Probes for INS

The motor cortico-basal ganglion loop is critical for motor planning, execution, and learning. Balanced excitation and inhibition in this loop is crucial for proper motor output. Excitatory neurons have been thought to be the only source of motor cortical input to the striatum. Here, we identify long-range projecting GABAergic neurons in the primary (M1) and secondary (M2) motor cortex that target the dorsal striatum. This population of projecting GABAergic neurons comprises both somatostatin-positive (SOM+) and parvalbumin-positive (PV+) neurons that target direct and indirect pathway striatal output neurons as well as cholinergic interneurons differentially. Notably, optogenetic stimulation of M1 PV+ and M2 SOM+ projecting neurons reduced locomotion, whereas stimulation of M1 SOM+ projecting neurons enhanced locomotion. Thus, corticostriatal GABAergic projections modulate striatal output and motor activity.

During birth in mammals, a pronounced surge of fetal peripheral stress hormones takes place to promote survival in the transition to the extrauterine environment. However, it is not known whether the hormonal signaling involves central pathways with direct protective effects on the perinatal brain. Here, we show that arginine vasopressin specifically activates interneurons to suppress spontaneous network events in the perinatal hippocampus. Experiments done on the altricial rat and precocial guinea pig neonate demonstrated that the effect of vasopressin is not dependent on the level of maturation (depolarizing vs. hyperpolarizing) of postsynaptic GABAA receptor actions. Thus, the fetal mammalian brain is equipped with an evolutionarily conserved mechanism well-suited to suppress energetically expensive correlated network events under conditions of reduced oxygen supply at birth.

The dorsal horn of the spinal cord is critical to processing distinct modalities of noxious and innocuous sensation, but little is known of the neuronal subtypes involved, hampering efforts to deduce principles governing somatic sensation. Here we used single-cell RNA sequencing to classify sensory neurons in the mouse dorsal horn. We identified 15 inhibitory and 15 excitatory molecular subtypes of neurons, equaling the complexity in cerebral cortex. Validating our classification scheme in vivo and matching cell types to anatomy of the dorsal horn by spatial transcriptomics reveals laminar enrichment for each of the cell types. Neuron types, when combined, define a multilayered organization with like neurons layered together. Employing our scheme, we find that heat and cold stimuli activate discrete sets of both excitatory and inhibitory neuron types. This work provides a systematic and comprehensive molecular classification of spinal cord sensory neurons, enabling functional interrogation of sensory processing.

Immune recognition of tumor-expressed antigens by cytotoxic CD8+ T cells is the foundation of adoptive T cell therapy (ACT) and has been shown to elicit significant tumor regression. However, therapy-induced selective pressure can sculpt the antigenicity of tumors, resulting in outgrowth of variants that lose the target antigen. We demonstrate that tumor relapse from ACT and subsequent oncolytic viral vaccination can be prevented using class I HDACi, MS-275. Drug delivery subverted the phenotype of tumor-infiltrating CD11b+ Ly6Chi Ly6G- myeloid cells, favoring NOS2/ROS secretion and pro-inflammatory genes characteristic of M1 polarization. Simultaneously, MS-275 abrogated the immunosuppressive function of tumor-infiltrating myeloid cells and reprogrammed them to eliminate antigen-negative tumor cells in a caspase-dependent manner. Elevated IFN-γ within the tumor microenvironment suggests that MS-275 modulates the local cytokine landscape to favor antitumor myeloid polarization through the IFN-γR/STAT1 signaling axis. Exploiting tumor-infiltrating myeloid cell plasticity thus complements T cell therapy in targeting tumor heterogeneity and immune escape.