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Parvalbumin interneuron dysfunction in a thalamo-prefrontal cortical circuit in Disc1 locus impairment mice
Get PDFAltered cortical excitation-inhibition (E-I) balance resulting from abnormal parvalbumin interneuron (PV IN) function is a proposed pathophysiological mechanism of schizophrenia (SZ) and other major psychiatric disorders. Preclinical studies have indicated that disrupted-in-schizophrenia-1 (DISC1) is a useful molecular lead to address the biology of prefrontal cortex dependent cognition and PV IN function. To date, prefrontal cortical inhibitory circuit function has not been investigated in depth in Disc1 locus impairment (LI) mouse models. Therefore, we used a Disc1 LI mouse model to investigate E-I balance in medial prefrontal cortical (mPFC) circuits. We found that inhibition onto layer 3 excitatory pyramidal neurons in the mPFC was significantly reduced in Disc1 LI mice. This reduced inhibition was accompanied by decreased GABA release from local PV, but not somatostatin (SOM) interneurons, and by impaired feedforward inhibition in the mediodorsal thalamus (MD) to mPFC circuit. Our mechanistic findings of abnormal PV IN function in a Disc1 LI model provide insight into biology that may be relevant to neuropsychiatric disorders including schizophrenia.SIGNIFICANCE STATEMENT A popular theory suggests that dysregulation of fast-spiking parvalbumin interneurons (PV INs) and elevated excitation-inhibition (E-I) balance contribute to the pathophysiology of various psychiatric disorders. Previous studies suggest that genetic perturbations of the disrupted-in-schizophrenia-1 (Disc1) gene affect prefrontal cortex-dependent cognition and PV IN function, but synaptic and circuit physiology data are lacking. Here, we provide evidence that the presynaptic function of PV INs in the medial prefrontal cortex is altered in Disc1 LI mice and that E-I balance is elevated within a thalamofrontal circuit known to be important for cognition. These findings may contribute to our understanding of the biology that gives rise to cognitive symptoms in a range of neuropsychiatric disorders
Neuroendocrine and Behavioral Consequences of Hyperglycemia in Cancer
No full textA hallmark of cancer is the disruption of cellular metabolism during the course of malignant growth. Major focus is now on how these cell-autonomous processes propagate to the tumor microenvironment, and more generally, to the entire host system. This chain of events can have major consequences for a patient's health and wellbeing. For example, metabolic 'waste' produced by cancer cells activates systemic inflammatory responses, which can interfere with hepatic insulin receptor signaling and glucose homeostasis. Research is just now beginning to understand how these processes occur, and how they contribute to systemic symptoms prevalent across cancers, including hyperglycemia, fatigue, pain, and sleep disruption. Indeed, it is only recently that we have begun to appreciate that the brain does not play a passive role in responding to cancer-induced changes in physiology. In this review, we provide a brief discussion of how oncogene-directed metabolic reprogramming disrupts host metabolism, with a specific emphasis on cancer-induced hyperglycemia. We further discuss how the brain senses circulating glucose concentrations and how this process goes awry as a response to distant neoplastic growth. Finally, as glucose-sensing neurons control diverse aspects of physiology and behavior, we link cancer-induced changes in energy balance to neuroendocrine and behavioral consequences for the host organism
Amino Acid and Carbohydrate Metabolism Are Coordinated to Maintain Energetic Balance during Drought in Sugarcane
No full textThe ability to expand crop plantations without irrigation is a major goal to increase agriculture sustainability. To achieve this end, we need to understand the mechanisms that govern plant growth responses under drought conditions. In this study, we combined physiological, transcriptomic, and genomic data to provide a comprehensive picture of drought and recovery responses in the leaves and roots of sugarcane. Transcriptomic profiling using oligoarrays and RNA-seq identified 2898 (out of 21,902) and 46,062 (out of 373,869) transcripts as differentially expressed, respectively. Co-expression analysis revealed modules enriched in photosynthesis, small molecule metabolism, alpha-amino acid metabolism, trehalose biosynthesis, serine family amino acid metabolism, and carbohydrate transport. Together, our findings reveal that carbohydrate metabolism is coordinated with the degradation of amino acids to provide carbon skeletons to the tricarboxylic acid cycle. This coordination may help to maintain energetic balance during drought stress adaptation, facilitating recovery after the stress is alleviated. Our results shed light on candidate regulatory elements and pave the way to biotechnology strategies towards the development of drought-tolerant sugarcane plants
D40 signaling induces type I interferon and immune control in mouse pancreatic cancer lacking the CXCL12-coat
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Oncogenic KRAS engages an RSK1/NF1 complex in pancreatic cancer
No full textPancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Although activating mutations of the KRAS GTPase are the predominant dependency present in >90% of PDAC patients, targeting KRAS mutants directly has been challenging in PDAC.
