The effect of sex on retinopathy of prematurity severity among premature mixed-sex multiple gestation infants.

This retrospective study of 68 premature infants examined whether there was a difference between male and female mixed-sex multiple gestation infants with regard to stage of retinopathy of prematurity (ROP) developed or need for ROP treatment. We found that among mixed-sex twin infants there was no statistically significant difference between sexes in most severe ROP stage developed or need for ROP treatment, but males were treated at an earlier postmenstrual age (PMA) than females, despite females having a lower mean birthweight and slower mean growth velocity compared to males.

Author Correction: Dopamine transients are sufficient and necessary for acquisition of model-based associations.

In the version of this article initially published, the laser activation at the start of cue X in experiment 1 was described in the first paragraph of the Results and in the third paragraph of the Experiment 1 section of the Methods as lasting 2 s; in fact, it lasted only 1 s. The error has been corrected in the HTML and PDF versions of the article.

Dopamine transients are sufficient and necessary for acquisition of model-based associations.

Associative learning is driven by prediction errors. Dopamine transients correlate with these errors, which current interpretations limit to endowing cues with a scalar quantity reflecting the value of future rewards. We tested whether dopamine might act more broadly to support learning of an associative model of the environment. Using sensory preconditioning, we show that prediction errors underlying stimulus-stimulus learning can be blocked behaviorally and reinstated by optogenetically activating dopamine neurons. We further show that suppressing the firing of these neurons across the transition prevents normal stimulus-stimulus learning. These results establish that the acquisition of model-based information about transitions between nonrewarding events is also driven by prediction errors and that, contrary to existing canon, dopamine transients are both sufficient and necessary to support this type of learning. Our findings open new possibilities for how these biological signals might support associative learning in the mammalian brain in these and other contexts.

Midbrain dopamine neurons compute inferred and cached value prediction errors in a common framework.

Midbrain dopamine neurons have been proposed to signal reward prediction errors as defined in temporal difference (TD) learning algorithms. While these models have been extremely powerful in interpreting dopamine activity, they typically do not use value derived through inference in computing errors. This is important because much real world behavior - and thus many opportunities for error-driven learning - is based on such predictions. Here, we show that error-signaling rat dopamine neurons respond to the inferred, model-based value of cues that have not been paired with reward and do so in the same framework as they track the putative cached value of cues previously paired with reward. This suggests that dopamine neurons access a wider variety of information than contemplated by standard TD models and that, while their firing conforms to predictions of TD models in some cases, they may not be restricted to signaling errors from TD predictions.

Orbitofrontal neurons acquire responses to 'valueless' Pavlovian cues during unblocking.

The orbitofrontal cortex (OFC) has been described as signaling outcome expectancies or value. Evidence for the latter comes from the studies showing that neural signals in the OFC correlate with value across features. Yet features can co-vary with value, and individual units may participate in multiple ensembles coding different features. Here we used unblocking to test whether OFC neurons would respond to a predictive cue signaling a 'valueless' change in outcome flavor. Neurons were recorded as the rats learned about cues that signaled either an increase in reward number or a valueless change in flavor. We found that OFC neurons acquired responses to both predictive cues. This activity exceeded that exhibited to a 'blocked' cue and was correlated with activity to the actual outcome. These results show that OFC neurons fire to cues with no value independent of what can be inferred through features of the predicted outcome.

Learning theory: a driving force in understanding orbitofrontal function.

Since it was demonstrated the orbitofrontal cortex (OFC) is critical to reversal learning, there has been considerable interest in specifying its role in flexible, outcome-guided behavior. Behavioral paradigms from the learning theory tradition, such as outcome devaluation, blocking, Pavlovian to instrumental transfer, and overexpectation have been a driving force in this research. The use of these procedures has revealed OFC's unique role in forming and integrating information about specific features of events and outcomes to drive behavior and learning. These studies highlight the power and importance of learning theory principles in guiding neuroscience research.

Disruption of model-based behavior and learning by cocaine self-administration in rats.

