Mathematical model of subthalamic nucleus neuron: Characteristic activity patterns and bifurcation analysis.

The subthalamic nucleus (STN) has an important role in the pathophysiology of the basal ganglia in Parkinson's disease. The ability of STN cells to generate bursting rhythms under either transient or sustained hyperpolarization may underlie the excessively synchronous beta rhythms observed in Parkinson's disease. In this study, we developed a conductance-based single compartment model of an STN neuron, which is able to generate characteristic activity patterns observed in experiments including hyperpolarization-induced bursts and post-inhibitory rebound bursts. This study focused on the role of three currents in rhythm generation: T-type calcium (CaT) current, L-type calcium (CaL) current, and hyperpolarization-activated cyclic nucleotide-gated (HCN) current. To investigate the effects of these currents in rhythm generation, we performed a bifurcation analysis using slow variables in these currents. Bifurcation analysis showed that the HCN current promotes single-spike activity patterns rather than bursting in agreement with experimental results. It also showed that the CaT current is necessary for characteristic bursting activity patterns. In particular, the CaT current enables STN neurons to generate these activity patterns under hyperpolarizing stimuli. The CaL current enriches and reinforces these characteristic activity patterns. In hyperpolarization-induced bursts or post-inhibitory rebound bursts, the CaL current allows STN neurons to generate long bursting patterns. Thus, the bifurcation analysis explained the synergistic interaction of the CaT and CaL currents, which enables STN neurons to respond to hyperpolarizing stimuli in a salient way. The results of this study implicate the importance of CaT and CaL currents in the pathophysiology of the basal ganglia in Parkinson's disease.

Temporal patterns of synchrony in a pyramidal-interneuron gamma (PING) network.

Synchronization in neural systems plays an important role in many brain functions. Synchronization in the gamma frequency band (30-100 Hz) is involved in a variety of cognitive phenomena; abnormalities of the gamma synchronization are found in schizophrenia and autism spectrum disorder. Frequently, the strength of synchronization is not high, and synchronization is intermittent even on short time scales (few cycles of oscillations). That is, the network exhibits intervals of synchronization followed by intervals of desynchronization. Neural circuit dynamics may show different distributions of desynchronization durations even if the synchronization strength is fixed. We use a conductance-based neural network exhibiting pyramidal-interneuron gamma rhythm to study the temporal patterning of synchronized neural oscillations. We found that changes in the synaptic strength (as well as changes in the membrane kinetics) can alter the temporal patterning of synchrony. Moreover, we found that the changes in the temporal pattern of synchrony may be independent of the changes in the average synchrony strength. Even though the temporal patterning may vary, there is a tendency for dynamics with short (although potentially numerous) desynchronizations, similar to what was observed in experimental studies of neural synchronization in the brain. Recent studies suggested that the short desynchronizations dynamics may facilitate the formation and the breakup of transient neural assemblies. Thus, the results of this study suggest that changes of synaptic strength may alter the temporal patterning of the gamma synchronization as to make the neural networks more efficient in the formation of neural assemblies and the facilitation of cognitive phenomena.

Temporal patterns of dispersal-induced synchronization in population dynamics.

The mechanisms and properties of synchronization of oscillating ecological populations attract attention because it is a fairly common phenomenon and because spatial synchrony may elevate a risk of extinction and may lead to other environmental impacts. Conditions for stable synchronization in a system of linearly coupled predator-prey oscillators have been considered in the past. However, the spatial dispersal coupling may be relatively weak and may not necessarily lead to a stable, complete synchrony. If the coupling between oscillators is too weak to induce a stable synchrony, oscillators may be engaged into intermittent synchrony, when episodes of synchronized dynamics are interspersed with the episodes of desynchronized dynamics. In the present study we consider the temporal patterning of this kind of intermittent synchronized dynamics in a system of two dispersal-coupled Rosenzweig-MacArthur predator-prey oscillators. We consider the properties of the distributions of durations of desynchronized intervals and their dependence on the model parameters. We show that the temporal patterning of synchronous dynamics (an ecological network phenomenon) may depend on the properties of individual predator-prey patch (individual oscillator) and may vary independently of the strength of dispersal. We also show that if the dynamics of predator is slow relative to the dynamics of the prey (a situation that may promote brief but large outbreaks), dispersal-coupled predator-prey oscillating populations exhibit numerous short desynchronizations (as opposed to few long desynchronizations) and may require weaker dispersal in order to reach strong synchrony.

