Learned Motor Responses Research Articles

Interplay Between Inhibitory Control and Behavioural Flexibility: Impact of Dorsomedial Striatal Dopamine Denervation in Mice

In Parkinson’s disease, nigrostriatal dopamine (DA) degeneration is commonly associated with motor symptomatology. However, non-motor symptoms affecting cognitive function, such as behavioural flexibility and inhibitory control may also appear early in the disease. Here we addressed the role of DA innervation of the dorsomedial striatum (DMS) in mediating these functions in 6-hydroxydopamine (6-OHDA)-lesioned mice using instrumental conditioning in various tasks. Behavioural flexibility was studied in a simple reversal task (nose-poke discrimination) or in reversal of a two-step sequence of actions (central followed by lateral nose-poke). Our results show that mild DA lesions of the DMS induces behavioural flexibility deficits in the sequential reversal learning only. In the first sessions following reversal of contingency, lesioned mice enhanced perseverative sequence of actions to the initial rewarded side then produced premature responses directly to the correct side omitting the central response, thus disrupting the two-step sequence of actions. These deficits may be linked to increased impulsivity as 6-OHDA-lesioned mice were unable to inhibit a previously learned motor response in a cued response inhibition task assessing proactive inhibitory control. Our findings show that partial DA denervation restricted to DMS impairs behavioural flexibility and proactive response inhibition in mice. Such striatal DA lesion may thus represent a valuable animal model for exploring deficits in executive control documented in early stage of Parkinson’s disease.

Mechanisms of Choice Behavior Shift Using Cue-approach Training.

Cue-approach training has been shown to effectively shift choices for snack food items by associating a cued button-press motor response to particular food items. Furthermore, attention was biased toward previously cued items, even when the cued item is not chosen for real consumption during a choice phase. However, the exact mechanism by which preferences shift during cue-approach training is not entirely clear. In three experiments, we shed light on the possible underlying mechanisms at play during this novel paradigm: (1) Uncued, wholly predictable motor responses paired with particular food items were not sufficient to elicit a preference shift; (2) Cueing motor responses early – concurrently with food item onset – and thus eliminating the need for heightened top–down attention to the food stimulus in preparation for a motor response also eliminated the shift in food preferences. This finding reinforces our hypothesis that heightened attention at behaviorally relevant points in time is key to changing choice behavior in the cue-approach task; (3) Crucially, indicating choice using eye movements rather than manual button presses preserves the effect, thus demonstrating that the shift in preferences is not governed by a learned motor response but more likely via modulation of subjective value in higher associative regions, consistent with previous neuroimaging results. Cue-approach training drives attention at behaviorally relevant points in time to modulate the subjective value of individual items, providing a mechanism for behavior change that does not rely on external reinforcement and that holds great promise for developing real world behavioral interventions.

The cerebellum: from development to structural complexity and motor learning.

The cerebellum: from development to structural complexity and motor learning.

SY35-2 * DORSAL STRIATAL INDIRECT PATHWAY REGULATES THE PERFORMANCE OF AUDITORY CONDITIONAL DISCRIMINATION

The dorsal striatum, which contains the dorsolateral striatum (DLS) and dorsomedial striatum (DMS), is known to be involved in the performance of discrimination learning. The dorsal striatum regulates the basal ganglia circuitry through direct and indirect pathways. However the mechanism by which the striatopallidal pathway regulates the learning processes of discriminative actions remains unclear. To induce selective elimination of the striatopallidal pathway by injecting the recombinant immunotoxin into the DLS or DMS, we used transgenic rats that expressed human interleukin-2 receptor alpha-subunit under the control of dopamine D2 receptor gene promoter. Intrastriatal immunotoxin treatment induced a selective elimination of the striatopallidal neurons while persisting normally the number of other striatal neuronal types. Ablation of the DLS- or DMS-derived striatopallidal pathway transiently impaired the performance of conditional discrimination, showing a marked reduction in the selection accuracy of learned motor responses. In addition, the probability of perseverative errors was significantly increased in the animals lacking the striatopallidal pathway from the DMS, but not from the DLS. Although there is a distinct role in modulating perseverative behavior between the DLS- and DMS-derived striatopallidal pathways, these two pathways are necessary for controlling the accuracy of response selection.

