Hippocampal Theta Rhythm Research Articles

Spatial maps in piriform cortex during olfactory navigation.

Odors are a fundamental part of the sensory environment used by animals to inform behaviors such as foraging and navigation1,2. Primary olfactory (piriform) cortex is thought to be dedicated to encoding odor identity3-8. Here, using neural ensemble recordings in freely moving rats performing a novel odor-cued spatial choice task, we show that posterior piriform cortex neurons also carry a robust spatial map of the environment. Piriform spatial maps were stable across behavioral contexts independent of olfactory drive or reward availability, and the accuracy of spatial information carried by individual neurons depended on the strength of their functional coupling to the hippocampal theta rhythm. Ensembles of piriform neurons concurrently represented odor identity as well as spatial locations of animals, forming an "olfactory-place map". Our results reveal a previously unknown function for piriform cortex in spatial cognition and suggest that it is well-suited to form odor-place associations and guide olfactory cued spatial navigation.

Distinct Disruptions in CA1 and CA3 Place Cell Function in Alzheimer's Disease Mice.

The hippocampus, a critical brain structure for spatial learning and memory, is susceptible to neurodegenerative disorders such as Alzheimer's disease (AD). The APPswe/PSEN1dE9 (APP/PS1) transgenic mouse model is widely used to study the pathology of AD. Although previous research has established AD-associated impairments in hippocampal-dependent learning and memory, the neurophysiological mechanisms underlying these cognitive dysfunctions remain less understood. To address this gap, we investigated the activities of place cells in both CA1 and CA3 hippocampal subregions, which have distinct yet complementary computational roles. Behaviorally, APP/PS1 mice demonstrated impaired spatial recognition memory compared to wild-type (WT) mice in the object location test. Physiologically, place cells in APP/PS1 mice showed deterioration in spatial representation compared to WT. Specifically, CA1 place cells exhibited significant reductions in coherence and spatial information, while CA3 place cells displayed a significant reduction in place field size. Both CA1 and CA3 place cells in APP/PS1 mice also showed significant disruptions in their ability to stably encode the same environment. Furthermore, the burst firing properties of these cells were altered to forms correlated with reduced cognition. Additionally, the theta rhythm was significantly attenuated in CA1 place cells of APP/PS1 mice compared to WT. Our results suggest that distinct alteration in the physiological properties of CA1 and CA3 place cells, coupled with disrupted hippocampal theta rhythm in CA1, may collectively contribute to impaired hippocampal-dependent spatial learning and memory in AD.

The posterior hypothalamic area as an independent generator of rhythmic theta oscillatory activity

Theta rhythm is one of the most prominent examples of rhythmic oscillatory activity in mammalian brain and it is generated mainly in structures of the limbic cortex, including the hippocampal formation. In the 1970s it was shown that theta rhythm may be also recorded in diencephalic region including the posterior hypothalamic nuclei and supramammillary nucleus, together considered as the posterior hypothalamic area (PHa). For decades it was stated that local posterior hypothalamic oscillatory activity is controlled by the descending inputs going to the PHa from the septohippocampal system. However, the latest studies indicated that theta rhythm can be recorded in deafferented PHa in vitro preparations which indicates that the posterior hypothalamic area should be considered as an independent of the other brain structures theta generator. In subsequent research the neurochemical and cellular basis of PHa theta were examined in both in vivo and in vitro conditions. In the light of multiple evidence obtained in these studies, it is the author’s intent to summarize the data concerning the role of the posterior hypothalamic area in hippocampal theta rhythm generation as well as the ability of that brain structure to independently generate theta rhythmicity.

Rat anterior cingulate neurons responsive to rule or strategy changes are modulated by the hippocampal theta rhythm and sharp-wave ripples.

