Theta And Gamma Oscillations Involved In The Regulation Of Synaptic Plasticity In Rats And Its Underlying Mechanism

BackgroundExecution of complex cognitive functions by the brain requires coordination across many neurons in multiple brain areas. Brain rhythms (or oscillations) provide a mechanism for such coordination by linking the activity of related ensembles of neurons. Theta and gamma rhythms are the most intriguing brain rhythms in the central neural system, which are not only considered as a crucial factor for cognition and memory, but also involved in the dysfunction of several neurological and psychotic disorders. Furthermore, it is currently believed that synaptic plasticity comprises the cellular basis for memory formation and cognition in neuroscience. Therefore, a hypothesis has been raised that the cognitive function could be modulated under a mechanism by linking neural oscillations with synaptic plasticity.ObjectiveIn this study, we established the pathologic models on rats and combined electrophysiology experiments with computational methods, in order to investigate the underlying mechanism that how neural oscillations reflect synaptic plasticity by phase synchronization and phase coupling of theta and gamma rhythms, and theta-gamma phase-amplitude coupling (PAC), and then further modulate the cognition function.MethodsThe animal experiments were divided into three parts.Part1:18male Wistar rats were randomly divided into three groups, which were control group (Con, n=6), stressed group (Dep, n=6) and stressed+memantine treated group (MEM, n=6). The chronic unpredictable stress (CUS) procedure was performed in both Dep and MEM groups for21days. The rats of MEM group received daily i.p. injections of memantine hydrochloride from the2nd to the22nd day counting from the beginning day of CUS model. During the model establishment, body weights of animals were measured and the sucrose intake/consumption experiments were performed, in order to test if the model was successful. In the following electrophysiology experiment, LFPs were recorded in thalamus LDDM and mPFC respectively, and then long term potentiation (LTP) was induced on the pathway. Several kinds of computational approaches were used to analyze the LFPs signals, such as multi-taper spectral estimation method for power spectrum, sample entropy (SampEn) for complex degree, phase locking value (PLV) for phase synchronization, evolution map approach (EMA) and conditional mutual information (CMI) for phase coupling direction and undirectional coupling strength.Part2:44male Wistar rats were randomly divided into four groups, which were control group (Con, n=14), CUS group (Dep, n=14), dopamine D1receptor antagonist treated group (SCH, n=8), and5-HT1A agonist treated group (8-OH, n=8). Six rats respectively in Con and Dep groups were used for additional experiments. The chronic unpredictable stress (CUS) procedure was performed in Dep groups for21days. The rats of SCH and8-OH groups received acute i.c.v. injections of SCH-23390and8-OH-DPAT. In the following electrophysiology experiments for all the groups, LFPs were recorded in the ventral part of hippocampal CA1and mPFC for both before and after the drug injection and LTP induction respectively, during which LTP was induced on this pathway. Several computational approaches were employed to analyze the LFPs signals, such as multi-taper spectral estimation method for power spectrum, PLV for phase synchronization, EMA and CMI for phase coupling direction and unidirectional coupling strength, and PAC methods for cross frequency coupling strength, i.e. theta-low gamma (LG) and theta-high gamma (HG) PAC.Part3:24male Sprague-Dawley rats were randomly divided into control group (CTRL, n=12) and C6glioma group (GLIO, n=12). The rats of CTRL and GLIO groups received intracerebral injections of DMEM and C6glioma cell, respectively. In the following electrophysiology experiment, LFPs were recorded in both dorsal hippocampal CA3and CA1areas which were contralateral to tumor. Two novel algorithms, called CF-CMI and CF-EMA, were developed to analyze the LFPs signals for cross frequency coupling strength based on time lags.Results1. The power spectrum of mPFC LFPs was increased by CUS, especially on delta, theta and beta frequency bands. While the SampEn of mPFC was decreased in CUS model rats. Both the power and SampEn didn’t go back to normal after memantine treatment.2. The LDDMâ†'mPFC coupling direction index d and unidirectional coupling strength indices cLDDMâ†'mPFC (EMA) and iLDDMâ†'mPFC (CMI) at theta rhythm were significantly decreased in CUS model rats, with a recovery in the memantine treated rats.3. CUS inhibited the phase coupling between hippocampal CA1and mPFC at theta rhythm, which was consistent with the changes by D1receptor antagonist; while the coupling strength at gamma rhythm was increased in CUS rats, which was corresponding to the impact of5-HT1A receptor agonist.4. In the rats of both Con and Dep groups, the unidirectional phase coupling at theta rhythm from hippocampal CA1to mPFC was enhanced by LTP induction, whereas the increment of Con rats was higher than that of CUS model rats. These results were in line with the changes of synaptic plasticity on hippocampal CA1-mPFC pathway.5. The theta-LG PAC strength in hippocampal CA1was enhanced after high frequency stimulus (HFS) in long term (>60min); while theta-HG PAC strength was just enhanced within short term (<30min).6. Theta-LG PAC occurred in both hippocampal CA3and CA1areas, while theta-HG PAC existed only in CA1, and theta-LG PAC in CA1was most likely to be modulated by CA3. The brain glioma impaired the theta-LG PAC of both CA3per se and its transmission to CA1to a great extent, and might influence the theta-LG PAC in CA1.7. Two novel measurements CF-CMI and CF-EMA for PAC strength, which were developed based on time lags, showed that the CA3-CA1PAC strength was obtained to its maximum value at time lags-20ms. The maximum of coupling strength was possibly used to signify the real interaction of cross frequency in the neural network.Conclusions1. Depression inhibited the unidirectional phase coupling at theta rhythm from thalamus to mPFC, in line with the LTP impairments on the pathway, which showed that there was an association between phase coupling of theta rhythm and synaptic plasticity.2. The enhancement of theta coupling strength after LTP induction from hippocampal CA1to mPFC was decreased in CUS model rats, demonstrating that the phase coupling of theta was related to hippocampal CA1-mPFC synaptic plasticity. Furthermore in CA1area, theta-LG PAC was involved in LTP, while theta-HG PAC was only related to STP.3. Dopamine was implicated in the modulation of phase coupling at theta rhythm in depression, while the phase coupling enhancement at gamma rhythm might attribute to the5-HT1A receptor activation. On the other hand, the5-HT1A receptor was also involved in theta-HG PAC modulation in CA1area.4. The intracerebral implantation of C6glioma cell could attenuate the theta-LG strength in hippocampal CA3-CA1network, which might associate with the cognition impairments.5. The PAC phenomenon in hippocampal CA3-CA1network was time delay depended. The coupling strength could be estimated precisely by time-lag, which might relate to synaptic transmission.