Role of motor cortex NMDA receptors in learning-dependent synaptic plasticity of behaving mice

The primary motor cortex has an important role in the precise execution of learned motor responses. During motor learning, synaptic efficacy between sensory and primary motor cortical neurons is enhanced, possibly involving long-term potentiation and N-methyl-D-aspartate (NMDA)-specific glutamate receptor function. To investigate whether NMDA receptor in the primary motor cortex can act as a coincidence detector for activity-dependent changes in synaptic strength and associative learning, here we generate mice with deletion of the Grin1 gene, encoding the essential NMDA receptor subunit 1 (GluN1), specifically in the primary motor cortex. The loss of NMDA receptor function impairs primary motor cortex long-term potentiation in vivo. Importantly, it impairs the synaptic efficacy between the primary somatosensory and primary motor cortices and significantly reduces classically conditioned eyeblink responses. Furthermore, compared with wild-type littermates, mice lacking primary motor cortex show slower learning in Skinner-box tasks. Thus, primary motor cortex NMDA receptors are necessary for activity-dependent synaptic strengthening and associative learning.

Striatal indirect pathway contributes to selection accuracy of learned motor actions.

The dorsal striatum, which contains the dorsolateral striatum (DLS) and dorsomedial striatum (DMS), integrates the acquisition and implementation of instrumental learning in cooperation with the nucleus accumbens (NAc). The dorsal striatum regulates the basal ganglia circuitry through direct and indirect pathways. The mechanism by which these pathways mediate the learning processes of instrumental actions remains unclear. We investigated how the striatal indirect (striatopallidal) pathway arising from the DLS contributes to the performance of conditional discrimination. Immunotoxin targeting of the striatal neuronal type containing dopamine D(2) receptor in the DLS of transgenic rats resulted in selective, efficient elimination of the striatopallidal pathway. This elimination impaired the accuracy of response selection in a two-choice reaction time task dependent on different auditory stimuli. The impaired response selection was elicited early in the test sessions and was gradually restored as the sessions continued. The restoration from the deficits in auditory discrimination was prevented by excitotoxic lesion of the NAc but not by that of the DMS. In addition, lesion of the DLS mimicked the behavioral consequence of the striatopallidal removal at the early stage of test sessions of discriminative performance. Our results demonstrate that the DLS-derived striatopallidal pathway plays an essential role in the execution of conditional discrimination, showing its contribution to the control of selection accuracy of learned motor responses. The results also suggest the presence of a mechanism that compensates for the learning deficits during the repetitive sessions, at least partly, demanding accumbal function.

Striatal direct pathway modulates response time in execution of visual discrimination

The dorsal striatum in the basal ganglia circuitry is a principal structure that mediates the acquisition and performance of instrumental learning. The projections from the dorsal striatum are composed of two subpopulations of medium spiny neurons that constitute the direct and indirect pathways. The mechanism by which these striatal projections control the learning processes of instrumental actions remains unknown. We addressed the behavioral role of the striatal direct (striatonigral) pathway in the performance of visual discrimination. Immunotoxin targeting of the striatal neuronal type containing dopamine D(1) receptor in mice resulted in a moderate level of elimination of the striatonigral pathway. Targeting of the neural pathway from the whole region of the dorsal striatum lengthened the response time but did not affect the accuracy of response selection in a two-choice reaction time task dependent on light stimulus. This lengthened motor response was induced early in the test sessions and was gradually restored to normal levels during repetitive sessions. In addition, subregion-specific pathway targeting revealed that the delay in learned motor response was generated by the elimination of the striatonigral pathway arising from the dorsomedial striatum but not from the dorsolateral striatum. Our findings indicate that the striatonigral pathway, in particular from the dorsomedial striatum, contributes to the regulation of response time in the execution of visual discrimination. The restoration of motor response deficits during repetitive sessions suggests the presence of a mechanism by which the response facilitation is acquired through continuation of learning despite the removal of the striatonigral pathway.

