Stress is highly pervasive in humans, impacting motivated behaviors with an enormous toll on life quality. Many of the effects of stress are orchestrated by neuropeptides such as ...corticotropin-releasing factor (CRF). It has previously been shown that in stress-naïve male mice, CRF acts in the core of the nucleus accumbens (NAc) to produce appetitive effects and to increase dopamine release; yet in stress-exposed male mice, CRF loses its capacity to modulate NAc dopamine release and is aversive. In the current research, we tested whether this effect is comparable in females to males and whether the neuroadaptation is susceptible to social transmission. We found that, like in males, CRF increased dopamine release in stress-naïve but not stress-exposed female mice. Importantly, this persistent physiological change was not accompanied by overt behavioral changes that would be indicative of depression- or anxiety-like phenotype. Nonetheless, when these mice were housed for 7 days with stress-naïve conspecifics, the cage mates also exhibited a loss of dopamine potentiation by CRF. These data demonstrate the asymptomatic, yet pervasive transmission of stress-related neuroadaptations in the population.
The prototypical member of the receptor-inactivating kappa opioid receptor (KOR) antagonists, norbinaltorphimine (norBNI), produces prolonged receptor inactivation by a cJun kinase mechanism. These ...antagonists have potential therapeutic utility in the treatment of stress disorders; however, additional preclinical characterization is necessary to understand important aspects of their action. In this study, we report that norBNI does not work as effectively in female mice as in males because of estrogen regulation of G protein receptor kinase (GRK); pretreatment of ovary-intact female mice with the selective GRK2/3 inhibitor, Compound 101, made females equally sensitive to norBNI as males. Prior observations suggested that in vivo treatment with norBNI does not produce long-lasting inhibition of KOR regulation of dopamine release in the nucleus accumbens. We assessed the persistence of norBNI receptor inactivation in subcellular compartments. Fast-scan cyclic voltammetry recordings confirmed that presynaptic inhibition of dopamine release by the KOR agonist U69,593 was not blocked by in vivo pretreatment with norBNI under conditions that prevented KOR-mediated aversion and analgesia. We employed a novel in vivo proxy sensor of KOR activation, adenovirus associated double floxed inverted–HyPerRed, and demonstrated that KOR activation stimulates cJun kinase–dependent reactive oxygen species (ROS) production in somatic regions of ventral tegmental area dopamine neurons, but did not activate ROS production in dopamine terminals. The compartment selective action helps explain how dopamine somatic, but not terminally expressed, KORs are inactivated by norBNI. These results further elucidate molecular signaling mechanisms mediating receptor-inactivating KOR antagonist action and advance medication development for this novel class of stress-resilience medications.
•Kappa opioid activation in dopamine neurons enhances cocaine reward after stress.•Stress initially inhibits and then excites dopamine neurons through kappa opioid activation.•Inhibition of VTA ...dopamine neurons can initially suppress then enhance cocaine reward.•Projections from DRN neurons release dynorphins in the VTA to regulate excitability.
Behavioral stress exposure increases the risk of drug-taking in individuals with substance use disorders by mechanisms involving the dynorphins, which are the endogenous neuropeptides for the kappa opioid receptor (KOR). KOR agonists have been shown to encode dysphoria, aversion, and changes in reward valuation, and kappa opioid antagonists are in clinical development for treating substance use disorders. In this study, we confirmed that KORs were expressed in dopaminergic neurons in the ventral tegmental area (VTA) of male C57BL6/J mice. Genetic ablation of KORs from dopamine neurons blocked the potentiating effects of repeated forced swim stress on cocaine conditioned place preference (CPP). KOR activation inhibited dopamine neuron GCaMP6m calcium activity in VTA during swim stress and caused a rebound enhancement during the period after stress exposure. Transient optogenetic inhibition of VTA dopamine neurons with AAV5-DIO-SwiChR was acutely aversive in a real time place preference assay and blunted cocaine CPP when inhibition was administered concurrently with cocaine conditioning. However, when inhibition preceded cocaine conditioning by 30 min, cocaine CPP was enhanced. Retrograde tracing with CAV2-DIO-ZsGreen identified a population of prodynorphinCre neurons in the dorsal raphe nucleus (DRN) projecting to the VTA. Optogenetic stimulation of dynorphinergic neurons within the DRN by Channelrhodopsin2 activated KOR in VTA and ablation of prodynorphin blocked stress potentiation of cocaine CPP. Together, these studies demonstrate the presence of a dynorphin/KOR midbrain circuit that projects from the DRN to VTA and is involved in altering the dynamic response of dopamine neuron activity to enhance drug reward learning.
