Lessons for Today by the Deregulation of Yesteryear: Analyzing Modern Capital Market Deregulation with Historical Examples

Financial market regulators in the US have proposed cutting down their own rulebooks in recent years. However, when it comes to deregulating modern capital markets, the outcomes of historical alterations of similar natures should serve as lessons in what works and what doesn’t. This comment analyzes three modern-day proposals to deregulate US financial markets, using historical actions to argue for the likely efficacy of each

Prior Cocaine Experience Impairs Normal Phasic Dopamine Signals of Reward Value in Accumbens Shell

Dopamine signals have repeatedly been linked to associative learning and motivational processes. However, there is considerably less agreement on a role for dopamine in reward processing, and therefore whether neuroplastic changes in dopamine function following chronic exposure to drugs of abuse such as cocaine may impair appropriate valuation of rewarding stimuli. To quantify this, we voltammetrically measured real-time dopamine release in the nucleus accumbens (NAc) core or shell while rats received unsignaled deliveries of either a small (1 pellet) or large (2 pellets) reward. In drug-naive controls, core dopamine signals did not discriminate between reward size at any point, while in the shell dopamine encoded magnitude differences only in a slower postpeak period. Despite this lack of discrimination between rewards by the peak DA response, controls easily discriminated between reward options in a subsequent choice task. In contrast, phasic dopamine reward signals were strongly altered by cocaine experience; core dopamine decreased peak response but increased discrimination between reward magnitudes while shell lost phasic responses to reward receipt altogether. Notably, animals with cocaine-associated alterations in dopamine signals for reward magnitude failed to subsequently discriminate between reward options. These findings suggest that cocaine self-administration alters the ability for dopamine signals to appropriately assign value to rewards and thus may in part contribute to later deficits in behaviors that depend on appropriate outcome valuation

Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats

Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse

Cocaine Self-Administration Abolishes Associative Neural Encoding in the Nucleus Accumbens Necessary for Higher-Order Learning

Cocaine use is often associated with diminished cognitive function, persisting even after abstinence from the drug. Likely targets for these changes are the core and shell of the nucleus accumbens (NAc), which are critical for mediating the rewarding aspects of drugs of abuse as well as supporting associative learning. To understand this deficit, we recorded neural activity in the NAc of rats with either a history of cocaine self-administration or controls while they learned Pavlovian first- and second-order associations

Differential Dopamine Release Dynamics in the Nucleus Accumbens Core and Shell Reveal Complementary Signals for Error Prediction and Incentive Motivation

Mesolimbic dopamine (DA) is phasically released during appetitive behaviors, though there is substantive disagreement about the specific purpose of these DA signals. For example, prediction error (PE) models suggest a role of learning, while incentive salience (IS) models argue that the DA signal imbues stimuli with value and thereby stimulates motivated behavior. However, within the nucleus accumbens (NAc) patterns of DA release can strikingly differ between subregions, and as such, it is possible that these patterns differentially contribute to aspects of PE and IS. To assess this, we measured DA release in subregions of the NAc during a behavioral task that spatiotemporally separated sequential goal-directed stimuli. Electrochemical methods were used to measure subsecond NAc dopamine release in the core and shell during a well learned instrumental chain schedule in which rats were trained to press one lever (seeking; SL) to gain access to a second lever (taking; TL) linked with food delivery, and again during extinction. In the core, phasic DA release was greatest following initial SL presentation, but minimal for the subsequent TL and reward events. In contrast, phasic shell DA showed robust release at all task events. Signaling decreased between the beginning and end of sessions in the shell, but not core. During extinction, peak DA release in the core showed a graded decrease for the SL and pauses in release during omitted expected rewards, whereas shell DA release decreased predominantly during the TL. These release dynamics suggest parallel DA signals capable of supporting distinct theories of appetitive behavior

Neural correlates of Pavlovian-to-instrumental transfer in the nucleus accumbens shell are selectively potentiated following cocaine self-administration

During Pavlovian-to-instrumental transfer (PIT), learned Pavlovian cues significantly modulate ongoing instrumental actions. This phenomenon is suggested as a mechanism under which conditioned stimuli may lead to relapse in addicted populations. Following discriminative Pavlovian learning and instrumental conditioning with sucrose, one group of rats (naive) underwent electrophysiological recordings in the nucleus accumbens core and shell during a single PIT session. Other groups, following Pavlovian and instrumental conditioning, were subsequently trained to self-administer cocaine with nosepoke responses, or received yoked saline infusions and nosepoked for water rewards, and then performed PIT while electrophysiological recordings were taken in the nucleus accumbens. Behaviorally, although both naive and saline-treated groups showed increases in lever pressing during the conditioned stimulus cue, this effect was significantly enhanced in the cocaine-treated group. Neurons in the core and shell tracked these behavioral changes. In control animals, core neurons were significantly more likely to encode general information about cues, rewards and responses than those in the shell, and positively correlated with behavioral PIT performance, whereas PIT-specific encoding in the shell, but not core, tracked PIT performance. In contrast, following cocaine exposure, there was a significant increase in neural encoding of all task-relevant events that was selective to the shell. Given that cocaine exposure enhanced both behavior and shell-specific task encoding, these findings suggest that, whereas the core is important for acquiring the information about cues and response contingencies, the shell is important for using this information to guide and modulate behavior and is specifically affected following a history of cocaine self-administration

Nucleus Accumbens Neurons Track Behavioral Preferences and Reward Outcomes During Risky Decision Making

In order to make appropriate decisions, organisms must evaluate the risks and benefits of action selection. The nucleus accumbens (NAc) has been shown to be critical for this processing, and is necessary for appropriate risk-based decision making behavior. However, it is not clear how NAc neurons encode this information to promote appropriate behavioral responding

Nucleus accumbens core neurons encode value-independent associations necessary for sensory preconditioning.

