Biology subjects

Burke, S. N.

Publications and source records attributed to Burke, S. N..

At least 19 recordsLinked to original sources

bioRxiv2024

Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats

Many of the hallmarks of aging involve alterations in cellular and organismal metabolism. One pathway with the potential to impact several traditional markers of impaired function with aging is the PI3K/AKT metabolic pathway. Regulation of this pathway includes many aspects of cellular function, including protein synthesis, proliferation and survival, as well as many downstream targets, including mTOR and FOXOs. Importantly, this pathway is pivotal to the function of every organ system in the human body. Thus, we investigated the expression of several genes along this pathway in multiple organs, including the brain, liver and skeletal muscle, in aged subjects that had been on different experimental diets to regulate metabolic function since mid-life. Specifically, rats were fed a control ad lib diet (AL), a time restricted feeding diet (cTRF), or a time restricted feeding diet with ketogenic macronutrients (kTRF) for the majority of their adult lives (from 8-25 months). We previously reported that regardless of macronutrient ratio, TRF-fed rats in both macronutrient groups required significantly less training to acquire a biconditional association task than their ad lib fed counterparts. The current experiments expand on this work by quantifying metabolism-related gene expression across tissues and interrogating for potential relationships with cognitive performance. AKT expression was significantly reduced in kTRF fed rats within liver and muscle tissue. However, AKT expression within the perirhinal cortex (PER) was higher in kTRF rats with the best cognitive performance. Within CA3, higher levels of FOXO1 gene expression correlated with poorer cognitive performance in ad libitum fed rats. Together, these data demonstrate diet- and tissue-specific alterations in metabolism-related gene expression and their correlation with cognitive status.

neuroscience↗

bioRxiv2023

MetaVision3D: Automated framework for the Generation of Spatial Metabolome Atlas in 3D

High-resolution spatial imaging is transforming our understanding of foundational biology. Spatial metabolomics is an emerging field that enables the dissection of the complex metabolic landscape and heterogeneity from a thin tissue section. Currently, spatial metabolism highlights the remarkable complexity in two-dimensional space and is poised to be extended into the three-dimensional world of biology. Here, we introduce MetaVision3D, a novel pipeline driven by computer vision techniques for the transformation of serial 2D MALDI mass spectrometry imaging sections into a high-resolution 3D spatial metabolome. Our framework employs advanced algorithms for image registration, normalization, and interpolation to enable the integration of serial 2D tissue sections, thereby generating a comprehensive 3D model of unique diverse metabolites across host tissues at mesoscale. As a proof of principle, MetaVision3D was utilized to generate the mouse brain 3D metabolome atlas (available at https://metavision3d.rc.ufl.edu/) as an interactive online database and web server to further advance brain metabolism and related research.

neuroscience↗

bioRxiv2023

Spatial Metabolome Lipidome and Glycome from a Single brain Section

Metabolites, lipids, and glycans are fundamental biomolecules involved in complex biological systems. They are metabolically channeled through a myriad of pathways and molecular processes that define the physiology and pathology of an organism. Here, we present a blueprint for the simultaneous analysis of spatial metabolome, lipidome, and glycome from a single tissue section using mass spectrometry imaging. Complimenting an original experimental protocol, our workflow includes a computational framework called Spatial Augmented Multiomics Interface (Sami) that offers multiomics integration, high dimensionality clustering, spatial anatomical mapping with matched multiomics features, and metabolic pathway enrichment to providing unprecedented insights into the spatial distribution and interaction of these biomolecules in mammalian tissue biology.

systems biology↗

bioRxiv2023

A long-term ketogenic diet in young and aged rats has dissociable effects on prelimbic cortex and CA3 ensemble activity

