Brain's Traffic Lights

NATURE|Vol 466|22 July 2010 NEWS & VIEWS

NEUROSCIENCE that NMDA-dependent neuronal activity and plasticity may be essential for the brain to store learned behaviours. The start/stop activ- Brain’s traffic lights ity that Jin and Costa observe in the nigrostri- Paolo Calabresi and Massimiliano Di Filippo atal circuit can be compared to a traffic light, organizing actions by specifically signalling The organization of behaviour as sequences of actions requires proper the initiation and termination of each action initiation and termination of each action sequence. The neural circuit that sequence during sequence learning (Fig. 1). Initiation and termination of action signals instructions to start and stop is now revealed. sequences is usually impaired in human disorders involving the basal ganglia. Par- Learning to execute a new action in a sequence kinson’s disease, for example, is a typical — from start to finish — is essential for sur- basal-ganglion neurodegenerative disorder vival and subserves many routine behaviours Cortex in which the activity of the nigrostriatal cir- and everyday activities, such as shifting the cuit is deeply compromised. In this disease, gear in a car or playing a musical instrument. dopamine-releasing neurons of the substantia Glutamate Basal ganglia Action sequences are learned, and eventu- output neurons nigra degenerate; the nucleus striatum loses its ally, with practice, are performed automati- connection to dopamine-releasing neurons; cally, through an implicit learning process Substantia and motor and cognitive symptoms surface6. that involves changes in neuronal activity in nigra Nucleus In parallel, striatal synapses can no longer specific brain structures. On page 457 of this striatum undergo the main forms of synaptic plastic- issue, Jin and Costa1 show that neurons in two Dopamine ity5. Given the important role of the nigros- brain structures — the nucleus striatum and Nigrostriatal circuit triatal circuit in motor learning and control, the substantia nigra, constituting the nigro- patients with Parkinson’s disease often cannot striatal circuit — can signal the initiation and learn new action sequences7 and show a selec- termination of self-paced action sequences, tive difficulty in initiating and terminating 6 and that this ‘start/stop’ neuronal activity Start Stop motor sequences . For instance, they usually emerges as animals learn how to execute a Action sequence have great difficulty in initiating gait, in rising specific action sequence. from deep chairs or in rolling over in bed; but, This neuronal circuit in the basal ganglia at the same time, once they start to walk, their — an interconnected set of neuronal clusters, gait may rapidly and involuntarily quicken in in the subcortical region of the brain, that Figure 1 | Learning the sequence of an action. the forward direction, making them fall. includes the nucleus striatum and the sub- Jin and Costa1 find that, in mice, neurons in the For these reasons, Jin and Costa’s results1 in stantia nigra — contributes to the learning and substantia nigra and in the nucleus striatum mice not only are an important step towards execution of acquired behavioural sequences (constituting the nigrostriatal circuit) signal understanding striatal physiology, but also by interacting with the brain’s cortex2 (Fig. 1). the initiation and termination of self-paced could have potentially significant implications action sequences. This ‘start/stop’ neuronal In particular, the input structure of the circuit activity emerges as animals learn how to execute for unravelling the mechanisms of disabling — the nucleus striatum — is essential in the a specific action sequence. In the circuit, neurological diseases such as Parkinson’s. control of behavioural outputs. This structure’s glutamate released from cortical terminals acts Indeed, it could be that, in Parkinson’s disease, activity is modulated by the neurotransmit- together with dopamine to induce long-lasting functional alterations in the nigrostriatal cir- ter dopamine, which is released by neurons changes in striatal neuronal activity. Alterations cuit impair striatal start/stop activity during of the substantia nigra. The activity of the in the start/stop activity of this circuit may sequence learning. In turn, loss of a ‘traffic nucleus striatum is believed to have a crucial underlie neurodegenerative disorders such as light’ organizing the initiation and termina- role in learning how to select actions that lead Parkinson’s disease. tion of each action sequence might lead to to reward and to avoiding punishment3. It is the onset of deficits in sequence learning in also thought to be involved in various forms — long-term depression (LTD) and long- patients, and to clinical symptoms mirroring of learning and memory, such as procedural term potentiation (LTP)5; these represent the the inability of the circuit to signal when each learning, skill learning, habit learning and molecular basis of learning and memory. In action sequence should start and stop. Fur- reward-associated learning4. the nucleus striatum, LTD and LTP depend ther experiments in animal models, as well as Jin and Costa’s finding1, that the neurons of on the interaction between dopamine and clinical studies should explore this intriguing the nucleus striatum and the substantia nigra another key neurotransmitter, glutamate. hypothetical possibility. ■ make a circuit to signal the start/stop of action In particular, LTP depends on activation of Paolo Calabresi and Massimiliano Di Filippo are sequences, highlights the crucial role played both the D1 dopamine receptor and NMDA at the Clinica Neurologica, Università degli Studi by the basal ganglia, and in particular the (N-methyl-d-aspartate)-type glutamate di Perugia, Ospedale S. Maria della Misericordia, striatum, in learning and ‘crystallizing’ newly receptors5. 06156 Perugia, Italy. They are also at the IRCCS acquired action sequences4. It also points Jin and Costa1 show that, in mutant mice Fondazione Santa Lucia, Rome, Italy. to the potential part played by long-lasting carrying a striatal-specific deletion in the e-mail: [email protected] changes in the activity of striatal neurons in NMDA receptor, the percentage of neurons 1. Jin, X. & Costa, R. M. Nature 466, 457–462 (2010). motor learning and behavioural control. displaying start/stop activity is significantly 2. Schultz, W., Tremblay, L. & Hollerman, J. R. Trends Neurosci. The strength of the synaptic junctions that lower than in normal animals, and that this 26, 321–328 (2003). connect neurons can change with experience percentage does not increase with training. 3. Surmeier, D. J., Plotkin, J. & Shen, W. Curr. Opin. Neurobiol. 19, 621–628 (2009). — a concept known as synaptic plasticity. Sev- Moreover, the mutant mice show little evi- 4. Yin, H. H. & Knowlton, B. J. Nature Rev. Neurosci. 7, eral mechanisms can lead to synaptic plast- dence of sequence learning. These observa- 464–476 (2006). icity in the nigrostriatal circuit. The excitatory tions suggest that a functional NMDA receptor 5. Calabresi, P., Picconi, B., Tozzi, A. & Di Filippo, M. Trends Neurosci. 30, 211–219 (2007). synapses connecting to a type of nucleus stria- in the striatum is essential for sequence learn- 6. Lees, A. J., Hardy, J. & Revesz, T. Lancet 373, 2055–2066 tum neuron called a projecting spiny neuron ing, by affecting learning-related start/stop (2009). exhibit the main forms of synaptic plasticity activity, and thus provides further evidence 7. Doyon, J. Curr. Opin. Neurol. 21, 478–483 (2008).