Syndecan-1 induction in lung microenvironment supports the establishment of breast tumor metastases.

BACKGROUND: Syndecan-1 (Sdc1), a cell surface heparan sulfate proteoglycan normally expressed primarily by epithelia and plasma cells, is aberrantly induced in stromal fibroblasts of breast carcinomas. Stromal fibroblast-derived Sdc1 participates in paracrine growth stimulation of breast carcinoma cells and orchestrates stromal extracellular matrix fiber alignment, thereby creating a migration and invasion-permissive microenvironment. Here, we specifically tested the role of stromal Sdc1 in metastasis. METHODS: The metastatic potential of the aggressive mouse mammary carcinoma cell lines, 4T1 and E0776, was tested in wild-type and genetically Sdc1-deficient host animals. Metastatic lesions were characterized by immunohistochemical analysis. RESULTS: After orthotopic inoculation, the lung metastatic burden was reduced in Sdc1-/- animals by 97% and more than 99%, in BALB/cJ and C57BL/6 animals, respectively. The difference in metastatic efficiency was maintained when the tumor cells were injected into the tail vein, suggesting that host Sdc1 exerts its effect during later stages of the metastatic cascade. Co-localization studies identified Sdc1 expression in stromal fibroblasts within the metastatic microenvironment and in normal airway epithelial cells but not in other cells (endothelial cells, α-smooth muscle actin positive cells, leucocytes, macrophages). The Ki67 proliferation index and the rate of apoptosis of the metastatic tumor cells were diminished in Sdc1-/- vs. Sdc1+/+ animals, and leucocyte density was indistinguishable. Sdc1-mediated metastatic efficiency was abolished when the animals were housed at a thermoneutral ambient temperature of 31 °C, suggesting that the host Sdc1 effect on metastasis requires mild cold stress. CONCLUSIONS: In summary, Sdc1 is induced in the lung microenvironment after mammary carcinoma cell dissemination and promotes outgrowth of metastases in a temperature-dependent manner.

Entorhinal cortex glutamatergic and GABAergic projections bidirectionally control discrimination and generalization of hippocampal representations.

Discrimination and generalization are crucial brain-wide functions for memory and object recognition that utilize pattern separation and completion computations. Circuit mechanisms supporting these operations remain enigmatic. We show lateral entorhinal cortex glutamatergic (LEC GLU ) and GABAergic (LEC GABA ) projections are essential for object recognition memory. Silencing LEC GLU during in vivo two-photon imaging increased the population of active CA3 pyramidal cells but decreased activity rates, suggesting a sparse coding function through local inhibition. Silencing LEC GLU also decreased place cell remapping between different environments validating this circuit drives pattern separation and context discrimination. Optogenetic circuit mapping confirmed that LEC GLU drives dominant feedforward inhibition to prevent CA3 somatic and dendritic spikes. However, conjunctively active LEC GABA suppresses this local inhibition to disinhibit CA3 pyramidal neuron soma and selectively boost integrative output of LEC and CA3 recurrent network. LEC GABA thus promotes pattern completion and context generalization. Indeed, without this disinhibitory input, CA3 place maps show decreased similarity between contexts. Our findings provide circuit mechanisms whereby long-range glutamatergic and GABAergic cortico-hippocampal inputs bidirectionally modulate pattern separation and completion, providing neuronal representations with a dynamic range for context discrimination and generalization.

Corticostriatal Flow of Action Selection Bias.

The posterior parietal cortex (PPC) performs many functions, including decision making and movement control. It remains unknown which input and output pathways of PPC support different functions. We addressed this issue in mice, focusing on PPC neurons projecting to the dorsal striatum (PPC-STR) and the posterior secondary motor cortex (PPC-pM2). Projection-specific, retrograde labeling showed that PPC-STR and PPC-pM2 represent largely distinct subpopulations, with PPC-STR receiving stronger inputs from association areas and PPC-pM2 receiving stronger sensorimotor inputs. Two-photon calcium imaging during decision making revealed that the PPC-STR population encodes history-dependent choice bias more strongly than PPC-pM2 or general PPC populations. Furthermore, optogenetic inactivation of PPC-STR neurons or their terminals in STR decreased history-dependent bias, while inactivation of PPC-pM2 neurons altered movement kinematics. Therefore, PPC biases action selection through its STR projection while controlling movements through PPC-pM2 neurons. PPC may support multiple functions through parallel subpopulations, each with distinct input-output connectivity.

Reorganization of corticospinal output during motor learning.

Motor learning is accompanied by widespread changes within the motor cortex, but it is unknown whether these changes are ultimately funneled through a stable corticospinal output channel or whether the corticospinal output itself is plastic. We investigated the consistency of the relationship between corticospinal neuron activity and movement through in vivo two-photon calcium imaging in mice learning a lever-press task. Corticospinal neurons exhibited heterogeneous correlations with movement, with the majority of movement-modulated neurons decreasing activity during movement. Individual cells changed their activity across days, which led to changed associations between corticospinal activity and movement. Unlike previous observations in layer 2/3, activity accompanying learned movements did not become more consistent with learning; instead, the activity of dissimilar movements became more decorrelated. These results indicate that the relationship between corticospinal activity and movement is dynamic and that the types of activity and plasticity are different from and possibly complementary to those in layer 2/3.