Cortical-hippocampal processing: prefrontal-hippocampal contributions to the spatiotemporal relationship of events

The hippocampus and prefrontal cortex play distinct roles in the generation and retrieval of episodic memory. The hippocampus is crucial for binding inputs across behavioral timescales, whereas the prefrontal cortex is found to influence retrieval. Spiking of hippocampal principal neurons contains environmental information, including information about the presence of specific objects and their spatial or temporal position relative to environmental and behavioral cues. Neural activity in the prefrontal cortex is found to map behavioral sequences that share commonalities in sensory input, movement, and reward valence. Here I conducted a series of four experiments to test the hypothesis that external inputs from cortex update cell assemblies that are organized within the hippocampus. I propose that cortical inputs coordinate with CA3 to rapidly integrate information at fine timescales. Extracellular tetrode recordings of neurons in the orbitofrontal cortex were performed in rats during a task where object valences were dictated by the spatial context in which they were located. Orbitofrontal ensembles, during object sampling, were found to organize all measured task elements in inverse rank relative to the rank previously observed in the hippocampus, whereby orbitofrontal ensembles displayed greater differentiation for object valence and its contextual identity than spatial position. Using the same task, a follow-up experiment assessed coordination between prefrontal and hippocampal networks by simultaneously recording medial prefrontal and hippocampal activity. The circuit was found to coordinate at theta frequencies, whereby hippocampal theta engaged prefrontal signals during contextual sampling, and the order of engagement reversed during object sampling. Two additional experiments investigated hippocampal temporal representations. First, hippocampal patterns were found to represent conjunctions of time and odor during a head-fixed delayed match-to-sample task. Lastly, I assessed the dependence of hippocampal firing patterns on intrinsic connectivity during the delay period versus active navigation of spatial routes, as rats performed a delayed-alternation T-maze. Stimulation of the ventral hippocampal commissure induced remapping of hippocampal activity during the delay period selectively. Despite temporal reorganization, different hippocampal populations emerged to predict temporal position. These results show hippocampal representations are guided by stable cortical signals, but also, coordination between cortical and intrinsic circuitry stabilizes flexible CA1 temporal representations

Constitutivism

A brief explanation and overview of constitutivism

The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease

Philosophy of action

The philosophical study of human action begins with Plato and Aristotle. Their influence in late antiquity and the Middle Ages yielded sophisticated theories of action and motivation, notably in the works of Augustine and Aquinas.1 But the ideas that were dominant in 1945 have their roots in the early modern period, when advances in physics and mathematics reshaped philosophy

The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease