The θ-γ neural code

Abstract

Theta and gamma frequency oscillations occur in the same brain regions and interact with each other, a process called cross-frequency coupling. Here, we review evidence for the following hypothesis: that the dual oscillations form a code for representing multiple items in an ordered way. This form of coding has been most clearly demonstrated in the hippocampus, where different spatial information is represented in different gamma subcycles of a theta cycle. Other experiments have tested the functional importance of oscillations and their coupling. These involve correlation of oscillatory properties with memory states, correlation with memory performance, and effects of disrupting oscillations on memory. Recent work suggests that this coding scheme coordinates communication between brain regions and is involved in sensory as well as memory processes.

Fig. 1

Neural code organized by theta and gamma oscillations. (A) Simultaneous extracellular (top) and intracellular (bottom) recordings from the hippocampus. Intracellular gamma is due to IPSPs, the amplitude of which is modulated by the phase of theta. From Fig. 4C of (Penttonen et al., 1998). (B) Schematic of the theta-gamma code. The ovals at top represent states of the same network during two gamma cycles (active cells are black and constitute the ensemble that codes for a particular item). Different ensembles are active in different gamma cycles.

Fig. 2

Spiking in the rat CA1 region depends on the phase of both theta and gamma oscillations. (A) Phase precession: as the rat runs through a place field, a process that takes several seconds, theta phase becomes progressively earlier (closer to zero phase) on successive theta cycles. From Fig. 1A of (Mehta et al., 2002). The phase precession can be understood as cued, time-compressed readout of the sequences of places ahead of the animal. Such “sweeps” provide information to other brain regions of what is to come. Consider that the place field (210 cm to 270 cm) can be divided into seven subregions, a, b, c, d, e, f, and g. The rat enters the field from the left at position a, which cues the ordered prediction of upcoming positions (Battaglia et al., 2004), thereby producing a “sweep.” The “true” place field of this cell is the position g; the firing of this cell at position a represents a prediction that g is ahead of the animal. By the time of the second theta cycle, the rat has moved to b, so b is the cue and produces the sweep b, c, d, e, f, g, h in the second theta cycle. One can see from this example why the g cell fires with earlier theta phase on each successive theta cycle. According to one hypothesis, the successive activation of cells during a sweep results from simple chaining of excitation between the ensembles (Burgess and O’Keefe, 2011; Jensen and Lisman, 1996; Tsodyks et al., 1996). The results shown are combined data from many passages through the place field; the linkage of phase to position is even more exact when individual passages are analyzed (Schmidt et al., 2009), perhaps because theta can occur during different modes (see below) having different phase-position relationships. (B) Many CA1 place cells fire at a preferred phase of gamma cycles (‘in’ and ‘out’ refer to the firing probability as a function of gamma phase when the rat is respectively inside or outside of the place field; the line with no error bars is the LFP filtered in the gamma band). From Fig. 6B of (Senior et al., 2008). Because the analysis averages over different functional modes (Colgin et al., 2009; de Almeida et al., 2012; Gupta et al., 2012; Senior et al., 2008) and gamma generators (Belluscio et al., 2012), the actual modulation by gamma phase may be stronger than shown.)

Fig. 3

Cells that fire in sequence during a theta cycle form a sweep. Three examples are shown. (Top) Top panels show track. Current position of rat is marked by arrowhead, and it is at this position that the sweep shown below occurs. Different cells active during the sweep have place field centers marked by the colored dots. (Bottom) The spikes of different cells during a theta cycle (start to end). Cells are positioned on the y axis according to the position of their place field centers. In these examples, activity sweeps represent positions along the path ahead of the animal. From Fig. 3 of (Gupta et al., 2012).

Fig. 4

Cells that code for the same position (part of a cell assembly) and then fire in synchrony (within a gamma cycle). (A) Firing rate as a function of distance on a linear track for five place cells in CA1 (different colors). Green and red cells have peak firing rates at nearly the same position. (B) The cross-correlation between green and red cells (in A) has a peak very near 0 ms (red line), indicating that the cells tend to fire in the same gamma cycle. This is true even though the particular gamma subcycle changes during the theta-phase precession. Green and blue cells (in A) have different place field centers and tend to fire with a temporal offset that peaks at 40 ms (cyan line) (i.e., in different gamma cycles). From Fig. 1 of (Dragoi and Buzsaki, 2006).

Fig. 5

Theta-gamma cross-frequency coupling in CA3 predicts behavior. (A) Exposure to empty context A or B (light gray/dark gray) cues the rat about which cup (blue/yellow) when subsequently presented will contain reward. (B) While exploring context, cross-frequency coupling occurs (left) and can vary in the degree to which theta phase modulates gamma power (right). (C) Theta-gamma modulation occurs during recall of the association between the context and the type of rewarded cup; this modulation is predictive of whether the rat correctly goes to the rewarded cup. From Fig. 1 and 2 of (Tort et al., 2009).

Fig. 6

Phase precession, an indicator of theta-gamma coupling, is evident in the hippocampus (HC) (top) but is also evident in a hippocampal target area, the ventral striatum (bottom). The data are taken as the rat begins its approach to the reward site. Taken from Fig. 3B (van der Meer and Redish, 2011).

Fig. 7

Role of the firing pause between items. Firing as a function of time for two sequential items in schemes with or without a firing pause between items. (Top) An ensemble representing one item (green) followed by rapid state change to an ensemble representing another item (red). (Bottom) Firing for the first item is clustered in one-third of a gamma cycle followed by a pause. Firing for the second item then occurs in the first part of the second gamma cycle, followed by another pause. Downstream networks detect patterns by integrating inputs that arrive within the coincidence detection window (yellow bar). If green is represented by cells 1,2,3, red by cells 4,5,6, and blue by 1,2,6, then the message detected in the state-change case is green, blue, red. In contrast, when firing is clustered, the message is correctly read as green, red.

Fig. 8

How inhibition during gamma oscillations determines which cells fire. Interneurons fired during a previous gamma cycle (left) and generated global inhibition in pyramidal cells. Inhibition decays with the time constant of the IPSP (tau; this equals the membrane time constant) (left). The voltage in three pyramidal cells having different tonic excitation is shown (red/green/black). As inhibition decays, the most excited cell (red) reaches threshold. This triggers an interneuron spike and feedback inhibition, which arrives at all pyramidal cells with delay, d. During this delay, the cell (green) with excitation that is close to that of the most excited cell will also fire.

Fig. 9

Theta power is gated up at some cortical sites and down at others during the period of working memory. (A) With intracranial recordings, large-amplitude theta can be observed in single trials of the Sternberg task. First black bar is the time of cue presentation; second black bar indicates presentation of the item to be remembered; at the red bar, the test item is presented and the subject indicates (at the blue bar) whether it is the same as the remembered item. In other trials, more items were presented. (B) Recordings from three sites where task (white bar) had little effect on theta power (top), where it produced an increase in theta power (middle), or where it produced a decrease in theta power (bottom). Color code at right indicates theta power. From Fig. 8 of (Raghavachari et al., 2001).