Ann M. Graybiel

Neurotransmitters and neuromodulators in the basal ganglia.

The basal ganglia have become a focus for work on neurotransmitter interactions in the brain. These structures contain a remarkable diversity of neuroactive substances, organized into functional subsystems that have unique developmental histories and vulnerabilities in neurodegenerative diseases. A new view of the basal ganglia is emerging on the basis of this neurochemical heterogeneity, suggesting that dynamic regulation of transmitter expression may be a key to extrapyramidal function.

Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease

In idiopathic Parkinsons disease massive cell death occurs in the dopamine-containing substantia nigra1,24. A link between the vulnerability of nigral neurons and the prominent pigmentation of the substantia nigra, though long suspected, has not been proved2. This possibility is supported by evidence that N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite MPP+, the latter of which causes destruction of nigral neurons, bind to neuromelanin3,4. We have directly tested this hypothesis by a quantitative analysis of neuromelanin-pigmented neurons in control and parkinsonian midbrains. The findings demonstrate first that the dopamine-containing cell groups of the normal human midbrain differ markedly from each other in the percentage of neuromelanin-pigmented neurons they contain. Second, the estimated cell loss in these cell groups in Parkinsons disease is directly correlated (r = 0.97, P = 0.0057) with the percentage of neuromelanin-pigmented neurons normally present in them. Third, within each cell group in the Parkinsons brains, there is greater relative sparing of non-pigmented than of neuromelanin-pigmented neurons. This evidence suggests a selective vulnerability of the neuromelanin-pigmented subpopulation of dopamine-containing mesencephalic neurons in Parkinsons disease.

Habits, Rituals, and the Evaluative Brain

Scientists in many different fields have been attracted to the study of habits because of the power habits have over behavior and because they invoke a dichotomy between the conscious, voluntary control over behavior, considered the essence of higher-order deliberative behavioral control, and lower-order behavioral control that is scarcely available to consciousness. A broad spectrum of behavioral routines and rituals can become habitual and stereotyped through learning. Others have a strong innate basis. Repetitive behaviors can also appear as cardinal symptoms in a broad range of neurological and neuropsychiatric illness and in addictive states. This review suggests that many of these behaviors could emerge as a result of experience-dependent plasticity in basal ganglia-based circuits that can influence not only overt behaviors but also cognitive activity. Culturally based rituals may reflect privileged interactions between the basal ganglia and cortically based circuits that influence social, emotional, and action functions of the brain.

The Basal Ganglia and Chunking of Action Repertoires

The basal ganglia have been shown to contribute to habit and stimulus-response (S-R) learning. These forms of learning have the property of slow acquisition and, in humans, can occur without conscious awareness. This paper proposes that one aspect of basal ganglia-based learning is the recoding of cortically derived information within the striatum. Modular corticostriatal projection patterns, demonstrated experimentally, are viewed as producing recoded templates suitable for the gradual selection of new input-output relations in cortico-basal ganglia loops. Recordings from striatal projection neurons and interneurons show that activity patterns in the striatum are modified gradually during the course of S-R learning. It is proposed that this recoding within the striatum can chunk the representations of motor and cognitive action sequences so that they can be implemented as performance units. This scheme generalizes Millers notion of information chunking to action control. The formation and the efficient implementation of action chunks are viewed as being based on predictive signals. It is suggested that information chunking provides a mechanism for the acquisition and the expression of action repertoires that, without such information compression would be biologically unwieldy or difficult to implement. The learning and memory functions of the basal ganglia are thus seen as core features of the basal ganglias influence on motor and cognitive pattern generators.

Toward a neurobiology of obsessive-compulsive disorder.

