Teruko Uwano

Retrospective and prospective coding for predicted reward in the sensory thalamus.

Reward is important for shaping goal-directed behaviour. After stimulus–reward associative learning, an organism can assess the motivational value of the incoming stimuli on the basis of past experience (retrospective processing), and predict forthcoming rewarding events (prospective processing). The traditional role of the sensory thalamus is to relay current sensory information to cortex. Here we find that non-primary thalamic neurons respond to reward-related events in two ways. The early, phasic responses occurred shortly after the onset of the stimuli and depended on the sensory modality. Their magnitudes resisted extinction and correlated with the learning experience. The late responses gradually increased during the cue and delay periods, and peaked just before delivery of the reward. These responses were independent of sensory modality and were modulated by the value and timing of the reward. These observations provide new evidence that single thalamic neurons can code for the acquired significance of sensory stimuli in the early responses (retrospective coding) and predict upcoming reward value in the late responses (prospective coding).

Neuronal responsiveness to various sensory stimuli, and associative learning in the rat amygdala

Neuronal activities were recorded from the amygdala and amygdalostriatal transition area of behaving rats during discrimination of conditioned auditory, visual, olfactory, and somatosensory stimuli associated with positive and/or negative reinforcements. Neurons were also tested with taste solution and various sensory stimuli that were not associated with reinforcement. Of the 1195 neurons tested, 475 responded to one or more sensory stimuli. Of these, 256 neurons responded exclusively to a unimodal sensory stimulus, 128 to multimodal sensory stimuli, and the remaining 91 could not be classified. Distribution of unimodal neurons was correlated with anatomical projections to the amygdala from sensory thalamus or sensory cortices. Multimodal neurons were located mainly in the basolateral and central nuclei of the amgydala. Response latencies of neurons in the basolateral nucleus were longer than those in other nuclei and neurons in the central nucleus had both short and long latencies. Neurons responsive to a given stimulus were more frequently encountered in the amygdalas of the trained rats than in those of the rats not trained to associate that stimulus with a reinforcement. Multimodal neurons that responded to conditioned and/or unconditioned stimuli used in the associative learned tasks were concentrated in the basolateral and central nuclei. The results indicate that some amygdalar neurons receive exclusive single sensory information, and the others receive information from two or more sensory inputs. Considering the long latencies and multimodal responsiveness, the basolateral and central nuclei of the amygdala might be foci where various kinds of sensory information converge. It is also suggested that the basolateral and central nuclei of the amygdala have critical roles in associative learning to relate sensory information to reinforcement or affective significance.

Amygdala role in conditioned associative learning

Amygdala role in emotion was reviewed in reference to recent amygdala lesion studies and neuronal responses in the rat amygdala to conditioned stimuli. Extensive lesion studies suggest that the amygdala is crucial in various kinds of motivated and emotional behavior, and related autonomic responses. These amygdala functions critically depend on learning and memory. Amygdala lesions, both before and after training of conditioned associative learning, impaired emotional expression without simple sensory-motor deficits. Pharmacological experiments indicated neurotransmission in the amygdala is mediated through NMDA and AMPA receptors. These results strongly suggest the amygdala involvement in acquiring and storing associative memory (i.e. stimulus-affect association), by which animals recognize and evaluate the biological significance of a stimulus. This information is then transferred to the brainstem executing system. In the neurophysiological experiments, there were topographic distributions of sensory-responsive neurons within the amygdala, which were well correlated to anatomical data. The responses of rat amygdala neurons changed plastically during learning. Furthermore, more sensory-responsive neurons were encountered in the amygdala of rats trained to associate the sensory stimuli with a reinforcement than in the amygdala of rats that were not trained. In trained rats, multimodal neurons that responded to conditioned and unconditioned stimuli were frequently found in the basolateral and central nuclei of the amygdala. The results suggest that basolateral and central nuclei are foci where various sensory modalities converge, and which might perform critical functions in acquiring and storing long-term associative memory to link between sensory information and affective significance.