To better understand neural processing during adaptive learning of stimulus-response-reward contingencies, we recorded synchrony of neuronal activity in anterior cingulate cortex (ACC) and hippocampal rhythms in male rats acquiring and switching between spatial and visual discrimination tasks in a Y-maze. ACC population activity as well as single unit activity shifted shortly after task rule changes or just before the rats adopted different task strategies. Hippocampal theta oscillations (associated with memory encoding) modulated an elevated proportion of rule-change responsive neurons (70%), but other neurons that were correlated with strategy-change, strategy value and reward-rate were not. However, hippocampal sharp wave-ripples modulated significantly higher proportions of rule-change, strategy-change and reward-rate responsive cells during post-session sleep but not pre-session sleep. This suggests an underestimated mechanism for hippocampal mismatch and contextual signals to facilitate ACC to detect contingency changes for cognitive flexibility, a function that is attenuated after it is damaged.

Development of spontaneous recurrent seizures accompanied with increased rates of interictal spikes and decreased hippocampal delta and theta activities following extended kindling in mice

Interictal epileptiform discharges refer to aberrant brain electrographic signals between seizures and feature intermittent interictal spikes (ISs), sharp waves, and/or abnormal rhythms. Recognition of these epileptiform activities by electroencephalographic (EEG) examinations greatly aids epilepsy diagnosis and localization of the seizure onset zone. ISs are a major form of interictal epileptiform discharges recognized in animal models of epilepsy. Progressive changes in IS waveforms, IS rates, and/or associated fast ripple oscillations have been shown to precede the development of spontaneous recurrent seizures (SRS) in various animal models. IS expressions in the kindling model of epilepsy have been demonstrated but IS changes during the course of SRS development in extended kindled animals remain to be detailed. We hence addressed this issue using a mouse model of kindling-induced SRS. Adult C57 black mice received twice daily hippocampal stimulations until SRS occurrence, with 24-h EEG monitoring performed following 50, 80, and ≥ 100 stimulations and after observation of SRS. In the stimulated hippocampus, increases in spontaneous ISs rates, but not in IS waveforms nor IS-associated fast ripples, along with decreased frequencies of hippocampal delta and theta rhythms, were observed before SRS onset. Comparable increases in IS rates were further observed in the unstimulated hippocampus, piriform cortex, and entorhinal cortex, but not in the unstimulated parietal cortex and dorsomedial thalamus. These data provide original evidence suggesting that increases in hippocampal IS rates, together with reductions in hippocampal delta and theta rhythms are closely associated with development of SRS in a rodent kindling model.

Optogenetic stimulation of medial septal glutamatergic neurons modulates theta-gamma coupling in the hippocampus

Hippocampal cross-frequency theta-gamma coupling (TGC) is a basic mechanism for information processing, retrieval, and consolidation of long-term and working memory. While the role of entorhinal afferents in the modulation of hippocampal TGC is widely accepted, the influence of other main input to the hippocampus, from the medial septal area (MSA, the pacemaker of the hippocampal theta rhythm) is poorly understood. Optogenetics allows us to explore how different neuronal populations of septohippocampal circuits control neuronal oscillations in vivo. Rhythmic activation of septal glutamatergic neurons has been shown to drive hippocampal theta oscillations, but the role of these neuronal populations in information processing during theta activation has remained unclear. Here we investigated the influence of phasic activation of MSA glutamatergic neurons expressing channelrhodopsin II on theta-gamma coupling in the hippocampus. During the experiment, local field potentials of MSA and hippocampus of freely behaving mice were modulated by 470 nm light flashes with theta frequency (2–10) Hz. It was shown that both the power and the strength of modulation of gamma rhythm nested on hippocampal theta waves depend on the frequency of stimulation. The modulation of the amplitude of slow gamma rhythm (30–50 Hz) prevailed over modulation of fast gamma (55–100 Hz) during flash trains and the observed effects were specific for theta stimulation of MSA. We discuss the possibility that phasic depolarization of septal glutamatergic neurons controls theta-gamma coupling in the hippocampus and plays a role in memory retrieval and consolidation.