Interaction of synchronized dynamics in cortex and basal ganglia in Parkinson's disease.

Parkinson's disease pathophysiology is marked by increased oscillatory and synchronous activity in the beta frequency band in cortical and basal ganglia circuits. This study explores the functional connections between synchronized dynamics of cortical areas and synchronized dynamics of subcortical areas in Parkinson's disease. We simultaneously recorded neuronal units (spikes) and local field potentials (LFP) from subthalamic nucleus (STN) and electroencephalograms (EEGs) from the scalp in parkinsonian patients, and analysed the correlation between the time courses of the spike-LFP synchronization and inter-electrode EEG synchronization. We found the (non-invasively obtained) time course of the synchrony strength between EEG electrodes and the (invasively obtained) time course of the synchrony between spiking units and LFP in STN to be weakly, but significantly, correlated with each other. This correlation is largest for the bilateral motor EEG synchronization, followed by bilateral frontal EEG synchronization. Our observations suggest that there may be multiple functional modes by which the cortical and basal ganglia circuits interact with each other in Parkinson's disease: not only may synchronization be observed between some areas in cortex and the basal ganglia, but also synchronization within cortex and within basal ganglia may be related, suggesting potentially a more global functional interaction. More coherent dynamics in one brain region may modulate or activate the dynamics of another brain region in a more powerful way, causing correlations between changes in synchrony strength in the two regions.

Dynamical reorganization of synchronous activity patterns in prefrontal cortex-hippocampus networks during behavioral sensitization.

Neural synchrony exhibits temporal variability and, therefore, the temporal patterns of synchronization and desynchronization may have functional relevance. This study employs novel time-series analysis to explore how neural signals become transiently phase locked and unlocked in the theta frequency band in prefrontal cortex and hippocampus of awake, behaving rats during repeated injections of the psychostimulant, d-Amphetamine (AMPH). Short (but frequent) desynchronized events dominate synchronized dynamics in each of the animals we examined. After the first AMPH injection, only increases in the relative prevalence of short desynchronization episodes (but not in average synchrony strength) were significant. Throughout sensitization, both strength and the fine temporal structure of synchrony (measured as the relative prevalence of short desynchronizations) were similarly altered with AMPH injections, with each measure decreasing in the preinjection epoch and increasing after injection. Sensitization also induced decoupling between locomotor activity and synchrony. The increase in numerous short desynchronizations (as opposed to infrequent, but long desynchronizations) in AMPH-treated animals may indicate that synchrony is easy to form yet easy to break. These data yield a novel insight into how synchrony is dynamically altered in cortical networks by AMPH and identify neurophysiological changes that may be important to understand the behavioral pathologies of addiction.

Fine temporal structure of cardiorespiratory synchronization.

Cardiac and respiratory rhythms are known to exhibit a modest degree of phase synchronization, which is affected by age, diseases, and other factors. We study the fine temporal structure of this synchrony in healthy young, healthy elderly, and elderly subjects with coronary artery disease. We employ novel time-series analysis to explore how phases of oscillations go in and out of the phase-locked state at each cycle of oscillations. For the first time we show that cardiorespiratory system is engaged in weakly synchronized dynamics with a very specific temporal pattern of synchrony: the oscillations go out of synchrony frequently, but return to the synchronous state very quickly (usually within just 1 cycle of oscillations). Properties of synchrony depended on the age and disease status. Healthy subjects exhibited more synchrony at the higher (1:4) frequency-locking ratio between respiratory and cardiac rhythms, whereas subjects with coronary artery disease exhibited relatively more 1:2 synchrony. However, multiple short desynchronization episodes prevailed regardless of the age and disease status. The same average synchrony level could be alternatively achieved with few long desynchronizations, but this was not observed in the data. This implies functional importance of short desynchronization dynamics. These dynamics suggest that a synchronous state is easy to create if needed but is also easy to break. Short desynchronization dynamics may facilitate the mutual coordination of cardiac and respiratory rhythms by creating intermittent synchronous episodes. It may be an efficient background dynamics to promote adaptation of cardiorespiratory coordination to various external and internal factors.

Short desynchronization episodes prevail in synchronous dynamics of human brain rhythms.