Age-related cognitive decline has been linked to distinct patterns of cellular dysfunction in the prelimbic cortex (PL) and the CA3 subregion of the hippocampus. Because higher cognitive functions require both structures, selectively targeting a neurobiological change in one region, at the expense of the other, is not likely to restore normal behavior in older animals. One change with age that both the PL and CA3 share, however, is a reduced ability to utilize glucose, which can produce aberrant neural activity patterns. The current study used a ketogenic diet (KD) intervention, which reduces the brains reliance on glucose, and has been shown to improve cognition, as a metabolic treatment for restoring neural ensemble dynamics in aged rats. Expression of the immediate-early genes Arc and Homer1a were used to quantify the neural ensembles that were active in the home cage prior to behavior, during a working memory/biconditional association task, and a continuous spatial alternation task. Aged rats on the control diet had increased activity in CA3 and less ensemble overlap in PL between different task conditions than did the young animals. In the PL, the KD was associated with increased activation of neurons in the superficial cortical layers. The KD did not lead to any significant changes in CA3 activity. These observations suggest that the KD does not restore neuron activation patterns in aged animals, but rather the availability of ketone bodies in the frontal cortices may permit the engagement of compensatory mechanisms that produce better cognitive outcomes. Significance StatementThis study extends understanding of how a ketogenic diet (KD) intervention may improve cognitive function in older adults. Young and aged rats were given 3 months of a KD or a calorie-match control diet and then expression of the immediate-early genes Arc and Homer1a were measured to examine neural ensemble dynamics during cognitive testing. The KD diet was associated with increased activation of neurons in the superficial layers of the PL, but there were no changes in CA3. These observations are significant because they suggest that compensatory mechanisms for improving cognition are engaged in the presence of elevated ketone bodies. This metabolic shift away from glycolysis can meet the energetic needs of the frontal cortices when glucose utilization is compromised.

neuroscience↗

bioRxiv2022

Unilateral Perforant Path Transection Does Not Alter Lateral Entorhinal Cortical or Hippocampal CA3 Arc Expression

It is well established that degradation of perforant path fibers is associated with age-related cognitive dysfunction and CA3 hyperactivity. Whether this fiber loss triggers a cascade of other functional changes within the hippocampus circuit has not been causatively established, however. Thus, the current study evaluated the effect of perforant path fiber loss on neuronal activity in CA3 and layer II of the lateral entorhinal cortex (LEC) in relation to mnemonic similarity task performance. Expression of the immediate early gene Arc was quantified in rats that received a unilateral right hemisphere transection of the perforant path or sham surgery that cut the cortex but left the fibers intact. Behavior-related expression of Arc mRNA was measured to test the hypothesis that fiber loss leads to elevated activation of CA3 and LEC neurons, as previously observed in aged rats that were impaired on the mnemonic similarity task. Transection of perforant path fibers, which has previously been shown to lead to a decline in mnemonic similarity task performance, did not alter Arc expression. Arc expression in CA3, however, was correlated with task performance on the more difficult discrimination trials across both surgical groups. These observations further support a link between CA3 activity and mnemonic similarity task performance but suggest the reduced input from the entorhinal cortex to the hippocampus, as observed in old age, does not causatively elevate CA3 activity.

neuroscience↗

bioRxiv2022

Paired Associates Learning is Disrupted After Unilateral Parietal Lobe Controlled Cortical Impact in Rats: A Trial-by-Trial Behavioral Analysis

Approximately 60-70 million people suffer from a traumatic brain injury (TBI) each year. As animal models continue to be paramount in understanding and treating cognitive impairment following TBI, the necessity of testing intervention strategies in clinically relevant settings cannot be ignored. This study used a unilateral parietal lobe controlled cortical impact (CCI) model of TBI and tested rats on a touchscreen-based associative learning task, Paired Associates Learning (PAL). In humans, PAL has been used to assess cognitive deficits in stimulus-location association in a multitude of disease states, including TBI. To date, the extent to which a rat model of TBI produces deficits in PAL has not yet been reported, although the usage of PAL will be important for understanding the clinical consequences of cognitive impairment post-injury and throughout intervention treatment. This study details the behavioral and histological consequences of the CCI injury model and closes a translational research gap between basic and clinical TBI research. HIGHLIGHTSO_LIPAL performance declines in a rat model of TBI. C_LIO_LIResponse-driven bias in PAL becomes elevated after TBI. C_LIO_LIInflammatory microglial response in the thalamus correlates with PAL deficit. C_LI