RATIONALE: Addiction is characterized by maladaptive decision-making, in which individuals seem unable to use adverse outcomes to modify their behavior. Adverse outcomes are often infrequent, delayed, and even rare events, especially when compared to the reliable rewarding drug-associated outcomes. As a result, recognizing and using information about their occurrence put a premium on the operation of so-called model-based systems of behavioral control, which allow one to mentally simulate outcomes of different courses of action based on knowledge of the underlying associative structure of the environment. This suggests that addiction may reflect, in part, drug-induced dysfunction in these systems. Here, we tested this hypothesis. OBJECTIVES: This study aimed to test whether cocaine causes deficits in model-based behavior and learning independent of requirements for response inhibition or perception of costs or punishment. METHODS: We trained rats to self-administer sucrose or cocaine for 2 weeks. Four weeks later, the rats began training on a sensory preconditioning and inferred value blocking task. Like devaluation, normal performance on this task requires representations of the underlying task structure; however, unlike devaluation, it does not require either response inhibition or adapting behavior to reflect aversive outcomes. RESULTS: Rats trained to self-administer cocaine failed to show conditioned responding or blocking to the preconditioned cue. These deficits were not observed in sucrose-trained rats nor did they reflect any changes in responding to cues paired directly with reward. CONCLUSIONS: These results imply that cocaine disrupts the operation of neural circuits that mediate model-based behavioral control.

Orbitofrontal cortex supports behavior and learning using inferred but not cached values.

Computational and learning theory models propose that behavioral control reflects value that is both cached (computed and stored during previous experience) and inferred (estimated on the fly on the basis of knowledge of the causal structure of the environment). The latter is thought to depend on the orbitofrontal cortex. Yet some accounts propose that the orbitofrontal cortex contributes to behavior by signaling "economic" value, regardless of the associative basis of the information. We found that the orbitofrontal cortex is critical for both value-based behavior and learning when value must be inferred but not when a cached value is sufficient. The orbitofrontal cortex is thus fundamental for accessing model-based representations of the environment to compute value rather than for signaling value per se.

Cocaine cues drive opposing context-dependent shifts in reward processing and emotional state.

BACKGROUND: Prominent neurobiological theories of addiction posit a central role for aberrant mesolimbic dopamine release but disagree as to whether repeated drug experience blunts or enhances this system. Although drug withdrawal diminishes dopamine release, drug sensitization augments mesolimbic function, and both processes have been linked to drug seeking. One possibility is that the dopamine system can rapidly switch from dampened to enhanced release depending on the specific drug-predictive environment. To test this, we examined dopamine release when cues signaled delayed cocaine delivery versus imminent cocaine self-administration. METHODS: Fast-scan cyclic voltammetry was used to examine real-time dopamine release while simultaneously monitoring behavioral indexes of aversion as rats experienced a sweet taste cue that predicted delayed cocaine availability and during self-administration. Furthermore, the impact of cues signaling delayed drug availability on intracranial self-stimulation, a broad measure of reward function, was assessed. RESULTS: We observed decreased mesolimbic dopamine concentrations, decreased reward sensitivity, and negative affect in response to the cocaine-predictive taste cue that signaled delayed cocaine availability. Importantly, dopamine concentration rapidly switched to elevated levels to cues signaling imminent cocaine delivery in the subsequent self-administration session. CONCLUSIONS: These findings show rapid, bivalent contextual control over brain reward processing, affect, and motivated behavior and have implications for mechanisms mediating substance abuse.

Normal Aging does Not Impair Orbitofrontal-Dependent Reinforcer Devaluation Effects.

Normal aging is associated with deficits in cognitive flexibility thought to depend on prefrontal regions such as the orbitofrontal cortex (OFC). Here, we used Pavlovian reinforcer devaluation to test whether normal aging might also affect the ability to use outcome expectancies to guide appropriate behavioral responding, which is also known to depend on the OFC. Both young and aged rats were trained to associate a 10-s conditioned stimulus (CS+) with delivery of a sucrose pellet. After training, half of the rats in each age group received the sucrose pellets paired with illness induced by LiCl injections; the remaining rats received sucrose and illness explicitly unpaired. Subsequently, responding to the CS+ was assessed in an extinction probe test. Although aged rats displayed lower responding levels overall, both young and aged rats conditioned to the CS+ and developed a conditioned taste aversion following reinforcer devaluation. Furthermore, during the extinction probe test, both young and aged rats spontaneously attenuated conditioned responding to the cue as a result of reinforcer devaluation. These data show that normal aging does not affect the ability to use expected outcome value to appropriately guide Pavlovian responding. This result indicates that deficits in cognitive flexibility are dissociable from other known functions of prefrontal - and particularly orbitofrontal - cortex.

