Nicholas C. Foley

Two Antiphase Oscillations Occur in Each Suprachiasmatic Nucleus of Behaviorally Split Hamsters

The suprachiasmatic nuclei (SCNs) control circadian rhythms of numerous behavioral and physiological responses. In hamsters, constant light causes “splitting” of circadian rhythms, such that a single daily bout of activity separates into two components, 12 h apart, with antiphase circadian oscillations in the left and right SCN. Given the phenotypic and functional heterogeneity of the SCN, in which ventrolateral but not dorsomedial neurons are retinorecipient, we asked how these two compartments respond to the constant lighting conditions that produce splitting, using three different phase markers of neuronal activity: PER1 (Period 1), c-FOS, and pERK (phosphorylated extracellular signal-regulated kinase). We report the emergence of a coherent novel network in which each side of the SCN exhibits two antiphase oscillating subregions, here termed “core-like” and “shell-like,” in addition to the known antiphase oscillation between the right and left SCN. The novel SCN response entails a coherent rhythm in a core-like region of the SCN, which otherwise is not cycling. A mathematical model is presented, and this model interprets the observed changes in the proportion of in-phase and antiphase populations of SCN oscillators and suggests novel testable hypotheses. Finally, the functional significance of this network was explored by investigating the adjacent hypothalamus. Activation of the paraventricular nucleus is in-phase with the ipsilateral core-like SCN, whereas activation of the lateral subparaventricular zone is in-phase with the ipsilateral shell-like SCN, pointing to a multiplicity of SCN output signals. These results suggest a neural basis for internal coincidence of SCN oscillators, and a novel mechanism of plasticity in SCN neural networks and outputs.

Gates and Oscillators II: Zeitgebers and the Network Model of the Brain Clock

Circadian rhythms in physiology and behavior are regulated by the SCN. When assessed by expression of clock genes, at least 2 distinct functional cell types are discernible within the SCN: nonrhythmic, light-inducible, retinorecipient cells and rhythmic autonomous oscillator cells that are not directly retinorecipient. To predict the responses of the circadian system, the authors have proposed a model based on these biological properties. In this model, output of rhythmic oscillator cells regulates the activity of the gate cells. The gate cells provide a daily organizing signal that maintains phase coherence among the oscillator cells. In the absence of external stimuli, this arrangement yields a multicomponent system capable of producing a self-sustained consensus rhythm. This follow-up study considers how the system responds when the gate cells are activated by an external stimulus, simulating a response to an entraining (or phase-setting) signal. In this model, the authors find that the system can be entrained to periods within the circadian range, that the free-running system can be phase shifted by timed activation of the gate, and that the phase response curve for activation is similar to that observed when animals are exposed to a light pulse. Finally, exogenous triggering of the gate over a number of days can organize an arrhythmic system, simulating the light-dependent reappearance of rhythmicity in a population of disorganized, independent oscillators. The model demonstrates that a single mechanism (i.e., the output of gate cells) can account for not only free-running and entrained rhythmicity but also other circadian phenomena, including limits of entrainment, a PRC with both delay and advance zones, and the light-dependent reappearance of rhythmicity in an arrhythmic animal.

Characterization of orderly spatiotemporal patterns of clock gene activation in mammalian suprachiasmatic nucleus

Because we can observe oscillation within individual cells and in the tissue as a whole, the suprachiasmatic nucleus (SCN) presents a unique system in the mammalian brain for the analysis of individual cells and the networks of which they are a part. While dispersed cells of the SCN sustain circadian oscillations in isolation, they are unstable oscillators that require network interactions for robust cycling. Using cluster analysis to assess bioluminescence in acute brain slices from PERIOD2::Luciferase (PER2::LUC) knockin mice, and immunochemistry of SCN from animals harvested at various circadian times, we assessed the spatiotemporal activation patterns of PER2 to explore the emergence of a coherent oscillation at the tissue level. The results indicate that circadian oscillation is characterized by a stable daily cycle of PER2 expression involving orderly serial activation of specific SCN subregions, followed by a silent interval, with substantial symmetry between the left and right side of the SCN. The biological significance of the clusters identified in living slices was confirmed by co‐expression of LUC and PER2 in fixed, immunochemically stained brain sections, with the spatiotemporal pattern of LUC expression resembling that revealed in the cluster analysis of bioluminescent slices. We conclude that the precise timing of PER2 expression within individual neurons is dependent on their location within the nucleus, and that small groups of neurons within the SCN give rise to distinctive and identifiable subregions. We propose that serial activation of these subregions is the basis of robustness and resilience of the daily rhythm of the SCN.