Computational study of the progression of Alzheimer's disease and changes in hippocampal theta rhythm activities due to beta-amyloid altered calcium dependent ionic channels

Computational study of the progression of Alzheimer's disease and changes in hippocampal theta rhythm activities due to beta-amyloid altered calcium dependent ionic channels

Does Proprioception Involve Synchronization with Theta Rhythms by a Novel Piezo2 Initiated Ultrafast VGLUT2 Signaling?

This opinion manuscript outlines how the hippocampal theta rhythm could receive two novel peripheral inputs. One of the ways this could be achieved is through Piezo2 channels and atypical hippocampal-like metabotropic glutamate receptors coupled to phospholipase D containing proprioceptive primary afferent terminals. Accordingly, activated proprioceptive terminal Piezo2 on Type Ia fibers synchronizes to the theta rhythm with the help of hippocampal Piezo2 and medial septal glutamatergic neurons. Second, after baroreceptor Piezo2 is entrained to activated proprioceptive Piezo2, it could turn on the Cav1.3 channels, which pace the heart rhythm and regulate pacemaker cells during cardiac sympathetic activation. This would allow the Cav1.3 channels to synchronize to theta rhythm pacemaker hippocampal parvalbumin-expressing GABAergic neurons. This novel Piezo2-initiated proton–proton frequency coupling through VGLUT2 may provide the ultrafast long-range signaling pathway for the proposed Piezo2 synchronization of the low-frequency glutamatergic cell surface membrane oscillations in order to provide peripheral spatial and speed inputs to the space and speed coding of the hippocampal theta rhythm, supporting locomotion, learning and memory. Moreover, it provides an ultrafast signaling for postural and orthostatic control. Finally, suggestions are made as to how Piezo2 channelopathy could impair this ultrafast communication in many conditions and diseases with not entirely known etiology, leading to impaired proprioception and/or autonomic disbalance.

The defects of the hippocampal ripples and theta rhythm in depression, and the effects of physical exercise on their amelioration

Adverse environmental stress causes depressive symptoms with the impairments of memory formation, cognition, and motivation, however, their underlying neural bases have not been well understood, especially based on the observation of living animals. In the present study, therefore, the mice model of restraint-induced stress was examined electrophysiologically to investigate the alterations of hippocampal sharp wave ripples (SWRs) and theta rhythms. In addition, the therapeutic effects of physical exercise on the amelioration of those hippocampal impairments were examined in combination with a series of behavioral tests. The data demonstrated that chronic restraint stress caused the reductions of occurrence and amplitude of hippocampal SWRs and the decreases of occurrence, duration, and power of theta rhythms, while physical exercise significantly reverted them to the levels of healthy control. Furthermore, hippocampal adult neurogenesis and microglial activation, previously reported to be involved in the etiology of depression, were histologically examined in the mice. The results showed that the impairment of neurogenesis and alleviation of microglial activation were induced in the depressed mice. On the other hand, physical exercise considerably ameliorated those pathological conditions in the affected brain. Consistently, the data of behavioral tests in mice suggested that physical exercise ameliorated the symptomatic defects of motivation, memory formation, and cognition in the depressed mice. The impairments of hippocampal SWRs and theta rhythms in the affected hippocampus are linked with the symptomatic impairments of cognition and motivation, and the defect of memory formation, respectively, in depression. Taken together, this study demonstrated the implications of impairment of the hippocampal SWRs and theta rhythms in the etiology of depression and their usefulness as diagnostic markers of depression.

Kapβ2 Inhibits Perioperative Neurocognitive Disorders in Rats with Mild Cognitive Impairment by Reversing the Nuclear-Cytoplasmic Mislocalization of hnRNPA2/B1.