Nucleus accumbens neurons encode predicted and ongoing reward costs in rats.

Efficient decision-making requires that animals consider both the benefits and the costs of potential actions, such as the amount of effort or temporal delay involved in reward seeking. The nucleus accumbens (NAc) has been implicated in the ability to choose between options with different costs and overcome high costs when necessary, but it is not clear how NAc processing contributes to this role. Here, neuronal activity in the rat NAc was monitored using multi-neuron electrophysiology during two cost-based decision tasks in which either reward effort or reward delay was manipulated. In each task, distinct visual cues predicted high-value (low effort/immediate) and low-value (high effort/delayed) rewards. After training, animals exhibited a behavioral preference for high-value rewards, yet overcame high costs when necessary to obtain rewards. Electrophysiological analysis indicated that a subgroup of NAc neurons exhibited phasic increases in firing rate during cue presentations. In the effort-based decision task (but not the delay-based task), this population reflected the cost-discounted value of the future response. In contrast, other subgroups of cells were activated during response initiation or reward delivery, but activity did not differ on the basis of reward cost. Finally, another population of cells exhibited sustained changes in firing rate while animals completed high-effort requirements or waited for delayed rewards. These findings are consistent with previous reports that implicate NAc function in reward prediction and behavioral allocation during reward-seeking behavior, and suggest a mechanism by which NAc activity contributes to both cost-based decisions and actual cost expenditure.

Phasic nucleus accumbens dopamine release encodes effort- and delay-related costs.

BACKGROUND: Optimal decision-making requires that organisms correctly evaluate both the costs and benefits of potential choices. Dopamine transmission within the nucleus accumbens (NAc) has been heavily implicated in reward-learning and decision-making, but it is unclear how dopamine release might contribute to decisions that involve costs. METHODS: Cost-based decision-making was examined in rats trained to associate visual cues with either immediate or delayed rewards (delay manipulation) or low-effort or high-effort rewards (effort manipulation). After training, dopamine concentration within the NAc was monitored on a rapid time scale with fast-scan cyclic voltammetry. RESULTS: Animals exhibited a preference for immediate or low-effort rewards over delayed or high-effort rewards of equal magnitude. Reward-predictive cues but not response execution or reward delivery evoked increases in NAc dopamine concentration. When only one response option was available, cue-evoked dopamine release reflected the value of the future reward, with larger increases in dopamine signaling higher-value rewards. In contrast, when both options were presented simultaneously, dopamine signaled the better of two options, regardless of the future choice. CONCLUSIONS: Phasic dopamine signals in the NAc reflect two different types of reward cost and encode potential rather than chosen value under choice situations.

Basolateral amygdala modulates terminal dopamine release in the nucleus accumbens and conditioned responding.

BACKGROUND: Dopamine signaling in the nucleus accumbens (NAc) is essential for goal-directed behaviors and primarily arises from burst firing of ventral tegmental area neurons. However, the role of associative neural substrates such as the basolateral amygdala (BLA) in regulating phasic dopamine release in the NAc, particularly during reward seeking, remains unknown. METHODS: Male Sprague-Dawley rats learned to discriminate two cues: a discriminative stimulus (DS) that predicted sucrose reinforcement contingent upon a lever press and a nonassociated stimulus (NS) that predicted a second lever never reinforced with sucrose. Following training, a test session was completed in which NAc dopamine was measured using fast-scan cyclic voltammetry in conjunction with inactivation of the ipsilateral BLA (gamma-aminobutyric acid agonists; baclofen/muscimol) to determine the contribution of BLA activity to dopamine release in the NAc core during the task. RESULTS: Under vehicle conditions, DS and NS presentation elicited dopamine release within the NAc core. The DS evoked significantly more dopamine than the NS. Inactivation of the BLA selectively attenuated the magnitude of DS-evoked dopamine release, concurrent with an attenuation of DS-evoked conditioned approaches. Other behavioral responses (e.g., lever pressing) and dopamine release concomitant with those events were unaltered by BLA inactivation. Furthermore, neither ventral tegmental area electrically stimulated dopamine release nor the probability of high concentration dopamine release events was altered following BLA inactivation. CONCLUSIONS: These results demonstrate that the BLA terminally modulates dopamine signals within the NAc core under specific, behaviorally relevant conditions, illustrating a functional mechanism by which the BLA selectively facilitates responding to motivationally salient environmental stimuli.

