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...

The ability to control the electrical activity of a neuronal subtype is a valuable tool in deciphering the role of discreet cell populations in complex neural circuits. Recent techniques that allow remote control of neurons are either labor intensive and invasive or indirectly coupled to neural electrical potential with low temporal resolution. Here we show the rapid, reversible and direct activation of genetically identified neuronal subpopulations by generating two inducible transgenic mouse models. Confined expression of the capsaicin receptor, TRPV1, allows cell-specific activation after peripheral or oral delivery of ligand in freely moving mice. Capsaicin-induced activation of dopaminergic or serotonergic neurons reversibly alters both physiological and behavioural responses within minutes, and lasts ~10 min. These models showcase a robust and remotely controllable genetic tool that modulates a distinct cell population without the need for invasive and labour-intensive approaches.

These results suggest that the deficit in goal-directed behavior observed in mice without dopamine signaling is the result of decreased motivation to obtain reward, and that dopamine signaling in the dorsal striatum is sufficient to restore normal goal-directed behavior on a variety of operant responding tasks.