Voluntary exercise can strengthen the circadian system in aged mice

Consistent daily rhythms are important to healthy aging according to studies linking disrupted circadian rhythms with negative health impacts. We studied the effects of age and exercise on baseline circadian rhythms and on the circadian system's ability to respond to the perturbation induced by an 8 h advance of the light:dark (LD) cycle as a test of the system's robustness. Mice (male, mPer2luc/C57BL/6) were studied at one of two ages: 3.5 months (n = 39) and >18 months (n = 72). We examined activity records of these mice under entrained and shifted conditions as well as mPER2::LUC measures ex vivo to assess circadian function in the suprachiasmatic nuclei (SCN) and important target organs. Age was associated with reduced running wheel use, fragmentation of activity, and slowed resetting in both behavioral and molecular measures. Furthermore, we observed that for aged mice, the presence of a running wheel altered the amplitude of the spontaneous firing rate rhythm in the SCN in vitro. Following a shift of the LD cycle, both young and aged mice showed a change in rhythmicity properties of the mPER2::LUC oscillation of the SCN in vitro, and aged mice exhibited longer lasting internal desynchrony. Access to a running wheel alleviated some age-related changes in the circadian system. In an additional experiment, we replicated the effect of the running wheel, comparing behavioral and in vitro results from aged mice housed with or without a running wheel (>21 months, n = 8 per group, all examined 4 days after the shift). The impact of voluntary exercise on circadian rhythm properties in an aged animal is a novel finding and has implications for the health of older people living with environmentally induced circadian disruption

In Synch but Not in Step: Circadian Clock Circuits Regulating Plasticity in Daily Rhythms

The suprachiasmatic nucleus (SCN) is a network of neural oscillators that program daily rhythms in mammalian behavior and physiology. Over the last decade much has been learned about how SCN clock neurons coordinate together in time and space to form a cohesive population. Despite this insight, much remains unknown about how SCN neurons communicate with one another to produce emergent properties of the network. Here we review the current understanding of communication among SCN clock cells and highlight a collection of formal assays where changes in SCN interactions provide for plasticity in the waveform of circadian rhythms in behavior. Future studies that pair analytical behavioral assays with modern neuroscience techniques have the potential to provide deeper insight into SCN circuit mechanisms

Global neural rhythm control by local neuromodulation

Neural oscillations are a ubiquitous form of neural activity seen across scales and modalities. These neural rhythms correlate with diverse cognitive functions and brain states. One mechanism for changing the oscillatory dynamics of large neuronal populations is through neuromodulator activity. An intriguing phenomenon explored here is when local neuromodulation of a distinct neuron type within a single brain nucleus exerts a powerful influence on global cortical rhythms. One approach to investigate the impact of local circuits on global rhythms is through optogenetic techniques. My first project involves the statistical analysis of electrophysiological recordings of an optogenetically-mediated Parkinsonian phenotype. Empirical studies demonstrate that Parkinsonian motor deficits correlate with the emergence of exaggerated beta frequency (15-30 Hz) oscillations throughout the cortico-basal ganglia-thalamic network. However, the mechanism of these aberrant oscillatory dynamics is not well understood. A previous modeling study predicted that cholinergic neuromodulation of medium spiny neurons in the striatum of the basal ganglia may mediate the pathologic beta rhythm. Here, this hypothesis was tested using selective optogenetic stimulation of striatal cholinergic interneurons in normal mice; stimulation robustly and reversibly amplified beta oscillations and Parkinsonian motor symptoms. The modulation of global rhythms by local networks was further studied using computational modeling in the context of intrathalamic neuromodulation. While intrathalamic vasoactive intestinal peptide (VIP) is known to cause long-lasting excitation in vitro, its in vivo dynamical effects have not been reported. Here, biophysical computational models were used to elucidate the impact of VIP on thalamocortical dynamics during sleep and propofol general anesthesia. The modeling results suggest that VIP can form robust sleep spindle oscillations and control aspects of sleep architecture through a novel homeostatic mechanism. This homeostatic mechanism would be inhibited by general anesthesia, representing a new mechanism contributing to anesthetic-induced loss of consciousness. While the previous two projects differed in their use of empirical versus theoretical methods, a challenge common to both domains is the difficulty in visualizing and analyzing large multi-dimensional datasets. A tool to mitigate these issues is introduced here: GIMBL-Vis is a Graphical Interactive Multi-dimensional extensiBLe Visualization toolbox for Matlab. This toolbox simplifies the process of exploring multi-dimensional data in Matlab by providing a graphical interface for visualization and analysis. Furthermore, it provides an extensible open platform for distributed development by the community

