Mechanisms


Introduction

Several theories exist for the generation of gamma oscillations in various parts of the brain. They all need further experimental testing. It is possible that gamma oscillations arise by different mechanisms in different parts of the brain, and that several mechanisms combine in individual regions. The cartoons in the figure are highly simplified representations of some of their components. We will consider the various mechanisms roughly in chronological order, and indicate the main regions where they have been implicated immediately after their respective headings.

Feedback loops between excitatory and inhibitory neurons (olfactory bulb, piriform cortex, entorhinal cortex, primary visual cortex). Freeman and colleagues developed a model for induced rhythms in several olfactory structures, which proposed that the synchronous oscillation is generated by a feedback loop between excitatory and inhibitory neurons [2]. They proposed that some mutual connectivity was also required within the pools of both excitatory and inhibitory neurons to stabilize the oscillations. Ermentrout [3] has shown that mutual excitation amongst the excitatory neurons is necessary for stable oscillations to be generated by a recurrent inhibitory loop. However, our recent simulations suggest that other conditions may suffice for stable oscillations (R.D. Traub, unpublished).

Freeman et al [2] predicted that inhibitory cells should lag behind the excitatory by 0.25 cycle (6.5 ms at 40 Hz). Experimental support came from single unit and EEG recordings in vivo from: olfactory bulb, anterior olfactory nucleus, prepiriform cortex, and entorhinal cortex [2]. The signals fell into two groups: one set fired in phase with the gamma EEG, and one led or lagged by 0.25 cycle; unfortunately these measurements cannot identify the neurons in each group. In contrast, hippocampal interneurons recorded during gamma fire in phase with pyramidal cells [1]. This is predicted by our inhibitory network model (see below), both when isolated from the excitatory network [13], and when connected with pyramidal cells (Traub et al, unpublished simulations). Why the hippocampal and superficially similar olfactory cortical circuitry should differ remains unclear [2].

Wilson and Bower made similar models of piriform cortex [14] and primary visual cortex [15]. The geometric structure of these models differed, but the essential idea in both was that the amplitude and frequency of coherent 30-60 Hz oscillations evoked by afferent volleys were determined or "tuned" by a fast feedback inhibitory loop (Fig. A). Essentially, if the stimulus is appropriate (not too strong), enough activity in the recurrent excitatory connections between pyramidal cells persists after recurrent inhibition wanes in order to re-excite the pyramidal cell population. In the case of the piriform cortex model, they showed that the time constant of inhibition "tuned" the frequency of the gamma rhythm, so that longer open times for the chloride channels resulted in slower rhythms (and also a loss of power).

In their model of the primary visual cortex Wilson and Bower [15] note in passing that local mutual inhibition between the interneurons "...improved frequency locking and produced auto- and cross-correlations with more pronounced oscillatory characteristics". This differs from the central role of the same kinds of connections in the generation of gamma rhythms in the hippocampus where they were both necessary and sufficient [11,13].

In the visual cortex model horizontal pyramidal cell axons were essential for long range (upwards of 1mm) cross correlations [15]. These had zero phase lag as long as the EPSPs they generated were not too strong. Stronger EPSPs result in phase lags consistent with axonal conduction delays, while weaker ones were reminiscent of other kinds of loosely-coupled oscillators. In both the visual cortex and the piriform cortex versions of this model, gamma rhythms: arose from interactions between networks of excitatory neurons, could depend on the conduction velocities of intrinsic cortical connections (Fig. 2B), and were tuned by the time constants of excitatory and inhibitory synapses. We are not aware of any attempts to dissect these complex interactions experimentally; in particular an investigation of the effects of conduction delays on cortical oscillations would be instructive.

Intrinsic oscillations in individual neurons (thalamus, neocortex; Fig. 2C). Neurons in many parts of the brain have the intrinsic capacity to oscillate at about 40 Hz. Several types of neuron in the thalamocortical system do so, e.g. reticular [9] and intralaminar [10] neurons. In neocortex itself, intrinsic cellular oscillators include: sparsely spiny layer 4 neurons [6], about 20% of long axon projection neurons in layers 5 and 6 [8], and "chattering cells" (that fire brief trains of action potentials at 200Hz about 40 times a second) recently reported in vivo [7].

Slice studies revealed that 40 Hz oscillations in sparsely spiny neurons in frontal cortex are generated by voltage-dependent persistent sodium and delayed rectifier currents [6]. Other frontal cortex neurons use fast persistent sodium currents, leak and slow non-inactivating potassium currents to generate 4-20 Hz [4]; models suggest that similar mechanisms can generate 40 Hz [12]. At least some cortical neurons with intrinsic oscillator mechanisms project to contralateral areas, and to the thalamus, providing routes for long range synchronisation of these oscillations [8]. The existence of cells with intrinsic oscillations at 40 Hz does not in itself explain the synchronization of local populations of neurons, but it is likely to pace population rhythms when the neurons are suitably coupled by chemical and/or electrical synapses [5].


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