The Neural Encoding of Cocaine-Induced Devaluation in The Ventral Pallidum

Cocaine experience affects motivation structures such as the nucleus accumbens (NAc) and its major output target, the ventral pallidum (VP). Previous studies demonstrated that both NAc activity and hedonic responses change reliably as a taste cue comes to predict cocaine availability. Here we extended this investigation to examine drug-experience induced changes in hedonic encoding in the VP. VP activity was first characterized in adult male Sprague–Dawley rats in response to intraoral infusions of palatable saccharin and unpalatable quinine solutions. Next, rats received 7 daily pairings of saccharin that predicted either a cocaine (20 mg/kg, ip) or saline injection. Finally, the responses to saccharin and quinine were again assessed. Of 109 units recorded in 11 rats that received saccharin–cocaine pairings, 71% of responsive units significantly reduced firing rate during saccharin infusions and 64% increased firing rate during quinine exposure. However, as saccharin came to predict cocaine, and elicited aversive taste reactivity, VP responses changed to resemble quinine. After conditioning, 70% of saccharin-responsive units increased firing rate. Most units that encoded the palatable taste (predominantly reduced firing rate) were located in the anterior VP, while most units that were responsive to aversive tastes were located in the posterior VP. This study reveals an anatomical complexity to the nature of hedonic encoding in the VP

Drug Predictive Cues Activate Aversion-Sensitive Striatal Neurons That Encode Drug Seeking

Drug-associated cues have profound effects on an addict’s emotional state and drug-seeking behavior. Although this influence must involve the motivational neural system that initiates and encodes the drug-seeking act, surprisingly little is known about the nature of such physiological events and their motivational consequences. Three experiments investigated the effect of a cocaine-predictive stimulus on dopamine signaling, neuronal activity, and reinstatement of cocaine seeking. In all experiments, rats were divided into two groups (paired and unpaired), and trained to self-administer cocaine in the presence of a tone that signaled the immediate availability of the drug. For rats in the paired group, self-administration sessions were preceded by a taste cue that signaled delayed drug availability. Assessments of hedonic responses indicated that this delay cue became aversive during training. Both the self-administration behavior and the immediate cue were subsequently extinguished in the absence of cocaine. After extinction of self-administration behavior, the presentation of the aversive delay cue reinstated drug seeking. In vivo electrophysiology and voltammetry recordings in the nucleus accumbens measured the neural responses to both the delay and immediate drug cues after extinction. Interestingly, the presentation of the delay cue simultaneously decreased dopamine signaling and increased excitatory encoding of the immediate cue. Most importantly, the delay cue selectively enhanced the baseline activity of neurons that would later encode drug seeking. Together these observations reveal how cocaine cues can modulate not only affective state, but also the neurochemical and downstream neurophysiological environment of striatal circuits in a manner that promotes drug seeking

Aversive Stimuli Drive Drug Seeking in a State of Low Dopamine Tone

Background Stressors negatively impact emotional state and drive drug seeking, in part, by modulating the activity of the mesolimbic dopamine system. Unfortunately, the rapid regulation of dopamine signaling by the aversive stimuli that cause drug seeking is not well characterized. In a series of experiments, we scrutinized the subsecond regulation of dopamine signaling by the aversive stimulus, quinine, and tested its ability to cause cocaine seeking. Additionally, we examined the midbrain regulation of both dopamine signaling and cocaine seeking by the stress-sensitive peptide, corticotropin releasing factor (CRF). Methods Combining fast-scan cyclic voltammetry with behavioral pharmacology, we examined the effect of intraoral quinine administration on nucleus accumbens dopamine signaling and hedonic expression in 21 male Sprague-Dawley rats. We tested the role of CRF in modulating aversion-induced changes in dopamine concentration and cocaine seeking by bilaterally infusing the CRF antagonist, CP-376395, into the ventral tegmental area (VTA). Results We found that quinine rapidly reduced dopamine signaling on two distinct time scales. We determined that CRF acted in the VTA to mediate this reduction on only one of these time scales. Further, we found that the reduction of dopamine tone and quinine-induced cocaine seeking were eliminated by blocking the actions of CRF in the VTA during the experience of the aversive stimulus. Conclusions These data demonstrate that stress-induced drug seeking can occur in a terminal environment of low dopamine tone that is dependent on a CRF-induced decrease in midbrain dopamine activity

Cytosolic Glucosylceramide regulates endolysosomal function in Niemann-Pick type C disease