Making Memories: Why Time Matters

In the last decade advances in human neuroscience have identified the critical importance of time in creating long-term memories. Circadian neuroscience has established biological time functions via cellular clocks regulated by photosensitive retinal ganglion cells and the suprachiasmatic nuclei. Individuals have different circadian clocks depending on their chronotypes that vary with genetic, age, and sex. In contrast, social time is determined by time zones, daylight savings time, and education and employment hours. Social time and circadian time differences can lead to circadian desynchronization, sleep deprivation, health problems, and poor cognitive performance. Synchronizing social time to circadian biology leads to better health and learning, as demonstrated in adolescent education. In-day making memories of complex bodies of structured information in education is organized in social time and uses many different learning techniques. Research in the neuroscience of long-term memory (LTM) has demonstrated in-day time spaced learning patterns of three repetitions of information separated by two rest periods are effective in making memories in mammals and humans. This time pattern is based on the intracellular processes required in synaptic plasticity. Circadian desynchronization, sleep deprivation, and memory consolidation in sleep are less well-understood, though there has been considerable progress in neuroscience research in the last decade. The interplay of circadian, in-day and sleep neuroscience research are creating an understanding of making memories in the first 24-h that has already led to interventions that can improve health and learning

Maturation trajectories of cortical resting-state networks depend on the mediating frequency band

The functional significance of resting state networks and their abnormal manifestations in psychiatric disorders are firmly established, as is the importance of the cortical rhythms in mediating these networks. Resting state networks are known to undergo substantial reorganization from childhood to adulthood, but whether distinct cortical rhythms, which are generated by separable neural mechanisms and are often manifested abnormally in psychiatric conditions, mediate maturation differentially, remains unknown. Using magnetoencephalography (MEG) to map frequency band specific maturation of resting state networks from age 7 to 29 in 162 participants (31 independent), we found significant changes with age in networks mediated by the beta (13–30 Hz) and gamma (31–80 Hz) bands. More specifically, gamma band mediated networks followed an expected asymptotic trajectory, but beta band mediated networks followed a linear trajectory. Network integration increased with age in gamma band mediated networks, while local segregation increased with age in beta band mediated networks. Spatially, the hubs that changed in importance with age in the beta band mediated networks had relatively little overlap with those that showed the greatest changes in the gamma band mediated networks. These findings are relevant for our understanding of the neural mechanisms of cortical maturation, in both typical and atypical development.This work was supported by grants from the Nancy Lurie Marks Family Foundation (TK, SK, MGK), Autism Speaks (TK), The Simons Foundation (SFARI 239395, TK), The National Institute of Child Health and Development (R01HD073254, TK), National Institute for Biomedical Imaging and Bioengineering (P41EB015896, 5R01EB009048, MSH), and the Cognitive Rhythms Collaborative: A Discovery Network (NFS 1042134, MSH). (Nancy Lurie Marks Family Foundation; Autism Speaks; SFARI 239395 - Simons Foundation; R01HD073254 - National Institute of Child Health and Development; P41EB015896 - National Institute for Biomedical Imaging and Bioengineering; 5R01EB009048 - National Institute for Biomedical Imaging and Bioengineering; NFS 1042134 - Cognitive Rhythms Collaborative: A Discovery Network

