Cortical Processing of Multimodal Sensory Learning in Human Neonates.

Following birth, infants must immediately process and rapidly adapt to the array of unknown sensory experiences associated with their new ex-utero environment. However, although it is known that unimodal stimuli induce activity in the corresponding primary sensory cortices of the newborn brain, it is unclear how multimodal stimuli are processed and integrated across modalities. The latter is essential for learning and understanding environmental contingencies through encoding relationships between sensory experiences; and ultimately likely subserves development of life-long skills such as speech and language. Here, for the first time, we map the intracerebral processing which underlies auditory-sensorimotor classical conditioning in a group of 13 neonates (median gestational age at birth: 38 weeks + 4 days, range: 32 weeks + 2 days to 41 weeks + 6 days; median postmenstrual age at scan: 40 weeks + 5 days, range: 38 weeks + 3 days to 42 weeks + 1 days) with blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (MRI) and magnetic resonance (MR) compatible robotics. We demonstrate that classical conditioning can induce crossmodal changes within putative unimodal sensory cortex even in the absence of its archetypal substrate. Our results also suggest that multimodal learning is associated with network wide activity within the conditioned neural system. These findings suggest that in early life, external multimodal sensory stimulation and integration shapes activity in the developing cortex and may influence its associated functional network architecture.

Social behavior in a genetic model of dopamine dysfunction at different neurodevelopmental time points.

Impairments in social behavior characterize many neurodevelopmental psychiatric disorders. In fact, the temporal emergence and trajectory of these deficits can define the disorder, specify their treatment and signal their prognosis. The sophistication of mouse models with neurobiological endophenotypes of many aspects of psychiatric diseases has increased in recent years, with the necessity to evaluate social behavior in these models. We adapted an assay for the multimodal characterization of social behavior at different development time points (juvenile, adolescent and adult) in control mice in different social contexts (specifically, different sex pairings). Although social context did not affect social behavior in juvenile mice, it did have an effect on the quantity and type of social interaction as well as ultrasonic vocalizations in both adolescence and adulthood. We compared social development in control mice to a transgenic mouse model of the increase in postsynaptic striatal D2R activity observed in patients with schizophrenia (D2R-OE mice). Genotypic differences in social interactions emerged in adolescence and appeared to become more pronounced in adulthood. That vocalizations emitted from dyads with a D2R-OE subject were negatively correlated with active social behavior while vocalizations from control dyads were positively correlated with both active and passive social behavior also suggest social deficits. These data show that striatal dopamine dysfunction plays an important role in the development of social behavior and mouse models such as the one studied here provide an opportunity for screening potential therapeutics at different developmental time points.

Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation.

A decrease in dopamine D2 receptor (D2R) binding in the striatum is one of the most common findings in disorders that involve a dysregulation of motivation, including obesity, addiction and attention deficit hyperactivity disorder. As disruption of D2R signaling in the ventral striatum--including the nucleus accumbens (NAc)--impairs motivation, we sought to determine whether potentiating postsynaptic D2R-dependent signaling in the NAc would improve motivation. In this study, we used a viral vector strategy to overexpress postsynaptic D2Rs in either the NAc or the dorsal striatum. We investigated the effects of D2R overexpression on instrumental learning, willingness to work, use of reward value representations and modulation of motivation by reward associated cues. Overexpression of postsynaptic D2R in the NAc selectively increased motivation without altering consummatory behavior, the representation of the value of the reinforcer, or the capacity to use reward associated cues in flexible ways. In contrast, D2R overexpression in the dorsal striatum did not alter performance on any of the tasks. Thus, consistent with numerous studies showing that reduced D2R signaling impairs motivated behavior, our data show that postsynaptic D2R overexpression in the NAc specifically increases an animal's willingness to expend effort to obtain a goal. Taken together, these results provide insight into the potential impact of future therapeutic strategies that enhance D2R signaling in the NAc.

Classical conditioned learning using transcranial magnetic stimulation.

This study examined whether brain responses to transcranial magnetic stimulation (TMS) would be amenable to classical conditioning. Motor cortex in human participants was stimulated with TMS pulses, which elicited a peripheral motor response in the form of a motor evoked potential (MEP). The TMS pulses were paired with audio-visual cues that served as conditioned stimuli. Over the course of training, MEPs following the conditioned stimuli decreased in amplitude. Two experiments demonstrated that the attenuated response only occurred when the TMS was preceded by the conditioned stimulus. Unsignaled TMS and TMS preceded by a cue that was not previously paired did not attenuate the response. The experiments demonstrate that the modulation of the motor response depended on the prior pairings of the conditioned stimuli and TMS and that the effects were stimulus specific. Thus we demonstrate here, for the first time, that TMS can serve as the unconditioned stimulus in Pavlovian conditioning.