A new paradigm for Niemann-Pick C disease is presented where lysosomal storage leads to a deficit in cytoplasmic glucosylceramide (GlcCer) where it performs important functions. Previously it had been reported that Gaucher cells have defective endolysosomal pH. GlcCer also accumulates in Niemann-Pick C disease and also shows this defect. Niemann-Pick C cells were found to have reduced cytoplasmic glucosylceramide (GlcCer) transport. Inhibiting cytoplasmic glucocerebrosidase (GBA2), increased GlcCer, decreased endolysosomal pH in normal cells, reversed increases in endolysosomal pH and restored disrupted BODIPY-LacCer trafficking and increased expression of vATPase a subunit in Niemann-Pick C fibroblasts. The results are consistent with a model where both endolysosomal pH and Golgi targeting of BODIPY-LacCer are dependent on adequate levels of cytosolic GlcCer which are reduced in NPC disease. This work consequently suggests GBA2 and vATPase as new therapeutic targets in Niemann-Pick C and related neurodegenerative diseases. The work was in collaboration with colleagues in the Netherlands and Leicester University. The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Niemann-Pick type C disease (NPCD) is a neurodegenerative disease associated with increases in cellular cholesterol and glycolipids and most commonly caused by defective NPC1, a late endosomal protein. Using ratiometric probes we find that NPCD cells show increased endolysosomal pH. In addition U18666A, an inhibitor of NPC1, was found to increase endolysosomal pH, and the number, size and heterogeneity of endolysosomal vesicles. NPCD fibroblasts and cells treated with U18666A also show disrupted targeting of fluorescent lipid BODIPY-LacCer to high pH vesicles. Inhibiting non-lysosomal glucocerebrosidase (GBA2) reversed increases in endolysosomal pH and restored disrupted BODIPY-LacCer trafficking in NPCD fibroblasts. GBA2 KO cells also show decreased endolysosomal pH. NPCD fibroblasts also show increased expression of a key subunit of the lysosomal proton pump vATPase on GBA2 inhibition. The results are consistent with a model where both endolysosomal pH and Golgi targeting of BODIPY-LacCer are dependent on adequate levels of cytosolic-facing GlcCer, which are reduced in NPC disease

Genetic and environmental variation impact transferability of polygenic risk scores

Even when polygenic risk scores (PRSs) are trained in African ancestral populations, Kamiza and colleagues showed that genetic and environmental variation within sub-Saharan African populations impacts prediction performance, highlighting the challenges of clinical implementation of PRSs for risk assessment

Optogenetic Interrogation of Functional Synapse Formation by Corticospinal Tract Axons in the Injured Spinal Cord

To restore function after injury to the CNS, axons must be stimulated to extend into denervated territory and, critically, must form functional synapses with appropriate targets. We showed previously that forced overexpression of the transcription factor Sox11 increases axon growth by corticospinal tract (CST) neurons after spinal injury. However, behavioral outcomes were not improved, raising the question of whether the newly sprouted axons are able to form functional synapses. Here we developed an optogenetic strategy, paired with single-unit extracellular recordings, to assess the ability of Sox11-stimulated CST axons to functionally integrate in the circuitry of the cervical spinal cord. Initial time course experiments established the expression and function of virally expressed Channelrhodopsin (ChR2) in CST cell bodies and in axon terminals in cervical spinal cord. Pyramidotomies were performed in adult mice to deprive the left side of the spinal cord of CST input, and the right CST was treated with adeno-associated virus (AAV)–Sox11 or AAV–EBFP control, along with AAV–ChR2. As expected, Sox11 treatment caused robust midline crossing of CST axons into previously denervated left spinal cord. Clear postsynaptic responses resulted from optogenetic activation of CST terminals, demonstrating the ability of Sox11-stimulated axons to form functional synapses. Mapping of the distribution of CST-evoked spinal activity revealed overall similarity between intact and newly innervated spinal tissue. These data demonstrate the formation of functional synapses by Sox11-stimulated CST axons without significant behavioral benefit, suggesting that new synapses may be mistargeted or otherwise impaired in the ability to coordinate functional output. SIGNIFICANCE STATEMENT As continued progress is made in promoting the regeneration of CNS axons, questions of synaptic integration are increasingly prominent. Demonstrating direct synaptic integration by regenerated axons and distinguishing its function from indirect relay circuits and target field plasticity have presented technical challenges. Here we force the overexpression of Sox11 to stimulate the growth of corticospinal tract axons in the cervical spinal cord and then use specific optogenetic activation to assess their ability to directly drive postsynaptic activity in spinal cord neurons. By confirming successful synaptic integration, these data illustrate a novel optogenetic-based strategy to monitor and optimize functional reconnection by newly sprouted axons in the injured CNS

Corticosterone Regulates Both Naturally Occurring and Cocaine‐Induced Dopamine Signaling by Selectively Decreasing Dopamine Uptake