Even if imaging studies identify the cascades of activity in cortico-basal ganglia circuits occurring during expression of OCD symptoms, it still will be unclear what form of neural encoding is responsible for the symptoms or for their resolution. One interesting possibility is that the neural circuits that normally mediate habits and automated behaviors become hyperactive or inaccessible to a stop signal in OCD and related disorders. Three recent models for studying what goes on in cortico-basal ganglia circuits when habits are formed are pertinent here. In the first, monkeys were taught a sensorimotor conditioning task in which light or sound cues were associated with reward, and recordings were made from the tonically active neurons of the striatum thought to be the cholinergic interneurons. As the monkeys learned the task, the neurons acquired responses to the conditioning stimuli, and they maintained those responses as long as dopamine was present in the striatum. Removal of dopamine reduced the acquired responses (2xEffects of the nigrostriatal dopamine system on acquired neural responses in the striatum of behaving monkeys. Aosaki, T, Graybiel, A.M, and Kimura, M. Science. 1994; 265: 412–415Crossref | PubMedSee all References, 3xResponses of tonically active neurons in the primates striatum undergo systematic changes during behavioral sensorimotor conditioning. Aosaki, T, Tsubokawa, H, Ishida, A, Watanabe, K, Graybiel, A.M, and Kimura, M. J. Neurosci. 1994; 14: 3969–3984PubMedSee all References), and so did inactivation of the intralaminar thalamus (Matsumoto et al. 2000xNeurons in the thalamic CM-Pf complex supply neurons in the striatum with polysensory information with orienting value. Matsumoto, N, Minamimoto, T, Graybiel, A.M, and Kimura, M. J. Neurophysiol. 2000; in pressSee all ReferencesMatsumoto et al. 2000). In related work, removal of dopamine in the striatum before learning of a simple sequential push-button task prevented the task from being executed without cues as a unified behavioral sequence (Matsumoto et al. 1999xRole of nigrostriatal dopamine system in learning to perform sequential motor tasks in a predictive manner. Matsumoto, N, Hanakawa, T, Maki, S, Graybiel, A.M, and Kimura, M. J. Neurophysiol. 1999; 82: 978–998PubMedSee all ReferencesMatsumoto et al. 1999). In the second set of experiments, the activity of projection neurons in the sensorimotor striatum of rats was monitored with chronically implanted tetrodes. The ensemble activity of these neurons was found to undergo large-scale and long-lasting changes as the rats learned the procedure and then performed it after learning (Jog et al. 1999xBuilding neural representations of habits. Jog, M, Kubota, Y, Connolly, C.I, Hillegaart, V, and Graybiel, A.M. Science. 1999; 286: 1745–1749Crossref | PubMed | Scopus (489)See all ReferencesJog et al. 1999; see also Carelli et al. 1997xLoss of lever press-related firing of rat striatal forelimb neurons after repeated sessions in a lever pressing task. Carelli, R.M, Wolske, M, and West, M.O. J. Neurosci. 1997; 17: 1804–1814PubMedSee all ReferencesCarelli et al. 1997). These studies suggest that, with experience, striatal neurons can develop new responses to environmental stimuli. Given the activity changes in striatal projection neurons, this plasticity is likely to affect basal ganglia outputs and thus cortico-basal ganglia loop function. In the third set of experiments, the expression of stereotypies induced in rats by repeated doses of psychomotor stimulant drugs was found to be closely correlated with heightened activation of the striosomal compartment of the striatum—the compartment preferentially interconnected with the anterior cingulate and orbitofrontal cortex (Canales and Graybiel 2000xA measure of striatal function predicts motor stereotypy. Canales, J.J and Graybiel, A.M. Nat. Neurosci. 2000; 3: 377–383Crossref | PubMed | Scopus (249)See all ReferencesCanales and Graybiel 2000). Such experiments highlight the potential for identifying the changes in neuronal activity that occur in cortico-basal ganglia circuits as repetitive action repertoires come to dominate behavior. A first step toward testing whether such striatal function could be affected in OCD has been carried out by testing people with OCD on implicit learning tasks that normally activate the striatum. Striatal activation was found to be deficient in the OCD subjects, but activation of the hippocampal system (normally recruited during explicit learning tasks) was abnormally high (Rauch et al. 1997xProbing striatal function in obsessive compulsive disorder (a PET study of implicit sequence learning) . Rauch, S, Savage, C, Alpert, N, Dougherty, D, Kendrick, A, Curran, T, Brown, H, Manzo, P, Fischman, A, and Jenike, M. J Neuropsych. Clin. Neurosci. 1997; 9: 568–573PubMedSee all ReferencesRauch et al. 1997). Coordination of human brain imaging of this sort with laboratory-based experiments holds great promise for uncovering the neurobiology of OCD.‡To whom correspondence should be addressed (e-mail: graybiel@mit.edu).

The basal ganglia: learning new tricks and loving it

The field of basal ganglia research is exploding on every level - from discoveries at the molecular level to those based on human brain imaging. A remarkable series of new findings support the view that the basal ganglia are essential for some forms of learning-related plasticity. Other new findings are challenging some of the basic tenets of the field as it now stands. Combined with the new evidence on learning-related functions of the basal ganglia, these studies suggest that the basal ganglia are parts of a brain-wide set of adaptive neural systems promoting optimal motor and cognitive control.

Building action repertoires: memory and learning functions of the basal ganglia.

