Motor thalamus integration of cortical, cerebellar and basal ganglia information: implications for normal and parkinsonian conditions

Abstract

Motor thalamus (Mthal) is implicated in the control of movement because it is strategically located between motor areas of the cerebral cortex and motor-related subcortical structures, such as the cerebellum and basal ganglia (BG). The role of BG and cerebellum in motor control has been extensively studied but how Mthal processes inputs from these two networks is unclear. Specifically, there is considerable debate about the role of BG inputs on Mthal activity. This review summarizes anatomical and physiological knowledge of the Mthal and its afferents and reviews current theories of Mthal function by discussing the impact of cortical, BG and cerebellar inputs on Mthal activity. One view is that Mthal activity in BG and cerebellar-receiving territories is primarily "driven" by glutamatergic inputs from the cortex or cerebellum, respectively, whereas BG inputs are modulatory and do not strongly determine Mthal activity. This theory is steeped in the assumption that the Mthal processes information in the same way as sensory thalamus, through interactions of modulatory inputs with a single driver input. Another view, from BG models, is that BG exert primary control on the BG-receiving Mthal so it effectively relays information from BG to cortex. We propose a new "super-integrator" theory where each Mthal territory processes multiple driver or driver-like inputs (cortex and BG, cortex and cerebellum), which are the result of considerable integrative processing. Thus, BG and cerebellar Mthal territories assimilate motivational and proprioceptive motor information previously integrated in cortico-BG and cortico-cerebellar networks, respectively, to develop sophisticated motor signals that are transmitted in parallel pathways to cortical areas for optimal generation of motor programmes. Finally, we briefly review the pathophysiological changes that occur in the BG in parkinsonism and generate testable hypotheses about how these may affect processing of inputs in the Mthal.

Keywords: LTS burst; Parkinson’s disease; basal ganglia; cerebellum; motor cortex; motor thalamus.

Figure 1

Synaptic organisation of cortical, BG and cerebellar afferents on Mthal neurons. Schematic diagram summarizing afferent inputs onto Mthal neurons (yellow) in BG-receiving (orange background) and cerebellum-receiving (purple background) territories. Afferents from the cerebral cortex (blue) innervate Mthal neurons in both BG (left) and cerebellar (right) receiving territories. Afferents from layer V of the cortex (large dark blue terminals) innervate somatic and perisomatic areas. Conversely, cortical layer VI afferents (small light blue terminals) innervate distal dendrites. In contrast, BG afferents (red terminals) innervate somatic and perisomatic areas of Mthal neurons, only in the BG receiving territory. The inset shows a multiple synapse formed by BG inputs. Cerebellar afferents (purple terminals) are located on primary dendrites of Mthal neurons in the cerebellar-receiving territory.

Figure 2

Cortical, BG and cerebellar connections with Mthal. Schematic diagram illustrates anatomical connections between the cerebral cortex, BG and cerebellum, and individual nuclei of the Mthal. Reciprocal connections between layer V of the cortex and Mthal nuclei are indicated by thick double-headed arrows, whereas thin arrows indicate modulator afferent inputs from layer VI of the cortex to Mthal nuclei. The ventromedial (VM) nucleus receives inputs from SNpr and associative areas of the cortex. Major inputs to the ventroanterior (VA) nucleus are from SNpr and premotor areas of the cortex, and minor inputs are from globus pallidus internus (GPi) and associative areas of the cortex. Major inputs to the anterior region of the ventrolateral nucleus (VLa) are from GPi and premotor cortex and to a lesser extent from the cerebellum. Primary inputs to the posterior region of the ventrolateral nucleus (VLp) nucleus are from the motor cortex and cerebellum, with a minor input from premotor cortex. The VLp nucleus receives inputs from collateral axons arising in layer V neurons in the primary motor cortex that descend the spinal cord. Note, (1) although some regions receive inputs from both BG and cerebellum, these two afferents do not overlap at the neuronal level and (2) that inputs from layer VI of one cortical region reach Mthal regions that are also innervated from layer V of another cortical region, allowing for integration of different cortical functions. The orange-purple color gradient represents the associative to motor continuum that exists in the cortex, BG, cerebellum and Mthal.

Figure 3

Mechanism of LTS bursts in thalamic neurons. (A) Membrane potential of a thalamic neuron recorded in current-clamp during and after injection of negative current (I Inj), which hyperpolarizes the membrane. There is a prominent sag associated with continued injection of the negative current. At the offset of the injected current, the membrane potential depolarizes and a short burst of action potentials is evoked. Note, to clearly illustrate the spikes in the LTS burst different time scales are used for the first hyperpolarization phase, prior to the dashed part of the trace (100 ms scale bar) and the spiking phase (20 ms scale bar). (B) Diagram represents the major conductances underlying the membrane potential changes shown in (A). The I_h cationic current is activated by hyperpolarization of the membrane potential, which depolarizes the membrane potential and is the current mainly responsible for the sag. When the neuron repolarizes after current injection, the I_T current is activated, which augments depolarization of the membrane potential. When the threshold for voltage-gated sodium channels is reached, action potentials occur and they are represented in (B) by the successive I_NA and I_K currents. Progressively, the I_T current is reduced, which favors activation of I_K currents and the neuron is repolarized to its resting membrane potential. (C) Conductances associated with inactivation (red) and activation (blue) gates of the T-type calcium channel underlying the I_T current. Once the membrane potential is hyperpolarized, the inactivation gate opens slowly. As the membrane potential depolarizes, the inactivation gate closes slowly and at the same time the activation gate is opened. When both gates are open, the I_T current occurs. Finally, the activation gate closes as the membrane potential returns to rest. (D) Illustration of a T-type calcium channel with its activation (blue) and inactivation (red) gates. Calcium ions are represented in yellow. The left example illustrates the configuration of the channel when the neuron is hyperpolarized. The middle and right examples illustrate the channel configuration when the I_T current occurs and when the neuron is at its resting membrane potential, respectively. a.u: arbitrary units.

Figure 4

Mthal acts as a “super integrator” of cognitive and proprioceptive information from the cortex, BG and cerebellum. In the model proposed here, pyramidal neurons in layer V of cortical motor areas send a copy of the developing motor programme (blue arrows) simultaneously to the BG, Mthal and cerebellum. The BG integrates motivational context through inputs from the dopaminergic system. The cerebellum integrates proprioceptive context by its innervation from the sensory spinal cord. The BG (orange pathway) and cerebellum (purple pathway) contribute these separately integrated inputs to BG (orange background) and cerebellar territories (purple background) of Mthal. Arrowheads from the cortex, BG and cerebellum to the Mthal are of equal size signifying that these inputs all strongly influence Mthal activity. Modulator inputs from layer VI of the cortex (thin blue arrow) are proposed to transfer information from cortex receiving particularly strong input from one Mthal area, back to the other Mthal area. The respective Mthal areas process all converging inputs (green zones) and forward a “super-integrated” signal back to the cortex (green arrows) for development of the motor programme. Dashed lines in the cerebral cortex separate superficial layers (top), from layers V (middle) and VI (bottom).