Differential contributions of intra‐cellular and inter‐cellular mechanisms to the spatial and temporal architecture of the suprachiasmatic nucleus circadian circuitry in wild‐type, cryptochrome‐null and vasoactive intestinal peptide receptor 2‐null mutant mice

To serve as a robust internal circadian clock, the cell‐autonomous molecular and electrophysiological activities of the individual neurons of the mammalian suprachiasmatic nucleus (SCN) are coordinated in time and neuroanatomical space. Although the contributions of the chemical and electrical interconnections between neurons are essential to this circuit‐level orchestration, the features upon which they operate to confer robustness to the ensemble signal are not known. To address this, we applied several methods to deconstruct the interactions between the spatial and temporal organisation of circadian oscillations in organotypic slices from mice with circadian abnormalities. We studied the SCN of mice lacking Cryptochrome genes (Cry1 and Cry2), which are essential for cell‐autonomous oscillation, and the SCN of mice lacking the vasoactive intestinal peptide receptor 2 (VPAC2‐null), which is necessary for circuit‐level integration, in order to map biological mechanisms to the revealed oscillatory features. The SCN of wild‐type mice showed a strong link between the temporal rhythm of the bioluminescence profiles of PER2::LUC and regularly repeated spatially organised oscillation. The Cry‐null SCN had stable spatial organisation but lacked temporal organisation, whereas in VPAC2‐null SCN some specimens exhibited temporal organisation in the absence of spatial organisation. The results indicated that spatial and temporal organisation were separable, that they may have different mechanistic origins (cell‐autonomous vs. interneuronal signaling) and that both were necessary to maintain robust and organised circadian rhythms throughout the SCN. This study therefore provided evidence that the coherent emergent properties of the neuronal circuitry, revealed in the spatially organised clusters, were essential to the pacemaking function of the SCN.

Modeling the Behavior of Coupled Cellular Circadian Oscillators in the Suprachiasmatic Nucleus

The suprachiasmatic nucleus (SCN) in the hypothalamus is the site of the master circadian clock in mammals, a complex tissue composed of multiple, coupled, single-cell circadian oscillators. Mathematical modeling is now providing insights on how individual SCN cells might interact and assemble to create an integrated pacemaker that governs the circadian behavior of whole animals. In this article, we will discuss the neurobiological constraints for modeling SCN behavior, system precision, implications of cellular heterogeneity, and analysis of heterogeneously coupled oscillator networks. Mathematical approaches will be critical for better understanding intercellular interactions within the SCN.

Novelty Enhances Visual Salience Independently of Reward in the Parietal Lobe

Novelty modulates sensory and reward processes, but it remains unknown how these effects interact, i.e., how the visual effects of novelty are related to its motivational effects. A widespread hypothesis, based on findings that novelty activates reward-related structures, is that all the effects of novelty are explained in terms of reward. According to this idea, a novel stimulus is by default assigned high reward value and hence high salience, but this salience rapidly decreases if the stimulus signals a negative outcome. Here we show that, contrary to this idea, novelty affects visual salience in the monkey lateral intraparietal area (LIP) in ways that are independent of expected reward. Monkeys viewed peripheral visual cues that were novel or familiar (received few or many exposures) and predicted whether the trial will have a positive or a negative outcome—i.e., end in a reward or a lack of reward. We used a saccade-based assay to detect whether the cues automatically attracted or repelled attention from their visual field location. We show that salience—measured in saccades and LIP responses—was enhanced by both novelty and positive reward associations, but these factors were dissociable and habituated on different timescales. The monkeys rapidly recognized that a novel stimulus signaled a negative outcome (and withheld anticipatory licking within the first few presentations), but the salience of that stimulus remained high for multiple subsequent presentations. Therefore, novelty can provide an intrinsic bonus for attention that extends beyond the first presentation and is independent of physical rewards.

Parietal neurons encode expected gains in instrumental information

Significance We examine how the brain guides active sensing in awake, behaving primates using a paradigm in which information sampling is dissociated from reinforcement variables, such as cumulative future reward or reward prediction errors. We show that target selective cells in lateral intraparietal cortex encode decision variables based on expected gains in instrumental information—the extent to which a visual cue, when discriminated, is expected to reduce the uncertainty of a subsequent action. In natural behavior, animals have access to multiple sources of information, but only a few of these sources are relevant for learning and actions. Beyond choosing an appropriate action, making good decisions entails the ability to choose the relevant information, but fundamental questions remain about the brain’s information sampling policies. Recent studies described the neural correlates of seeking information about a reward, but it remains unknown whether, and how, neurons encode choices of instrumental information, in contexts in which the information guides subsequent actions. Here we show that parietal cortical neurons involved in oculomotor decisions encode, before an information sampling saccade, the reduction in uncertainty that the saccade is expected to bring for a subsequent action. These responses were distinct from the neurons’ visual and saccadic modulations and from signals of expected reward or reward prediction errors. Therefore, even in an instrumental context when information and reward gains are closely correlated, individual cells encode decision variables that are based on informational factors and can guide the active sampling of action-relevant cues.

The object advantage can be eliminated under equiluminant conditions

A key phenomenon supporting the existence of object-based attention is the object advantage, in which responses are faster for within-object, relative to equidistant between-object, shifts of attention. The origins of this effect have been variously ascribed to low-level “bottom-up” sensory processing and to a cognitive “top-down” strategy of within-object attention prioritization. The degree to which the object advantage depends on lower-level sensory processing was examined by differentially stimulating the magnocellular (M) and parvocellular (P) retino-geniculo-cortical visual pathways by using equiluminant and nonequiluminant conditions. We found that the object advantage can be eliminated when M activity is reduced using psychophysically equiluminant stimuli. This novel result in normal observers suggests that the origin of the object advantage is found in lower-level sensory processing rather than a general cognitive process, which should not be so sensitive to differential activation of the bottom-up P and M pathways. Eliminating the object advantage while maintaining a spatial-cueing advantage with reduced M activity suggests that the notion of independent M-driven spatial attention and P-driven object attention requires revision.