Persistent neural activity: prevalence and mechanisms

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Persistent neural activity refers to a sustained change in action potential discharge that long outlasts a stimulus. It is found in a diverse set of brain regions and organisms and several in vitro systems, suggesting that it can be considered a universal form of circuit dynamics that can be used as a mechanism for short-term storage and accumulation of sensory or motor information. Both single cell and network mechanisms are likely to co-operate in generating persistent activity in many brain areas.

Introduction

The importance of persistent activity for proper motor function is immediately evident from oculomotor fixation behavior. As shown in Figure 1ai, holding the eyes at an eccentric angle after a brief saccadic command is accompanied by a sustained discharge of pre-motor neurons in the oculomotor neural integrator, with different fixation angles produced by different sustained levels. The fact that this can be produced without visual or proprioceptive feedback [1] demonstrates that the persistent activity must be generated by the internal cellular and/or network dynamics of a neural circuit. This example illustrates a more general postural motor control problem that must be solved when, for example, holding your arm extended at different positions.

In fact, the behavioral importance of persistent neural activity appears to be even more general. For example, sustained action potential firing in response to a brief sensory stimulus is observed in many areas of cerebral cortex during working memory behaviors requiring short-term retention of a sensory stimulus, such as delayed match tasks [2]. Qualitatively similar sustained discharges have also been observed in subcortical brain areas, such as the basal ganglia [3], thalamus [4], superior colliculus [5], brainstem [6] and spinal cord [7]. The qualitative similarities of persistent activity in such a diversity of brain areas and species suggest the possibility that it represents a very general and fundamental form of brain dynamics.

The past few years have been a very active period in persistent firing research. This review attempts to bring together references on experimental observations of persistent neural activity across species and brain areas. First, we summarize important characteristic features of different forms of persistent activity and provide a table of references (see Supplementary table) to examples of each in different brain areas. Second, we review experiments aimed at uncovering the mechanisms of persistent neural activity. Two hypothesized general mechanisms frame the discussion: recurrent networks and intrinsic biophysical cellular properties, for example plateau potentials. (We define a plateau potential as a relatively rapid onset and offset long-lasting change in stable membrane potential dependent on intrinsic membrane conductances and/or intracellular messengers.)

Section snippets

Classification and prevalence of persistent neural activity

It is useful to compare and contrast persistent activity across the widely different brain areas and preparations in which it is found (see Supplementary table, previous reviews 2., 3., 8., 9., 10., 11., 12., 13., 14., 15.•, 16.). Several questions can be asked in each case.

Dominance of intrinsic cellular mechanisms?

There is increasing evidence that intrinsic cellular mechanisms 12., 17. are both widespread and can produce multi-stability. In many cases, persistent firing is driven by an underlying plateau potential [9]. A soma-dendritic tree can have more than one possible stable spatial pattern of membrane potential at any given time. The number of stable voltage patterns, their spatial structure and the soma voltage can change with time because of channel and intracellular signaling dynamics, and can

Lack of persistent changes in firing in oculomotor integrator cells following intracellular current pulses

If goldfish Area 1 cells have an intrinsic plateau potential conductance near the cell body, it should be possible to switch it on and off by intracellular current injections. When this experiment was done in vivo [1], current pulses failed to cause persistent changes in firing (Figure 2c), suggesting network mechanisms dominate this system. However, distal dendritic or NMDA plateau potentials have not been ruled out. Other intrinsic mechanisms such as calcium wavefronts might not depend

Future directions

What would be definitive tests for recurrent network mechanisms? One approach is to remove precisely one cell or a subset of the network and to examine the effect on the remaining neurons. Many network models predict that even a small reduction in overall positive feedback will lead to a profound loss of persistence. These experiments have already been done at a crude level. In primates, localized cortical cooling changes the level of persistent firing of particular neurons, but generally the

Conclusions

The diversity of CNS areas demonstrating persistent activity is immense (see Supplementary table), suggesting its importance and the possibility that a small set of common mechanisms will be found. The biophysical machinery for intrinsic cellular mechanisms has been found in many of these same areas, and might help to explain the robustness of persistent firing. Nevertheless, there are serious challenges to intrinsic cellular persistent activity being the dominant mechanism in higher brain

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to thank E Aksay, AA Alonso, CD Brody, SA Deadwyler, R Dubuc, RE Hampson, J Hounsgaard, O Kiehn, T Ono, JS Taube, other colleagues and an anonymous referee for their help and contributions.

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