Scientific Understanding of Consciousness
Frontal Thalamocortical Loop Persistent Activity
Nature 545, 181–186 (11 May 2017)
Maintenance of persistent activity in a frontal thalamocortical loop
Zengcai V. Guo, et.al.
School of Medicine, Tsinghua University, Beijing 100084, China.
Janelia Research Campus, HHMI, Ashburn, Virginia 20147, USA
Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, Maryland 20892, USA
Persistent neural activity maintains information that connects past and future events. Models of persistent activity often invoke reverberations within local cortical circuits, but long-range circuits could also contribute. Neurons in the mouse anterior lateral motor cortex (ALM) have been shown to have selective persistent activity that instructs future actions. The ALM is connected bidirectionally with parts of the thalamus, including the ventral medial and ventral anterior–lateral nuclei. We recorded spikes from the ALM and thalamus during tactile discrimination with a delayed directional response. Here we show that, similar to ALM neurons, thalamic neurons exhibited selective persistent delay activity that predicted movement direction. Unilateral photoinhibition of delay activity in the ALM or thalamus produced contralesional neglect. Photoinhibition of the thalamus caused a short-latency and near-complete collapse of ALM activity. Similarly, photoinhibition of the ALM diminished thalamic activity. Our results show that the thalamus is a circuit hub in motor preparation and suggest that persistent activity requires reciprocal excitation across multiple brain areas.
Short-term memory is represented by changes in spike rates that are maintained internally, in the absence of sustained sensory input. Neurons in the frontal cortex show persistent activity related to different types of short-term memory. Motor preparation is a particular short-term memory that links past events and anticipation of future movements. Motor preparation has been studied extensively using delayed-response tasks, in which a sensory stimulus instructs a future action. During the delay epoch, neurons in the motor cortex and related structures show persistent and ramping activity related to specific movements, long before movement onset. We refer here to persistent activity during the delay epoch as ‘preparatory activity’
Individual neurons have time constants on the order of ten milliseconds. Persistent activity over seconds is therefore an emergent property of neural circuits, which probably involves positive feedback. Circuit models of cortical persistent activity often invoke reverberations within local circuits mediated by excitatory connections. However, persistent activity could also arise from multi-regional interactions. Frontal and parietal cortical areas, together with associated thalamic nuclei, form a network and show persistent activity during memory-guided tasks. Identifying the essential anatomical substrates for persistent activity is necessary to understand the neural mechanisms underlying short-term memory.
A large fraction of mouse ALM neurons exhibit direction-selective persistent and ramping preparatory activity in a directional licking task. Preparatory activity is distributed across both ALM hemispheres, similar to human premotor cortex. Three types of manipulation experiments have shown that ALM preparatory activity instructs directed licking in a tactile delayed-response task. First, unilateral inactivation of ALM during motor preparation impairs upcoming movements in the contralateral direction. Second, brief unilateral activation of ALM pyramidal tract neurons has persistent effects on ALM population activity and biases the direction of future movements towards the contralateral direction. Third, brief bilateral inactivation destroys selectivity of preparatory activity on average and randomizes future movements; but on a trial-by-trial basis movement direction can still be predicted on the basis of ALM population activity. Preparatory activity in one hemisphere remains largely unchanged after perturbation of the other hemisphere, implying that ALM hemispheres can maintain preparatory activity independently. Here we report that the maintenance of persistent activity in the ALM requires direct excitation from the thalamus and vice versa, revealing that the thalamus is a key circuit node in motor preparation.
Mice performed a discrimination task with a delayed response.In each trial, mice judged the location of an object with their whiskers. During the subsequent delay epoch (1.2 or 1.3 s), mice maintained a memory of the previous sensory experience and planned an upcoming response. Following an auditory ‘go’ cue, mice reported object location with directional licking (left or right, mean per cent correct 77.6%; lick-early before ‘go’ cue 10.3%, no response 1.1%).
Local recurrent connectivity is often invoked as a mechanism for persistent activity. Our results show that persistent preparatory activity cannot be sustained by recurrent excitation within cortical circuits alone, but in addition require recurrent excitation through a thalamocortical loop. Inactivation of the thalALM resulted in strong hyperpolarization of ALM neurons. The mechanisms underlying this powerful driving influence of the thalALM on the ALM, compared to the influence of cortical areas, represent an important area for future investigation.
We further identify the frontal cortex (ALM) as a major source of driving excitation to the higher-order thalamus (thalALM ). The thalamus also receives input from the deep cerebellar nuclei, the superior colliculus and the SNr, and these subcortical structures in turn receive direct or indirect input from the ALM. The precise roles of these more complex loops during motor preparation and movement initiation remain to be elucidated. Thalamus may work as a hub to convey subcortical signals to the ALM.
Besides the VM/VAL, ALM interacts with the posterior, intralaminar and midline thalamic nuclei. These nuclei project axons widely across the cerebral cortex and have been implicated in attention, awareness, arousal, consciousness, memory, voluntary movements and other functions. Dissecting the distinct roles of these different nuclei will require manipulating specific nuclei using molecular methods. Given the widespread reciprocal connectivity between the frontal cortex and thalamus, persistent activity in cortical areas outside of the ALM in different behavioural contexts probably also depends on thalamocortical loops.
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