▪ Abstract The prefrontal cortex has long been suspected to play an important role in cognitive control, in the ability to orchestrate thought and action in accordance with internal goals. Its neural basis, however, has remained a mystery. Here, we propose that cognitive control stems from the active maintenance of patterns of activity in the prefrontal cortex that represent goals and the means to achieve them. They provide bias signals to other brain structures whose net effect is to guide the flow of activity along neural pathways that establish the proper mappings between inputs, internal states, and outputs needed to perform a given task. We review neurophysiological, neurobiological, neuroimaging, and computational studies that support this theory and discuss its implications as well as further issues to be addressed

/pdf/an-integrative-theory-of-prefrontal-cortex-function-2j9unprn5f.pdf

An integrative theory of prefrontal cortex function

1980 Preface * 1999 Preface * 1999 Acknowledgements * Introduction * 1 Circular Logic * 2 Phase Singularities (Screwy Results of Circular Logic) * 3 The Rules of the Ring * 4 Ring Populations * 5 Getting Off the Ring * 6 Attracting Cycles and Isochrons * 7 Measuring the Trajectories of a Circadian Clock * 8 Populations of Attractor Cycle Oscillators * 9 Excitable Kinetics and Excitable Media * 10 The Varieties of Phaseless Experience: In Which the Geometrical Orderliness of Rhythmic Organization Breaks Down in Diverse Ways * 11 The Firefly Machine 12 Energy Metabolism in Cells * 13 The Malonic Acid Reagent ('Sodium Geometrate') * 14 Electrical Rhythmicity and Excitability in Cell Membranes * 15 The Aggregation of Slime Mold Amoebae * 16 Numerical Organizing Centers * 17 Electrical Singular Filaments in the Heart Wall * 18 Pattern Formation in the Fungi * 19 Circadian Rhythms in General * 20 The Circadian Clocks of Insect Eclosion * 21 The Flower of Kalanchoe * 22 The Cell Mitotic Cycle * 23 The Female Cycle * References * Index of Names * Index of Subjects

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/596B270197FE27DE5FABB598B6210622/S0025557200150892a.pdf/div-class-title-span-class-italic-the-geometry-of-biological-time-span-by-a-t-winfree-pp-544-dm68-corrected-second-printing-1990-isbn-3-540-52528-9-springer-div.pdf

The geometry of biological time , by A. T. Winfree. Pp 544. DM68. Corrected Second Printing 1990. ISBN 3-540-52528-9 (Springer)

Molecular Bases for Circadian Clocks

▪ Abstract It has long been assumed that sensory neurons are adapted, through both evolutionary and developmental processes, to the statistical properties of the signals to which they are exposed. Attneave (1954), Barlow (1961) proposed that information theory could provide a link between environmental statistics and neural responses through the concept of coding efficiency. Recent developments in statistical modeling, along with powerful computational tools, have enabled researchers to study more sophisticated statistical models for visual images, to validate these models empirically against large sets of data, and to begin experimentally testing the efficient coding hypothesis for both individual neurons and populations of neurons.

/pdf/natural-image-statistics-and-neural-representation-4w6r9kucbm.pdf

Natural image statistics and neural representation

https://www.cell.com/cell/pdf/S0092-8674(02)00825-5.pdf

The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator.

A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless.

Circadian clocks organize behavior and physiology to adapt to daily environmental cycles. Genetic approaches in the fruit fly, Drosophila melanogaster, have revealed widely conserved molecular gears of these 24-h timers. Yet much less is known about how these cell-autonomous clocks confer temporal information to modulate cellular functions. Here we discuss our current knowledge of circadian clock function in Drosophila, providing an overview of the molecular underpinnings of circadian clocks. We then describe the neural network important for circadian rhythms of locomotor activity, including how these molecular clocks might influence neuronal function. Finally, we address a range of behaviors and physiological systems regulated by circadian clocks, including discussion of specific peripheral oscillators and key molecular effectors where they have been described. These studies reveal a remarkable complexity to circadian pathways in this “simple” model organism.

Circadian Organization of Behavior and Physiology in Drosophila

Circadian clocks drive rhythmic behaviour in animals and are regulated by transcriptional feedback loops1,2. For example, the Drosophila proteins Clock (Clk) and Cycle (Cyc) activate transcription of period (per) and timeless (tim). Per and Tim then associate, translocate to the nucleus, and repress the activity of Clk and Cyc. However, post-translational modifications are also critical to proper timing. Per and Tim undergo rhythmic changes in phosphorylation1, and evidence supports roles for two kinases in this process: Doubletime (Dbt) phosphorylates Per3,4, whereas Shaggy (Sgg) phosphorylates Tim5. Yet Sgg and Dbt often require a phosphoserine in their target site6,7, and analysis of Per phosphorylation in dbt mutants3,8 suggests a role for other kinases. Here we show that the catalytic subunit of Drosophila casein kinase 2 (CK2α) is expressed predominantly in the cytoplasm of key circadian pacemaker neurons. CK2α mutant flies show lengthened circadian period, decreased CK2 activity, and delayed nuclear entry of Per. These effects are probably direct, as CK2α specifically phosphorylates Per in vitro. We propose that CK2 is an evolutionary link between the divergent circadian systems of animals, plants and fungi.

A role for casein kinase 2α in the Drosophila circadian clock

The fruitfly Drosophila is well established as a genetic model for the study of sleep. The flies have a behavioural pattern resembling what we call sleep, but the signature EEG changes characteristic of sleep and its stages have not been identified, so it is not possible to say if sleep in flies is a neural process and, if so, what neural substrates are involved. Answering this question is an essential step towards interpreting the mechanisms by which genes influence sleep. Two groups have now tackled the problem, and both identify the structures known as the mushroom bodies as the part of the brain involved in sleep regulation. This discovery brings a neural dimension to sleep in Drosophila and also links sleep to the other known functions of the mushroom bodies — learning and memory. The fruitfly, Drosophila melanogaster, exhibits many of the cardinal features of sleep, yet little is known about the neural circuits governing its sleep1. Here we have performed a screen of GAL4 lines expressing a temperature-sensitive synaptic blocker shibirets1 (ref. 2) in a range of discrete neural circuits, and assayed the amount of sleep at different temperatures. We identified three short-sleep lines at the restrictive temperature with shared expression in the mushroom bodies, a neural locus central to learning and memory3. Chemical ablation of the mushroom bodies also resulted in reduced sleep. These studies highlight a central role for the mushroom bodies in sleep regulation.

A dynamic role for the mushroom bodies in promoting sleep in Drosophila

Forward genetic analyses in flies and mice have uncovered conserved transcriptional feedback loops at the heart of circadian pacemakers. Conserved mechanisms of posttranslational regulation, most notably phosphorylation, appear to be important for timing feedback. Transcript analyses have indicated that circadian clocks are not restricted to neurons but are found in several tissues. Comparisons between flies and mice highlight important differences in molecular circuitry and circadian organization. Future studies of pacemaker mechanisms and their control of physiology and behavior will likely continue to rely on forward genetics.

Ravi Allada

Papers

A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless.

Circadian Organization of Behavior and Physiology in Drosophila

A role for casein kinase 2α in the Drosophila circadian clock

A dynamic role for the mushroom bodies in promoting sleep in Drosophila

Stopping Time: The Genetics of Fly and Mouse Circadian Clocks