Stressful and aversive events promote maladaptive reward‐seeking behaviors such as drug addiction by acting, in part, on the mesolimbic dopamine system. Using animal models, data from our laboratory and others show that stress and cocaine can interact to produce a synergistic effect on reward circuitry. This effect is also observed when the stress hormone corticosterone is administered directly into the nucleus accumbens (NAc), indicating that glucocorticoids act locally in dopamine terminal regions to enhance cocaine\u27s effects on dopamine signaling. However, prior studies in behaving animals have not provided mechanistic insight. Using fast‐scan cyclic voltammetry, we examined the effect of systemic corticosterone on spontaneous dopamine release events (transients) in the NAc core and shell in behaving rats. A physiologically relevant systemic injection of corticosterone (2 mg/kg i.p.) induced an increase in dopamine transient amplitude and duration (both voltammetric measures sensitive to decreases in dopamine clearance), but had no effect on the frequency of transient release events. This effect was compounded by cocaine (2.5 mg/kg i.p.). However, a second experiment indicated that the same injection of corticosterone had no detectable effect on the dopaminergic encoding of a palatable natural reward (saccharin). Taken together, these results suggest that corticosterone interferes with naturally occurring dopamine uptake locally, and this effect is a critical determinant of dopamine concentration specifically in situations in which the dopamine transporter is pharmacologically blocked by cocaine

Corticosterone Acts in the Nucleus Accumbens to Enhance Dopamine Signaling and Potentiate Reinstatement of Cocaine Seeking

Stressful life events are important contributors to relapse in recovering cocaine addicts, but the mechanisms by which they influence motivational systems are poorly understood. Studies suggest that stress may “set the stage” for relapse by increasing the sensitivity of brain reward circuits to drug-associated stimuli. We examined the effects of stress and corticosterone on behavioral and neurochemical responses of rats to a cocaine prime after cocaine self-administration and extinction. Exposure of rats to acute electric footshock stress did not by itself reinstate drug-seeking behavior but potentiated reinstatement in response to a subthreshold dose of cocaine. This effect of stress was not observed in adrenalectomized animals, and was reproduced in nonstressed animals by administration of corticosterone at a dose that reproduced stress-induced plasma levels. Pretreatment with the glucocorticoid receptor antagonist RU38486 did not block the corticosterone effect. Corticosterone potentiated cocaine-induced increases in extracellular dopamine in the nucleus accumbens (NAc), and pharmacological blockade of NAc dopamine receptors blocked corticosterone-induced potentiation of reinstatement. Intra-accumbens administration of corticosterone reproduced the behavioral effects of stress and systemic corticosterone. Corticosterone treatment acutely decreased NAc dopamine clearance measured by fast-scan cyclic voltammetry, suggesting that inhibition of uptake2-mediated dopamine clearance may underlie corticosterone effects. Consistent with this hypothesis, intra-accumbens administration of the uptake2 inhibitor normetanephrine potentiated cocaine-induced reinstatement. Expression of organic cation transporter 3, a corticosterone-sensitive uptake2 transporter, was detected on NAc neurons. These findings reveal a novel mechanism by which stress hormones can rapidly regulate dopamine signaling and contribute to the impact of stress on drug intake

Lorentz transformations of open systems

We consider open dynamical systems, subject to external interventions by agents that are not completely described by the theory (classical or quantal). These interventions are localized in regions that are relatively spacelike. Under these circumstances, no relativistic transformation law exists that relates the descriptions of the physical system by observers in relative motion. Still, physical laws are the same in all Lorentz frames.Comment: Final version submitted to J. Mod. Opt. (Proc. of Gdansk conference

Developmental trends in voice onset time: some evidence for sex differences

This study reports on an investigation into the voice onset time (VOT) patterns of the plosives /p b t d/ in a group of 30 children aged 7 (n = 10), 9 (n = 10) and 11 (n = 10) years. Equal numbers of girls and boys participated in the study. Each child named a series of letter objects to elicit /p b t d/ in a syllable onset position with a fixed vowel context. VOT data were examined for age, sex and plosive differences with the following hypotheses: Firstly, that there would be sex differences in the VOT patterns of preadolescent children. Secondly, that the sex differences in VOT patterns would be linked to age and development, and that these would eventually become marked by the age of 11 years, by which time adult-like VOT values should have been achieved. Finally, that the extent of sex and age differences would be dependent upon the plosive being investigated. Results indicated patterns of decrease with age in the VOT values of /p b/ for the boys, with some evidence of increases in the VOT values of /t/ for the girls. In addition, 'voiced' and 'voiceless' cognates showed a more marked bimodal distribution in the girls' VOT patterns. This bimodal distribution was investigated by examining the degree of difference between the VOT values of voiced and voiceless cognate pairs /p b/ and /t d/, and examining the effects of age, sex and cognate pair. These results indicated that more marked sex differences in the 'voiced'/'voiceless' contrast emerged between the data of the 9- and 11-year-olds, a pattern, which was more marked for the alveolar plosives. These preliminary results confirmed all three hypotheses. The findings are presented and discussed both within a developmental and sociophonetic framework