Highlights d Proteogenomics characterization of 218 pediatric brain tumor samples of 7 histologies d Proteomic clusters reveal actionable biological features spanning histological boundaries d Proteomics reveal downstream effects of DNA alterations not evident in transcriptomics d Kinase activity analyses provide insights into pathway activities and druggable targets

Primary somatosensory cortex (S1) receives two distinct classes of thalamocortical input via the lemniscal and paralemniscal pathways, the former via ventral posterior medial nucleus (VPM), and the latter, from the posterior medial nucleus (POm). These projections have been described as parallel thalamocortical pathways. Although the VPM thalamocortical projection has been studied in depth, several details of the POm projection to S1 are unknown. We studied the synaptic properties and anatomical features in the mouse of the projection from POm to all layers of S1 and to layer 4 of secondary somatosensory cortex (S2). Neurons in S1 responded to stimulation of POm with what has been termed Class 2 properties (paired-pulse facilitation, small initial excitatory postsynaptic potentials (EPSPs), a graded activation profile, and a metabotropic receptor component; thought to be modulatory), whereas neurons in layer 4 of S2 responded with Class 1A properties (paired-pulse depression, large initial EPSPs, an all-or-none activation profile, and no metabotropic receptor component, thought to be a main information input). Also, labeling from POm produced small boutons in S1, whereas both small and large boutons were found in S2. Our data suggest that the lemniscal and paralemniscal projections should not be thought of as parallel information pathways to S1 and that the paralemniscal projection may instead provide modulatory inputs to S1. driver | modulator | glutamatergic | barrel cortex | synapse P rimary somatosensory (also barrel or S1) cortex in rodents receives two distinct types of input from thalamus that are thought to convey different types of sensory information (1, 2). The lemniscal projection is relayed through the ventral posterior medial nucleus (VPM), whereas the paralemniscal projection is routed through posterior medial nucleus (POm) (3, 4). These projections are not only separated in thalamus, but remain largely segregated across cortical layers and in barrels and septa (3-8).The synaptic properties of the VPM or lemniscal projection to S1 have been described (9-12). VPM inputs to layer 4 and the subgranular layers have Class 1* (or driver) properties, suggesting that they are main information routes, whereas the projections to layers 2/3 have predominantly Class 2 properties, suggesting a modulatory rather than information-bearing function. If the paralemniscal projection to S1 is a parallel information route (3, 4), the prediction is that the synaptic properties of this pathway should be largely or exclusively Class 1A (for detailed explanation of classification terms, see refs. 11-13). POm is known to provide Class 1A input to layer 4 of secondary somatosensory cortex (S2) (10), but the POm projection to S1 has yet to be described. We thus studied the properties of the POm thalamocortical projection and found that the POm projection to S1 is entirely Class 2 in nature, suggesting that it provides modulatory inputs to S1 rather than functioning as a parallel information pathway. ResultsGlutamate Uncaging...

We studied the synaptic profile of thalamic inputs to cells in layers 2/3 and 4 of primary somatosensory (S1) and auditory (A1) cortices using thalamocortical slices from mice age postnatal days 10-18. Stimulation of the ventral posterior medial nucleus (VPM) or ventral division of the medial geniculate body (MGBv) resulted in two distinct classes of responses. The response of all layer 4 cells and a minority of layers 2/3 cells to thalamic stimulation was Class 1, including paired-pulse depression, all-or-none responses, and the absence of a metabotropic component. On the other hand, the majority of neurons in layers 2/3 showed a markedly different, Class 2 response to thalamic stimulation: paired-pulse facilitation, graded responses, and a metabotropic component. The Class 1 and Class 2 response characteristics have been previously seen in inputs to thalamus and have been described as drivers and modulators, respectively. Driver input constitutes a main information bearing pathway and determines the receptive field properties of the postsynaptic neuron, whereas modulator input influences the response properties of the postsynaptic neuron but is not a primary information bearing input. Because these thalamocortical projections have comparable properties to the drivers and modulators in thalamus, we suggest that a driver/modulator distinction may also apply to thalamocortical projections. In addition, our data suggest that thalamus is likely to be more than just a simple relay of information and may be directly modulating cortex.

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