PD-L1/PD-1 checkpoint pathway regulates hippocampal neuronal excitability and learning and memory behavior.

Programmed death protein 1 (PD-1) and its ligand PD-L1 constitute an immune checkpoint pathway. We report that neuronal PD-1 signaling regulates learning/memory in health and disease. Mice lacking PD-1 (encoded by Pdcd1) exhibit enhanced long-term potentiation (LTP) and memory. Intraventricular administration of anti-mouse PD-1 monoclonal antibody (RMP1-14) potentiated learning and memory. Selective deletion of PD-1 in excitatory neurons (but not microglia) also enhances LTP and memory. Traumatic brain injury (TBI) impairs learning and memory, which is rescued by Pdcd1 deletion or intraventricular PD-1 blockade. Conversely, re-expression of Pdcd1 in PD-1-deficient hippocampal neurons suppresses memory and LTP. Exogenous PD-L1 suppresses learning/memory in mice and the excitability of mouse and NHP hippocampal neurons through PD-1. Notably, neuronal activation suppresses PD-L1 secretion, and PD-L1/PD-1 signaling is distinctly regulated by learning and TBI. Thus, conditions that reduce PD-L1 levels or PD-1 signaling could promote memory in both physiological and pathological conditions.

Foretelling the Flex-Vertebral Shape Predicts Behavior and Ecology of Fishes.

We modeled swimming kinematics and body mechanics of several fish species of varying habitat and body shape based on measurements of internal vertebral morphology. SYNOPSIS: One key evolutionary innovation that separates vertebrates from invertebrates is the notochord, a central element that provides the stiffness needed for powerful movements. Later, the notochord was further stiffened by the vertebrae, cartilaginous, and bony elements, surrounding the notochord. The ancestral notochord is retained in modern vertebrates as intervertebral material, but we know little about its mechanical interactions with surrounding vertebrae. In this study, the internal shape of the vertebrae-where this material is found-was quantified in 16 species of fishes with various body shapes, swimming modes, and habitats. We used micro-computed tomography to measure the internal shape. We then created and mechanically tested physical models of intervertebral joints. We also mechanically tested actual vertebrae of five species. Material testing shows that internal morphology of the centrum significantly affects bending and torsional stiffness. Finally, we performed swimming trials to gather kinematic data. Combining these data, we created a model that uses internal vertebral morphology to make predictions about swimming kinematics and mechanics. We used linear discriminant analysis (LDA) to assess the relationship between vertebral shape and our categorical traits. The analysis revealed that internal vertebral morphology is sufficient to predict habitat, body shape, and swimming mode in our fishes. This model can also be used to make predictions about swimming in fishes not easily studied in the laboratory, such as deep sea and extinct species, allowing the development of hypotheses about their natural behavior.

Emerging Role of PD-1 in the Central Nervous System and Brain Diseases.

Programmed cell death protein 1 (PD-1) is an immune checkpoint modulator and a major target of immunotherapy as anti-PD-1 monoclonal antibodies have demonstrated remarkable efficacy in cancer treatment. Accumulating evidence suggests an important role of PD-1 in the central nervous system (CNS). PD-1 has been implicated in CNS disorders such as brain tumors, Alzheimer's disease, ischemic stroke, spinal cord injury, multiple sclerosis, cognitive function, and pain. PD-1 signaling suppresses the CNS immune response via resident microglia and infiltrating peripheral immune cells. Notably, PD-1 is also widely expressed in neurons and suppresses neuronal activity via downstream Src homology 2 domain-containing protein tyrosine phosphatase 1 and modulation of ion channel function. An improved understanding of PD-1 signaling in the cross-talk between glial cells, neurons, and peripheral immune cells in the CNS will shed light on immunomodulation, neuromodulation, and novel strategies for treating brain diseases.

Anatomical basis of diverse jaw protrusion directionality in ponyfishes (Family Leiognathidae).

Protrusion of the oral jaws is a key morphological innovation that enhances feeding performance in fishes. The mechanisms of protrusion and the basis of variation in its magnitude are well studied, but little attention has been paid to the functional morphology of protrusion directionality, despite wide variation among teleost species from slightly dorsal to strongly ventral. Ponyfishes (Leiognathidae) comprise a group of 52 species that exhibit striking diversity in the directionality of jaw protrusion, providing a promising system for exploring its underlying basis in a single clade. We examined the anatomical basis of protrusion directionality by measuring eight traits associated with the size and positioning of oral jaw bones. Measurements were made on cleared and stained specimens of 20 ponyfish species, representing every major lineage within the family. Species fell into three nonoverlapping clusters with respect to directionality including dorsal, rostral, and ventral protruders. A key correlate of protrusion direction is the anterior-posterior position of the articular-quadrate jaw joint. As the joint position moves from a posterior to a more anterior location, the orientation of the relaxed mandible rotates from an almost horizontal resting position to an upright vertical posture. Abduction of the mandible from the horizontal position results in ventrally directed protrusion, while the more upright mandible rotates to a position that maintains dorsal orientation. The resting orientation of the premaxilla and maxilla, thus, vary consistently with protrusion direction. Mouth size, represented by length of the mandible and maxilla, is a second major axis of variation in ponyfishes that is independent of variation in protrusion directionality.

Evolution of skeletal and muscular morphology within the functionally integrated lower jaw adduction system of sculpins and relatives (Cottoidei).

Vertebrate lever mechanics are defined by the morphology of skeletal elements and the properties of their muscular actuators; these metrics characterize functional diversity. The components of lever systems work in coordination ("functional integration") and may show strong covariation across evolutionary history ("evolutionary integration"), both of which have been hypothesized to constrain phenotypic diversity. We quantified evolutionary integration in a functionally integrated system - the lower jaw of sculpins and relatives (Actinopterygii: Cottoidei). Sculpins primarily rely on suction feeding for prey capture, but there is considerable variation in evasiveness of their prey, resulting in variation in anatomy of the lower jaw-closing mechanism. We used functionally-relevant linear measurements to characterize skeletal and muscular components of this system among 25 cottoid species and two outgroup Hexagrammoidei (greenling) species. We quantified evolutionary covariation and correlation of jaw-closing mechanical advantage (i.e., skeletal leverage) and muscle architecture (i.e., gearing) by correlating phylogenetically independent contrasts and fitting phylogenetically corrected generalized least squares models. We found no evidence of evolutionary covariation in muscle architecture and skeletal leverage. While we found a positive evolutionary correlation between out-lever length and adductor muscle fiber length, there was no significant evolutionary correlation between in-lever length and adductor muscle fiber length. We also found a positive evolutionary correlation between in- and out-lever lengths. These results suggest that skeletal morphology and muscle morphology contribute independently to biomechanical diversity among closely related species, indicating the importance of considering both skeletal and muscular variation in studies of ecomorphological diversification.