Neural synchronization is believed to be critical for many brain functions. It frequently exhibits temporal variability, but it is not known if this variability has a specific temporal patterning. This study explores these synchronization/desynchronization patterns. We employ recently developed techniques to analyze the fine temporal structure of phase-locking to study the temporal patterning of synchrony of the human brain rhythms. We study neural oscillations recorded by electroencephalograms in α and ß frequency bands in healthy human subjects at rest and during the execution of a task. While the phase-locking strength depends on many factors, dynamics of synchrony has a very specific temporal pattern: synchronous states are interrupted by frequent, but short desynchronization episodes. The probability for a desynchronization episode to occur decreased with its duration. The transition matrix between synchronized and desynchronized states has eigenvalues close to 0 and 1 where eigenvalue 1 has multiplicity 1, and therefore if the stationary distribution between these states is perturbed, the system converges back to the stationary distribution very fast. The qualitative similarity of this patterning across different subjects, brain states and electrode locations suggests that this may be a general type of dynamics for the brain. Earlier studies indicate that not all oscillatory networks have this kind of patterning of synchronization/desynchronization dynamics. Thus, the observed prevalence of short (but potentially frequent) desynchronization events (length of one cycle of oscillations) may have important functional implications for the brain. Numerous short desynchronizations (as opposed to infrequent, but long desynchronizations) may allow for a quick and efficient formation and break-up of functionally significant neuronal assemblies.

Intermittent neural synchronization in Parkinson's disease.

Motor symptoms of Parkinson's disease are related to the excessive synchronized oscillatory activity in the beta frequency band (around 20Hz) in the basal ganglia and other parts of the brain. This review explores the dynamics and potential mechanisms of these oscillations employing ideas and methods from nonlinear dynamics. We present extensive experimental documentation of the relevance of synchronized oscillations to motor behavior in Parkinson's disease, and we discuss the intermittent character of this synchronization. The reader is introduced to novel time-series analysis techniques aimed at the detection of the fine temporal structure of intermittent phase locking observed in the brains of parkinsonian patients. Modeling studies of brain networks are reviewed, which may describe the observed intermittent synchrony, and we discuss what these studies reveal about brain dynamics in Parkinson's disease. The parkinsonian brain appears to exist on the boundary between phase-locked and nonsynchronous dynamics. Such a situation may be beneficial in the healthy state, as it may allow for easy formation and dissociation of transient patterns of synchronous activity which are required for normal motor behavior. Dopaminergic degeneration in Parkinson's disease may shift the brain networks closer to this boundary, which would still permit some motor behavior while accounting for the associated motor deficits. Understanding the mechanisms of the intermittent synchrony in Parkinson's disease is also important for biomedical engineering since efficient control strategies for suppression of pathological synchrony through deep brain stimulation require knowledge of the dynamics of the processes subjected to control.

Intermittent synchronization in a network of bursting neurons.

Synchronized oscillations in networks of inhibitory and excitatory coupled bursting neurons are common in a variety of neural systems from central pattern generators to human brain circuits. One example of the latter is the subcortical network of the basal ganglia, formed by excitatory and inhibitory bursters of the subthalamic nucleus and globus pallidus, involved in motor control and affected in Parkinson's disease. Recent experiments have demonstrated the intermittent nature of the phase-locking of neural activity in this network. Here, we explore one potential mechanism to explain the intermittent phase-locking in a network. We simplify the network to obtain a model of two inhibitory coupled elements and explore its dynamics. We used geometric analysis and singular perturbation methods for dynamical systems to reduce the full model to a simpler set of equations. Mathematical analysis was completed using three slow variables with two different time scales. Intermittently, synchronous oscillations are generated by overlapped spiking which crucially depends on the geometry of the slow phase plane and the interplay between slow variables as well as the strength of synapses. Two slow variables are responsible for the generation of activity patterns with overlapped spiking, and the other slower variable enhances the robustness of an irregular and intermittent activity pattern. While the analyzed network and the explored mechanism of intermittent synchrony appear to be quite generic, the results of this analysis can be used to trace particular values of biophysical parameters (synaptic strength and parameters of calcium dynamics), which are known to be impacted in Parkinson's disease.

Noise effect on the temporal patterns of neural synchrony.