animal behavior and cognition↗

bioRxiv2021

Advanced Age Has Dissociable Effects on Hippocampal CA1 and CA3 Ripples

Sharp-wave/ripples are brief, high-frequency events in hippocampal subregions CA3 and CA1 that occur during rest or pauses in behavior. Ripples detected in CA1 have lower frequency in aged compared to young rats. Although CA1 ripples are theorized to manifest from CA3, ripple dynamics in CA3 have not been examined in aged animals. The current study obtained simultaneous recordings between CA1 and CA3 in young and aged rats to examine sharp-wave/ripple characteristics in both regions in relation to age. While CA1 ripple frequency was reduced with age, there were no age differences in CA3 ripples. In aged, but not young, rats there was also a significant increase in the probability of CA3 and CA1 ripples co-occurring between the pre- and post-behavior rest epochs. Moreover, in both age groups, CA1 ripples that co-occurred with a CA3 ripple had increased frequency, power, and duration. These findings suggest age differences in CA1 are not due to altered afferent input from CA3, but instead reflect distinct mechanisms of ripple generation with age. HIGHLIGHTSO_LICA1 ripple frequency is reduced with age. C_LIO_LICA3 ripple characteristics do not change with age. C_LIO_LIIn aged rats only, CA3-CA1 ripple co-occurrence increased following behavior. C_LIO_LICA1 ripples that co-occurred with CA3 had greater frequency, power, and duration. C_LI

animal behavior and cognition↗

bioRxiv2020

Spectrum Degradation of Hippocampal LFP during Euthanasia

AO_SCPLOWBSTRACTC_SCPLOWThe hippocampal local field potential (LFP) exhibits a strong correlation with behavior. During rest, the theta rhythm is not prominent, but during active behavior, there are strong rhythms in the theta, theta harmonics, and gamma ranges. With increasing running velocity, theta, theta harmonics and gamma increase in power and in cross-frequency coupling, suggesting that neural entrainment is a direct consequence of the total excitatory input. While it is common to study the parametric range between the LFP and its complementing power spectra between deep rest and epochs of high running velocity, it is also possible to explore how the spectra degrades as the energy is completely quenched from the system. Specifically, it is unknown whether the 1/f slope is preserved as synaptic activity becomes diminished, as low frequencies are generated by large pools of neurons while higher frequencies comprise the activity of more local neuronal populations. To test this hypothesis, we examined rat LFPs recorded from the hippocampus and entorhinal cortex during barbiturate overdose euthanasia. Within the hippocampus, the initial stage entailed a quasi-stationary stage when the LFP spectrum exhibited power-law feature while the frequency components over 20 Hz exhibited a power decay with a similar decay rate. This stage was followed by a rapid collapse of power spectrum towards the absolute electrothermal noise background. As the collapse of activity occurred later in hippocampus compared with medial entorhinal cortex or visual cortex, it suggests that the ability of a neural network to maintain the 1/f slope with decreasing energy is a function of general connectivity. Broadly, these data support the energy cascade theory where there is a cascade of energy from large cortical populations into smaller loops, such as those that supports the higher frequency gamma rhythm. As energy is pulled from the system, neural entrainment at gamma frequency (and higher) decline first. The larger loops, comprising a larger population, are fault-tolerant to a point capable of maintaining their activity before a final collapse.

neuroscience↗

bioRxiv2020

Age-related alterations in prelimbic cortical neuron Arc expression vary by behavioral state and cortical layer

Prefrontal cortical and medial temporal lobe connectivity is critical for higher cognitive functions that decline in older adults. Likewise, these cortical areas are among the first to show anatomical, functional, and biochemical alterations in advanced age. The prelimbic subregion of the prefrontal cortex and the perirhinal cortex of the medial temporal lobe are densely reciprocally connected and well-characterized as undergoing age-related neurobiological changes that correlate with behavioral impairment. Despite this fact, it remains to be determined how changes within these brain regions manifest as alterations in their functional connectivity. In our previous work, we observed an increased probability of age-related dysfunction for perirhinal cortical neurons that projected to the prefrontal cortex in old rats compared to neurons that were not identified as projection neurons. The current study was designed to investigate the extent to which aged prelimbic cortical neurons also had altered patterns of Arc expression during behavior, and if this was more evident in those cells that had long-range projections to the perirhinal cortex. The expression patterns of the immediate-early gene Arc were quantified in behaviorally characterized rats that also received the retrograde tracer cholera toxin B (CTB) in the perirhinal cortex to identify projection neurons to this region. As in our previous work, the current study found that CTB+ cells were more active than those that did not have the tracer. Moreover, there were age-related reductions in prelimbic cortical neuron Arc expression that correlated with a reduced ability of aged rats to multitask. Unlike the perirhinal cortex, however, the age-related reduction in Arc expression was equally likely in CTB+ and CTB- negative cells. Thus, the selective vulnerability of neurons with long-range projections to dysfunction in old age may be a unique feature of the perirhinal cortex. Together, these observations identify a mechanism involving prelimbic-perirhinal cortical circuit disruption in cognitive aging.