Harmful stimuli trigger mutations lead to uncontrolled accumulation of hnRNPA2/B1 in the cytoplasm, exacerbating neuronal damage. Kapβ2 mediates the bidirectional transport of most substances between the cytoplasm and the nucleus. Kapβ2 guides hnRNPA2/B1 back into the nucleus and restores its function, alleviating related protein toxicity. Here, we aim to explore the involvement of Kapβ2 in neurodegeneration in rats with MCI following sevoflurane anesthesia and surgery. Firstly, novel object recognition test and Barnes maze were conducted to assess behavioral performances, and we found Kapβ2 positively regulated the recovery of memory and cognitive function. In vivo electrophysiological experiments revealed that the hippocampal theta rhythm energy distribution was disrupted, coherence was reduced, and long-term potentiation was attenuated in MCI rats. LTP was greatly improved with positive modulation of Kapβ2. Next, functional MRI and BOLD imaging will be employed to examine the AFLL and FC values of dynamic connectivity between the cortex and hippocampus of the brain. The findings show that regulating Kapβ2 in the hippocampus region enhances functional activity and connections between brain regions in MCI rats. WB results showed that increasing Kapβ2 expression improved the expression and recovery of cognitive-related proteins in the hippocampus of MCI rats. Finally, WB and immunofluorescence were used to examine the changes in hnRNPA2/B1 expression in the nucleus and cytoplasm after overexpression of Kapβ2, and it was found that nucleocytoplasmic mis location was alleviated. Overall, these data show that Kapβ2 reverses the nucleoplasmic misalignment of hnRNPA2/B1, which slows neurodegeneration towards dementia in MCI after sevoflurane anesthesia and surgery. Our findings may lead to new approaches for perioperative neuroprotection of MCI patients.

Low-frequency amplitude modulation of hippocampal theta rhythm in rats during treadmill running

The hippocampus is the main structure involved in the generation of the theta rhythm (4–12 Hz), which is among the most regular neural oscillations in electroencephalography (EEG) signals recorded during locomotion. However, whether changes in hippocampal theta rhythm amplitude provide any information remains unclear, primarily because traditional analytical methods cannot directly quantify such changes. ObjectiveThis study was conducted to (1) examine the characteristics of signal addition or multiplication through Holo-Hilbert spectral analysis (HHSA), (2) determine whether hippocampal EEG signals recorded in rats during locomotion provide high-dimensional information, and (3) investigate the physiological importance of high-dimensional information obtained from hippocampal EEG recordings. MethodsWe conducted HHSA to analyze hippocampal EEG signals recorded in rats. HHSA enabled us to determine carrier frequency and amplitude modulation (AM) characteristics. ResultsHHSA revealed that hippocampal EEG signals recorded before and after treadmill running were concentrated in the delta band and were characterized by AM at 0.5–1 Hz (P < 0.05). Throughout the treadmill exercise, the hippocampal EEG signals were concentrated in the theta band and were characterized by AM at 0.5–4 Hz (P < 0.05). ConclusionHippocampal theta signals recorded in the rats during treadmill running exhibited low-frequency AM. The hippocampal theta rhythm can provide insights into functional brain connectivity. SignificanceHHSA could be used to obtain high-dimensional EEG information; moreover, EEG signals recorded in rats during treadmill running exhibited low-frequency AM.

Pontine Waves Accompanied by Short Hippocampal Sharp Wave-Ripples During Non-rapid Eye Movement Sleep.

Ponto-geniculo-occipital or pontine (P) waves have long been recognized as an electrophysiological signature of rapid eye movement (REM) sleep. However, P-waves can be observed not just during REM sleep, but also during non-REM (NREM) sleep. Recent studies have uncovered that P-waves are functionally coupled with hippocampal sharp wave ripples (SWRs) during NREM sleep. However, it remains unclear to what extent P-waves during NREM sleep share their characteristics with P-waves during REM sleep and how the functional coupling to P-waves modulates SWRs. Here, we address these issues by performing multiple types of electrophysiological recordings and fiber photometry in both sexes of mice. P-waves during NREM sleep share their waveform shapes and local neural ensemble dynamics at a short (~100 milliseconds) timescale with their REM sleep counterparts. However, the dynamics of mesopontine cholinergic neurons are distinct at a longer (~10 seconds) timescale: although P-waves are accompanied by cholinergic transients, the cholinergic tone gradually reduces before P-wave genesis during NREM sleep. While P-waves are coupled to hippocampal theta rhythms during REM sleep, P-waves during NREM sleep are accompanied by a rapid reduction in hippocampal ripple power. SWRs coupled with P-waves are short-lived and hippocampal neural firing is also reduced after P-waves. These results demonstrate that P-waves are part of coordinated sleep-related activity by functionally coupling with hippocampal ensembles in a state-dependent manner.