Auditory thalamus integrates visual inputs into behavioral gains

By binding multisensory signals, we get robust percepts and respond to our surroundings more correctly and quickly. How and where does the brain link cross-modal sensory information to produce such behavioral advantages? The classical role of sensory thalamus is to relay modality-specific information to the cortex. Here we find that, in the rat thalamus, visual cues influence auditory responses, which have two distinct components: an early phasic one followed by a late gradual buildup that peaks before reward. Although both bimodal presentation and reward value had similar effects on behavioral performance, the cross-modal effect on neural activity showed unique temporal dynamics: it affected the amplitude of the early component and starting level of the late component, whereas reward value affected only the slope of the late component. These results demonstrate that cross-modal cueing modulates gain in the sensory thalamus, potentially providing a priming influence on the choice of an optimal behavior.

Emotional and behavioral correlates of the anterior cingulate cortex during associative learning in rats.

Neuronal activity was recorded from the anterior cingulate cortex of behaving rats during discrimination and learning of conditioned stimuli associated with or without reinforcements. The rats were trained to lick a protruding spout just after a conditioned stimulus to obtain reward (intracranial self-stimulation or sucrose solution) or to avoid aversion. The conditioned stimuli included both elemental (auditory or visual stimuli) and configural (simultaneous presentation of auditory and visual stimuli predicting reward outcome opposite to that predicted by each stimulus presented alone) stimuli. Of the 62 anterior cingulate neurons responding during the task, 38 and four responded differentially and non-differentially to the conditioned stimuli (conditioned stimulus-related neurons), respectively. Of the 38 differential conditioned stimulus-related neurons, 33 displayed excitatory (n = 10) and inhibitory (n = 23) responses selectively to the conditioned stimuli predicting reward. These excitatory and inhibitory differential conditioned stimulus-related neurons were located mainly in the cingulate cortex areas 1 and 3 of the rostral and ventral parts of the anterior cingulate cortex, respectively. The remaining 20 neurons responded mainly during intracranial self-stimulation and/or ingestion of sucrose (ingestion/intracranial self-stimulation-related neurons). Increase in activity of the ingestion/intracranial self-stimulation-related neurons was correlated to the first lick to obtain rewards during the task, suggesting that the activity reflected some aspects of motor functions for learned instrumental behaviors. These ingestion/intracranial self-stimulation-related neurons were located sparsely in cingulate cortex area 1 of the rostral part of the anterior cingulate cortex and densely in frontal area 2 of the caudal and dorsal parts of the anterior cingulate cortex. Analysis by the multidimensional scaling of responses of 38 differential conditioned stimulus-related neurons indicated that the anterior cingulate cortex categorized the conditioned stimuli into three groups based on reward contingency, regardless of the physical characteristics of the stimuli, in a two-dimensional space; the three conditioned (two elemental and one configural) stimuli predicting sucrose solution, the three conditioned (two elemental and one configural) stimuli predicting no reward, and the lone conditioned stimulus predicting intracranial self-stimulation. The results suggest that the anterior cingulate cortex is organized topographically; stimulus attributes predicting reward or no reward are represented in the rostral and ventral parts of the anterior cingulate cortex, while the caudal and dorsal parts of the anterior cingulate cortex are related to execution of learned instrumental behaviors. These results are in line with recent neuropsychological studies suggesting that the rostral part of the anterior cingulate cortex plays a crucial role in socio-emotional behaviors by assigning a positive or negative value to future outcomes.

Single neuron responses in the monkey anterior cingulate cortex during visual discrimination.

Single neuron activity was recorded from the monkey anterior cingulate cortex during operant behavior based on discrimination of rewarding, aversive, and neutral objects. Of 550 neurons recorded, 116 responded during the task; 36, during visual discrimination; 40, during bar pressing for operant responding. Of these, 26 vision-related neurons responded differentially to rewarding, aversive and neutral objects, and 11 bar press-related neurons differentiated bar pressing to avoid shock from bar pressing to obtain reward. Responses of these neurons depended on associative meaning (aversive or rewarding) of the objects since these neuronal responses were modulated by the reversal learning. The results provide neuronal bases for involvement of the anterior cingulate cortex in emotional and motivational processes.

Red ginseng ameliorated place navigation deficits in young rats with hippocampal lesions and aged rats.