Neural synchrony in the brain is often present in an intermittent fashion, i.e., there are intervals of synchronized activity interspersed with intervals of desynchronized activity. A series of experimental studies showed that this kind of temporal patterning of neural synchronization may be very specific and may be correlated with behaviour (even if the average synchrony strength is not changed). Prior studies showed that a network with many short desynchronized intervals may be functionally different from a network with few long desynchronized intervals as it may be more sensitive to synchronizing input signals. In this study, we investigated the effect of channel noise on the temporal patterns of neural synchronization. We employed a small network of conductance-based model neurons that were mutually connected via excitatory synapses. The resulting dynamics of the network was studied using the same time-series analysis methods as used in prior experimental and computational studies. While it is well known that synchrony strength generally degrades with noise, we found that noise also affects the temporal patterning of synchrony. Noise, at a sufficient intensity (yet too weak to substantially affect synchrony strength), promotes dynamics with predominantly short (although potentially very numerous) desynchronizations. Thus, channel noise may be one of the mechanisms contributing to the short desynchronization dynamics observed in multiple experimental studies.

Fine temporal structure of beta oscillations synchronization in subthalamic nucleus in Parkinson's disease.

Synchronous oscillatory dynamics in the beta frequency band is a characteristic feature of neuronal activity of basal ganglia in Parkinson's disease and is hypothesized to be related to the disease's hypokinetic symptoms. This study explores the temporal structure of this synchronization during episodes of oscillatory beta-band activity. Phase synchronization (phase locking) between extracellular units and local field potentials (LFPs) from the subthalamic nucleus (STN) of parkinsonian patients is analyzed here at a high temporal resolution. We use methods of nonlinear dynamics theory to construct first-return maps for the phases of oscillations and quantify their dynamics. Synchronous episodes are interrupted by less synchronous episodes in an irregular yet structured manner. We estimate probabilities for different kinds of these "desynchronization events." There is a dominance of relatively frequent yet very brief desynchronization events with the most likely desynchronization lasting for about one cycle of oscillations. The chances of longer desynchronization events decrease with their duration. The observed synchronization may primarily reflect the relationship between synaptic input to STN and somatic/axonal output from STN at rest. The intermittent, transient character of synchrony even on very short time scales may reflect the possibility for the basal ganglia to carry out some informational function even in the parkinsonian state. The dominance of short desynchronization events suggests that even though the synchronization in parkinsonian basal ganglia is fragile enough to be frequently destabilized, it has the ability to reestablish itself very quickly.

Spike-Timing Dependent Plasticity Effect on the Temporal Patterning of Neural Synchronization.

Neural synchrony in the brain at rest is usually variable and intermittent, thus intervals of predominantly synchronized activity are interrupted by intervals of desynchronized activity. Prior studies suggested that this temporal structure of the weakly synchronous activity might be functionally significant: many short desynchronizations may be functionally different from few long desynchronizations even if the average synchrony level is the same. In this study, we used computational neuroscience methods to investigate the effects of spike-timing dependent plasticity (STDP) on the temporal patterns of synchronization in a simple model. We employed a small network of conductance-based model neurons that were connected via excitatory plastic synapses. The dynamics of this network was subjected to the time-series analysis methods used in prior experimental studies. We found that STDP could alter the synchronized dynamics in the network in several ways, depending on the time scale that plasticity acts on. However, in general, the action of STDP in the simple network considered here is to promote dynamics with short desynchronizations (i.e., dynamics reminiscent of that observed in experimental studies). Complex interplay of the cellular and synaptic dynamics may lead to the activity-dependent adjustment of synaptic strength in such a way as to facilitate experimentally observed short desynchronizations in the intermittently synchronized neural activity.

Dysregulation of temporal dynamics of synchronous neural activity in adolescents on autism spectrum.

Autism spectrum disorder is increasingly understood to be based on atypical signal transfer among multiple interconnected networks in the brain. Relative temporal patterns of neural activity have been shown to underlie both the altered neurophysiology and the altered behaviors in a variety of neurogenic disorders. We assessed brain network dynamics variability in autism spectrum disorders (ASD) using measures of synchronization (phase-locking) strength, and timing of synchronization and desynchronization of neural activity (desynchronization ratio) across frequency bands of resting-state electroencephalography (EEG). Our analysis indicated that frontoparietal synchronization is higher in ASD but with more short periods of desynchronization. It also indicates that the relationship between the properties of neural synchronization and behavior is different in ASD and typically developing populations. Recent theoretical studies suggest that neural networks with a high desynchronization ratio have increased sensitivity to inputs. Our results point to the potential significance of this phenomenon to the autistic brain. This sensitivity may disrupt the production of an appropriate neural and behavioral responses to external stimuli. Cognitive processes dependent on the integration of activity from multiple networks maybe, as a result, particularly vulnerable to disruption. Autism Res 2020, 13: 24-31. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Parts of the brain can work together by synchronizing the activity of the neurons. We recorded the electrical activity of the brain in adolescents with autism spectrum disorder and then compared the recording to that of their peers without the diagnosis. We found that in participants with autism, there were a lot of very short time periods of non-synchronized activity between frontal and parietal parts of the brain. Mathematical models show that the brain system with this kind of activity is very sensitive to external events.

