Abstract
Neuronal circuits of the spinal dorsal horn integrate sensory information from the periphery with inhibitory and facilitating input from higher central nervous system areas. Most previous work focused on projections descending from the hindbrain. Less is known about inputs descending from the cerebral cortex. Here, we identified cholecystokinin (CCK) positive layer 5 pyramidal neurons of the primary somatosensory cortex (CCK + S1-corticospinal tract [CST] neurons) as a major source of input to the spinal dorsal horn. We combined intersectional genetics and virus-mediated gene transfer to characterize CCK+ S1-CST neurons and to define their presynaptic input and postsynaptic target neurons. We found that S1-CST neurons constitute a heterogeneous population that can be subdivided into distinct molecular subgroups. Rabies-based retrograde tracing revealed monosynaptic input from layer 2/3 pyramidal neurons, from parvalbumin positive cortical interneurons, and from thalamic relay neurons in the ventral posterolateral nucleus. Wheat germ agglutinin-based anterograde tracing identified postsynaptic target neurons in dorsal horn laminae III and IV. About 60% of these neurons were inhibitory and about 60% of all spinal target neurons expressed the transcription factor c-Maf. The heterogeneous nature of both S1-CST neurons and their spinal targets suggest complex roles in the fine-tuning of sensory processing.
Highlights
In addition to the hindbrain, the cerebral cortex is a major source of descending input to the spinal cord (Lemon and Griffiths 2005; Abraira et al 2017; Wang et al 2017; Liu et al 2018; Ueno et al 2018)
corticospinal tract (CST) neurons are the subset of excitatory long-range pyramidal projection neurons in layer 5 of the somatosensory cortex that terminate in the dorsal spinal horn where they release glutamate as their fast neurotransmitter
We injected a rAAV2-retro encoding a Cre-dependent enhanced green fluorescent protein (AAV2-retro.flex.eGFP) into the spinal cord of these mice (Fig. 1A). This strategy uncovered a population of layer 5 pyramidal neurons in the primary somatosensory cortex that projects directly to the spinal dorsal horn (Fig. 1B and Supplementary Fig. 2A,B)
Summary
In addition to the hindbrain, the cerebral cortex is a major source of descending input to the spinal cord (Lemon and Griffiths 2005; Abraira et al 2017; Wang et al 2017; Liu et al 2018; Ueno et al 2018). The Emx or Thy1-H fluorescent reporter mice used in these studies label many neurons in addition to CST neurons (Bareyre et al 2005; Porrero et al 2010; Willenberg and Steward 2015; Zeisel et al 2015), and do not allow specific targeting of CST neurons for characterization and functional manipulation To this end, it will be crucial to restrict transgene expression to the layer 5 pyramidal neurons in an area of the cortex (S1 in this case) that projects to the spinal region of interest such as the dorsal horn. This approach permitted the expression of fluorescent or effector proteins in S1 cortical neurons that project directly to a predefined region of the spinal cord and allowed us to demonstrate that S1-CST neurons with terminations in the spinal dorsal horn constitute a heterogeneous population of neurons that receive monosynaptic input from forebrain sensory circuits and target dorsal horn interneurons known to be involved in the gating of somatosensory and nociceptive signals
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