Evolving schema representations in orbitofrontal ensembles during learning.

How do we learn about what to learn about? Specifically, how do the neural elements in our brain generalize what has been learned in one situation to recognize the common structure of-and speed learning in-other, similar situations? We know this happens because we become better at solving new problems-learning and deploying schemas1-5-through experience. However, we have little insight into this process. Here we show that using prior knowledge to facilitate learning is accompanied by the evolution of a neural schema in the orbitofrontal cortex. Single units were recorded from rats deploying a schema to learn a succession of odour-sequence problems. With learning, orbitofrontal cortex ensembles converged onto a low-dimensional neural code across both problems and subjects; this neural code represented the common structure of the problems and its evolution accelerated across their learning. These results demonstrate the formation and use of a schema in a prefrontal brain region to support a complex cognitive operation. Our results not only reveal a role for the orbitofrontal cortex in learning but also have implications for using ensemble analyses to tap into complex cognitive functions.

Leukemia Cutis As the Initial Manifestation of Chronic Lymphocytic Leukemia Progression.

Chronic lymphocytic leukemia (CLL) is a malignant proliferation of monoclonal mature B-cells in peripheral blood. Leukemia cells can commonly spread from the blood to other sites such as the lymph nodes, liver, and spleen. However, contrary to T-cell lymphomas that can involve the skin, CLL metastasis to the skin is unusual and is rarely the first manifestation of systemic disease. When leukemia cells invade the skin, it is termed leukemia cutis. Furthermore, multiple skin morphologies can be present in leukemia cutis making diagnosis challenging. Likewise, it can be mistaken for other common etiologies such as drug or substance allergy, infection, and scabies, among others. We herein present a case of CLL with leukemia cutis as the initial manifestation of systemic disease. The initial punch biopsy results were non-specific for inflammatory changes, but a subsequent biopsy revealed findings confirming leukemia cutis. This case not only demonstrates that identifying malignant skin manifestations in a timely manner and treating them is essential, as it improves the quality of life and survival, but also demonstrates that leukemia cutis can be a dynamic disease where multiple biopsies may be needed to confirm the diagnosis, as histopathology can change over time.

Decreased pericellular matrix production and selection for enhanced cell membrane repair may impair osteocyte responses to mechanical loading in the aging skeleton.

Transient plasma membrane disruptions (PMD) occur in osteocytes with in vitro and in vivo loading, initiating mechanotransduction. The goal here was to determine whether osteocyte PMD formation or repair is affected by aging. Osteocytes from old (24 months) mice developed fewer PMD (-76% females, -54% males) from fluid shear than young (3 months) mice, and old mice developed fewer osteocyte PMD (-51%) during treadmill running. This was due at least in part to decreased pericellular matrix production, as studies revealed that pericellular matrix is integral to formation of osteocyte PMD, and aged osteocytes produced less pericellular matrix (-55%). Surprisingly, osteocyte PMD repair rate was faster (+25% females, +26% males) in osteocytes from old mice, and calcium wave propagation to adjacent nonwounded osteocytes was blunted, consistent with impaired mechanotransduction downstream of PMD in osteocytes with fast PMD repair in previous studies. Inducing PMD via fluid flow in young osteocytes in the presence of oxidative stress decreased postwounding cell survival and promoted accelerated PMD repair in surviving cells, suggesting selective loss of slower-repairing osteocytes. Therefore, as oxidative stress increases during aging, slower-repairing osteocytes may be unable to successfully repair PMD, leading to slower-repairing osteocyte death in favor of faster-repairing osteocyte survival. Since PMD are an important initiator of mechanotransduction, age-related decreases in pericellular matrix and loss of slower-repairing osteocytes may impair the ability of bone to properly respond to mechanical loading with bone formation. These data suggest that PMD formation and repair mechanisms represent new targets for improving bone mechanosensitivity with aging.

Complementary Task Structure Representations in Hippocampus and Orbitofrontal Cortex during an Odor Sequence Task.

Both hippocampus (HPC) and orbitofrontal cortex (OFC) have been shown to be critical for behavioral tasks that require use of an internal model or cognitive map, composed of the states and the relationships between them, which define the current environment or task at hand. One general idea is that the HPC provides the cognitive map, which is then transformed by OFC to emphasize information of relevance to current goals. Our previous analysis of ensemble activity in OFC in rats performing an odor sequence task revealed a rich representation of behaviorally relevant task structure, consistent with this proposal. Here, we compared those data to recordings from single units in area CA1 of the HPC of rats performing the same task. Contrary to expectations that HPC ensembles would represent detailed, even incidental, information defining the full task space, we found that HPC ensembles-like those in OFC-failed to distinguish states when it was not behaviorally necessary. However, hippocampal ensembles were better than those in OFC at distinguishing task states in which prospective memory was necessary for future performance. These results suggest that, in familiar environments, the HPC and OFC may play complementary roles, with the OFC maintaining the subjects' current position on the cognitive map or state space, supported by HPC when memory demands are high.

Prefrontal circuits signaling active avoidance retrieval and extinction.

OBJECTIVE: Neurons in PL and IL project densely to two areas implicated in active avoidance: the basolateral amygdala (BLA) and the ventral striatum (VS). We therefore combined c-Fos immunohistochemistry with retrograde tracers to characterize signaling in platform-mediated active avoidance. METHODS: Male rats  were infused with retrograde tracers (CTB, FB) into basolateral amygdala and ventral striatum and conditioned to avoid tone-signaled footshocks by stepping onto a nearby platform. In a subsequent test session, rats received either 2 unreinforced tones (avoidance retrieval) or 15 unreinforced tones (avoidance extinction) followed by analysis of c-Fos combined with fluorescent imaging of retrograde tracers. RESULTS: Retrieval of avoidance did not activate IL neurons, but did activate PL neurons projecting to BLA, and to a lesser extent VS. Extinction of avoidance activated IL neurons projecting to both BLA and VS, as well as PL neurons projecting to VS. CONCLUSIONS: Our observation that avoidance retrieval is signaled by PL projections to BLA suggests that PL may modulate VS indirectly via BLA, and agrees with other findings implicating BLA in active avoidance. Less expected was the signaling of extinction via PL inputs to VS, which may converge with IL inputs to VS to inhibit expression of avoidance.

Persistent active avoidance correlates with activity in prelimbic cortex and ventral striatum.

Persistent avoidance is a prominent symptom of anxiety disorders and is often resistant to extinction-based therapies. Little is known about the circuitry mediating persistent avoidance. Using a recently described platform-mediated active avoidance task, we assessed activity in several structures with c-Fos immuno-labeling. In Task 1, rats were conditioned to avoid a tone-signaled shock by moving to a safe platform, and then were extinguished over two days. One day later, failure to retrieve extinction correlated with increased activity in the prelimbic prefrontal cortex (PL), ventral striatum (VS), and basal amygdala (BA), and decreased activity in infralimbic prefrontal cortex (IL), consistent with pharmacological inactivation studies. In Task 2, the platform was removed during extinction training and fear (suppression of bar pressing) was extinguished to criterion over 3-5 days. The platform was then returned in a post-extinction test. Under these conditions, avoidance levels were equivalent to Experiment 1 and correlated with increased activity in PL and VS, but there was no correlation with activity in IL or BA. Thus, persistent avoidance can occur independently of deficits in fear extinction and its associated structures.