Similarly, strategies targeting known KRAS downstream effectors have had limited clinical success due to feedback mechanisms, alternate pathways and toxicity due to the targeting of normal tissues. Therefore, identifying additional functionally relevant KRAS interactions in PDAC may allow for a better understanding of feedback mechanisms and unveil new potential therapeutic targets. Here, we used proximity labelling to identify protein interactors of active KRAS in PDAC cells. Fusions of wildtype (BirA-KRAS4B), mutant (BirA-KRAS4BG12D) and non-transforming and cytosolic double mutant (BirA-KRAS4BG12D/C185S) KRAS with the BirA biotin ligase were expressed in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 was enriched among proteins that selectively interacted with membrane-bound KRASG12D. RSK1 required the NF1 and SPRED proteins to interact with KRAS-GTP at the membrane. In both murine and human PDAC lines, membrane-targeted RSK1 was tolerated but inhibited cell proliferation following oncogenic KRAS abrogation to reveal a negative feedback role for membrane-localized RSK1 on wild-type KRAS. Inhibition of the wild-type KRAS, which has been previously proposed to suppress KRAS oncogenesis, may partially explain how RSK1 has been identified as a dependency in some KRAS mutant cells and may provide an additional function for NF1 in tumorigenesis
Slice and Dice: DCL2 Mediates the Production of 22-Nucleotide siRNAs that Influence Trait Variation in Soybean.
No full textPancreatic cancer cells assemble a CXCL12-keratin 19 coating to resist immunotherapy
Get PDFHow pancreatic ductal adenocarcinoma (PDA) cells stimulate CXCR4 to exclude T cells and resist T cell checkpoint inhibitors is not known. Here, we find that CXCL12, the ligand for CXCR4 that is produced by the cancer-associated fibroblast, “coats” human PDA and colorectal cancer cells as covalent heterodimers with keratin 19 (KRT19). Modeling the formation of the heterodimer with three proteins shows that KRT19 binds CXCL12 and transglutaminase-2 (TGM2), and that TGM2 converts the reversible KRT19-CXCL12 complex into a covalent heterodimer. We validate this model by showing that cancer cells in mouse PDA tumors must express KRT19 and TGM2 to become coated with CXCL12, exclude T cells, and resist immunotherapy with anti-PD-1 antibody. Thus, PDA cells have a cell-autonomous means by which they capture CXCL12 to mediate immune suppression, which is potentially amenable to therapy.
One Sentence Summary Cancer cells in pancreatic ductal adenocarcinoma use transglutaminase-2 to assemble a coating comprised of covalent CXCL12-keratin 19 heterodimers that excludes T cells and mediates resistance to inhibition of the PD-1 T cell checkpoint
Representations in Rodent Primary Visual Cortex During Visual Discrimination
Get PDFAlthough the hierarchical pathways underlying visual decision making in primates have been studied extensively, the neural circuits underlying visual decision making in rodents are not as well understood. Meanwhile, there is increasing evidence to suggest that while sensory cortices have been largely studied for their feedforward processing role, massive feedback projections distribute representations of nonsensory variables such as movement and choice across cortex, even dominating activity within early sensory cortices. The role of these representations is not well understood within a sensory discrimination paradigm. We therefore set out to investigate the representations and contributions of rodent primary visual cortex (V1) in a visual decision making task. In this thesis, I describe a novel visual discrimination task for freely moving rats. Subjects are presented with a set of distributed flickering dots (a “cloud of dots”), and are asked to judge whether there are more dots in the upper or lower visual hemifield. Subjects report their choice with a nosepoke into the corresponding water delivery port. To facilitate experimental access in this task, I developed a software-based approach to control viewing angle at the center port by reinforcing head position using closed-loop online video tracking. While subjects are able to find and stably carry out the comparison rule when it is necessitated by the statistics of the stimulus distribution over trials, behavioral experiments revealed that at baseline, subjects reliably converge on an abbreviated strategy, such that only half of the full stimulus is necessary and sufficient to drive the behavior. I used tetrode recordings to interrogate neuronal responses in primary visual cortex (V1) of behaving animals. In addition to classically responsive visual neurons, I report overlapping subpopulations of V1 single neurons that are not only responsive, but also selective to choice side and outcome. I show that despite a lack of clear structure to the organization of sensory and nonsensory information in V1 single neurons, the trial-to-trial variability of stimulus-driven activity depends on the behavioral relevance of visual information streams. I further quantified the intrinsic behavioral bias towards the lower visual field. I found that animals could adapt their strategy to the statistics of their stimulus environment over many trials, but at baseline overwhelmingly preferred to base their decisions on the lower visual field, even when this strategy was suboptimal. Preliminary optogenetic inactivation experiments showed that stimulus period V1 activity was necessary for accurate discrimination behavior, while outcome period V1 activity had little effect on next trial choice. Finally, motivated by the role of corticostriatal projections in the analogous auditory "cloud of tones" task, I explored the organization of the corticostriatal projection from V1. Here I observed an asymmetry in the pattern of projections from V1 to the striatum, coinciding with V1 mapping of visual space and the asymmetry in stimulus usage by our subjects