Start/stop signals emerge in nigrostriatal circuits during sequence learning

Learning new action sequences subserves a plethora of different abilities such as escaping a predator, playing the piano, or producing fluent speech. Proper initiation and termination of each action sequence is critical for the organization of behaviour, and is compromised in nigrostriatal disorders like Parkinson’s and Huntington’s diseases. Using a self-paced operant task in which mice learn to perform a particular sequence of actions to obtain an outcome, we found neural activity in nigrostriatal circuits specifically signalling the initiation or the termination of each action sequence. This start/stop activity emerged during sequence learning, was specific for particular actions, and did not reflect interval timing, movement speed or action value. Furthermore, genetically altering the function of striatal circuits disrupted the development of start/stop activity and selectively impaired sequence learning. These results have important implications for understanding the functional organization of actions and the sequence initiation and termination impairments observed in basal ganglia disorders.

[1]  K. Lashley The problem of serial order in behavior , 1951 .

[2]  L. A. Jeffress,et al.  Cerebral Mechanisms in Behavior , 1953 .

[3]  H. Meltzer Cerebral Mechanisms in Behavior. , 1953 .

[4]  R. Gulley,et al.  The fine structure of the neurons in the rat substantia nigra. , 1971, Tissue & cell.

[5]  P. Groves,et al.  The substantia nigra of the rat: A golgi study , 1977, The Journal of comparative neurology.

[6]  C. Gallistel The Organization of Action: A New Synthesis , 1982 .

[7]  A. Grace,et al.  The control of firing pattern in nigral dopamine neurons: burst firing , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[8]  S Grillner,et al.  Central pattern generators for locomotion, with special reference to vertebrates. , 1985, Annual review of neuroscience.

[9]  C. Marsden,et al.  Disturbance of sequential movements in patients with Parkinson's disease. , 1987, Brain : a journal of neurology.

[10]  M. Kimura Behaviorally contingent property of movement-related activity of the primate putamen. , 1990, Journal of neurophysiology.

[11]  P. Calabresi,et al.  Long‐term Potentiation in the Striatum is Unmasked by Removing the Voltage‐dependent Magnesium Block of NMDA Receptor Channels , 1992, The European journal of neuroscience.

[12]  N Accornero,et al.  Sequential arm movements in patients with Parkinson's disease, Huntington's disease and dystonia. , 1992, Brain : a journal of neurology.

[13]  Daniel B. Willingham,et al.  Evidence for dissociable motor skills in Huntington’s disease patients , 1993, Psychobiology.

[14]  Umberto Castiello,et al.  Temporal dissociation of the prehension pattern in Parkinson's disease , 1993, Neuropsychologia.

[15]  Robert Iansek,et al.  Impaired movement sequencing in patients with Huntington's disease: A kinematic analysis , 1995, Neuropsychologia.

[16]  J. Joseph,et al.  Activity in the caudate nucleus of monkey during spatial sequencing. , 1995, Journal of neurophysiology.

[17]  Peter Dayan,et al.  A Neural Substrate of Prediction and Reward , 1997, Science.

[18]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[19]  A. Graybiel The Basal Ganglia and Chunking of Action Repertoires , 1998, Neurobiology of Learning and Memory.

[20]  O. Hikosaka,et al.  Differential Roles of the Frontal Cortex, Basal Ganglia, and Cerebellum in Visuomotor Sequence Learning , 1998, Neurobiology of Learning and Memory.

[21]  J. W. Aldridge,et al.  Coding of Serial Order by Neostriatal Neurons: A “Natural Action” Approach to Movement Sequence , 1998, The Journal of Neuroscience.

[22]  C. I. Connolly,et al.  Building neural representations of habits. , 1999, Science.

[23]  K. Doya,et al.  Parallel neural networks for learning sequential procedures , 1999, Trends in Neurosciences.

[24]  V. Kostic,et al.  Visuomotor skill learning on serial reaction time task in patients with early Parkinson's disease , 2000, Movement disorders : official journal of the Movement Disorder Society.