A recent paper in Nature (Lim et al., 2012) describes the effects of melanocortin receptors in the nucleus accumbens. The studies connect a hypothalamic peptide system with brain reward centers and ...show effects on specific neuronal populations and behavioral components of mood.
The influence of micronutrients on dopamine systems is not well defined. Using mice, we show a potential role for reduced dietary vitamin D3 (cholecalciferol) in promoting diet-induced obesity (DIO), ...food intake, and drug consumption while on a high fat diet. To complement these deficiency studies, treatments with exogenous fully active vitamin D3 (calcitriol, 10 µg/kg, i.p.) were performed. Nondeficient mice that were made leptin resistant with a high fat diet displayed reduced food intake and body weight after an acute treatment with exogenous calcitriol. Dopamine neurons in the midbrain and their target neurons in the striatum were found to express vitamin D3 receptor protein. Acute calcitriol treatment led to transcriptional changes of dopamine-related genes in these regions in naive mice, enhanced amphetamine-induced dopamine release in both naive mice and rats, and increased locomotor activity after acute amphetamine treatment (2.5 mg/kg, i.p.). Alternatively, mice that were chronically fed either the reduced D3 high fat or chow diets displayed less activity after acute amphetamine treatment compared with their respective controls. Finally, high fat deficient mice that were trained to orally consume liquid amphetamine (90 mg/L) displayed increased consumption, while nondeficient mice treated with calcitriol showed reduced consumption. Our findings suggest that reduced dietary D3 may be a contributing environmental factor enhancing DIO as well as drug intake while eating a high fat diet. Moreover, these data demonstrate that dopamine circuits are modulated by D3 signaling, and may serve as direct or indirect targets for exogenous calcitriol.
Repeated forced-swim stress (FSS) produced analgesia, immobility and potentiation of cocaine-conditioned place preference (CPP) in wild-type C57Bl/6 mice, but not in littermates lacking the kappa ...opioid receptor (KOR) gene. These results were surprising because kappa agonists are known to produce conditioned place aversion and to suppress cocaine-CPP when coadministered with cocaine. The possibility that disruption of the kappa system blocked the stress response by adversely affecting the hypothalamic-pituitary axis was examined by measuring plasma corticosterone levels. However, disruption of the dynorphin/kappa system by gene deletion or receptor antagonism did not reduce the FSS-induced elevation of plasma corticosterone levels. A second explanation for the difference is that kappa receptor activation caused by FSS occurred prior to cocaine conditioning rather than contemporaneously. To test this hypothesis, we measured the effects of the kappa agonist (trans)-3,4-dichloro-N-methyl-N-2-(1-pyrrolidinyl)-cyclohexylbenzeneacetamide (U50,488) administered to mice at various intervals preceding cocaine conditioning. The results showed that the interaction between the kappa system and cocaine reinforcement depended on the timing of the drug pairing. Mice given U50,488 60 min prior to cocaine showed a robust, nor-BNI-sensitive potentiation of cocaine-CPP, whereas administration 15 min before cocaine significantly suppressed cocaine-CPP. In the absence of cocaine, U50,488 given 60 min prior to saline conditioning produced no place preference, whereas administration 15 min before saline conditioning produced significant place aversion. The results of this study suggest that kappa receptor activation induced by FSS prior to the cocaine-conditioning session may be both necessary and sufficient for potentiation of the reinforcing actions of cocaine.