Reinforcement-based learning models predict that the strength of association between cues and outcomes is driven by aspects of outcome value. However, animals routinely make associations between contingent stimuli in the world, even if those associations hold no value to the organism. At the neural level, the nucleus accumbens (NAc) is known to encode associative information, but it is not known whether this encoding is specific for value-based information (consistent with reinforcement-based models), or if the NAc additionally plays a more general role in forming predictive associations, independent of outcome value. To test this, we employed a sensory preconditioning (SPC) task where rats initially (Preconditioning) received either contingent pairings of two neutral stimuli (e.g., tone [A] and light [X]; ‘Paired’), or random non-contingent presentations (‘Unpaired’). After cue X was subsequently conditioned with food (First-Order Conditioning), the effect of preconditioning was assessed in phase 3 (Test) by presentations of cue A alone. Electrophysiological recordings from the NAc core showed significant increases in phasic encoding for the stimuli in the Paired (but not Unpaired) condition as well as during Test. Further, these effects were only seen in Paired rats that showed successful behavior during Test (Good Learners), but not those who did not (Poor Learners) or Unpaired controls. These findings reveal a role for the NAc in the encoding of associative contingencies independent of value, and suggest that this structure also plays a more general role in forming associations necessary for predictive behavior

Differential dopamine release dynamics in the nucleus accumbens core and shell track distinct aspects of goal-directed behavior for sucrose

Mesolimbic dopamine projections to the nucleus accumbens (NAc) have been implicated in goal-directed behaviors for natural rewards and in learning processes involving cue-reward associations. The NAc has been traditionally subdivided into two anatomically distinct sub-regions with different functional properties: the shell and the core. The aim of the present study was to characterize rapid dopamine transmission across the two NAc sub-regions during cue-signaled operant behavior for a natural (sucrose) reward in rats. Using fast-scan cyclic voltammetry (FSCV) we observed differences in the magnitude and dynamics of dopamine release events between the shell and core. Specifically, although cue-evoked dopamine release was observed in both sub-regions, it was larger and longer lasting in the shell compared with the core. Further, secondary dopamine release events were observed following the lever press response for sucrose in the NAc shell, but not the core. These findings demonstrate that the NAc displays regional specificity in dopamine transmission patterns during cued operant behavior for natural reward

Impact of a direct-fed microbial supplementation on intestinal permeability and immune response in broiler chickens during a coccidia challenge

Maintaining intestinal health supports optimal gut function and influences overall performance of broilers. Microlife® Prime (MLP) contains a unique combination of four strains of Bacillus spp. selected to support a healthy gut which may improve performance. The aim of this study was to determine the effects of MLP supplementation on intestinal health and immunity of broilers challenged with a mixed coccidia infection during peak [0 to 6-day post-infection (dpi)] and recovery phases (6 to 13 dpi). A total of 120 male, 4 days-old Ross 708, broiler chicks were allotted to 3 treatment groups (8 replicate cages; 5 birds/cage) in a randomized complete block design. Treatments included a non-challenge (NEG), a coccidia challenge (POS), and coccidia challenge fed MLP (5 × 105 CFU/g of diet). Diets were corn-soybean meal-based. At 11 days of age, all birds, except for NEG, were orally gavaged with 15 doses (3 × the recommended commercial dose). On 6, 9, and 13 dpi, birds were orally gavaged with fluorescein isothiocyanate conjugate dextran (FITC-d). Plasma and mid-jejunum tissues were collected 2 h later. On 6 dpi, duodenal lesions from 2 birds/cage were scored and droppings were collected for oocyst enumeration. Body weight gain (BWG) and feed conversion ratio (FCR) were calculated over the experimental period. Data were analyzed with GLIMMIX procedure of SAS. During the peak phase, POS birds had reduced BWG (23%) and FCR (15%) compared to NEG birds (P < 0.05), while birds fed MLP had similar BWG (209 and 208 g) and FCR (1.17 and 1.21) compared to NEG (P > 0.05). On 6 dpi, POS birds had higher lesion scores and oocyst shedding, 2 × increase in serum FITC-d, and higher jejunum IL-10, and IFN-γ mRNA compared to NEG (P < 0.05). Birds fed MLP had reduced plasma FITC-d compared to POS birds (P < 0.05) and similar IL-10 and IFN-γ mRNA. On 13 dpi, birds fed MLP had lower plasma FITC-d, jejunum IL-10 and IFN-γ mRNA compared to POS birds (P < 0.05), but similar IL-10 to NEG birds (P > 0.05). This study confirms MLP improves intestinal health and positively modulates mucosal immune response post-coccidia challenge