An agonist–antagonist cerebellar nuclear system controlling eyelid kinematics during motor learning

The presence of two antagonistic groups of deep cerebellar nuclei neurons has been reported as necessary for a proper dynamic control of learned motor responses. Most models of cerebellar function seem to ignore the biomechanical need for a double activation–deactivation system controlling eyelid kinematics, since most of them accept that, for closing the eyelid, only the activation of the orbicularis oculi (OO) muscle (via the red nucleus to the facial motor nucleus) is necessary, without a simultaneous deactivation of levator palpebrae motoneurons (via unknown pathways projecting to the perioculomotor area). We have analyzed the kinetic neural commands of two antagonistic types of cerebellar posterior interpositus neuron (IPn) (types A and B), the electromyographic (EMG) activity of the OO muscle, and eyelid kinematic variables in alert behaving cats during classical eyeblink conditioning, using a delay paradigm. We addressed the hypothesis that the interpositus nucleus can be considered an agonist–antagonist system controlling eyelid kinematics during motor learning. To carry out a comparative study of the kinetic–kinematic relationships, we applied timing and dispersion pattern analyses. We concluded that, in accordance with a dominant role of cerebellar circuits for the facilitation of flexor responses, type A neurons fire during active eyelid downward displacements—i.e., during the active contraction of the OO muscle. In contrast, type B neurons present a high tonic rate when the eyelids are wide open, and stop firing during any active downward displacement of the upper eyelid. From a functional point of view, it could be suggested that type B neurons play a facilitative role for the antagonistic action of the levator palpebrae muscle. From an anatomical point of view, the possibility that cerebellar nuclear type B neurons project to the perioculomotor area—i.e., more or less directly onto levator palpebrae motoneurons—is highly appealing.

Dynamic Changes in the Cerebellar-Interpositus/Red-Nucleus-Motoneuron Pathway During Motor Learning

Understanding the role played by the cerebellum in the genesis and control of learned motor responses requires a precise knowledge of interdependent relationships between kinetic neural commands and the performance (kinematics) of the acquired movements. The eyelid motor system is a useful model for studying how simple motor responses are generated and performed. Here, we recorded the activity of interpositus, red nucleus, and/or facial motor neurons during classical eyeblink conditioning, using a delay paradigm. Experiments were carried out in behaving cats, and in conscious wild-type and (Purkinje cell devoid) Lurcher mice. Kinetic variables were determined by recording the firing activities of identified neurons at the mentioned nuclei, whilst kinematic variables were selected from the electromyographic activity of the orbicularis oculi muscle and/or from eyelid position recorded during the conditioned-stimulus/unconditioned-stimulus interval. Whereas motoneurons encoded eyelid kinematics for acquired eyelid responses, interpositus, and red nucleus neurons did not directly encode eyelid performance, and the dynamic association between their neuronal activities was barely significant (from moderate to weak correlation, nonlinear coupling with high asymmetry, and neural firing activities that always lagged the beginning of the conditioned response). Nevertheless, interpositus and red nucleus neurons seem to play a modulating role in the dynamic control of this type of learned motor response, and present interesting adaptive properties in Lurcher mice. The analytical procedures proposed here could be very helpful in defining the functional state corresponding to each stage across the acquisition of new motor and cognitive abilities.