Visual cortical LFP in relation to the hippocampal theta rhythm in track running rats.

Theta oscillations in the primary visual cortex (VC) have been observed during running tasks, but the mechanism behind their generation is not well understood. Some studies have suggested that theta in the VC is locally generated, while others have proposed that it is volume conducted from the hippocampus. The present study aimed to investigate the relationship between hippocampal and VC LFP dynamics. Analysis of power spectral density revealed that LFP in the VC was similar to that in the hippocampus, but with lower overall magnitude. As running velocity increased, both the power and frequency of theta and its harmonics increased in the VC, similarly to what is observed in the hippocampus. Current source density analysis triggered to theta did not identify distinct current sources and sinks in the VC, supporting the idea that theta in the VC is conducted from the adjacent hippocampus. Phase coupling between theta, its harmonics, and gamma is a notable feature in the hippocampus, particularly in the lacunosum moleculare. While some evidence of coupling between theta and its harmonics in the VC was found, bicoherence estimates did not reveal significant phase coupling between theta and gamma. Similar results were seen in the cross-region bicoherence analysis, where theta showed strong coupling with its harmonics with increasing velocity. Thus, theta oscillations observed in the VC during running tasks are likely due to volume conduction from the hippocampus.

Hippocampal place cells exhibit impairments in spatial information coding in an APP‐knock in model of Alzheimer’s Disease

AbstractBackgroundThe hippocampus is one of the first cortical regions to exhibit Alzheimer’s Disease (AD) pathology. The spatially‐related firing of hippocampal place cells provides the cellular basis for spatial memory and this is impaired relatively early in AD, yet few studies examine place cell activity in AD mouse models. We undertook an in‐depth characterisation of hippocampal pyramidal cell activity in an APP knock‐in model of AD.MethodMicrodrives carrying 8 tetrodes were implanted into the left CA1 hippocampal subfield of 14‐month female mice (four APPNL‐G‐F, four wild‐type littermates). Mice undertook daily foraging sessions in an open field and ran on a linear track as CA1 activity was recorded. On completion of experiments, 40µm coronal sections of fixed brain tissue were stained using Cresyl Violet to verify tetrode placement and Thioflavin‐S to quantify amyloid β plaque burden.Result270 cells were recorded (119 wild‐type, 151 APPNL‐G‐F). CA1 pyramidal cells were classified as “place cells” or “non‐place cells” based on their spatial information content (bits/spike). Pyramidal cells recorded in wild‐type mice had significantly greater spatial information content than APPNL‐G‐F pyramidal cells (Figure 1), and a higher proportion were classified as place cells. Wild‐type place cells had significantly greater spatial information content than APPNL‐G‐F place cells. Corresponding differences were identified in place field size (Figures 2, 3). A positive correlation was identified between Aβ plaque burden and pyramidal cell spatial information content in the four APPNL‐G‐F mice (Figure 4).Coordination of place cell firing by the hippocampal theta rhythm was disrupted in APPNL‐G‐F mice; phase‐locking of pyramidal cells and place cells was significantly reduced (Figure 5), there was less coherence in the preferred theta phase across the pyramidal cell population, and a reduction in theta phase precession was observed.ConclusionAPPNL‐G‐F CA1 place cells exhibited deficits in both rate coding and temporal coding of spatial information indicating that amyloid β pathology, in the absence tau tangles, was associated with a disruption of hippocampal place cell function. These results provide preliminary support for the hypothesis that disruption of hippocampal function by AD pathology manifests as altered place cell activity and spatial behaviour.