A theoretical model is developed to predict the trajectory of magnetized spheres falling through a copper pipe. The derive magnetic point dipole model agrees well with the experimental trajectories ...for NdFeB spherical magnets of varying diameter, which are embedded inside 3D printed shells with fixed outer dimensions. This demonstration of electrodynamic phenomena and Lenz's law serves as a good laboratory exercise for physics, electromagnetics, and dynamics classes at the undergraduate level.
Background Mounting evidence suggests that overeating may be conceptualized within the same behavioral and neurobiological framework as drug addiction. One potentially important difference between ...overeating versus drug abuse refers to the sensory stimulation of oral receptors by palatable foods, a feature that may be required for reinforcement during intake. Likewise, postingestive effects and caloric content of food also contribute to reinforcing behavior and might influence the development of compulsive eating behavior. The purpose of the current study was to establish whether intragastric self-administration of fat emulsions, that is, bypassing the oral cavity, recapitulates some of the behavioral and neurobiological hallmarks of psychostimulant self-administration. Methods We used behavioral assays in mice to assess acquisition, maintenance, extinction, and reinstatement of intragastric self-administration of lipid emulsions to determine the extent to which postoral fat self-administration recapitulates psychostimulant self-administration. Striatal dopamine efflux during behavioral tasks was determined by brain microdialysis coupled to chromatographic-electrochemical analyses. Results We show that in direct analogy to drug self-administration, 1) decreases in fat dose concentration were met with compensatory increases in response rates aimed at maintaining constant hourly caloric intake; 2) rates of responding markedly increased during both extinction and progressive ratio schedules of reinforcement; and 3) elevations in striatal dopamine levels observed during maintenance were markedly attenuated during extinction sessions, only to be restored on reinstatement. Conclusions Our data thus support the contention that stimulation of oral receptors by caloric foods may not be required for the expression of certain addiction-related neurobehavioral markers.
Optogenetics is an extremely powerful tool for selective neuronal activation/inhibition and dissection of neural circuits. However, a limitation of in vivo optogenetics is that an animal must be ...tethered to an optical fiber for delivery of light. Here, we describe a new method for in vivo, optogenetic inhibition of neural activity using an internal, animal-generated light source based on firefly luciferase. Two adeno-associated viruses encoding luciferase were tested and both produced concentration-dependent light after administration of the substrate, luciferin. Mice were co-infected with halorhodopsin- and luciferase-expressing viruses in the striatum, and luciferin administration significantly reduced Fos activity compared to control animals infected with halorhodopsin only. Recordings of neuronal activity in behaving animals confirmed that firing was greatly reduced after luciferin administration. Finally, amphetamine-induced locomotor activity was reduced in halorhodopsin/luciferase mice pre-injected with luciferin compared to controls. This demonstrates that virally encoded luciferase is able to generate sufficient light to activate halorhodopsin and suppress neural activity and change behavior. This approach could be used to generate inhibition in response to activation of specific molecular pathways.
The grooming invitation dance is a striking behavior in honey bee colonies that has not been extensively studied. The objectives of this study were (1) to describe the dance through video analysis, ...(2) to test the functional hypothesis that it is a grooming solicitation signal, and (3) to analyze the stimuli that cause its production. A worker bee producing the grooming invitation dance stands stationary and vibrates her whole body from side‐to‐side at a frequency of 4.2 ± 0.2 Hz for 9.3 ± 1.0 s. Sometimes the bee mixes bouts of body vibration with brief bouts of self‐grooming (average duration = 1.4 s). Bees that perform the grooming invitation dance have a far higher probability of being quickly groomed by a nest mate than do bees that do not perform the dance. Bees that had chalk dust puffed onto the bases of their wings produced significantly more grooming invitation dances than did control bees that received only puffs of air. This shows that it may be the accumulation of small particles at the bases of the wings that normally triggers the dance. We suggest that the evolutionary origin of this signal is self‐grooming behavior.
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