Dynamic Associations in the Cerebellar–Motoneuron Network during Motor Learning

We assessed here true causal directionalities in cerebellar-motoneuron (MN) network associations during the classical conditioning of eyelid responses. For this, the firing activities of identified facial MNs and cerebellar interpositus (IP) nucleus neurons were recorded during the acquisition of this type of associative learning in alert behaving cats. Simultaneously, the eyelid conditioned response (CR) and the EMG activity of the orbicularis oculi (OO) muscle were recorded. Nonlinear association analysis and time-dependent causality method allowed us to determine the asymmetry, time delays, direction in coupling, and functional interdependences between neuronal recordings and learned motor responses. We concluded that the functional nonlinear association between the IP neurons and OO muscle activities was bidirectional and asymmetric, and the time delays in the two directions of coupling always lagged the start of the CR. Additionally, the strength of coupling depended inversely on the level of expression of eyeblink CRs, whereas causal inferences were significantly dependent on the phase information status. In contrast, the functional association between OO MNs and OO muscle activities was unidirectional and quasisymmetric, and the time delays in coupling were always of opposed signs. Moreover, information transfer in cerebellar-MN network associations during the learning process required a "driving common source" that induced the mere "modulating coupling" of the IP nucleus with the final common pathway for the eyelid motor system. Thus, it can be proposed that the cerebellum is always looking back and reevaluating its own function, using the information acquired in the process, to play a modulating-reinforcing role in motor learning.

The cerebellar interpositus nucleus and the dynamic control of learned motor responses.

The role played by the cerebellum in movement control requires knowledge of interdependent relationships between kinetic neural commands and the performance (kinematics) of learned motor responses. The eyelid motor system is an excellent model for studying how simple motor responses are elaborated and performed. Kinetic variables (n = 24) were determined here by recording the firing activities of orbicularis oculi motoneurons and cerebellar interpositus neurons in alert cats during classical conditioning, using a delay paradigm. Kinematic variables (n = 36) were selected from eyelid position, velocity, and acceleration traces recorded during the conditioned stimulus-unconditioned stimulus interval. Optimized experimental and analytical tools allowed us to determine the evolution of kinetic and kinematic variables, the dynamic correlation functions relating motoneuron and interpositus neuron firing to eyelid conditioning responses, the falling correlation property of the interpositus nucleus across the successive training sessions, the time and significance of the linear relationships between these variables, and finally, the phase-inversion property of interpositus neurons with respect to acquired conditioned responses. Whereas motoneurons encoded eyelid kinematics at every instant of the dynamic correlation range and generated the natural oscillatory properties of the neuromuscular elements involved in eyeblinks, interpositus neurons did not directly encode eyelid performance: namely, their contribution was only slightly significant in the dynamic correlation range, and this regularity caused the integrated neuronal activity to oscillate by progressively inverting phase information. Therefore, interpositus neurons seem to play a modulating role in the dynamic control of learned motor responses, i.e., they could be considered a neuronal phase-modulating device.

Physiology of the eyelid motor system.

The eyelid motor system represents an excellent experimental model for the study of reflex and learned motor responses. Eyelid responses can be recorded quantitatively with the search coil in a magnetic-field technique. Stimuli able to evoke reflex blinks (air puffs, flashes of light, tones) can also be controlled quantitatively. Eyelid movements can be classified as spontaneous, passive (such as those following eye saccades), reflex, and acquired with classical conditioning procedures. Information is available regarding the firing activity of brainstem motoneuronal pools (abducens, accessory abducens, and facial motoneurons) involved in these types of eyelid response. In particular, facial motoneurons present different encoding properties for the generation of reflex against learned eyelid responses. In cats, accessory abducens motoneurons are involved only in reflex (but not in learned) blinks. The recent description of the complete organization of premotoneuronal pathways related to eyelid motorics opens new experimental possibilities for the study of this particular motor system.

