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Thalamic input to motor cortex facilitates goal-directed action initiation.

ABSTRACT: Prompt execution of planned motor action is essential for survival. The interactions between frontal cortical circuits and the basal ganglia are central to goal-oriented action selection and initiation.^1-4 In rodents, the ventromedial thalamic nucleus (VM) is one of the critical nodes that conveys the output of the basal ganglia to the frontal cortical areas including the anterior lateral motor cortex (ALM).^5-9 Recent studies showed the critical role of ALM and its interplay with the motor thalamus in preparing sensory-cued rewarded movements, specifically licking.^10-12 Work in primates suggests that the basal ganglia output to the motor thalamus transmits an urgency or vigor signal,^13-15 which leads to shortened reaction times and faster movement initiation. As yet, little is known about what signals are transmitted from the motor thalamus to the cortex during cued movements and how these signals contribute to movement initiation. In the present study, we employed a tactile-cued licking task in mice while monitoring reaction times of the initial lick. We found that inactivation of ALM delayed the initiation of cued licking. Two-photon Ca²⁺ imaging of VM axons revealed that the majority of the axon terminals in ALM were transiently active during licking. Their activity was predictive of the time of the first lick. Chemogenetic and optogenetic manipulation of VM axons in ALM indicated that VM inputs facilitate the initiation of cue-triggered and impulsive licking in trained mice. Our results suggest that VM thalamocortical inputs increase the probability and vigor of initiating planned motor responses.

SUBMITTER: Takahashi N

PROVIDER: S-EPMC8478854 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The prelimbic prefrontal cortex (PL) has consistently been found to be necessary for the acquisition of goal-directed actions in rodents. Nevertheless, the specific cellular processes underlying this learning remain unknown. We assessed changes in learning-related expression of mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK1/2) phosphorylation (pERK) in layers 2-3 and 5-6 of the anterior and posterior PL and in the population of neurons projecting to posterior dorsomedial striatum (pDMS), also implicated in goal-directed learning. Rats were given either a single session of training to press a lever for a pellet reward or yoked reward deliveries without instrumental training and assessed 5 or 60 min after training for pERK expression. Relative to yoked training, instrumental training produced an increase in pERK expression in all regions of the PL both at 5 and 60 min, and this was accompanied by an increase in nuclear pERK expression in the posterior PL in rats given instrumental training. pDMS-projecting neurons showed a transient increase in pERK expression in posterior layer 5-6 projection neurons after 5 min, and a delayed increase in anterior layer 2-3 neurons after 60 min, suggesting that ERK expression in the PL is necessary for the consolidation of goal-directed learning. Consistent with this claim, we found that rats trained on two lever press actions for distinct outcomes and then infused with the MEK inhibitor PD98059 into the PL immediately after training failed to acquire specific action-outcome associations, suggesting that persistent pERK signaling in the PL is necessary for goal-directed learning.Significance statementThe prelimbic cortex is implicated in goal-directed learning in rodents; however, it is unclear whether it is involved in the consolidation of this learning, and what cellular processes are involved. We used pERK as a marker of activity-related synaptic plasticity to assess learning-induced changes in distinct layers and neuronal populations of the prelimbic prefrontal cortex (PL). Training produced long-lasting upregulation of pERK throughout the PL and specifically within neurons that project to the pDMS, another region critical for goal-directed learning. Next, we demonstrated that pERK signaling in the PL was necessary for the consolidation of goal-directed learning. Together, these results indicate that instrumental training induces ERK signaling in distinct layers and populations in the PL and this signaling underlies the consolidation of goal-directed learning.

Project description:The traditional classification of primary motor cortex (M1) as an agranular area has been challenged recently when a functional layer 4 (L4) was reported in M1. L4 is the principal target for thalamic input in sensory areas, which raises the question of how thalamocortical synapses formed in M1 in the mouse compare with those in neighboring sensory cortex (S1). We identified thalamic boutons by their immunoreactivity for the vesicular glutamate transporter 2 (VGluT2) and performed unbiased disector counts from electron micrographs. We discovered that the thalamus contributed proportionately only half as many synapses to the local circuitry of L4 in M1 compared with S1. Furthermore, thalamic boutons in M1 targeted spiny dendrites exclusively, whereas ∼9% of synapses were formed with dendrites of smooth neurons in S1. VGluT2+ boutons in M1 were smaller and formed fewer synapses per bouton on average (1.3 vs 2.1) than those in S1, but VGluT2+ synapses in M1 were larger than in S1 (median postsynaptic density areas of 0.064 μm2 vs 0.042 μm2). In M1 and S1, thalamic synapses formed only a small fraction (12.1% and 17.2%, respectively) of all of the asymmetric synapses in L4. The functional role of the thalamic input to L4 in M1 has largely been neglected, but our data suggest that, as in S1, the thalamic input is amplified by the recurrent excitatory connections of the L4 circuits. The lack of direct thalamic input to inhibitory neurons in M1 may indicate temporal differences in the inhibitory gating in L4 of M1 versus S1.SIGNIFICANCE STATEMENT Classical interpretations of the function of primary motor cortex (M1) emphasize its lack of the granular layer 4 (L4) typical of sensory cortices. However, we show here that, like sensory cortex (S1), mouse M1 also has the canonical circuit motif of a core thalamic input to the middle cortical layer and that thalamocortical synapses form a small fraction (M1: 12%; S1: 17%) of all asymmetric synapses in L4 of both areas. Amplification of thalamic input by recurrent local circuits is thus likely to be a significant mechanism in both areas. Unlike M1, where thalamocortical boutons typically form a single synapse, thalamocortical boutons in S1 usually formed multiple synapses, which means they can be identified with high probability in the electron microscope without specific labeling.

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Thalamic input to motor cortex facilitates goal-directed action initiation.

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