Diabetes alters neuroeconomically dissociable forms of mental accounting.

Those with diabetes mellitus are at high-risk of developing psychiatric disorders, yet the link between hyperglycemia and alterations in motivated behavior has not been explored in detail. We characterized value-based decision-making behavior of a streptozocin-induced diabetic mouse model on a naturalistic neuroeconomic foraging paradigm called Restaurant Row. Mice made self-paced choices while on a limited time-budget accepting or rejecting reward offers as a function of cost (delays cued by tone-pitch) and subjective value (flavors), tested daily in a closed-economy system across months. We found streptozocin-treated mice disproportionately undervalued less-preferred flavors and inverted their meal-consumption patterns shifted toward a more costly strategy that overprioritized high-value rewards. We discovered these foraging behaviors were driven by impairments in multiple decision-making systems, including the ability to deliberate when engaged in conflict and cache the value of the passage of time in the form of sunk costs. Surprisingly, diabetes-induced changes in behavior depended not only on the type of choice being made but also the salience of reward-scarcity in the environment. These findings suggest complex relationships between glycemic regulation and dissociable valuation algorithms underlying unique cognitive heuristics and sensitivity to opportunity costs can disrupt fundamentally distinct computational processes and could give rise to psychiatric vulnerabilities.

Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive type of cancer characterized by higher metastatic and reoccurrence rates, where approximately one-third of TNBC patients suffer from the metastasis in the brain. At the same time, TNBC shows good responses to chemotherapy, a feature that fuels the search for novel compounds with therapeutic potential in this area. Recently, we have identified novel urea-based compounds with cytotoxicity against selected cell lines and with the ability to cross the blood-brain barrier in vivo. We have synthesized and analyzed a library of more than 40 compounds to elucidate the key features responsible for the observed activity. We have also identified FGFR1 as a molecular target that is affected by the presence of these compounds, confirming our data using in silico model. Overall, we envision that these compounds can be further developed for the potential treatment of metastatic breast cancer.

Peroxisome proliferator activated receptor gamma (PPARγ) as a therapeutic target for improvement of cognitive performance in Fragile-X.

Rare disorders leading to intellectual disability, such as Fragile X syndrome (FXS) alter synaptic plasticity. Ligand identification of orphan nuclear receptors has led to the discovery of many signaling pathways and has revealed a direct link of nuclear receptors with human conditions such as mental retardation and neurodegenerative diseases. PPARγ agonists can act as neuroprotective agents, promoting synaptic plasticity and neurite outgrowth. Therefore, selective PPARγ agonists are good candidates for therapeutic evaluation in intellectual disabilities. Preliminary results suggest that PPARγ agonists such as Pioglitazone, Rosiglitazone and synthetic agonist, GW1929, are used as the therapeutic agent in neurological disorders. These components interact with intracellular transduction signals (e.g. GSK3ß, PI3K/Akt, Wnt/ß-Catenin, Rac1 and MMP-9). It seems that interaction with these pathways can improve memory recognition in FXS animal models. The present hypothesis consists of enhancing synaptic plasticity that may then rescue the learning and memory in FXS. This will open many new therapeutic avenues for a variety of human diseases.