Convergence of inputs from the basal ganglia with layer 5 of motor cortex and cerebellum in mouse motor thalamus
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eLife assessment
This investigation marks an important advancement in our understanding of motor thalamus connectivity, illustrating a complex integration of inputs that reshapes previous models. The study utilizes compelling methodologies that expose a dynamic synaptic network, although the evidence of triple-input convergence on individual neurons and for multiple driver type inputs onto motor thalamic neurons remains incomplete. Despite this, the findings provide a persuasive rationale for revisiting our perceptions of the thalamic role in motor control, with a call for further studies to substantiate the breadth of these functional interactions.
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Abstract
A key to motor control is the motor thalamus, where several inputs converge. One excitatory input originates from layer 5 of primary motor cortex (M1 L5 ), while another arises from the deep cerebellar nuclei (Cb). M1 L5 terminals distribute throughout the motor thalamus and overlap with GABAergic inputs from the basal ganglia output nuclei, the internal segment of the globus pallidus (GPi), and substantia nigra pars reticulata (SNr). In contrast, it is thought that Cb and basal ganglia inputs are segregated. Therefore, we hypothesized that one potential function of the GABAergic inputs from basal ganglia is to selectively inhibit, or gate, excitatory signals from M1 L5 in the motor thalamus. Here, we tested this possibility and determined the circuit organization of mouse (both sexes) motor thalamus using an optogenetic strategy in acute slices. First, we demonstrated the presence of a feedforward transthalamic pathway from M1 L5 through motor thalamus. Importantly, we discovered that GABAergic inputs from the GPi and SNr converge onto single motor thalamic cells with excitatory synapses from M1 L5 . Separately, we also demonstrate that, perhaps unexpectedly, GABAergic GPi and SNr inputs converge with those from the Cb. We interpret these results to indicate that a role of the basal ganglia is to gate the thalamic transmission of M1 L5 and Cb information to cortex.
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eLife assessment
This investigation marks an important advancement in our understanding of motor thalamus connectivity, illustrating a complex integration of inputs that reshapes previous models. The study utilizes compelling methodologies that expose a dynamic synaptic network, although the evidence of triple-input convergence on individual neurons and for multiple driver type inputs onto motor thalamic neurons remains incomplete. Despite this, the findings provide a persuasive rationale for revisiting our perceptions of the thalamic role in motor control, with a call for further studies to substantiate the breadth of these functional interactions.
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Reviewer #1 (Public Review):
The manuscript demonstrates an analysis of the synaptic organization within the motor thalamus, emphasizing the interplay between the ventrolateral (VL) and ventroanterior (VA) nuclei and their respective inputs. The primary aim is to unravel the complexities of synaptic interactions among the motor cortex's layer 5 (M1L5), the cerebellum (Cb), and the basal ganglia output nuclei (GPi and SNr), which converge upon the VA/VL nuclei of the motor thalamus. This examination is executed using a combination of anatomical tracing, optogenetics, and electrophysiological recordings in mouse brain slices, which together yield novel insights into the motor control circuitry.
The study uncovers that contrary to traditional models that presumed segregation, some motor thalamic neurons simultaneously integrate inputs from …
Reviewer #1 (Public Review):
The manuscript demonstrates an analysis of the synaptic organization within the motor thalamus, emphasizing the interplay between the ventrolateral (VL) and ventroanterior (VA) nuclei and their respective inputs. The primary aim is to unravel the complexities of synaptic interactions among the motor cortex's layer 5 (M1L5), the cerebellum (Cb), and the basal ganglia output nuclei (GPi and SNr), which converge upon the VA/VL nuclei of the motor thalamus. This examination is executed using a combination of anatomical tracing, optogenetics, and electrophysiological recordings in mouse brain slices, which together yield novel insights into the motor control circuitry.
The study uncovers that contrary to traditional models that presumed segregation, some motor thalamic neurons simultaneously integrate inputs from the cerebellum and basal ganglia. Furthermore, a subset of these neurons also receive convergent inputs from M1L5 and basal ganglia, underscoring the complexity of these synaptic networks. Notably, the study reveals that both M1L5 and Cb inputs exhibit driver-type synaptic properties, suggesting a significant impact on thalamic relay neurons.
The functional implications of this synaptic convergence suggest a complex gating mechanism by the inhibitory outputs of the basal ganglia, which could modulate information flow within the motor thalamus. This modulation is significant not only for transthalamic information processing but also for the integration of cerebellar inputs to the motor cortex. The study also highlights direct projections from M1L5 to the motor thalamus, indicating a potential direct influence on thalamic activity, in addition to the known indirect influence through the cortico-basal ganglia-thalamo-cortical loop.
The manuscript suggests that the traditional understanding of motor thalamic connectivity requires reconsideration, and it emphasizes the necessity of further investigation to understand fully the functional implications of this synaptic convergence. Future research may focus on more direct demonstrations of triple-input convergence and its behavioral consequences, as well as cross-species comparative studies to enhance the findings' applicability.
While the study provides valuable contributions to our knowledge of the motor thalamus, illuminating the intricate synaptic architecture of the motor thalamus and setting the stage for future explorations that will deepen our comprehension of motor control and thalamic function.
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Reviewer #2 (Public Review):
This study assesses how inputs from primary motor cortex layer 5 (M1L5), basal ganglia output nuclei (GPi and SNr), and cerebellum (Cb) converge onto motor thalamus nuclei (VA/VL).
Methodology includes anatomical tracing, optogenetics and electrophysiological recordings in mouse brain slices.
The major findings are:
- Some motor thalamic neurons receive input from both cerebellar and basal ganglia. This is contrary to the common belief that assumes these two inputs are segregated in the motor thalamus.- Some motor thalamus neurons receive converging input from both motor cortex (M1L5) and basal ganglia.
- Both M1L5 and Cb inputs to the motor thalamus have driver-type synaptic properties, indicating a strong influence on thalamic relay neurons.
Functional implications are:
- Given the inhibitory nature of …Reviewer #2 (Public Review):
This study assesses how inputs from primary motor cortex layer 5 (M1L5), basal ganglia output nuclei (GPi and SNr), and cerebellum (Cb) converge onto motor thalamus nuclei (VA/VL).
Methodology includes anatomical tracing, optogenetics and electrophysiological recordings in mouse brain slices.
The major findings are:
- Some motor thalamic neurons receive input from both cerebellar and basal ganglia. This is contrary to the common belief that assumes these two inputs are segregated in the motor thalamus.- Some motor thalamus neurons receive converging input from both motor cortex (M1L5) and basal ganglia.
- Both M1L5 and Cb inputs to the motor thalamus have driver-type synaptic properties, indicating a strong influence on thalamic relay neurons.
Functional implications are:
- Given the inhibitory nature of basal ganglia output neurons, the converging inputs can allow for basal ganglia to gate information flow through the motor thalamus. This applies to transthalamic information, ie information conveyed through the thalamus across cortical regions, as well as cerebellar information flow to motor cortex.- The direct projection from M1L5 to motor thalamus suggests that motor cortex can affect motor thalamic activity not only indirectly, through the traditional cortico-basal ganglia-thalamo-cortical loop, but also through direct projections.
The study is convincing and has important implications for the field. Methodology involves elegant viral techniques.
The main weakness is that there is no direct functional demonstration of all the 3 inputs from motor cortex, cerebellum, and basal ganglia, converging onto the same cells in motor thalamus. All the recordings concern dual area stimulations, and the anatomical studies show a very small overlap of all the 3 inputs onto motor thalamus.
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