Enriched environment attenuates hippocampal theta and gamma rhythms dysfunction in chronic cerebral hypoperfusion via improving imbalanced neural afferent levels.

Chronic cerebral hypoperfusion (CCH) is increasingly recognized as a common cognitive impairment-causing mechanism. However, no clinically effective drugs to treat cognitive impairment due to CCH have been identified. An abnormal distribution of neural oscillations was found in the hippocampus of CCH rats. By releasing various neurotransmitters, distinct afferent fibers in the hippocampus influence neuronal oscillations in the hippocampus. Enriched environments (EE) are known to improve cognitive levels by modulating neurotransmitter homeostasis. Using EE as an intervention, we examined the levels of three classical neurotransmitters and the dynamics of neural oscillations in the hippocampus of the CCH rat model. The results showed that EE significantly improved the balance of three classical neurotransmitters (acetylcholine, glutamate, and GABA) in the hippocampus, enhanced the strength of theta and slow-gamma (SG) rhythms, and dramatically improved neural coupling across frequency bands in CCH rats. Furthermore, the expression of the three neurotransmitter vesicular transporters-vesicular acetylcholine transporters (VAChT) and vesicular GABA transporters (VGAT)-was significantly reduced in CCH rats, whereas the expression of vesicular glutamate transporter 1 (VGLUT1) was abnormally elevated. EE partially restored the expression of the three protein levels to maintain the balance of hippocampal afferent neurotransmitters. More importantly, causal mediation analysis showed EE increased the power of theta rhythm by increasing the level of VAChT and VGAT, which then enhanced the phase amplitude coupling of theta-SG and finally led to an improvement in the cognitive level of CCH. These findings shed light on the role of CCH in the disruption of hippocampal afferent neurotransmitter balance and neural oscillations. This study has implications for our knowledge of disease pathways.

Postnatal development of the relaxin-3 innervation of the rat medial septum.

The septal area provides a rich innervation to the hippocampus regulating hippocampal excitability to different behavioral states and modulating theta rhythmogenesis. However, little is known about the neurodevelopmental consequences of its alterations during postnatal development. The activity of the septohippocampal system is driven and/or modulated by ascending inputs, including those arising from the nucleus incertus (NI), many of which contain the neuropeptide, relaxin-3 (RLN3). We examined at the molecular and cellular level the ontogeny of RLN3 innervation of the septal area in postnatal rat brains. Up until P13-15 there were only scattered fibers in the septal area, but a dense plexus had appeared by P17 that was extended and consolidated throughout the septal complex by P20. There was a decrease in the level of colocalization of RLN3 and synaptophysin between P15 and P20 that was reversed between P20 and adulthood. Biotinylated 3-kD dextran amine injections into the septum, revealed retrograde labeling present in the brainstem at P10-P13, but a decrease in anterograde fibers in the NI between P10-20. Simultaneously, a differentiation process began during P10-17, resulting in fewer NI neurons double-labeled for serotonin and RLN3. The onset of the RLN3 innervation of the septum complex between P17-20 is correlated with the onset of hippocampal theta rhythm and several learning processes associated with hippocampal function. Together, these data highlight the relevance and need for further analysis of this stage for normal and pathological septohippocampal development.

Gamma amplitude is coupled to opposed hippocampal theta-phase states during the encoding and retrieval of episodic memories in humans

Computational models and invivo studies in rodents suggest that the emergence of gamma activity (40-140Hz) during memory encoding and retrieval is coupled to opposed-phase states of the underlying hippocampal theta rhythm (4-9Hz).1,2,3,4,5,6,7,8,9,10 However, direct evidence for whether human hippocampal gamma-modulated oscillatory activity in memory processes is coupled to opposed-phase states of the ongoing theta rhythm remains elusive. Here, we recorded local field potentials (LFPs) directly from the hippocampus of 10 patients with epilepsy, using depth electrodes. We used a memory encoding and retrieval task whereby trialunique sequences of pictures depicting real-life episodes were presented, and 24h later, participants were asked to recall them upon the appearance of the first picture of the encoded episodic sequence. Wefound theta-to-gamma cross-frequency coupling that was specific to the hippocampus during both the encoding and retrieval of episodic memories. We also revealed that gamma was coupled to opposing theta phases during both encoding and recall processes. Additionally, we observed that the degree of theta-gamma phase opposition between encoding and recall was associated with participants' memory performance, so gamma power was modulated by theta phase for both remembered and forgotten trials, although only for remembered trials the dominant theta phase was different for encoding and recall trials. The current results offer direct empirical evidence in support of hippocampal theta-gamma phase opposition models in human long-term memory and provide fundamental insights into mechanistic predictions derived from computational and animal work, thereby contributing to establishing similarities and differences across species.

