NMDA Receptors in Dopaminergic Neurons Are Crucial for Habit Learning

Abstract

Summary Dopamine is crucial for habit learning. Activities of midbrain dopaminergic neurons are regulated by the cortical and subcortical signals among which glutamatergic afferents provide excitatory inputs. Cognitive implications of glutamatergic afferents in regulating and engaging dopamine signals during habit learning however remain unclear. Here we show that mice with dopaminergic neuron-specific NMDAR1 deletion are impaired in a variety of habit learning tasks while normal in some other dopamine-modulated functions such as locomotor activities, goal directed learning, and spatial reference memories. In vivo neural recording revealed that DA neurons in these mutant mice could still develop the cue-reward association responses, but their conditioned response robustness was drastically blunted. Our results suggest that integration of glutamatergic inputs to DA neurons by NMDA receptors, likely by regulating associative activity patterns, is a crucial part of the cellular mechanism underpinning habit learning.

Neuronal Reward and Decision Signals: From Theories to Data

“…Learning is somewhat less impaired by systemic D1 receptor blockade in tasks involving less direct reactions to stimuli and engaging less phasic dopamine responses (sign trackers versus goal trackers, FIGURE 18B) (45,163,415). The learning deficits occur irrespective of performance deficits (163,440,624,649,650). Thus prediction error responses of dopamine neurons are not indiscriminately involved in all learning forms and play more important roles when prediction errors have more direct effects.…”

“…Genetic NMDA receptor knockout on mice dopamine neurons reduces neuronal burst responses to reward-predicting stimuli and, in parallel, induce deficits in a wide range of learning situations including conditioned place preference, maze learning, and operant conditioning (FIGURE 18C) (624,649,650). Correspondingly, GABA A receptor knockout on dopamine neurons enhances dopamine release and T-maze and lever press learning (414).…”

Habits as action sequences: hierarchical action control and changes in outcome value

“…In addition, motor chunking appears not to occur in Parkinsons patients [46] due to a loss of dopaminergic activity in the sensorimotor putamen, which can be restored in patients on L-DOPA [47]. Similarly, insensitivity to outcome devaluation induced by over-training has been shown to depend on the ascending nigrostriatal dopamine pathway in rats [48], and the expression of NMDA receptors on dopamine neurons in mice [49].…”

For Value or for Worth? Part 2: A Neuroeconomical Thought-Action-Mood-Space Modulated by (Un-)Certainty as Sign- or Goal-tracking

“…TGFβ- [111] or NMDAR- [112] activity on striatal DA-neurons. The lack of the latter glutamatergic input slows down learning, social contacts and forced swimming, but not effortful performance [113].…”