neuroscience↗

bioRxiv2020

Rodent mnemonic similarity task performance requires the prefrontal cortex

Mnemonic similarity task performance, in which a known target stimulus must be distinguished from similar lures, is supported by the hippocampus and perirhinal cortex and is known to decline in advanced age. Interestingly, disrupting hippocampal activity leads to mnemonic discrimination impairments when lures are novel, but not when they are familiar. This observation suggests other brain structures can support discrimination abilities as stimuli are learned. The prefrontal cortex (PFC) is critical for retrieval of remote events and executive functions, such as working memory, and is also particularly vulnerable to dysfunction in aging. Importantly, the medial PFC is reciprocally connected to the perirhinal cortex and neuron firing in this region coordinates communication between lateral entorhinal and perirhinal cortices to presumably modulate hippocampal activity. This anatomical organization and function of the medial PFC suggests that it contributes to mnemonic discrimination; however, this notion has not been empirically tested. In the current study, young adult male and female F344 x Brown Norway F1 hybrid rats were trained on a rodent object-based mnemonic similarity task, and surgically implanted with guide cannulae targeting prelimbic and infralimbic regions of the medial PFC. Prior to mnemonic discrimination tests, rats received PFC infusions of the GABAA agonist muscimol. Analyses of expression of the neuronal activity-dependent immediate-early gene Arc in medial PFC and adjacent cortical regions confirmed muscimol infusions led to neuronal inactivation in the infralimbic and prelimbic cortices. Moreover, muscimol infusions in PFC impaired mnemonic discrimination performance relative to the vehicle control across all testing blocks when lures shared 50-90% feature overlap with the target. Thus, in contrast to prior results from rats given hippocampal muscimol infusions, PFC inactivation impaired target-lure discrimination regardless of the novelty or familiarity of the lures. These findings indicate the PFC plays a critical role in mnemonic similarity task performance, but the time course of PFC involvement is dissociable from that of the hippocampus.

neuroscience↗

bioRxiv2020

Time-restricted feeding from adulthood to old age improves biconditional associative learning in geriatric rats regardless of macronutrient composition

Declining health and cognition are hallmarks of advanced age that reduce both the quality and length of the lifespan. While caloric restriction has been highlighted as a dietary intervention capable of improving the healthspan by restoring metabolic function in late life, time-restricted feeding and changes in dietary macronutrient composition may be more feasible alternatives with similar health outcomes. To investigate the potential of these two interventions, a pilot cohort of fully mature adult rats were placed on a time-restricted feeding regimen of a ketogenic or micronutrient and calorically matched control diet from 8 to 21 months of age. A third group of rats was permitted to eat standard chow ad libitum. At 22 months, all rats were then placed on time-restricted feeding and tested on a biconditional association task. While the data presented here are preliminary (small sample size of 3-4/diet group), additional animals are currently undergoing the feeding regimen, and will be added into the behavioral studies at a later date. For the current data, regardless of dietary composition, time-restricted-fed rats performed significantly better than ad libitum-fed rats. This observation could not be accounted for by differences in motivation, procedural or sensorimotor impairments, indicating that mid-life dietary interventions capable of preventing metabolic impairments may also serve to prevent age-related cognitive decline.

neuroscience↗

bioRxiv2019

Metabolic switching is impaired by aging and facilitated by ketosis independent of glycogen

The ability to switch between glycolysis and ketosis promotes survival by enabling metabolism through fat oxidation during periods of fasting. Carbohydrate restriction or stress can also elicit metabolic switching. Keto-adapting from glycolysis is delayed in aged rats, but factors mediating this age-related impairment have not been identified. We measured metabolic switching between glycolysis and ketosis, as well as glycogen dynamics, in young and aged rats undergoing time-restricted feeding (TRF) with a standard diet or a low carbohydrate ketogenic diet (KD). TRF alone reversed markers of insulin-related metabolic deficits and accelerated metabolic switching in aged animals. A KD+TRF, however, provided additive benefits on these variables. Remarkably, the ability to keto-adapt was not related to glycogen levels and KD-fed rats showed an enhanced elevation in glucose following epinephrine administration. This study provides new insights into the mechanisms of keto-adaptation demonstrating the utility of dietary interventions to treat metabolic impairments across the lifespan.

