Divergent Subregional Information Processing in Mouse Prefrontal Cortex During Working Memory.

Working memory (WM) is a critical cognitive function allowing recent information to be temporarily held in mind to inform future action. This process depends on coordination between key subregions in prefrontal cortex (PFC) and other connected brain areas. However, few studies have examined the degree of functional specialization between these subregions throughout the phases of WM using electrophysiological recordings in freely-moving animals, particularly mice. To this end, we recorded single-units in three neighboring medial PFC (mPFC) subregions in mouse - supplementary motor area (MOs), dorsomedial PFC (dmPFC), and ventromedial (vmPFC) - during a freely-behaving non-match-to-position WM task. We found divergent patterns of task-related activity across the phases of WM. The MOs is most active around task phase transitions and encodes the starting sample location most selectively. Dorsomedial PFC contains a more stable population code, including persistent sample-location-specific firing during a five second delay period. Finally, the vmPFC responds most strongly to reward-related information during the choice phase. Our results reveal anatomically and temporally segregated computation of WM task information in mPFC and motivate more precise consideration of the dynamic neural activity required for WM.

Decoupling of cortical activity from behavioral state following administration of the classic psychedelic DOI.

Administration or consumption of classic psychedelics (CPs) leads to profound changes in experience which are often described as highly novel and meaningful. They have shown substantial promise in treating depressive symptoms and may be therapeutic in other situations. Although research suggests that the therapeutic response is correlated with the intensity of the experience, the neural circuit basis for the alterations in experience caused by CPs requires further study. The medial prefrontal cortex (mPFC), where CPs have been shown to induce rapid, 5-HT2A receptor-dependent structural and neurophysiological changes, is believed to be a key site of action. To investigate the acute neural circuit changes induced by CPs, we recorded single neurons and local field potentials in the mPFC of freely behaving male mice after administration of the 5-HT2A/2C receptor-selective CP, 2,5-Dimethoxy-4-iodoamphetamine (DOI). We segregated recordings into active and rest periods in order to examine cortical activity during desynchronized (active) and synchronized (rest) states. We found that DOI induced a robust decrease in low frequency power when animals were at rest, attenuating the usual synchronization that occurs during less active behavioral states. DOI also increased broadband gamma power and suppressed activity in fast-spiking neurons in both active and rest periods. Together, these results suggest that the CP DOI induces persistent desynchronization in mPFC, including during rest when mPFC typically exhibits more synchronized activity. This shift in cortical dynamics may in part underlie the longer-lasting effects of CPs on plasticity, and may be critical to their therapeutic properties.

Adaptive coding across visual features during free-viewing and fixation conditions.

Theoretical studies have long proposed that adaptation allows the brain to effectively use the limited response range of sensory neurons to encode widely varying natural inputs. However, despite this influential view, experimental studies have exclusively focused on how the neural code adapts to a range of stimuli lying along a single feature axis, such as orientation or contrast. Here, we performed electrical recordings in macaque visual cortex (area V4) to reveal significant adaptive changes in the neural code of single cells and populations across multiple feature axes. Both during free viewing and passive fixation, populations of cells improved their ability to encode image features after rapid exposure to stimuli lying on orthogonal feature axes even in the absence of initial tuning to these stimuli. These results reveal a remarkable adaptive capacity of visual cortical populations to improve network computations relevant for natural viewing despite the modularity of the functional cortical architecture.

High-order interactions explain the collective behavior of cortical populations in executive but not sensory areas.

One influential view in neuroscience is that pairwise cell interactions explain the firing patterns of large populations. Despite its prevalence, this view originates from studies in the retina and visual cortex of anesthetized animals. Whether pairwise interactions predict the firing patterns of neurons across multiple brain areas in behaving animals remains unknown. Here, we performed multi-area electrical recordings to find that 2nd-order interactions explain a high fraction of entropy of the population response in macaque cortical areas V1 and V4. Surprisingly, despite the brain-state modulation of neuronal responses, the model based on pairwise interactions captured ∼90% of the spiking activity structure during wakefulness and sleep. However, regardless of brain state, pairwise interactions fail to explain experimentally observed entropy in neural populations from the prefrontal cortex. Thus, while simple pairwise interactions explain the collective behavior of visual cortical networks across brain states, explaining the population dynamics in downstream areas involves higher-order interactions.

Dynamic states of population activity in prefrontal cortical networks of freely-moving macaque.

Neural responses in the cerebral cortex change dramatically between the 'synchronized' state during sleep and 'desynchronized' state during wakefulness. Our understanding of cortical state emerges largely from experiments performed in sensory areas of head-fixed or tethered rodents due to technical limitations of recording from larger freely-moving animals for several hours. Here, we report a system integrating wireless electrophysiology, wireless eye tracking, and real-time video analysis to examine the dynamics of population activity in a high-level, executive area - dorsolateral prefrontal cortex (dlPFC) of unrestrained monkey. This technology allows us to identify cortical substates during quiet and active wakefulness, and transitions in population activity during rest. We further show that narrow-spiking neurons exhibit stronger synchronized fluctuations in population activity than broad-spiking neurons regardless of state. Our results show that cortical state is controlled by behavioral demands and arousal by asymmetrically modulating the slow response fluctuations of local excitatory and inhibitory cell populations.

Challenges in the development of future treatments for breast cancer stem cells.

The recurrence of tumors after years of disease-free survival has spurred interest in the concept that cancers may have a stem cell basis. Current speculation holds that as few as 0.1% of the tumor mass may be chemoresistant and radioresistant, harboring stem-like properties that drive tumor survival, development, and metastasis. There are intense investigations to characterize cancer stem cells on the basis of self-renewal and multi-lineage differentiation. Thus far, no successful targeted therapies have been developed and reached the clinic, but as these cells are isolated and characterized, insights may be unraveled. In this review, we discuss the controversy over the origins of the cancer stem cell hypothesis and the unforeseen factors that may facilitate breast cancer stem cell survival and metastasis. We discuss the role of tumor microenvironment, including carcinoma-associated fibroblasts, epigenetic factors, and the Th1/Th2 balance, in supporting breast cancer stem cells. In addition, we have incorporated ideas on the epithelial-to-mesenchymal transition in metastatic dissemination of epithelial malignancies. This area is relevant since breast cancer stem cells have been suggested to revert to a mesenchymal phenotype during the progression of cancer. Finally we discuss prospects of developing targeted therapy including novel treatment modalities such as oncolytic viral therapy, differentiation therapy, and nanotechnology.

Multi- and inter-disciplinary science in personalized delivery of stem cells for tissue repair.

Stem cell therapy has a place for future application in the treatment of degenerative diseases. Regardless of the origin of the stem cell, when placed within a milieu of inflammatory mediator, they will show varied functions. This review focuses on human mesenchymal stem cells (MSCs) and discusses neuronal replacement using multi- and inter-disciplinary approaches. We caution the enthusiasm of scientists since there is always the potential for tumor formation, even for adult stem cells. The review places RE-1 silencing transcription factor (REST) gene as central to the understanding of stem cell behavior in the microenvironment of tissue injury. REST is relevant in the development of dopaminergic and peptidergic neurons from MSCs. Premature downregulation of REST by the pro-inflammatory mediator, IL-1alpha, can prematurely lead to the expression of neurotransmitters, which in turn, could develop rapid crosstalk with immune cells. In-depth inter- and multi-disciplinary research will lead to rapid and safe translation of MSCs to patients. An understanding of the changes induced in MSCs by cytokines and other mediators will establish future application of MSCs and other stem cells for safe and effective treatments. This study also alludes to the potential of personalized medicine through engineering and mathematics.