Conscious control over the content of unconscious cognition

Visual stimuli (primes) presented too briefly to be consciously identified can nevertheless affect responses to subsequent stimuli – an instance of unconscious cognition. There is a lively debate as to whether such priming effects originate from unconscious semantic processing of the primes or from reactivation of learned motor responses that conscious stimuli afford during preceding practice. In four experiments we demonstrate that unconscious stimuli owe their impact neither to automatic semantic categorization nor to memory traces of preceding stimulus-response episodes, but to their match with pre-specified cognitive action-trigger conditions. The intentional creation of such triggers allows actors to control the way unconscious stimuli bias their behaviour.

Neural organization of eyelid responses.

A blink is a fast narrowing of the palpebral fissure, involving the activity of the orbicularis oculi muscle and, in those species with a nictitating membrane, of the retractor bulbi motor system and most extraocular eye muscles. Reflex blinks can be triggered by stimuli of different sensory modalities (trigeminal, visual, acoustic, and vestibular). Blinks are not exclusively related to corneal protection and wetting, but are also associated with some stages of visual processing and with the complex motor displays involved in the expression of emotional states. Lid movements also accompany eye displacements, as during vertical eye saccades and fixations. Moreover, eyelid movements can be easily evoked using classical conditioning procedures. 1‐9 Because of the technical facilities available for the quantitative evoking and recording of nictitating membrane and/or eyelid movements, 3 this motor system has become an excellent experimental model for the study of learned motor responses. In addition, available relevant information on this motor system can be used as a very useful tool for the understanding of the different pathologies related to facial kinematics and expression in humans.

Cerebellar cortical inhibition and classical eyeblink conditioning.

The cerebellum is considered a brain structure in which memories for learned motor responses (e.g., conditioned eyeblink responses) are stored. Within the cerebellum, however, the relative importance of the cortex and the deep nuclei in motor learning/memory is not entirely clear. In this study, we show that the cerebellar cortex exerts both basal and stimulus-activated inhibition to the deep nuclei. Sequential application of a gamma-aminobutyric acid type A receptor (GABA(A)R) agonist and a noncompetitive GABA(A)R antagonist allows selective blockade of stimulus-activated inhibition. By using the same sequential agonist and antagonist methods in behaving animals, we demonstrate that the conditioned response (CR) expression and timing are completely dissociable and involve different inhibitory inputs; although the basal inhibition modulates CR expression, the conditioned stimulus-activated inhibition is required for the proper timing of the CR. In addition, complete blockade of cerebellar deep nuclear GABA(A)Rs prevents CR acquisition. Together, these results suggest that different aspects of the memories for eyeblink CRs are encoded in the cerebellar cortex and the cerebellar deep nuclei.

The effect of rubrospinal tractotomy on a conditioned limb response in the cat

Five cats were trained to perform a forelimb conditioned response to a paired tone CS/shock UCS. Rubrospinal tract section ipsilateral to the trained limb was carried out following criterion CR performance. Lesion sites were identified histologically and further confirmed by observation of cellular changes in the red nucleus contralateral to the trained limb. Tractotomy resulted in total or near-total loss of the CR. Prolonged postoperative training resulted in no increase in CR performance levels. The UCR remained unaffected, as did limb placing, accuracy of striking at moving objects, grooming, running and walking. Training of the opposite limb in two subjects resulted in mean scores of 90 and 85% within three sessions. Control lesions in those subjects resulted in no changes in CR performance scores. The red nucleus receives a substantial input from sensorimotor cortex and cerebellum, both of which have been shown to represent essential parts of the brain circuitry involved in associative learning and memory. Since pyramidotomy has no effect on limb CR performance [Vonedia TJ. Exp Neurol 1976;19:483–493], the possible role of the red nucleus/rubrospinal tract is discussed in terms of a critical trigger area for the expression of a learned motor response.

Loss of Lever Press-Related Firing of Rat Striatal Forelimb Neurons after Repeated Sessions in a Lever Pressing Task

Lateral striatal neurons that fire phasically in relation to active movement of the contralateral forelimb (determined via daily sensorimotor examination) were studied during acquisition of cued lever pressing. Rats were trained to lift the contralateral forepaw from the floor to press a lever in the presence of a tone. The tone was presented 70 times per day (session) for 18 consecutive days. All animals acquired the task, evidenced by gradual improvements across sessions and eventual asymptotic levels in tone discrimination, reaction time, and efficiency of the lever press. Forelimb neurons fired in relation to the lever press during early sessions of acquisition but not after repeated sessions on the task. This difference in firing could not be attributed to differences in forelimb movements during lever pressing or to sampling from different populations of neurons in early versus late sessions. In view of evidence that striatal damage impairs acquisition of motor skills, the change in firing suggests that the striatal activity present in early sessions may be necessary for the acquisition of, but not the automatic performance of, learned motor responses.

Cerebellar guidance of premotor network development and sensorimotor learning.

Single unit and imaging studies have shown that the cerebellum is especially active during the acquisition phase of certain motor and cognitive tasks. These data are consistent with the hypothesis that particular sensorimotor procedures are acquired and stored in the cerebellar cortex and that this knowledge can then be exported to the cerebral cortex and premotor networks for more efficient execution. In this article we present a model to illustrate how the cerebellar cortex might guide the development of cortical-cerebellar network connections and how a similar mechanism operating in the adult could mediate the exportation of sensorimotor knowledge from the cerebellum to the motor cortex. The model consists of a three-layered recurrent network representing the cerebello-thalamocortical-ponto-cerebellar limb premotor network. The cerebellar cortex is not explicitly modeled. Our simulations show that Hebbian learning combined with weight normalization allows the emergence of reciprocal and modular structure in the limb premotor network. Reciprocal connections allow activity to reverberate around specific loops. Modularity organizes the connections into specific channels. Furthermore, we show that cerebellar learning can be exported to motor cortex through these modular and reciprocal premotor circuits. In particular, we simulate developmental alignment of visuomotor relations and their realignment as a consequence of prism exposure. The exportation of sensorimotor knowledge from the cerebellum to the motor cortex may allow faster and more efficient execution of learned motor responses.

Response Biases: Tonic Neck Response and Aftercontraction Phenomenon

Abstract In the present experiments, an attempt was made to document possible response biases resulting from changes in head position and to determine if this source of bias is additive or interactive in its influence on learned motor responses when paired with response biases arising from the aftercontraction phenomenon (Shea, Shebilske, Kohl, & Guadagnoli, 1991). The results of Experiments 1 and 2 indicated that the influence of head position on response biases was dependent on head position during acquisition and on the direction in which the head was turned with respect to the flexors and extensors involved in the movement; the magnitude of the effect tended to increase as the force of the contraction increased. In Experiment 3, increases in the intensity of a prior contraction were reflected in the magnitude of the response bias and changes in head position were reflected in corresponding changes in response biases. These findings are consistent with the influence of the aftercontraction phenomenon a...

Participation of the nigro-striatal and mesolimbic dopaminergic systems of the brain in the control of components of learned motor responses in dogs

We studied the role of the striatal and limbic dopaminergic systems in the regulation of instrumentally conditioned avoidance behavior and postural adjustment in chronic experiments on dogs. Dopamine in doses of 3 micrograms was introduced bilaterally into the caudate nucleus head and the nucleus accumbens of the forebrain through implanted cannuli. Predominantly unidirectional effects were demonstrated, but a clear acceleration of the initiations of both conditioned-reflex postural adjustment and voluntary movement were obtained from the caudate nucleus; there was a marked degree of expressiveness to this movement. The greatest effects were obtained during simultaneous, bilateral introduction of dopamine into both structures in dogs with an akinetic form of motor pathology. We conclude that the integration of the striatal and limbic dopaminergic systems is of critical necessity for the initiation and regulation of the components of voluntary movement.