work has revealed that children/adolescents with disruptive behavior disorders (DBDs) show dysfunctional reward/non-reward processing of non-social reinforcements in the context of instrumental learning tasks. Neural responsiveness to social reinforcements during instrumental learning, despite the importance of this for socialization, has not yet been previously investigated. METHODS: Twenty-nine healthy children/adolescents and 19 children/adolescents with DBDs performed the fMRI social/non-social reinforcement learning task. Participants responded to random fractal image stimuli and received social and non-social rewards/non-rewards according to their accuracy. RESULTS: Children/adolescents with DBDs showed significantly reduced responses within the caudate and posterior cingulate cortex (PCC) to non-social (financial) rewards and social non-rewards (the distress of others). Connectivity analyses revealed that children/adolescents with DBDs have decreased positive functional connectivity between the ventral striatum (VST) and the ventromedial prefrontal cortex (vmPFC) seeds and the lateral frontal cortex in response to reward relative to non-reward, irrespective of its sociality. In addition, they showed decreased positive connectivity between the vmPFC seed and the amygdala in response to non-reward relative to reward. CONCLUSION: These data indicate compromised reinforcement processing of both non-social rewards and social non-rewards in children/adolescents with DBDs within core regions for instrumental learning and reinforcement-based decision-making (caudate and PCC). In addition, children/adolescents with DBDs show dysfunctional interactions between the VST, vmPFC, and lateral frontal cortex in response to rewarded instrumental actions potentially reflecting disruptions in attention to rewarded stimuli.
Amygdala ; Attention Deficit and Disruptive Behavior Disorders ; Conditioning, Operant ; Fractals ; Frontal Lobe ; Gyrus Cinguli ; Learning ; Magnetic Resonance Imaging* ; Prefrontal Cortex ; Problem Behavior* ; Reinforcement, Social* ; Reward ; Socialization ; Ventral Striatum

Caloric diet, such as fat and sugar intake, has rewarding effects, and has been indicated to affect the responses to addictive substances in animal experiments. However, the possible association between sucrose reward and the motivation for addictive drugs remains to be elucidated. Thus, we carried out behavioral tests after sucrose self-administration training to determine the effects of sucrose experience on rats' motivation for cocaine, locomotor sensitivity to cocaine, basal locomotor activity, anxiety level, and associative learning ability. The sucrose-experienced (sucrose) group exhibited higher lever press, cocaine infusion and break point, as well as upshift of cocaine dose-response curve in cocaine self-administration test, as compared with the control (chow) group. Additionally, despite similar locomotor activity in open field test and comparable score in cocaine-induced conditioned place preference, the sucrose group showed higher cocaine-induced locomotor sensitivity as compared with the chow group. The anxiety level and the performance in vocal-cue induced fear memory were similar between these two groups in elevated plus maze and fear conditioning tests, respectively. Taken together, our work indicates that sucrose experience promotes the rats' motivation for cocaine.
Animals ; Cocaine ; Conditioning, Classical ; Conditioning, Operant ; Memory ; Motivation ; Rats ; Reward ; Self Administration ; Sucrose

OBJECTIVETo analyze the electrical activity property changes in nucleus accumbens (NAc) of heroin-induced conditioned place preference (CPP) rats during different stages of heroin dependence and to explore NAc's roles in the formation of drug dependence.

METHODSRecording electrodes were bilaterally embedded into the NAcs of rats with the aid of stereotaxic apparatus, followed by establishment of heroin-dependent rat model. The NAc electrical activity during 3 different stages of heroin dependence, including heroin pre-exposure, immediate post-exposure and heroin withdrawal, were respectively recorded using EEG wireless telemetry techniques. The frequency distribution (ranging from 0.5 to 30 Hz) and the amplitude of NAc electrical activity were analyzed and measured.

RESULTSHeroin-dependent rat models were successfully established and their withdrawal symptoms were evident. All rats showed a conditioned place preference (CPP) for the white box after 5-10 days of heroin-exposure, and displayed a maximum withdrawal symptoms on 2d after heroin- withdrawal. During all statges of heroin-dependence, the NAc electrical activity contained the highest proportion of delta rhythm and the lowest proportion of alpha2 rhythm. The discharge frequence band was similar across different stages. There was a significantly increased ratio of low-frequency discharges (delta rhythm) and decreased ratio of high-frequency discharges (beta rhythm) in NAc of rats during the immediate post- heroin exposure stage when compared with that during pre-exposure and heroin withdrawal stages. During the withdrawal stage, the ratio of at rhythm was significantly lower than during pre- and post-heroin exposure stages (P < 0.01). Further, the mean discharge amplitude in NAcs during immediate post-exposure and withdrawal stages was significantly increased relative to pre-exposure stage. However, the mean discharge amplitude during heroin withdrawal stage was significantly lower than during immediate post-exposure stage.

