Learning is a complex brain function operating on different time scales, from milliseconds to years, which induces enduring changes in brain dynamics. The brain also undergoes continuous "spontaneous" shifts in states, which, amongst others, are characterized by rhythmic activity of various frequencies. Besides the most obvious distinct modes of waking and sleep, wake-associated brain states comprise modulations of vigilance and attention. Recent findings show that certain brain states, particularly during sleep, are essential for learning and memory consolidation. Oscillatory activity plays a crucial role on several spatial scales, for example in plasticity at a synaptic level or in communication across brain areas. However, the underlying mechanisms and computational rules linking brain states and rhythms to learning, though relevant for our understanding of brain function and therapeutic approaches in brain disease, have not yet been elucidated. Here we review known mechanisms of how brain states mediate and modulate learning by their characteristic rhythmic signatures. To understand the critical interplay between brain states, brain rhythms, and learning processes, a wide range of experimental and theoretical work in animal models and human subjects from the single synapse to the large-scale cortical level needs to be integrated. By discussing results from experiments and theoretical approaches, we illuminate new avenues for utilizing neuronal learning mechanisms in developing tools and therapies, e.g., for stroke patients and to devise memory enhancement strategies for the elderly.

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State-dependencies of learning across brain scales

Neurons in the medial superior olive (MSO) detect microsecond differences in the arrival time of sounds between the ears (interaural time differences or ITDs), a crucial binaural cue for sound localization. Synaptic inhibition has been implicated in tuning ITD sensitivity, but the cellular mechanisms underlying its influence on coincidence detection are debated. Here we determine the impact of inhibition on coincidence detection in adult Mongolian gerbil MSO brain slices by testing precise temporal integration of measured synaptic responses using conductance-clamp. We find that inhibition dynamically shifts the peak timing of excitation, depending on its relative arrival time, which in turn modulates the timing of best coincidence detection. Inhibitory control of coincidence detection timing is consistent with the diversity of ITD functions observed in vivo and is robust under physiologically relevant conditions. Our results provide strong evidence that temporal interactions between excitation and inhibition on microsecond timescales are critical for binaural processing.

/pdf/glycinergic-inhibition-tunes-coincidence-detection-in-the-2qkrogsb18.pdf

Glycinergic inhibition tunes coincidence detection in the auditory brainstem

The axon initial segment (AIS) serves as the site of action potential initiation in most neurons, but difficulties in isolating the effects of voltage-gated ion channels in the AIS from those of the soma and dendrites have hampered understanding how AIS properties influence neural coding. Here we have combined confocal microscopy, patch-clamp recordings and light-sensitive channel blockers ('photoswitches') in binaural auditory gerbil neurons to show that hyperpolarization and cyclic-nucleotide-gated (HCN) channels are expressed in the AIS and decrease spike probability, in a manner distinct from that of HCN channels in the soma and dendrites. Furthermore, the control of spike threshold by HCN channels in the AIS can be altered through serotonergic modulation of 5-hydroxytryptamine 1A (5-HT1A) receptors, which hyperpolarizes the activation range of HCN channels. As release of serotonin signals changes in motivation and attention states, axonal HCN channels provide a mechanism to translate these signals into changes in the threshold for sensory stimuli.

/pdf/serotonin-modulates-spike-probability-in-the-axon-initial-4vu2gux35n.pdf

Serotonin modulates spike probability in the axon initial segment through HCN channels

Plasticity of myelination represents a mechanism to tune the flow of information by balancing functional requirements with metabolic and spatial constraints. The auditory system is heavily myelinated and operates at the upper limits of action potential generation frequency and speed observed in the mammalian CNS. This study aimed to characterize the development of myelin within the trapezoid body, a central auditory fiber tract, and determine the influence sensory experience has on this process in mice of both sexes. Wefind that in vitro conduction speed doubles following hearing onset and the ability to support high-frequency firing increases concurrently. Also in this time, the diameter of trapezoid body axons and the thickness of myelin double, reaching mature-like thickness between 25 and 35 d of age. Earplugs were used to induce similar to 50 dB elevation in auditory thresholds. If introduced at hearing onset, trapezoid body fibers developed thinner axons and myelin than age-matched controls. If plugged during adulthood, the thickest trapezoid body fibers also showed a decrease in myelin. These data demonstrate the need for sensory activity in both development and maintenance of myelin and have important implications in the study of myelin plasticity and how this could relate to sensorineural hearing loss following peripheral impairment.

https://www.jneurosci.org/content/jneuro/37/34/8239.full.pdf

Sound-Evoked Activity Influences Myelination of Brainstem Axons in the Trapezoid Body.

Spatial coding and attractor dynamics of grid cells in the entorhinal cortex

Neurons in the medial superior olive (MSO) encode interaural time differences (ITDs) with sustained firing rates of >100 Hz. They are able to generate such high firing rates for several hundred milliseconds despite their extremely low-input resistances of only few megaohms and high synaptic conductances in vivo . The biophysical mechanisms by which these leaky neurons maintain their excitability are not understood. Since action potentials (APs) are usually assumed to be generated in the axon initial segment (AIS), we analyzed anatomical data of proximal MSO axons in Mongolian gerbils and found that the axon diameter is

https://www.jneurosci.org/content/jneuro/34/15/5370.full.pdf

Action Potential Generation in an Anatomically Constrained Model of Medial Superior Olive Axons

Rodent brains encode space in both the firing rate and the spike timing of neurons in the medial entorhinal cortex. The rate code is realized by grid fields, that is, the neurons fire at multiple places that are arranged on a hexagonal lattice. Such activity is accompanied by theta oscillations of the local field potential. The phase of spikes thereby encodes space as well, since it decreases with the distance traveled in the field-a phenomenon called phase precession. A likely candidate for grid cells are entorhinal cortex stellate cells, which are type II oscillators and have been suggested to act as pacemakers. It is unclear how spiking of such putative pacemaker neurons would be able to precess in phase relative to a self-generated oscillation. This article presents a computational model of how this paradox can be resolved although the periodicity of the grid fields interferes with the periodic firing of the neurons. Our simulations show that the connections between stellate cells synchronize small cell groups, which allows a population oscillation during grid field activity that is accompanied by theta phase precession. Direct excitatory coupling between the stellate cells, indirect inhibitory coupling via a gamma-oscillating network of interneurons, or both could mediate this phase coordination. Our model further suggests modulation of h-currents to be a feasible mechanism to adjust phase precession to running-speed. The coexistence of rate and timing code for space hence follows as a natural consequence of the self-organization in a recurrent network.

Franziska Hellmundt

Papers

Action Potential Generation in an Anatomically Constrained Model of Medial Superior Olive Axons

Phase precession of grid cells in a network model without external pacemaker.

Influence of Afterpotentials on the Recovery Cycle Modeling the Excitability of Mammalian Nerve Fibers

Detection in the Owl's Auditory System Passive Soma Facilitates Submillisecond Coincidence