Midbrain dopamine (DA) neurons fire in 2 characteristic modes, tonic and phasic, which are thought to modulate distinct aspects of behavior. However, the inability to selectively disrupt these patterns of activity has hampered the precise definition of the function of these modes of signaling. Here, we addressed the role of phasic DA in learning and other DA-dependent behaviors by attenuating DA neuron burst firing and subsequent DA release, without altering tonic neural activity. Disruption of phasic DA was achieved by selective genetic inactivation of NMDA-type, ionotropic glutamate receptors in DA neurons. Disruption of phasic DA neuron activity impaired the acquisition of numerous conditioned behavioral responses, and dramatically attenuated learning about cues that predicted rewarding and aversive events while leaving many other DA-dependent behaviors unaffected.cue-dependent learning ͉ mouse behavior ͉ electrophysiology ͉ cyclic voltammetry D opamine (DA) neurons of the ventral midbrain project to the dorsal and ventral striatum, as well as to other corticolimbic structures such as the hippocampus, amygdala, and prefrontal cortex. Differential DA release (tonic or phasic) is thought to activate distinct signal transduction cascades through the activation of postsynaptic inhibitory and excitatory G protein coupled receptors. Phasic DA is proposed to activate excitatory, low-affinity DA D1-like receptors (Rs) (1, 2) to facilitate long-term potentiation of excitatory synaptic transmission and enhance activity of the basal ganglia direct pathway facilitating appropriate action selection during goal-directed behavior. Conversely, tonic DA release is proposed to act on inhibitory, high-affinity DA D2Rs to facilitate long-term depression of cortico-striatal synapses and suppress activity of medium spiny neurons (MSNs) of the basal ganglia indirect pathway (1, 3-5). Thus, coordinate D1R and D2R activation modulates motor and cognitive function, and facilitates behavioral flexibility by a dichotomous control of striatal plasticity (5).During reinforcement learning shifts in phasic DA neuron responses from primary rewards, to reward predicting, stimuli are thought to reflect the acquisition of incentive salience for the predictive conditioned stimuli (6-10). Coincident DA and glutamate release onto MSNs during conditioned-stimulus response learning facilitates long-term potentiation of excitatory synapses that is thought to underlie reinforcement learning (1, 2, 11). Pharmacological or genetic disruption of D1R signaling impairs learning in numerous behavioral paradigms (2, 11); thus, phasic DA acting through D1R is thought to facilitate memory acquisition by ''stamping-in'' stimulus-response associations.Although considerable correlative electrophysiological evidence, as well as pharmacological and genetic evidence, supports an important role of phasic DA in stamping-in cue-reward associations, other evidence suggests that DA is not necessary for learning conditioned-stimulus responses. Mice genetically modified to...

No abstract

The hippocampal formation has been extensively studied for its special role in visual spatial learning and navigation. To ascertain the nature of the associations made, or computations performed, by hippocampus, it is important to delineate the functional contributions of its afferents. Therefore, single units were recorded in the lateral dorsal nucleus of the thalamus (LDN) as rats performed multiple trials on a radial maze. Many LDN neurons selectively discharged when an animal's head was aligned along particular directions in space, irrespective of its location in the test room. These direction-sensitive cells were localized to the dorsal aspect of the caudal two-thirds of the LDN, the site of innervation by retinal recipient pretectal and intermediate/deep-layer superior colliculus cells (Thompson and Robertson, 1987b). The directional specificity and preference of LDN cells were disrupted if rats were placed on the maze in darkness. If the room light was then turned on, the original preference was restored. If the light was again turned off, directional firing was maintained briefly. Normal directional firing lasted about 2-3 min. After this time, the directional preference (but not specificity) appeared to "rotate" systematically in either the clockwise or counterclockwise direction. The duration of normal directional discharge patterns in darkness could be extended to 30 min by varying the behavior of the animal. LDN cells required visual input to initialize reliable directional firing. After the rat viewed the environment, directional specificity was maintained in the absence of visual cues. Maximal directional firing was achieved only when the rat viewed the entire test room, and not just the scene associated with the directional preference of the cell. Thus, contextual information seems important. Also, a significant correlation was found between directional specificity and errors made on the maze during acquisition of the task. It was concluded that the LDN may pass on to the hippocampal formation directional information that is not merely a reflection of current sensory input. As such, the LDN may serve an important integrative function for limbic spatial learning systems.

Contextual information plays a key role in learning and memory. Learned information becomes associated with the context such that the context can cue the relevant memories and behaviors. An extensive literature involving experimental brain lesions has implicated the hippocampus in context processing. However, the neurophysiological mechanisms of context coding are not known. Although "context" has typically been defined in terms of the background cues, recent studies indicate that hippocampal neurons are sensitive to subtle changes in task demands, even in an unchanging environment. Thus, the context may also include non-environmental features of a learning situation. In the present study, hippocampal neuronal activity was recorded while rats learned to approach different reward locations in two contexts. Because all of the training took place in the same environment, the contexts were defined by the task demands rather than by environmental stimuli. Learning to differentiate two such contexts was associated with the development of highly contextspecific neuronal firing patterns. These included different place fields in pyramidal neurons and different event (e.g., reward) responses in pyramidal and interneurons. The differential firing patterns did not develop in a control condition that did not involve a context manipulation. The context-specific firing patterns could modulate activity in extrahippocampal structures to prime context-appropriate behavioral responses and memories. These results provide direct support for a context processing role of the hippocampus and suggest that the hippocampus contributes contextual representations to episodic memories.

These experiments examined the effects of dorsomedial striatal inactivation on the acquisition of a response and visual cue discrimination task, as well as a shift from a response to a visual cue discrimination, and vice versa. In Experiment 1, rats were tested on the response discrimination task followed by the visual cue discrimination task. In Experiment 2, the testing order was reversed. Infusions of 2% tetracaine did not impair acquisition of the response or visual cue discrimination but impaired performance when shifting from a response to a visual cue discrimination, and vice versa. Analysis of the errors revealed that the deficit was not due to perseveration of the previously learned strategy, but to an inability to maintain the new strategy. These results contrast with findings indicating that prelimbic inactivation impairs behavioral flexibility due to perseveration of a previously learned strategy. Thus, specific circuits in the prefrontal cortex and striatum may interact to enable behavioral flexibility, but each region may contribute to distinct processes that facilitate strategy switching.There have been several different theories regarding the function of the striatum in learning and memory over the past several