CONCLUSIONThe electrical activity properties in rat NAcs showed a significant change during different stages of heroin-dependence, which suggested that neuronal activities in NAcs might contribute to the modulation of drug-dependence.

Animals ; Conditioning, Operant ; Heroin ; pharmacology ; Heroin Dependence ; physiopathology ; Male ; Nucleus Accumbens ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Telemetry

Head restraining is an experimental technique that firmly secures the animal's head to a fixation apparatus for the precise control and sensing of behaviors. However, procedural and surgical difficulties and limitations have been obstructing the use of the technique in neurophysiological and behavioral experiments. Here, we propose a novel design of the head-restraining apparatus which is easy to develop and convenient for practical use. Head restraining procedure can be completed by sliding the head mounter, which is molded by dental cement during implantation surgery, into the port, which serves as matching guide rails for the mounter, of the fixation bar. So neither skull-attached plates nor screws for fixation are needed. We performed intracranial self stimulation experiment in rats using the newly designed device. Rats were habituated to acclimatize the head-restraint environment and trained to discriminate two spatially distinguished cues using a customized push-pull lever as an operandum. Direct electrical stimulation into the medial forebrain bundle served as reward. We confirmed that head restraining was stable throughout experiments and rats were able to learn to manipulate the lever after successful habituation. Our experimental framework might help precise control or sensing of behavior under head fixed rats using direct electrical brain stimulation as a reward.
Animals ; Brain ; Conditioning, Operant ; Cues ; Dental Cements ; Electric Stimulation ; Fungi ; Head* ; Medial Forebrain Bundle ; Rats* ; Reward ; Self Stimulation*

OBJECTIVETo study and compare the effect of Corydalis yanhusuo and L-THP on dopamine neurotransmitter and D2 receptor of reward circuitry in various cerebral areas of conditioned place preference model rats and the comparison of their effects.

METHODThe CPP model was established by injecting morphine in rats with increasing doses for 10 days. The initial dose of 10 mg x kg(-1), and the final dose of 100 mg x kg(-1), with 10 mg x kg(-1) increased each day. At 48 h after the final training, CPP was adopted to detect the successful establishment of the model. On the same day (12 d), they were orally administered with 2, 1, 0.5 g x kg(-1) C. yanhusuo (containing 0.153, 0.077 and 0.038 mg L-THP) and L-THP (3.76, 1.88, 0.94 mg x kg(-1)) for six days. On 18 d, CPP test was performed again. Next day, HPLC was adopted to determine the content of dopamine neurotransmitters of reward circuitry in VTA-NAc-PFC; Immunohistochemistry and Western blotting were adopted to detect the expression of D2 receptors.

RESULTCompared with the physiological saline treatment group, C. yanhusuo (2, 1 g x kg(-1)) and L-THP (3.76, 1.88 mg x kg(-1)) groups showed that rats stayed in a notably shorter period in white boxes (morphine-accompanied boxes) (P < 0.01 or P < 0.05), and revealed a remarkably lower dopamine content in VTA, NAc and PFC and the significant increase in the expression of D2 receptor (P < 0.01 or P < 0.05).

CONCLUSIONThe down-regulation of the increased dopamine content in reward nervous circuitry and the up-regulation of the expression of D2 receptor may be one of mechanisms of C. yanhusuo and L-THP in accelerating the recession of morphine's CPP effect Regarding the inhibition of morphine's CPP effect and the effect on dopamine system, the effect of C. yanhusuo traditional Chinese medicine containing one-fold L-THP monomer is equal to that of the independent application of around 24-fold L-THP monomer.

Animals ; Berberine Alkaloids ; administration & dosage ; Brain ; drug effects ; metabolism ; physiopathology ; Conditioning, Operant ; drug effects ; Corydalis ; chemistry ; Dopamine ; metabolism ; Humans ; Male ; Morphine ; adverse effects ; Plant Extracts ; administration & dosage ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine D2 ; genetics ; metabolism ; Substance-Related Disorders ; drug therapy ; genetics ; metabolism ; psychology