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Table 1 Animal findings regarding theta-gamma coupling (TGC)

From: Disturbed theta and gamma coupling as a potential mechanism for visuospatial working memory dysfunction in people with schizophrenia

Authors & Year of publication Subjects Measure Region of brain examined Task performed / behavior during measurement Relevant findings Conclusions
Studies featuring memory-related tasks
i. Tort et al. (2008) [80] 6 male Sprague–Dawley rats iEEG Striatum, hippocampus T-maze - Theta phase modulated high frequency (80-120Hz) but not low frequency (30-60Hz) gamma in striatum
- TGC between low and high gamma power and theta phase in hippocampus
- TGC strongest during decision making portions of task
- Striatal theta phase modulated hippocampal high gamma power
- Low and high frequency gamma may represent distinct physiological processes
- TGC phase-amplitude coupling likely related to engagement of cognitive processes across varying time scales
ii. Tort, Komorowski, Manns, Kopell, & Eichenbaum (2009) [81] 6 male Long-Evans rats iEEG Hippocampus (CA3) - Freely behaving
- Item-context learning task
- Theta phase modulated low gamma power in CA3 during free behavior
- TGC in CA3 increased during learning and remained high during overtraining sessions
- Strength of TGC predicted mean performance accuracy
TGC important to memory processing
iii. Shirvalkar, Rapp, & Shapiro (2010) [82] 6 male Long-Evans rats iEEG Hippocampus Matching-to-place task (six-arm radial water maze) - Power-power TGC increased during retrieval as compared to exploration (encoding)
- Power-power TGC higher for successful versus unsuccessful recall
- Strength of TGC predicted memory performance, while indices of theta or gamma power alone did not
Power-power TGC in hippocampus is important to memory-dependent behavior
iv. Belluscio, Mizuseki, Schmidt, Kempter, & Buzsáki (2012) [60] 6 male Long-Evans rats iEEG Hippocampus (CA1 pyramidal cells) - Maze exploration
- REM sleep
- Phase-phase and phase-amplitude TGC TGC aids in coordinating neuronal spiking across multiple time scales, potentially helpful in transfer of information and plasticity dependent upon spike timing
v. Cabral et al. (2014) [83] 8 NR1-KO mice (“knockouts” lacking NR1 NMDAR subunit in principal CA1 neurons), 7 littermate controls iEEG Hippocampus (dorsal CA1) Five-armed “starmaze” - Control mice showed increased TGC between theta phase and high-gamma amplitude for place-strategy/allocentric trials and increased TGC between theta phase and low-gamma amplitude during sequence-strategy/egocentric trials
- Excess high and low gamma observed in knockout mice
- Preferred frequency of gamma in TGC associated with spatial WM dependent on strategy used
- Dynamic strategy switching is disrupted by NMDAR disruption
vi. Igarashi, Lu, Colgin, Moser, & Moser (2014) [84] 17 male Long-Evans rats iEEG Entorhinal cortex (medial and lateral, layer III), hippocampus (CA1) Odor-place association task - Odor-place learning was accompanied by increased phase-amplitude TGC in CA1 during odor-sampling (retrieval)
- Phase-amplitude TGC was observed in lateral EC from beginning of task
- Gamma (20-40Hz) power in both regions was unaltered
- TGC in hippocampus important to retrieval of learned memories
- Learning associated with more extensive coupling of already-existing gamma rhythms
vii. Nishida, Takahashi, & Lauwereyns (2014) [85] 4 male Wistar/ST rats iEEG Hippocampus (CA1) Memory-guided spatial alternation task Modulation of gamma-activity by theta phase strengthened overall from beginning to end of session Increase in TGC may reflect plasticity of CA1-CA3/C
A1-EC network, suggestive of optimized communication between these areas
xiii. Schomburg et al. (2014) [57] 9 male Long-Evans, 3 male Sprague–Dawley rats iEEG Hippocampus, entorhinal cortex - Linear track
- T-maze
- Open field
- REM Sleep
- Strong TGC between theta phase and gamma power in hippocampus during memory recall
- Gamma amplitude also modulated by theta phase in EC
- Preferred theta phase dependent upon from where input is being received
Temporal coordination of activity in entorhinal-hippocampus complex primarily supported by theta- and low-frequency gamma activity
ix. Takahashi, Nishida, Redish, & Lauwereyns (2014) [86] 4 male Wistar/ST rats iEEG Hippocampus (CA1) Memory-guided spatial alternation task Gamma-amplitudes in CA1 were phase-locked to theta during a “fixation” period prior to task performance
- Preferred theta-phase differed between high- (60–90 Hz) and low- (30–45 Hz) gamma
- low-gamma activity increased with a concurrent decrease in high-gamma activity towards the end of the fixation period
High-gamma activity associated with externally cued information processing, low-gamma with internally generated information processing
x. Trimper, Stefanescu, & Manns (2014) [87] 6 male Long-Evans rats iEEG Entorhinal cortex Novel object recognition memory task - Increased theta-high-gamma phase-amplitude coupling in the hippocampi of rats exploring novel objects