The role of dopamine in the timing of Pavlovian conditioned keypecking in ring doves.

The effect of dopaminergic drugs on the timing of conditioned keypecking in ring doves was studied in two experiments. Subjects were given pairings of a keylight with food and the temporal distribution of keypecks was obtained during unreinforced probe trials. Experiment 1 demonstrated that injections of pimozide before each session immediately decreased response rates but shifted timing distributions gradually to the right over several days of treatment. Experiment 2 showed similar results using a longer interstimulus interval (ISI). No shifts were observed when the drug was injected after training sessions, or when a delay, identical to each subject's average latency to eat during the drug condition, was inserted between keylight offset and food presentation. Consequently, the shifts in timing were mediated neither by mere accumulation of the drug nor a delay from keylight offset to food presentation resulting from the drug's ability to slow motor processes. The results suggest that pimozide modulates response rate through its effect on motor processes or incentive value, and response timing through a conditioned response (CR) to injection-related cues established via their repeated pairings with the drug.

An optimal period for setting sustained variability levels.

In two experiments, we investigated how explicit reinforcement of highly variable behavior at different points in training affected performance after the requirement was eliminated. Two versions of a computer game, differing in the number of possible solution paths, were used. In each, an optimal period of training for producing sustained high variability was found. Exposure to a high lag requirement shortly after acquisition sustained variability. Rewarding variability at other times did not have a sustained effect. The implications for learning and problem solving are discussed.

Conditioned and unconditioned behavioral-cognitive effects of a dopamine antagonist in rats.

Many drugs need to be taken multiple times to achieve a therapeutic effect. Researchers have identified several mechanisms to account for the slow onset of drug action, including drug accumulation and structural changes induced by drugs. This article provides an example of a new mechanism to account for this change in drug action. Stimuli that accompany drug administration may come to evoke conditioned responses (CRs), and these CRs may be the basis for changes in drug efficacy. Specifically, this research shows that a dopamine antagonist, pimozide, changes response rates through the direct action of the drug but changes time perception through the CRs elicited by drug administration.

Organization of quinto-frontal structures in hatchling ring doves (Streptopelia risoria).

Transganglionic and retrograde tracing procedures were applied to peripheral and central trigeminal structures in hatchling ring doves. The organization of the trigeminal ganglion, its somatotopic projections upon the principal sensory nucleus (PrV), and the projections of PrV upon the telencephalon are similar in adult and hatchling Columbiformes. The results suggest that development of feeding patterns in these species involves experiential differentiation of trigeminal sensorimotor circuits present at hatching.

Systematic changes in gaping during the ontogeny of pecking in ring doves (Streptopelia risoria).

Food pecking in the ring dove is a skilled prehensile response that is similar to, but simpler than, many other prehensile responses. Previous work has shown that this response is initially poorly executed and requires experience for its accurate direction and coordination. The response involves two components: the thrusting of the bird's head toward food, and the opening and closure of the beak around food. Here, this second component, called gape, is followed through development with a precise measurement system. Four squabs moved through a similar sequence of three gape topographies, each of which is more efficient in picking up seed, during development. The present outcome, together with other work, argues for a substantial contribution of experience with pecking to the development of food pecking. We discuss the implications of these findings for understanding the ontogeny of motor control and for understanding how experience affects behavioral development.

Social and nutritional influences on the feeding of ring dove squab.

The effects of food deprivation on ring dove squabs' begging and pecking was examined during the period of transition from dependent to independent feeding. Food-deprived squabs begged more, pecked more, and were fed more by their parents than nondeprived squabs. When deprived, young squab primarily beg for food and older squab primarily peck. This difference may arise from the relative efficiencies of the two feeding responses at different ages. Additionally, parental state exerted control over the amount the squab pecked and begged. Parental food deprivation affected squab pecking, probably because hungry parents pecked more themselves and fed squabs less. Squab begging was not affected by parental food deprivation. However, parental separation from squab affected squab begging, as parents previously without squab were more likely to feed begging squab than were parents who were not separated from squab. Parental separation from squab did not affect squab pecking. The changes in the endogenous and exogenous controls of squab feeding allow for a great deal of plasticity in the transition from dependent to independent feeding.

Age differences in the controls of ring doves' pecking.

Three experiments investigated the endogenous and exogenous controls of ring dove pecking. Experiment 1 confirmed that deprivation modulates adult pecking although nondeprived subjects peak at high levels. Experiment 2 determined that the level of pecking in nondeprived birds is modulated by exogenous cues such as the salience of the seed. Experiment 3 analyzed some of the controls of pecking in squabs. Both nondeprived and deprived squabs pecked little on days 12 and 16 of life, but by day 18, deprived squabs pecked significantly more than nondeprived squabs. Squabs inexperienced with deprivation peck less when hungry than squab that have had previous experience with deprivation. The controls of feeding change between day 24 of life and adulthood as exogenous cues did not stimulate nondeprived squab pecking until day 24 of life.