Behavioral and electrophysiological indices of negative affect predict cocaine self-administration.

The motivation to seek cocaine comes in part from a dysregulation of reward processing manifested in dysphoria, or affective withdrawal. Learning is a critical aspect of drug abuse; however, it remains unclear whether drug-associated cues can elicit the emotional withdrawal symptoms that promote cocaine use. Here we report that a cocaine-associated taste cue elicited a conditioned aversive state that was behaviorally and neurophysiologically quantifiable and predicted subsequent cocaine self-administration behavior. Specifically, brief intraoral infusions of a cocaine-predictive flavored saccharin solution elicited aversive orofacial responses that predicted early-session cocaine taking in rats. The expression of aversive taste reactivity also was associated with a shift in the predominant pattern of electrophysiological activity of nucleus accumbens (NAc) neurons from inhibitory to excitatory. The dynamic nature of this conditioned switch in affect and the neural code reveals a mechanism by which cues may exert control over drug self-administration.

Behavioral responding and nucleus accumbens cell firing are unaltered following periods of abstinence from sucrose.

A critical feature of cocaine addiction is the strong propensity to relapse following periods of abstinence. Here, we examined whether abstinence from sucrose self-administration in rats altered behavioral responding and nucleus accumbens (NAc) cell firing in a manner similar to that observed following cocaine abstinence. Rats (n = 22) were trained to self-administer sucrose on a short-access schedule, previously shown to increase motivated behavior following sucrose abstinence, and then underwent either a 0, 7, or 30 day period of abstinence. Next, electrophysiological recording procedures were used to examine NAc activity (n = 199 neurons) during resumption of sucrose self-administration. Results showed no increase in sucrose-seeking or changes in cell firing of NAc neurons following any abstinence period. Furthermore, in a separate group of animals (n = 17) trained under identical conditions, sucrose-seeking behaviors were assessed during extinction and cue-induced reinstatement to further examine if any changes in motivated responding are evident following abstinence. Again, no evidence was obtained for any alterations in sucrose-seeking across abstinence conditions. These results suggest that natural rewards, such as sucrose, when provided in short access, do not always elicit robust changes in motivated responding, or NAc cell firing following abstinence unlike that observed in prior studies with cocaine. These findings are discussed with respect to the role of the NAc in processing goal-directed behaviors for drug vs. natural rewards following periods of abstinence.

Executive function and gait in older adults with cognitive impairment.

BACKGROUND: Cognitive impairment has been shown to predict falls risk in older adults. The ability to step accurately is necessary to safely traverse challenging terrain conditions such as uneven or slippery surfaces. However, it is unclear how well persons with cognitive impairment can step accurately to avoid such hazards and what specific aspects of cognition predict stepping ability in different patient populations. METHODS: Healthy older adults (NC), patients with Mild Cognitive Impairment with only memory impairment (MCI-EF) or memory and executive function impairments (MCI+EF) and early Alzheimer's patients (AD) were timed as they performed a stepping accuracy test with increasing cognitive demand (Walking Trail-Making Test; W-TMT), which required stepping on instrumented targets with either increasing sequential numbers (W-TMT A) or alternating sequential numbers and letters (W-TMT B). RESULTS: After accounting for age and baseline walking speed, the AD and MCI+EF groups were significantly slower than the NC and MCI-EF groups on the task with the highest cognitive demand, W-TMT B (interaction effect F = 6.781, p <.0001). No group differences were noted on the W-TMT A task that was less cognitively demanding. Neuropsychological measures of executive functioning were associated with slower W-TMT B performance, whereas memory, visual attention and visual spatial skills were not (adjusted R(2) = 0.42). CONCLUSIONS: Executive function is important for stepping performance, particularly under more complex environmental conditions.