[25]  E. Marder,et al.  Central pattern generators and the control of rhythmic movements , 2001, Current Biology.

[26]  O. Hikosaka,et al.  Differential activation of monkey striatal neurons in the early and late stages of procedural learning , 2002, Experimental Brain Research.

[27]  Michael S. Brainard,et al.  What songbirds teach us about learning , 2002, Nature.

[28]  J. W. Aldridge,et al.  Substantia nigra pars reticulata neurons code initiation of a serial pattern: implications for natural action sequences and sequential disorders , 2002, The European journal of neuroscience.

[29]  A. Graybiel,et al.  Representation of Action Sequence Boundaries by Macaque Prefrontal Cortical Neurons , 2003, Science.

[30]  K. Deisseroth,et al.  Millisecond-timescale, genetically targeted optical control of neural activity , 2005, Nature Neuroscience.

[31]  K. Doya,et al.  Representation of Action-Specific Reward Values in the Striatum , 2005, Science.

[32]  P. Redgrave,et al.  The short-latency dopamine signal: a role in discovering novel actions? , 2006, Nature Reviews Neuroscience.

[33]  R. Mair,et al.  The Role of Striatum in Initiation and Execution of Learned Action Sequences in Rats , 2006, The Journal of Neuroscience.

[34]  E. Vaadia,et al.  Midbrain dopamine neurons encode decisions for future action , 2006, Nature Neuroscience.

[35]  Henry H Yin,et al.  Disrupted motor learning and long-term synaptic plasticity in mice lacking NMDAR1 in the striatum , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[36]  R. Costa,et al.  Endocannabinoid Signaling is Critical for Habit Formation , 2007, Frontiers in integrative neuroscience.

[37]  W. Schultz Multiple dopamine functions at different time courses. , 2007, Annual review of neuroscience.

[38]  Joseph J. Paton,et al.  Expectation Modulates Neural Responses to Pleasant and Aversive Stimuli in Primate Amygdala , 2007, Neuron.

[39]  M. Roesch,et al.  Dopamine neurons encode the better option in rats deciding between differently delayed or sized rewards , 2007, Nature Neuroscience.

[40]  Charles R. Gerfen,et al.  Targeting Cre Recombinase to Specific Neuron Populations with Bacterial Artificial Chromosome Constructs , 2007, The Journal of Neuroscience.

[41]  Warren H Meck,et al.  Cortico-striatal Representation of Time in Animals and Humans This Review Comes from a Themed Issue on Cognitive Neuroscience Edited Evidence from Patient Populations and Electrical Potentials Neuroimaging Evidence Using Fmri and Pet , 2022 .

[42]  W. Pan,et al.  Tripartite Mechanism of Extinction Suggested by Dopamine Neuron Activity and Temporal Difference Model , 2008, The Journal of Neuroscience.

[43]  P. Glimcher,et al.  Value Representations in the Primate Striatum during Matching Behavior , 2008, Neuron.

[44]  M. Belluscio,et al.  NMDA Receptor Gating of Information Flow through the Striatum In Vivo , 2008, The Journal of Neuroscience.

[45]  P. Greengard,et al.  Dichotomous Dopaminergic Control of Striatal Synaptic Plasticity , 2008, Science.

[46]  J. Edwards,et al.  Motor sequence chunking is impaired by basal ganglia stroke , 2009, Neurobiology of Learning and Memory.

[47]  Susana Q. Lima,et al.  PINP: A New Method of Tagging Neuronal Populations for Identification during In Vivo Electrophysiological Recording , 2009, PloS one.

[48]  D. Lovinger,et al.  Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill , 2009, Nature Neuroscience.

[49]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[50]  Xin Jin,et al.  Frontiers in Integrative Neuroscience Integrative Neuroscience , 2022 .

[51]  K. Deisseroth,et al.  Phasic Firing in Dopaminergic Neurons Is Sufficient for Behavioral Conditioning , 2009, Science.