- Gamma-gamma phase synchrony between CA3 and CA1 LFPs that varied with relative theta- phase and was greatest for objects subsequently remembered
TGC associated with memory processing, but differentially dependent on frequency of gamma activity
xi. Siegle & Wilson (2014) [88] Male parvalbumin-Cre (PV-Cre) heterozygote mice iEEG Hippocampus T-maze - High-gamma modulated by theta-phase during T-maze performance
- Optogenetic stimulation of inhibitory interneurons at trough of theta improved task performance during retrieval, while stimulation at theta peaks improved performance during encoding
- Encoding and retrieval processes occur at different preferential theta phases
- Phase-specific inhibition may reduce the response to task-irrelevant inputs
Studies featuring free exploration, sleep or anesthetization
xii. Buzsáki, Leung, & Vanderwolf (1983) [53] 43 male Long Evans rats iEEG Hippocampus - Activity wheel
- Immobility
- Fast EEG (gamma: 25-70Hz) as well as interneuron spiking superimposed upon and modulated by theta phase
- More prominent in activity than immobility
Slow activity (theta) may be generated through feed-forward inhibition from septum and direct excitation from entorhinal cortex
xiii. Soltesz & Deschenes (1993) [89] Male and female Sprague Dawley rats iEEG Hippocampus (CA1, CA3) Ketamine-xylazine anesthesia - Injection of Cl ions into pyramidal cells brought on high frequency (25-50Hz) oscillation modulated at theta-frequency - Fast oscillations generated by Cl dependent GABAA receptors
- Theta modulation of fast oscillation in hippocampus likely arises through interaction between cholinergic and GABAergic neurotransmitter systems
xiv. Bragin et al. (1995) [90] 45 male and female Sprague–Dawley rats iEEG Hippocampus (dentate hilus) - Freely behaving
- Immobility
- REM Sleep
- Prominent theta-phase to gamma-amplitude coupling, particularly in dentate hilus region, during activity and REM sleep - TGC due to reciprocal connections between interneurons, hilar mossy cells and CA3 pyramidal cells
xv. Chrobak & Buzsáki (1998) [91] 19 Sprague Dawley rats iEEG Entorhinal cortex (layers II & III),
Freely behaving - Nesting of gamma oscillations within theta oscillations in the entorhinal cortex and hippocampus
- Neuronal spiking in entorhinal cortex in phase with the local, nested gamma oscillations
- Synchronization between theta-gamma rhythms in entorhinal cortex and dentate hilar region of hippocampus
Systematic phase-locking of gamma oscillations to nesting theta oscillations is necessary for communication within perforant pathway
xvi. Buzsáki et al. (2003) [92] 13 hybrid (C57B6/J & 129S6/SvEvTac) and 3 inbred (C57B6/J) mice iEEG Hippocampus (CA1 pyramidal layer, dentate gyrus) - Freely behaving
- Immobile awake
- Sleeping
Gamma, interneurons and pyramidal cells all phase-locked to concurrent theta rhythm during free behavior - Mouse brain is similar to rat brain
- Interneurons critical to gamma generation
xvii. Csicsvari, Jamieson, Wise, & Buzsáki (2003) [93] 12 male Sprague–Dawley rats iEEG Hippocampus (CA1, CA3, granule cell layers) - Freely behaving
- Immobility
- Slow wave sleep
- REM sleep
- Gamma power varied with theta phase when theta present but irregularly otherwise
- Gamma field power greater in CA1 during theta-associated behaviors
- Gamma CSD power greater in granule cell layer during theta-associated behaviors
Concurrent theta is not necessary for gamma oscillation, but theta enhances and modulates gamma when present
xviii. Hentschke, Perkins, Pearce, & Banks (2007) [94] B6129SF2⁄J wild-type mice iEEG Hippocampus (CA1, all laminae) - Freely behaving
- Immobile awake
- Phase-amplitude TGC during exploration and immobility, highest around hippocampal fissure
- Significantly decreased by injection of atropine, a muscarinic antagonist
Phase-amplitude TGC in CA1 influenced by neurons with muscarinic receptors
xix. Sirota et al. (2008) [95] 28 rats, 11 mice iEEG Hippocampus, neocortex - Active (n = 28 rats, 11 mice)
- Anesthetized (n = 27 rats)
- Phase-phase coupling between hippocampal theta rhythms and gamma oscillations in multiple regions of neocortex, including prefrontal cortex and primary sensory areas TGC between hippocampus and neocortex means for transfer of information from neocortex to hippocampus
xx. Wulff et al. (2009) [96] PV-Δγ2 mice (mice with GABAA receptor γ2 subunit ablated from parvalbumin-positive interneurons in hippocampus); normal litter-mates as controls iEEG Hippocampus Freely behaving - Phase-amplitude TGC nearly three times as weak in PV-Δγ2 as control mice PV+ neurons involved in coupling of theta to gamma activity
xxi. Quilichini, Sirota, & Buzsáki (2010) [97] 39 male Sprague–Dawley rats iEEG Entorhinal cortex (layers II, III, V) - Anesthetized - Gamma (including high frequency) power modulated by theta phase in all layers
- Different theta phase preferences from layer to layer
