A non-synaptic mechanism of complex learning: Modulation of intrinsic neuronal excitability

https://doi.org/10.1016/j.nlm.2017.11.015Get rights and content

Highlights

  • Training in a complex task induces ‘rule learning’.

  • Rule learning is first manifested in increased intrinsic neuronal excitability.

  • Enhanced excitability is mediated by reduction in late after hyperpolarization.

  • The induction of enhanced intrinsic excitability is protein synthesis dependent.

  • Learning-induced modulation of intrinsic excitability can be bi-directional.

Abstract

Training rats in a particularly difficult olfactory discrimination task initiates a period of accelerated learning of other odors, manifested as a dramatic increase in the rats' capacity to acquire memories for new odors once they have learned the first discrimination task, implying that rule learning has taken place.

At the cellular level, pyramidal neurons in the piriform cortex, hippocampus and bsolateral amygdala of olfactory-discrimination trained rats show enhanced intrinsic neuronal excitability that lasts for several days after rule learning. Such enhanced intrinsic excitability is mediated by long-term reduction in the post-burst after-hyperpolarization (AHP) which is generated by repetitive spike firing, and is maintained by persistent activation of key second messenger systems. Much like late-LTP, the induction of long-term modulation of intrinsic excitability is protein synthesis dependent. Learning-induced modulation of intrinsic excitability can be bi-directional, pending of the valance of the outcome of the learned task.

In this review we describe the physiological and molecular mechanisms underlying the rule learning-induced long-term enhancement in neuronal excitability and discuss the functional significance of such a wide spread modulation of the neurons' ability to sustain repetitive spike generation.

Introduction

Learning-related cellular changes can be divided into two general groups: modifications that occur at synapses and modifications in the intrinsic properties of the neurons. While it is commonly agreed that changes in strength of connections between neurons in the relevant networks underlie memory storage, ample evidence suggest that modifications in intrinsic neuronal properties may also account for learning related behavioral changes. Long-lasting modifications in intrinsic excitability are manifested in changes in the neuron's response to a given extrinsic current (generated by synaptic activity or applied via the recording electrode).

Learning induced enhancement in neuronal excitability has been shown in hippocampal neurons following classical conditioning of the trace eyeblink response (Moyer et al., 1996, Thompson et al., 1996) and the Morris watermaze task (Oh, Kuo, Wu, Sametsky, & Disterhoft, 2003), and in piriform cortex neurons following operant conditioning (Saar and Barkai, 2003, Saar et al., 1998, Saar et al., 2001). Learning specific modifications in neuronal excitability were shown also in cerebellar neurons (Schreurs, Gusev, Tomsic, Alkon, & Shi, 1998) and in Hermissenda (Alkon, Nelson, Zhao, & Cavallaro, 1998) after classical conditioning. In hippocampal and piriform cortex neurons, this enhanced excitability is manifested in reduced spike frequency adaptation in response to prolonged depolarizing current applications (Moyer et al., 1996, Saar et al., 2001, Thompson et al., 1996). Olfactory-discrimination learning also results in enhanced neuronal excitability in CA1 hippocampal neurons (Zelcer et al., 2006) and in the basolateral amygdala (Motanis, Maroun, & Barkai, 2014)

Neuronal adaptation in neocortical, hippocampal and piriform cortex pyramidal neurons is modulated by medium and slow afterhyperpolarizations (AHPs), generated by potassium currents, which develop following a burst of action potentials (Constanti and Sim, 1987, Madison and Nicoll, 1984, Saar et al., 2001, Schwindt et al., 1988). Indeed, two decades it was first shown in hippocampal and piriform cortex pyramidal neurons, that the post-burst AHP amplitude is reduced after learning (Moyer et al., 1996, Saar et al., 1998).

Section snippets

Functional significance of post-burst AHP reduction for rule-learning

Several findings suggested that AHP reduction and its consequent enhancement in neuronal excitability, which are induced by olfactory-discrimination rule-learning (Fig. 1), is not the mechanism by which memories for specific sensory inputs or sequences of events are stored. Rather, it may be the mechanism that enables neuronal ensembles to enter into a state which may be best termed “learning mode”. This state lasts for up to several days and its behavioral manifestation is enhanced learning

Learning-induced reduction in post-burst AHP is caused by reduction in a specific calcium–dependent potassium current

The potassium currents underlying the post-burst AHP have been studied most extensively in hippocampal neurons. They have been characterized based on their latency from the action potentials, their duration and their pharmacological properties. Five such currents are now identified: the voltage-dependent muscarin-sensitive IM, the calcium and voltage-dependent IC, the apamin-sensitive calcium-dependent IAHP, the hyperpolarization-activated cation-current Ih and the apamin-insensitive

Role of second messenger systems in maintaining prolonged AHP reduction

How is rule-learning induced reduction in the post-burst AHP maintained for periods of days after training completion? The sIAHP is reduced by PKC-dependent activation of glutamate-mediated kainate-receptors (Melyan et al., 2004, Melyan et al., 2002). Accordingly, olfactory learning-induced post-burst AHP reduction is mediated by persistent PKC activation (Seroussi, Brosh, & Barkai, 2002). Rule learning-induced long-lasting reduction in post burst AHP amplitude in piriform cortex neutrons

PKC-induced AHP reduction is ERK dependent

Recordings performed in pirifom cortex neurons after olfactory learning show that the PKC blocker, GF-109203X increases the AHP in neurons from trained rats only, and that the PKC activator, OAG, reduced the AHP in neurons from control groups more than in neurons from trained rats (Seroussi et al., 2002). In Particular, the PKC activator reduced the AHP in neurons from naïve rats by 40% (Seroussi et al., 2002). Hence, if PKC-induced reduction of the AHP is mediated via ERK activation,

Long-lasting activity-induced AHP reduction is protein-synthesis dependent

Synaptic activation-induced AHP reduction lasts for many hours, well into the range where late-LTP occurs (Cohen-Matsliah, Motanis, Rosenblum, & Barkai, 2010). Moreover, similar to late-LTP, long-lasting AHP reduction is protein synthesis dependent, at a specific well defined time window after synaptic activation. Cohen-Matsliah et al. (2010) showed repetitive synaptic stimulation results with post–burst AHP reduction, such that would be still evident at the time range in which late LTP is

Learning-induced modification in neuronal excitability can be bi-directional

Different learning paradigms may result in different long lasting modification in neuronal excitability, in the same brain area. The basolateral amygdala (BLA) is suggested to encode positive and negative significance of information, thus forming a unique experimental setting to monitor bidirectional changes as a function of the valence change. In a recent study (Motanis et al., 2014) we showed that intrinsic neuronal excitability in BLA pyramidal neurons is differentially modified by positive

Learning-induced enhancement and reduction of intrinsic excitability are mediated by two different mechanisms

As shown in the piriform cortex and the hippocampus, olfactory-discrimination learning also results with post-burst AHP reduction in BLA neurons (although no significant difference was found between neurons from the trained and the pseudo groups), in parallel with increased neuronal excitability (Fig. 7A and B). However, reduced olfactory-fear conditioning-induced reduction in intrinsic excitability was not accompanied by a parallel modification in the post burst AHP in BLA neurons (Fig. 7C and

Conclusions

Rule learning is expressed at the cellular level with enhanced intrinsic neuronal excitability that occurs in most neurons in the relevant neuronal networks at several key brain areas, such as the piriform cortex, the hippocampus and the basolateral amygdala. Induction of enhanced excitability is protein synthesis-dependent, mediated by reduction in the conductance of the slow calcium-dependent potassium current and is maintained for days by persistent activation of key second messenger

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