The Role of VIP SCN Neurons in Circadian Physiology and Behavior

Located in the ventral hypothalamus, the suprachiasmatic nucleus (SCN) is necessary for entraining daily rhythms in physiology and behavior to environmental cues. Though the 20,000 neurons of the SCN uniformly express GABA, they differ greatly in neuropeptide content. One anatomically and functionally distinct class of neuropeptidergic SCN neurons is vasoactive intestinal polypeptide (VIP). Expressed by approximately 10% of SCN neurons, VIP is necessary for synchronizing single-cell SCN rhythms to produce coherent output and sufficient for entrainment. However, little is known about the firing activity of these neurons releases VIP and results in circadian entrainment. We utilized multielectrode array technology and optogenetics to optically tag VIP neurons expressing Channelrhodopsin-2 (ChR2) following three days of spontaneous activity recordings. We find that VIP neurons have circadian firing rates with two distinct patterns, irregular and tonic, that constitute two separate electrophysiological classes. Using optogenetic stimulation in vitro and in vivo, we show that high frequency firing intervals are sufficient to phase shift and entrain circadian rhythms in gene expression and locomotor activity through VIP release. Interestingly, low frequency firing intervals do not phase shift the SCN in vitro and entrain behavioral rhythms more gradually. We also find that stimulation of VIP neurons can only phase delay and entrain rhythms during late subjective day and early subjective night. We conclude that VIP neurons entrain behavior in a time-of-day- and frequency- dependent manner. Complementary to testing the sufficiency of VIP neuronal firing for entrainment, we tested the necessity of VIP neurons for circadian rhythms in the adult SCN circuit. Using Cre-lox technology in vivo, we triggered adult-onset apoptosis in VIP SCN neurons. We found that over 80% of these mice retained circadian rhythms. We contrast this to Vip null mice, where over 60% lose rhythms. A majority of our mice lacking VIP neurons had decreased locomotor activity periods and increased daily onset variability, which strongly correlated with the intensity of VIP staining. In vitro, deletion of VIP neurons leads to a dramatically reduced amplitude of circadian gene expression and decreases in synchrony on the single-cell level. We conclude that the difference between adult deletion of VIP neurons and Vip null mice suggests a role for VIP in SCN development and in the developed adult circuit VIP neurons are not necessary for rhythmicity. Finally, we dissected the role of VIP SCN neurons in the daily rhythms in glucocorticoids, by characterizing the anatomy of VIP projections and testing the necessity of VIP neurons. We labeled VIP SCN neurons that project dorsally to the paraventricular nucleus of the hypothalamus (PVN) using a two-color tract tracing experiment. We concluded that a small bilateral subset of VIP SCN neurons projects to each side of the PVN. To test VIP neurons function, we deleted VIP SCN neurons in the adult and measured corticosterone rhythms under constant conditions for 2 days. We find that rhythms in corticosterone are severely dampened with the loss of VIP neurons with peak corticosterone only reaching approximately 50% of wild- type levels. We conclude that VIP SCN neurons contribute stimulatory input to the circadian rhythm in corticosterone. Taken together, these data suggest that VIP SCN neurons are a heterogeneous class of SCN neurons with multiple roles in adult SCN entrainment, development and the regulation of glucocorticoid rhythms

Hierarchy, not lexical regularity, modulates low-frequency neural synchrony during language comprehension

Neural responses appear to synchronize with sentence structure. However, researchers have debated whether this response in the delta band (0.5 - 3 Hz) really reflects hierarchical information, or simply lexical regularities. Computational simulations in which sentences are represented simply as sequences of high-dimensional numeric vectors that encode lexical information seem to give rise to power spectra similar to those observed for sentence synchronization, suggesting that sentence-level cortical tracking findings may reflect sequential lexical or part-of-speech information, and not necessarily hierarchical syntactic information. Using electroencephalography (EEG) data and the frequency-tagging paradigm, we develop a novel experimental condition to tease apart the predictions of the lexical and the hierarchical accounts of the attested low-frequency synchronization. Under a lexical model, synchronization should be observed even when words are reversed within their phrases (e.g. "sheep white grass eat" instead of "white sheep eat grass"), because the same lexical items are preserved at the same regular intervals. Critically, such stimuli are not syntactically well-formed, thus a hierarchical model does not predict synchronization of phrase- and sentence-level structure in the reversed phrase condition. Computational simulations confirm these diverging predictions. EEG data from N = 31 native speakers of Mandarin show robust delta synchronization to syntactically well-formed isochronous speech. Importantly, no such pattern is observed for reversed phrases, consistent with the hierarchical, but not the lexical, accounts

Diagrams as Vehicles for Scientific Reasoning

We argue that diagrams are not just a communicative tool but play important roles in the reasoning of biologists: in characterizing the phenomenon to be explained, identifying explanatory relations, and developing an account of the responsible mechanism. In the first two tasks diagrams facilitate applying visual processing to the detection of patterns that constitute phenomena or explanatory relations. Diagrams of a mechanism serve to guide reasoning about what parts and operations are needed and how potential parts of the mechanism are related to each other. Further they guide the development of computational models used to determine how the mechanism will behave. We illustrate each of these uses of diagrams with examples from research on circadian rhythm