Potential Mechanisms and Functions of Intermittent Neural Synchronization.

Neural synchronization is believed to play an important role in different brain functions. Synchrony in cortical and subcortical circuits is frequently variable in time and not perfect. Few long intervals of desynchronized dynamics may be functionally different from many short desynchronized intervals although the average synchrony may be the same. Recent analysis of imperfect synchrony in different neural systems reported one common feature: neural oscillations may go out of synchrony frequently, but primarily for a short time interval. This study explores potential mechanisms and functional advantages of this short desynchronizations dynamics using computational neuroscience techniques. We show that short desynchronizations are exhibited in coupled neurons if their delayed rectifier potassium current has relatively large values of the voltage-dependent activation time-constant. The delayed activation of potassium current is associated with generation of quickly-rising action potential. This "spikiness" is a very general property of neurons. This may explain why very different neural systems exhibit short desynchronization dynamics. We also show how the distribution of desynchronization durations may be independent of the synchronization strength. Finally, we show that short desynchronization dynamics requires weaker synaptic input to reach a pre-set synchrony level. Thus, this dynamics allows for efficient regulation of synchrony and may promote efficient formation of synchronous neural assemblies.

Effects of Electrical and Optogenetic Deep Brain Stimulation on Synchronized Oscillatory Activity in Parkinsonian Basal Ganglia.

Conventional deep brain stimulation of basal ganglia uses high-frequency regular electrical pulses to treat Parkinsonian motor symptoms but has a series of limitations. Relatively new and not yet clinically tested, optogenetic stimulation is an effective experimental stimulation technique to affect pathological network dynamics. We compared the effects of electrical and optogenetic stimulation of the basal gangliaon the pathologicalParkinsonian rhythmic neural activity. We studied the network response to electrical stimulation and excitatory and inhibitory optogenetic stimulations. Different stimulations exhibit different interactions with pathological activity in the network. We studied these interactions for different network and stimulation parameter values. Optogenetic stimulation was found to be more efficient than electrical stimulation in suppressing pathological rhythmicity. Our findings indicate that optogenetic control of neural synchrony may be more efficacious than electrical control because of the different ways of how stimulations interact with network dynamics.

Synchronized Beta-Band Oscillations in a Model of the Globus Pallidus-Subthalamic Nucleus Network under External Input.

Hypokinetic symptoms of Parkinson's disease are usually associated with excessively strong oscillations and synchrony in the beta frequency band. The origin of this synchronized oscillatory dynamics is being debated. Cortical circuits may be a critical source of excessive beta in Parkinson's disease. However, subthalamo-pallidal circuits were also suggested to be a substantial component in generation and/or maintenance of Parkinsonian beta activity. Here we study how the subthalamo-pallidal circuits interact with input signals in the beta frequency band, representing cortical input. We use conductance-based models of the subthalamo-pallidal network and two types of input signals: artificially-generated inputs and input signals obtained from recordings in Parkinsonian patients. The resulting model network dynamics is compared with the dynamics of the experimental recordings from patient's basal ganglia. Our results indicate that the subthalamo-pallidal model network exhibits multiple resonances in response to inputs in the beta band. For a relatively broad range of network parameters, there is always a certain input strength, which will induce patterns of synchrony similar to the experimentally observed ones. This ability of the subthalamo-pallidal network to exhibit realistic patterns of synchronous oscillatory activity under broad conditions may indicate that these basal ganglia circuits are directly involved in the expression of Parkinsonian synchronized beta oscillations. Thus, Parkinsonian synchronized beta oscillations may be promoted by the simultaneous action of both cortical (or some other) and subthalamo-pallidal network mechanisms. Hence, these mechanisms are not necessarily mutually exclusive.

Failure of delayed feedback deep brain stimulation for intermittent pathological synchronization in Parkinson's disease.