Operant and Pavlovian contributions to the ontogeny of pecking in ring doves.

This series of experiments analyzes the role of learning in the development of pecking in ring dove squab. Experiment 1 showed that there is a high probability that parents will feed squab after a period of separation (Experiment 1). Such feedings may have been essential for producing the previous observation (Graf, Balsam, & Silver, 1985) that pecking develops normally if squab which have been separated from their parents are given a daily 20-min interaction with seed followed by an immediate return to their parents. Experiment 2 showed that exposure to seed followed by experimenter-provided feedings were sufficient for inducing adult pecking levels. Experiment 3 showed that general experience with conspecifics was not necessary for the development of pecking and that maturation alone could not account for the pecking observed in previous experiments. Experiment 4 showed that Pavlovian contingencies consisting of visual exposure to seed followed by feeding was sufficient to induce high levels of pecking. There did not appear to be an additional contribution of an operant contingency present when squab were allowed to both see and peck at seed prior to feedings in Experiment 5. However, squab must actually be given experience in handling and ingesting seeds before adult levels of pecking can be obtained. These results are discussed in terms of the developmental pathways whereby experience leads to adult behavior.

Effects of reinforcing preselected approximations on the topography of the rat's bar press.

The effects of different shaping approximations on the topography of the rat's bar press were investigated in two experiments. Behavior was classified into discrete components, and changes in components and their sequential organization were analyzed. Experiment 1 examined response form early in training and found that specific components reinforced during shaping were incorporated into press sequences. Experiment 2 investigated how response form changed when a shaping contingency was relaxed later in training. Two topographies were selected for reinforcement, and both appeared in the press sequences of all subjects by the end of shaping. Subsequently, all variations of bar pressing were reinforced, and neither topography was necessary to satisfy the contingency. Although the frequency of the topographies reinforced during shaping declined for 3 of 4 subjects during this phase, the most frequent press sequence for 2 rats at the end of training included both unnecessary topographies. Variability in press topographies declined when all emitted variants were reinforced. However, all subjects emitted novel response forms throughout training. The results demonstrate that specific response-reinforcer contingencies influence response form by modulating component availability and organization.

Duration of signals for intertrial reinforcement and nonreinforcement in random control procedures.

In the random control procedure, responding to a conditioned stimulus (target CS) is prevented when the probability of unsignaled, unconditioned stimuli (USs) in the intertrial interval (ITI) is equal to the probability of the US in the presence of the target CS. Three experiments used an autoshaping procedure with White Carneaux pigeons to examine the effects of the temporal duration of signals for the ITI USs (cover CSs) and for concomitant periods of nonreinforcement. In Experiment 1, a short duration cover, but not a long duration cover, resulted in responding to the target CS. In Experiment 2, an explicit CS- cue during periods of nonreinforcement did not affect target acquisition. In Experiment 3, a long CS-, but not a short cover CS, was a sufficient condition for the acquisition of responding to the target CS. These results imply that the acquisition of responding to a target CS requires a discriminable period of nonreinforcement that is long relative to the target CS duration.

Formation of tone-US associations does not interfere with the formation of context-US associations in pigeons.

In four experiments we investigated whether signaled and unsignaled US presentations resulted in differential context conditioning. Experiments 1 and 2 showed that the presence of a tone during grain presentation facilitated the formation of tone-food associations in pigeons. Experiment 2 also showed that the acquisition of associative value by the tone did not diminish associations between context and the unconditioned stimulus (US). Experiment 3 showed that signaled USs did not interfere with the acquisition of context-US associations, and Experiment 4 showed that even when the signal was extensively pretrained, context-US associations could not be blocked. The results of these experiments are inconsistent with conditioning models that require competition between cues and contexts for associative value.

Associative factors and the development of pecking in the ring dove.

In these studies, descriptive information on the diet and feeding behavior of ring dove squab is considered in the context of an analysis of the mechanisms underlying the development of eating. Experiment I shows that squab begin to peck at grain around Day 13 and both the rate and efficiency of pecking increase through Day 21 when the squab are weaned. Experiment II shows that squab reared without seed in their home cage do not develop normal levels of pecking unless exposure to seed is followed in close temporal proximity by interaction with parents. It is concluded that an association between some aspect of squab's interaction with seed and a parentally provided unconditioned stimulus is sufficient for normal pecking to develop. The nature of these associations and their contribution to the ontogeny of independent feeding are discussed.