Gamma activity can be generated locally in individual EC layers and relate to phase of hippocampal theta activity
xxii. De Almeida, Idiart, Villavicencio, & Lisman (2012) [59] Rats iEEG Entorhinal cortex (grid cells) - Open field exploration
- Traversal of linear track
- Phase precession observed in grid cells with two varying “modes”: inbound (firing occurs as rat approaches center of place field) and outbound (firing occurs as rat leaves center) Grid cells have different modes which account for upcoming locations versus those recently passed, serving both storage and predictive functions of hippocampus
xxiii. Caixeta, Cornélio, Scheffer-Teixeira, Ribeiro, & Tort (2013) [65] 8 male Wistar rats iEEG Left hippocampus - Open field exploration
- Saline injection
- Ketamine injection
- Ketamine increased motor activity and gamma power
- Prominent phase-amplitude coupling between theta- and high-gamma (60–100Hz) as well as high frequency oscillations (HFO; 110–160Hz) pre-ketamine injection
- Theta-HFO coupling increased with ketamine, while theta-gamma coupling increased at the lowest dosage but markedly disturbed at the highest dosage
Some symptoms of schizophrenia may be explained by aberrant TGC and/or theta-HFO coupling
xxiv. Newman, Gillet, Climer, & Hasselmo (2013) [98] 6 male Long-Evans rats iEEG Entorhinal cortex (medial) - Lap-running on circular track
- With and without scopolamine injection
- Robust phase-power TGC for both low- (20-40Hz) and high- (60–120Hz) gamma
- Scopolamine selectively reduced high gamma power at peak of theta
- Encoding and retrieval may occur at peak and through of theta, respectively
- Acetylcholine influences balance between encoding and retrieval processes
xxv. Pernía-Andrade & Jonas (2014) [99] Wistar rats Whole cell recording Hippocampal (dentate gyrus) granule cells - Anesthetized
- Free exploration
- EPSCs coherent with LFP theta oscillations; IPSCs coherent with LFP gamma oscillations
- Action potentials phase locked to theta-gamma oscillations in LFP
- TGC in dentate gyrus may reflect inhibitory gamma currents phase locked to theta currents and initiated by excitation from the entorhinal cortex
- Compound signal may serve as temporal reference signal for encoding in granule cells
xxvi. Yamamoto, Suh, Takeuchi, & Tonegawa (2014) [100] MECIII-TeTX MT Mice (allow for reversible silencing of synaptic transmission of MEC layer III pyramidal cells), control litter-mates iEEG Hippocampus (CA1), entorhinal cortex (medial, layer III) Open field exploration - High-frequency and low-frequency gamma modulate to different phases of theta High-frequency gamma contributes uniquely to WM function
In vitro or isolate studies
xxvii. Cunningham, Davies, Buhl, Kopell, & Whittington (2003) [101] Male Sprague–Dawley rats iEEG Hippocampus, entorhinal cortex In vitro - Amplitude of field gamma activity modulated at theta frequency in presence of kainate receptor activation EC can generate intrinsic theta activity
xxviii. Goutagny et al. (2013) [102] TgCRND8 mice (develop at 3 months of age amyloid-beta plaques typical of Alzheimer’s disease and accompanied by similar cognitive decline) iEEG Hippocampus N/A (hippocampal isolate) - Some TgCRND8 showed alterations in phase-amplitude TGC prior to accumulation of amyloid-beta plaques or cognitive decline)
- Exclusive to theta coupling with fast gamma, not slow gamma
Declines in TGC are early electrophysiological indicators of hippocampal network dysfunction
xxix. Pastoll, Solanka, van Rossum, & Nolan (2013) [103] Adult Thy1-ChR2-YFP line 18 mice iEEG Entorhinal cortex (medial) N/A (isolated brain slices, though with simulated movement) - Optogenetic stimulation of medial entorhinal cortex at theta frequency sufficient to produce nested gamma activity with both phase and amplitude coupled to theta phase
- Nested gamma is mediated by feedback inhibition
Local medial entorhinal cortex circuit produces TGC with “clock-like” (p. 153) consistency; coupled signals may serve as temporal references for other neuronal computations
Primate studies
xxx. Lakatos et al. (2005) [104] 4 male macaque monkeys iEEG Primary auditory cortex Passive listening task Spontaneous gamma-activity found to fluctuate at theta-frequency, and theta-activity found to subsequently fluctuate at delta frequency Oscillatory activity is organized in a hierarchical manner, not exclusively limited to gamma and theta activity
xxxi. Voloh, Valiante, Everling, & Womelsdorf (2015) [105] 2 macaque monkeys iEEG Medial and lateral PFC (anterior cingulate cortex) Attention task - Theta-phase to gamma-amplitude TGC between various sites in ACC and PFC during task performance, but not before errors TGC essential to integration of varied and distributed activities, including attention, in neural networks
  1. WM working memory, TGC theta-gamma coupling, iEEG intracranial EEG, LFP local field potential, CSD current source density, EC entorhinal cortex, HFO high-frequency oscillation, ACC anterior cingulate cortex, PFC prefrontal cortex