Suppression of excessively synchronous beta-band oscillatory activity in the brain is believed to suppress hypokinetic motor symptoms of Parkinson's disease. Recently, a lot of interest has been devoted to desynchronizing delayed feedback deep brain stimulation (DBS). This type of synchrony control was shown to destabilize the synchronized state in networks of simple model oscillators as well as in networks of coupled model neurons. However, the dynamics of the neural activity in Parkinson's disease exhibits complex intermittent synchronous patterns, far from the idealized synchronous dynamics used to study the delayed feedback stimulation. This study explores the action of delayed feedback stimulation on partially synchronized oscillatory dynamics, similar to what one observes experimentally in parkinsonian patients. We employ a computational model of the basal ganglia networks which reproduces experimentally observed fine temporal structure of the synchronous dynamics. When the parameters of our model are such that the synchrony is unphysiologically strong, the feedback exerts a desynchronizing action. However, when the network is tuned to reproduce the highly variable temporal patterns observed experimentally, the same kind of delayed feedback may actually increase the synchrony. As network parameters are changed from the range which produces complete synchrony to those favoring less synchronous dynamics, desynchronizing delayed feedback may gradually turn into synchronizing stimulation. This suggests that delayed feedback DBS in Parkinson's disease may boost rather than suppress synchronization and is unlikely to be clinically successful. The study also indicates that delayed feedback stimulation may not necessarily exhibit a desynchronization effect when acting on a physiologically realistic partially synchronous dynamics, and provides an example of how to estimate the stimulation effect.

Basal ganglia modulation of thalamocortical relay in Parkinson's disease and dystonia.

Basal ganglia dysfunction has being implied in both Parkinson's disease and dystonia. While these disorders probably involve different cellular and circuit pathologies within and beyond basal ganglia, there may be some shared neurophysiological pathways. For example, pallidotomy and pallidal Deep Brain Stimulation (DBS) are used in symptomatic treatment of both disorders. Both conditions are marked by alterations of rhythmicity of neural activity throughout basal ganglia-thalamocortical circuits. Increased synchronized oscillatory activity in beta band is characteristic of Parkinson's disease, while different frequency bands, theta and alpha, are involved in dystonia. We compare the effect of the activity of GPi, the output nuclei of the basal ganglia, on information processing in the downstream neural circuits of thalamus in Parkinson's disease and dystonia. We use a data-driven computational approach, a computational model of the thalamocortical (TC) cell modulated by experimentally recorded data, to study the differences and similarities of thalamic dynamics in dystonia and Parkinson's disease. Our analysis shows no substantial differences in TC relay between the two conditions. Our results suggest that, similar to Parkinson's disease, a disruption of thalamic processing could also be involved in dystonia. Moreover, the degree to which TC relay fidelity is impaired is approximately the same in both conditions. While Parkinson's disease and dystonia may have different pathologies and differ in the oscillatory content of neural discharge, our results suggest that the effect of patterning of pallidal discharge is similar in both conditions. Furthermore, these results suggest that the mechanisms of GPi DBS in dystonia may involve improvement of TC relay fidelity.

Repeated injections of D-Amphetamine evoke rapid and dynamic changes in phase synchrony between the prefrontal cortex and hippocampus.

Repeated drug use evokes a number of persistent alterations in oscillatory power and synchrony. How synchronous activity in cortico-hippocampal circuits is progressively modified with repeated drug exposure, however, remains to be characterized. Drugs of abuse induce both short-term and long-term adaptations in cortical and hippocampal circuits and these changes are likely important for the expression of the altered behavioral and neurobiological phenotype associated with addiction. The present study explores how the initial (up to 1 h) pharmacological response to D-Amphetamine (AMPH) is altered with repeated injections in the rat. The methods employed herein allow for the progressive changes in synchronized dynamics with repeated intermittent AMPH exposure to be characterized over short time scales (minutes). Specifically, we examined the temporal variations of phase-locking strength in delta and theta bands within the prefrontal cortex (PFC) and between PFC and hippocampus (HC) shortly after drug injection. After the first injection of AMPH synchrony increased within the PFC in the delta band, which was followed, by an increase in theta synchrony between the PFC and HC several minutes later. This relationship switched after repeated AMPH injections, where increases in theta synchrony between the PFC and HC preceded increases in delta synchrony in the PFC. The time-course of increases in synchronous activity were negatively correlated between the PFC delta and the PFC-HC theta. Collectively these data highlight the potential role of PFC-HC circuits in the development of addiction and outline dynamic changes in the time-course that cortico-hippocampal circuits become synchronized with repeated AMPH exposure.