biochemistry↗

bioRxiv2019

Age and ketogenic diet have dissociable effects on synapse-related gene expression between hippocampal subregions

As the number of individuals living beyond the age of 65 is rapidly increasing, so is the need to develop strategies to combat the age-related cognitive decline that may threaten independent living. Although the link between altered neuronal signaling and age-related cognitive impairments is not completely understood, it is evident that declining cognitive abilities are at least partially due to synaptic dysfunction. Aging is accompanied by well-documented changes in both excitatory and inhibitory synaptic signaling across species. Age-related synaptic alterations are not uniform across the brain, however, with different regions showing unique patterns of vulnerability in advanced age. In the hippocampus, increased activity within the CA3 subregion has been observed across species, and this can be reversed with anti-epileptic medication (Bakker et al., 2012). In contrast to CA3, the dentate gyrus shows reduced activity with age and declining metabolic activity. Ketogenic diets have been shown to decrease seizure incidence and severity in epilepsy, improve metabolic function in diabetes type II, and improve cognitive function in aged rats. This link between neuronal activity and metabolism suggests that metabolic interventions may be able to ameliorate synaptic signaling deficits accompanying advanced age. We therefore investigated the ability of a dietary regimen capable of inducing nutritional ketosis and improving cognition to alter synapse-related gene expression across the dentate gyrus, CA3 and CA1 subregions of the hippocampus. Following 12 weeks of a ketogenic or calorie-matched standard diet, RTq-PCR was used to quantify expression levels of excitatory and inhibitory synaptic signaling genes within CA1, CA3 and dentate gyrus. While there were no age or diet-related changes in CA1 gene expression, expression levels were significantly altered within CA3 by age and within the dentate gyrus by diet for several genes involved in presynaptic glutamate regulation and postsynaptic excitation and plasticity. These data demonstrate subregion-specific alterations in synaptic signaling with age and the potential for a ketogenic diet to alter these processes in dissociable ways across different brain structures that are uniquely vulnerable in older animals.

neuroscience↗

bioRxiv2019

Sex Differences in Age-related Impairments Vary across Cognitive and Physical Assessments in Rats

Inclusion of female subjects in biomedical research is imperative for understanding the mechanisms of age-related cognitive decline, as more than half of individuals older than 65 are female. Few behavioral and physical assays, however, have been conducted in both sexes within the same study. In the current experiments young and aged male and female rats underwent a battery of cognitive and physical assessments to examine for potential sex and age differences. Physical performance was measured with a rotarod test of motor coordination, assessment of maximum grip strength and swim speed. While there were differences between males and females in rotarod and grip strength, there was also a clear age-dependent decline in physical performance in both sexes. Cognitive assessment included the Morris watermaze test of hippocampal dependent spatial navigation and a biconditional association task (BAT) with a working memory (WM) component. Notably, a similar BAT has previously been validated as a more sensitive assay of age-related cognitive decline than the watermaze in male rats, which is replicated here in both female and male rats. Furthermore, young and aged female rats both spent a similar percent of time in each estrus cycle phase and phase did not influence WM/BAT performance. In conclusion, robust age differences in biconditional association task performance are observed in both sexes with no need for increased cohort size. Thus, future studies utilizing similar behavioral paradigms should be representative of the human population they intend to model through the inclusion of female subjects.

neuroscience↗

bioRxiv2018

Experience-dependent effects of muscimol-induced hippocampal excitation on mnemonic discrimination