Research on the basal ganglia suggests that they are critically involved in building up sequences of behavior into meaningful, goal-directed repertoires. Work on rodents, monkeys and humans suggests that the basal ganglia act as part of a distributed forebrain system that helps to encode such repertoires through behavioral learning, and that is engaged in the expression of such repertoires once they have been internalized. The basal ganglia also may be critical to the expression of innate behavioral routines. Experimental findings on reward-based learning suggest that neural activity in the striatum and substantia nigra, pars compacta changes during behavioral learning. New evidence also suggests extreme specificity in the neural connections interrelating the basal ganglia, cerebral cortex and thalamus. Adaptive control of behavior may centrally depend on these circuits and the evaluator-reinforcement circuits that modulate them.

Responses of tonically active neurons in the primate's striatum undergo systematic changes during behavioral sensorimotor conditioning

The basal ganglia have been implicated in motor planning and motor learning. In the study reported here, we directly tested for response plasticity in striatal neurons of macaque monkeys undergoing Pavlovian conditioning. To focus the study, we recorded from the tonically active neurons (TANs) of the striatum, which are known to respond to conditioned sensory stimuli that signal reward delivery and elicit behavioral reactions. The activities of 858 TANs were recorded extracellularly from the striatum in alert behaving macaque monkeys before, during, and after the acquisition of a classical conditioning task. Two monkeys were trained to lick reward juice delivered on a spoon simultaneously with the presentation of a click. Almost no licks were triggered by the cues at the start of training, but by the fifth day more than 90% of licks were triggered, and values were near 100% for the remainder of the 3 week training period. In the striatum, only a small number of TANs responded to the clicks at the start before conditioning (about 17%). During training, the numbers of responding TANs gradually increased, so that by the end of training more than 50– 70% of the TANs recorded (51.3–73.5%) became responsive to the clicks. The responses consisted of a pause in firing that occurred approximately 90 msec after the click and that was in some cells preceded by a brief activation and in most cells was followed by a rebound excitation. Prolonged recordings from single TANs (n = 6) showed that individual TANs can acquire a conditioned response within at least as short a time as 10 min. TANs retained such responsiveness after overtraining, and also after a 4 week intermission in training. When the monkey was trained to receive rewards in relation to a new conditioning stimulus, TANs were capable of switching their sensory response to the new stimulus. Histological reconstruction showed that the TANs that became responsive were broadly distributed in the region of striatum explored, which included the dorsal half to two-thirds of the caudate nucleus and putamen over a large anteroposterior span. We conclude that, during the acquisition of a sensorimotor association, TANs widely distributed through the striatum become responsive to sensory stimuli that induce conditioned behavior. This distributed change in activity could serve to modulate the activity of surrounding projection neurons in the striatum engaged in mediating learned behavior.

Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses

The brain dopaminergic system is a critical modulator of basal ganglia function and plasticity. To investigate the contribution of the dopamine D1 receptor to this modulation, we have used gene targeting technology to generate D1 receptor mutant mice. Histological analyses suggested that there are no major changes in general anatomy of the mutant mouse brains, but indicated that the expression of dynorphin is greatly reduced in the striatum and related regions of the basal ganglia. The mutant mice do not respond to the stimulant and suppressive effects of D1 receptor agonists and antagonists, respectively, and they exhibit locomotor hyperactivity. These results suggest that the D1 receptor regulates the neurochemical architecture of the striatum and is critical for the normal expression of motor activity.

Activity of striatal neurons reflects dynamic encoding and recoding of procedural memories

Learning to perform a behavioural procedure as a well-ingrained habit requires extensive repetition of the behavioural sequence, and learning not to perform such behaviours is notoriously difficult. Yet regaining a habit can occur quickly, with even one or a few exposures to cues previously triggering the behaviour. To identify neural mechanisms that might underlie such learning dynamics, we made long-term recordings from multiple neurons in the sensorimotor striatum, a basal ganglia structure implicated in habit formation, in rats successively trained on a reward-based procedural task, given extinction training and then given reacquisition training. The spike activity of striatal output neurons, nodal points in cortico-basal ganglia circuits, changed markedly across multiple dimensions during each of these phases of learning. First, new patterns of task-related ensemble firing successively formed, reversed and then re-emerged. Second, task-irrelevant firing was suppressed, then rebounded, and then was suppressed again. These changing spike activity patterns were highly correlated with changes in behavioural performance. We propose that these changes in task representation in cortico-basal ganglia circuits represent neural equivalents of the explore–exploit behaviour characteristic of habit learning.