Trends in Neurosciences
Volume 36, Issue 12, December 2013, Pages 695-705
Journal home page for Trends in Neurosciences

Opinion
Basal ganglia output to the thalamus: still a paradox

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Highlights

  • We review disinhibition, rebound, and entrainment modes of basal ganglia output.

  • We propose a unifying framework for three types of basal ganglia–thalamic transmission.

  • We propose a resolution to the paradox of pallidothalamic coactivation.

  • Excitatory inputs to the thalamus determine the mode of the thalamic firing.

  • Pallidal interspike intervals are discrete units of basal ganglia output.

The basal ganglia (BG)-recipient thalamus controls motor output but it remains unclear how its activity is regulated. Several studies report that thalamic activation occurs via disinhibition during pauses in the firing of inhibitory pallidal inputs from the BG. Other studies indicate that thalamic spiking is triggered by pallidal inputs via post-inhibitory ‘rebound’ calcium spikes. Finally excitatory cortical inputs can drive thalamic activity, which becomes entrained, or time-locked, to pallidal spikes. We present a unifying framework where these seemingly distinct results arise from a continuum of thalamic firing ‘modes’ controlled by excitatory inputs. We provide a mechanistic explanation for paradoxical pallidothalamic coactivations observed during behavior that raises new questions about what information is integrated in the thalamus to control behavior.

Introduction

The BG integrates information from a wide array of cortical, thalamic, and brainstem inputs, and subsequently influences motor circuits through two major output pathways – a direct projection to brainstem circuitry and a distinct projection to several nuclei in the motor thalamus 1, 2, 3. Motor thalamus in turn projects widely to frontal and motor cortical areas (Figure 1A) 4, 5. Although much progress has been made in understanding how the BG may influence actions through the projection to behavior-generating circuits in the brainstem 6, 7, 8, less is known about how the BG influences motor behavior and learning through the thalamocortical output pathway 9, 10.

The BG–thalamic circuit is evolutionarily conserved 11, 12 (Figure 1). Across a wide range of behavioral paradigms and mammalian model systems, thalamic lesions cause severe deficits in motor initiation, control, and learning 13, 14, 15, 16, 17. Furthermore, most thalamic neurons exhibit behavior-locked firing patterns, including brisk peaks in activity immediately before movement onsets (Figure 2B) 18, 19, 20, 21, 22. We have recently found similar results in songbirds. Lesions of a song-related thalamic nucleus (DLM, dorsolateral nucleus of the anterior thalamus) abolish exploratory vocalizations (babbling) and learning in juvenile birds [23]. Furthermore, DLM neurons exhibit pronounced peaks in firing immediately before syllable onsets during vocal babbling (Figure 2B) [24]. Together, these findings support the idea that the BG-recipient thalamus plays a crucial role in activating motor cortical areas that generate movement or – in the songbird – that generate exploratory vocal gestures.

Here we aim to clarify how the thalamus integrates inhibitory inputs from the BG and excitatory inputs from cortex. First, we briefly review what may have been considered three mutually exclusive perspectives of BG–thalamic transmission: disinhibition, rebound, and entrainment. Next, we highlight recent mathematical simulations showing that rebound, disinhibition, and entrainment are not actually incompatible aspects of thalamic function. Instead, they arise from distinct firing states, or ‘modes’ of operation of the thalamic neuron. We use the term ‘mode’ to indicate a case where a single neuron can exhibit distinct firing patterns depending on conditions [25], and we suggest that neurons in the BG-recipient thalamus operate in rebound, gating, or entrainment mode depending on their excitability. Excitability in turn could be controlled by the level of activation provided by neuromodulatory or cortical inputs. Finally, we synthesize recent findings from songbird, rodent, and primate model systems – all of which point to the BG as a site where context, reward, and motor signals are integrated to produce learning. Notably, we highlight that, to our knowledge, none of these model systems has identified a role for the corticothalamic projection in these functions, and we propose testable hypotheses for future studies.

Section snippets

BG–thalamic disinhibition and gating

What are the origins of thalamic premotor signals? One simple but enduring idea is based on the observation that BG output neurons in the internal segment of the pallidum (internal globus pallidus, GPi) and the substantia nigra pars reticulata (SNr) are GABAergic and tonically active, and they exert powerful inhibition of thalamic activity 26, 27, 28. This inhibition is thought to suppress thalamic firing, thereby preventing movement initiation 29, 30, 31. (For simplicity, we will lump GPi and

The rebound mechanism

The best way to understand the relation between thalamic activity and its pallidal inputs is to record simultaneously from a thalamic neuron and its presynaptic pallidal input. This was first accomplished in anesthetized songbirds, where simultaneous pallidothalamic recordings are possible because each thalamic neuron is innervated by a single pallidal axon terminal large enough to be recorded extracellularly [64]. Thus, both pallidal axon and thalamic somatic spikes can be observed at the end

Cortical activation of BG-recipient thalamus

In the rebound model, thalamic premotor signals are primarily patterned by pallidal inputs. In contrast to this prediction, however, thalamic onset signals during primate reaching [69] and during songbird vocal babbling [24] persist after ablation of pallidal inputs, suggesting that non-pallidal inputs may be sufficient to drive thalamic premotor activity (Figure 2D). Songbirds, as in mammals, have a direct cortical projection to the BG-recipient thalamus 70, 71, and we hypothesized that this

High-frequency entrainment of thalamic neurons by BG outputs

How does this coactivation occur? Why don’t pallidal inputs suppress thalamic spiking more effectively? Do pallidal inputs really produce an effective inhibition of thalamic neurons, or do they contribute to increased thalamic spiking, perhaps by the post-inhibitory rebound mechanism observed in anesthetized birds? Close examination of the connected pallidal and thalamic spike trains recorded in singing birds answered these questions, ruled out the rebound mechanism, and revealed several novel

Five open questions of BG–thalamic function

First, by what mechanisms do pallidal and corticothalamic neurons exhibit similar movement-locked firing patterns? One possibility is that the cortical regions that directly activate the thalamus also indirectly inhibit the thalamus by activating BG outputs. For example, in the song system, HVC (used as a proper name; formerly high vocal center) and LMAN (lateral part of the magnocellular nucleus of anterior nidopallium) are two cortical premotor nuclei that also exhibit syllable-locked firing,

Acknowledgments

Funding to M.S.F. was provided by the National Institutes of Health (NIH; grant R01DC009183). Funding to J.H.G. was provided by the NIH (grant K99NS067062) and Charles King Trust and Damon Runyon Research Foundation post-doctoral fellowships, and to M.A.F by the NIH (grant NS047985).

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    Current address: Department of Neurobiology and Behavior, Cornell University, Ithaca, NY, USA.

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