Effects of hippocampal lesions and aging on spatial learning and memory and ameliorating effects of red ginseng on learning deficits were investigated in the following two experiments: performance of young rats with selective hippocampal lesions with red ginseng by mouth (p.o.; Experiment 1) and aged rats with red ginseng (p.o.; Experiment 2) in the spatial tasks was compared with that of sham-operated or intact young rats. Each rat in these two behavioral experiments was tested with the three types of spatial-learning tasks (distance movement task, DMT; random-reward place search task, RRPST; and place-learning task, PLT) in a circular open field using intracranial self-stimulation as reward. The results in the DMT and RRPST tasks indicated that motivational and motor activity of young rats with hippocampal lesions with and without ginseng were not significantly different from that of sham-operated young rats in Experiment 1. However, young rats with hippocampal lesions displayed significant deficits in the PLT task. Treatment with red ginseng significantly ameliorated place-navigation deficits in young rats with hippocampal lesions on the PLT task. Similarly, red ginseng improved performance of aged rats on the PLT task in Experiment 2. The results, along with previous studies showing significant effects of red ginseng on the central nervous system, suggest that red ginseng ameliorates learning and memory deficits through effects on the central nervous system, partly through effects on the hippocampal formation.

Altered accumbens neural response to prediction of reward associated with place in dopamine D2 receptor knockout mice

Midbrain dopaminergic activity seems to be important in forming the prediction of future events such as rewards. The nucleus accumbens (NAc) plays an important role in the integration of reward with motor function, and it receives dense dopamine innervation and extensive limbic and cortical afferents. Here, we examined the specific role of the dopamine D2 receptor (D2R) in mediating associative learning, locomotor activity, and regulating NAc neural responses by using D2R-knockout (KO) mice and their wild-type littermates. D2R-KO mice displayed reduced locomotor activity and slower acquisition of a place-learning task. D2R-KO eliminated the prereward inhibitory response of neurons in the NAc. In contrast, an increased number of neurons in D2R-KO mice displayed place-related activity. These results provide evidence that D2R in the NAc participates in coding for a specific type of neural response to incentive contingencies and partly in spatial learning.

Dopamine D1 Receptor Modulates Hippocampal Representation Plasticity to Spatial Novelty

The human hippocampus is critical for learning and memory. In rodents, hippocampal pyramidal neurons fire in a location-specific manner, forming relational representations of environmental cues. The importance of glutamatergic systems in learning and in hippocampal neural synaptic plasticity has been shown. However, the role of dopaminergic systems in the response of hippocampal neural plasticity to novel and familiar spatial stimuli remains unclear. To clarify this important issue, we recorded hippocampal neurons from dopamine D1 receptor knock-out (D1R-KO) mice and their wild-type (WT) littermates under the manipulation of distinct spatial cues in a familiar and a novel environment. Here we report that in WT mice, the majority of place cells quickly responded to the manipulations of distal and proximal cues in both familiar and novel environments. In contrast, the influence of distal cues on spatial firing in D1R-KO mice was abolished. In the D1R-KO mice, the influence of proximal cues was facilitated in a familiar environment, and in a novel environment most of the place cells were less likely to respond to changes of spatial cues. Our results demonstrate that hippocampal neurons in mice can rapidly and flexibly encode information about space from both distal and proximal cues to cipher a novel environment. This ability is necessary for many types of learning, and lacking D1R can radically alter this learning-related neural activity. We propose that D1R is crucially implicated in encoding spatial information in novel environments, and influences the plasticity of hippocampal representations, which is important in spatial learning and memory.

Effects of prenatal maternal stress by repeated cold environment on behavioral and emotional development in the rat offspring

It has been reported that many types of stresses, which caused physiological and psychological alterations in dams as prenatal maternal stress, affected behavioral and emotional traits of their offspring. However, effects of environmental temperature changes, which induce various stress responses in both animals and humans, have not been assessed as prenatal maternal stress. Repeated cold stress (RCS) is a type of chronic cold stress in which environmental temperature changes rapidly and frequently several times within a day. In the present study, to investigate effects of chronic maternal stress by the RCS on behavioral and emotional development of the rat offspring (prenatal RCS rats), the RCS stress was loaded to pregnant rats between day 9 and 19 after fertilization. The prenatal RCS rats showed similar locomotor activity in an open field to control rats that were borne by non-stressed pregnant rats. On the other hand, the prenatal RCS rats showed significantly higher startle responses than the control rats in a light enhanced startle paradigm. However, treatment of diazepam decreased the startle responses in the prenatal RCS rats to the same degree as those in the control rats. The results indicated that prenatal RCS affected emotional development of the rat offspring, but not locomotor activity. Comparison of the present results with the previous studies suggests that there might be unknown common mechanisms among different prenatal maternal stresses that induce similar behavioral developmental alteration.