History and Future Directions of rTMS for Treatment of Depressive Disorders

History and Future Directions of rTMS for Treatment of Depressive Disorders

Nonlinear Theta-Gamma Coupling between the Anterior Thalamus and Hippocampus Increases as a Function of Running Speed.

The hippocampal theta rhythm strongly correlates to awake behavior leading to theories that it represents a cognitive state of the brain. As theta has been observed in other regions of the Papez circuit, it has been theorized that activity propagates in a reentrant manner. These observations complement the energy cascade hypothesis in which large-amplitude, slow-frequency oscillations reflect activity propagating across a large population of neurons. Higher frequency oscillations, such as gamma, are related to the speed with which inhibitory and excitatory neurons interact and distribute activity on the local level. The energy cascade hypothesis suggests that the larger anatomic loops, maintaining theta, drive the smaller loops. As hippocampal theta increases in power with running speed, so does the power and frequency of the gamma rhythm. If theta is propagated through the circuit, it stands to reason that the local field potential (LFP) recorded in other regions would be coupled to the hippocampal theta, with the coupling increasing with running speed. We explored this hypothesis using open-source simultaneous recorded data from the CA1 region of the hippocampus and the anterior dorsal and anterior ventral thalamus. Cross-regional theta coupling increased with running speed. Although the power of the gamma rhythm was lower in the anterior thalamus, there was an increase in the coupling of hippocampal theta to anterior thalamic gamma. Broadly, the data support models of how activity moves across the nervous system, suggesting that the brain uses large-scale volleys of activity to support higher cognitive processes.

Dose and time-dependence of acute intermittent theta-burst stimulation on hippocampus-dependent memory in parkinsonian rats.

The treatment options for cognitive impairments in Parkinson's disease (PD) are limited. Repetitive transcranial magnetic stimulation has been applied in various neurological diseases. However, the effect of intermittent theta-burst stimulation (iTBS) as a more developed repetitive transcranial magnetic stimulation paradigm on cognitive dysfunction in PD remains largely unclear. Our aim was to explore the effect of acute iTBS on hippocampus-dependent memory in PD and the mechanism underlying it. Different blocks of iTBS protocols were applied to unilateral 6-hydroxidopamine-induced parkinsonian rats followed by the behavioral, electrophysiological and immunohistochemical analyses. The object-place recognition and hole-board test were used to assess hippocampus-dependent memory. Sham-iTBS and 1 block-iTBS (300 stimuli) didn't alter hippocampus-dependent memory, hippocampal theta rhythm and the density of c-Fos- and parvalbumin-positive neurons in the hippocampus and medial septum. 3 block-iTBS (900 stimuli) alleviated 6-hydroxidopamine-induced memory impairments, and increased the density of hippocampal c-Fos-positive neurons at 80 min post-stimulation but not 30 min compared to sham-iTBS. Interestingly, 3 block-iTBS first decreased and then increased normalized theta power during a period of 2 h following stimulation. Moreover, 3 block-iTBS decreased the density of parvalbumin-positive neurons in the medial septum at 30 min post-stimulation compared to sham-iTBS. The results indicate that multiple blocks of iTBS elicit dose and time-dependent effects on hippocampus-dependent memory in PD, which may be attributed to changes in c-Fos expression and the power of theta rhythm in the hippocampus.