Memory requires similar episodes with overlapping features to be represented distinctly, a process that is disrupted in many clinical conditions as well as normal aging. Data from humans have linked this ability to activity in hippocampal CA3 and dentate gyrus (DG). While animal models have shown the perirhinal cortex is critical for disambiguating similar stimuli, hippocampal activity has not been causally linked to discrimination abilities. The goal of the current study was to determine how disrupting CA3/DG activity would impact performance on a rodent mnemonic discrimination task. Rats were surgically implanted with bilateral guide cannulae targeting dorsal CA3/DG. In Exp.1, the effect of intra-hippocampal muscimol on target-lure discrimination was assessed within subjects in randomized blocks. Muscimol initially impaired discrimination across all levels of target-lure similarity, but performance improved on subsequent test blocks irrespective of stimulus similarity and infusion condition. To clarify these results, Exp.2 examined whether prior experience with objects influenced the effect of muscimol on target-lure discrimination. Rats that received vehicle infusions in a first test block, followed by muscimol in a second block, did not show discrimination impairments for target-lure pairs of any similarity. In contrast, rats that received muscimol infusions in the first test block were impaired across all levels of target-lure similarity. Sustained effects of muscimol in disrupting behavioral performance after repeated infusions were verified in a spatial alternation task. At the conclusion of behavioral experiments, fluorescence in situ hybridization for the immediate-early genes Arc and Homer1a was used to determine the proportion of neurons active following muscimol infusion. Contrary to expectations, muscimol increased neural activity in DG. An additional experiment was carried out to quantify neural activity in naive rats that received an intra-hippocampal infusion of vehicle or muscimol. Results confirmed that muscimol led to DG excitation, likely through its actions on interneuron populations in hilar and molecular layers of DG and consequent disinhibition of principal cells. Taken together, our results suggest disruption of coordinated neural activity across the hippocampus impairs mnemonic discrimination when lure stimuli are novel.

neuroscience↗

bioRxiv2018

Multi-scale Imaging Reveals Aberrant Connectome Organization and Elevated Dorsal Striatal Arc Expression in Advanced Age

The functional connectome reflects a network architecture enabling adaptive behavior that becomes vulnerable in advanced age. The cellular mechanisms that contribute to altered functional connectivity in old age, however, are not known. Here we used a multi-scale imaging approach to link age-related changes in the functional connectome to altered expression of the activity-dependent immediate-early gene Arc as a function of training to multi-task. Aged behaviorally-impaired, but not young, rats had a subnetwork of increased connectivity between the anterior cingulate cortex and dorsal striatum. Moreover, the old rats had less stable rich club participation that increased with cognitive training. The altered functional connectome of aged rats was associated with a greater engagement of neurons in the dorsal striatum during cognitive multi-tasking. These findings point to aberrant large-scale functional connectivity in aged animals that is associated with altered cellular activity patterns within individual brain regions.

neuroscience↗

bioRxiv2018

Theta-Gamma Cascades and Running Speed

The local field potentials (LFPs) of the hippocampus are primarily generated by the spatiotemporal accretion of electrical currents via activated synapses. Oscillations in the hippocampal LFP at theta and gamma frequencies are prominent during awake-behavior and have demonstrated several behavioral correlates. In particular, both oscillations have been observed to increase in amplitude and frequency as a function of running velocity. Previous investigations, however, have examined the relationship between velocity and each of these oscillation bands separately. Based on energy cascade models where \"...perturbations of slow frequencies cause a cascade of energy dissipation at all frequency scales\" (Buzsaki 2006), we hypothesized that the cross-frequency interactions between theta and gamma should increase as a function of velocity. We examined these relationships across multiple layers of the CA1 subregion and found a reliable correlation between the power of theta and the power of gamma, indicative of an amplitude-amplitude relationship. Moreover, there was an increase in the coherence between the power of gamma and the phase of theta, demonstrating increased phase-amplitude coupling with velocity. Finally, at higher velocities, phase entrainment between theta and gamma becomes stronger. These results have important implications and provide new insights regarding how theta and gamma are integrated for neuronal circuit dynamics, with coupling strength determined by the excitatory drive within the hippocampus.

neuroscience↗

bioRxiv2018

Theta-gamma coupling: a nonlinear dynamical model

Cross-frequency coupling in the hippocampus has been hypothesized to support higher-cognition functions. While gamma modulation by theta is widely accepted, evidence of phase-coupling between the two frequency components is so far unconvincing. Our observations show that theta and gamma energy increases with rat speed, while the overall nonlinearity of the LFP trace also increases, suggesting that energy flow is fundamental for hippocampal dynamics. This contradicts current representations based on the Kuramoto phase model. Therefore, we propose a new approach, based on the three-wave equation, a universally-valid nonlinear-physics paradigm that synthesizes the effects of leading order, quadratic nonlinearity. The paradigm identifies bispectral analysis as the natural tool for investigating LFP cross-frequency coupling. Our results confirm the effectiveness of the approach by showing unambiguous coupling between theta and gamma. Bispectra features agree with predictions of the three-wave model, supporting the conclusion that cross-frequency coupling is a manifestation of nonlinear energy transfers.

neuroscience↗