Anna K. Magnusson

Maturation of glycinergic inhibition in the gerbil medial superior olive after hearing onset

The neurones of the medial superior olive (MSO) are the most temporally sensitive neurones in the brain. They respond to the arrival time difference of sound at the two ears with a microsecond resolution; these interaural time differences are used to localize low‐frequency sounds. In addition to the excitatory inputs from each ear, the MSO neurones also receive binaural glycinergic projections, which have a critical role in sound localization processing. Recently, it was shown that the glycinergic input to the MSO undergoes an experience‐dependent structural reorganization after hearing onset. To explore the maturation of inhibition during the development of sound localization on a cellular level, glycinergic currents and potentials were measured in gerbil MSO principal cells from postnatal (P) day P12–P25 by whole‐cell patch‐clamp recordings. The synaptic glycinergic currents accelerated to rapid decay kinetics (∼2 ms) and rise times (∼0.4 ms) after hearing onset, reaching maturity around P17. Since the kinetics of miniature glycinergic currents did not change with age, it is likely that a higher degree of transmitter release synchrony is the underlying mechanism influencing the acceleration of the kinetics. During the same period, the synaptic glycinergic potentials accelerated four‐fold, largely as a result of a prominent decrease in input resistance. In accordance with a reorganization of the glycinergic inputs, the evoked peak conductances decreased more than two‐fold, together with a three‐fold reduction in the frequency of miniature events after hearing onset. These age‐dependent changes were absent in animals that had been reared in omni‐directional noise, indicating that an experience‐dependent pruning of synaptic inputs is important for the maturation of functional inhibition in the MSO. Taken together, these striking developmental adjustments of the glycinergic inhibition in the MSO most probably reflect an adaptation to improve the encoding of auditory cues with great temporal precision and fidelity during the maturation of sound localization behaviour.

Retrograde GABA Signaling Adjusts Sound Localization by Balancing Excitation and Inhibition in the Brainstem

Central processing of acoustic cues is critically dependent on the balance between excitation and inhibition. This balance is particularly important for auditory neurons in the lateral superior olive, because these compare excitatory inputs from one ear and inhibitory inputs from the other ear to compute sound source location. By applying GABA(B) receptor antagonists during sound stimulation in vivo, it was revealed that these neurons adjust their binaural sensitivity through GABA(B) receptors. Using an in vitro approach, we then demonstrate that these neurons release GABA during spiking activity. Consequently, GABA differentially regulates transmitter release from the excitatory and inhibitory terminals via feedback to presynaptic GABA(B) receptors. Modulation of the synaptic input strength, by putative retrograde release of neurotransmitter, may enable these auditory neurons to rapidly adjust the balance between excitation and inhibition, and thus their binaural sensitivity, which could play an important role as an adaptation to various listening situations.

Sound Rhythms Are Encoded by Postinhibitory Rebound Spiking in the Superior Paraolivary Nucleus

The superior paraolivary nucleus (SPON) is a prominent structure in the auditory brainstem. In contrast to the principal superior olivary nuclei with identified roles in processing binaural sound localization cues, the role of the SPON in hearing is not well understood. A combined in vitro and in vivo approach was used to investigate the cellular properties of SPON neurons in the mouse. Patch-clamp recordings in brain slices revealed that brief and well timed postinhibitory rebound spiking, generated by the interaction of two subthreshold-activated ion currents, is a hallmark of SPON neurons. The Ih current determines the timing of the rebound, whereas the T-type Ca2+ current boosts the rebound to spike threshold. This precisely timed rebound spiking provides a physiological explanation for the sensitivity of SPON neurons to sinusoidally amplitude-modulated (SAM) tones in vivo, where peaks in the sound envelope drive inhibitory inputs and SPON neurons fire action potentials during the waveform troughs. Consistent with this notion, SPON neurons display intrinsic tuning to frequency-modulated sinusoidal currents (1–15Hz) in vitro and discharge with strong synchrony to SAMs with modulation frequencies between 1 and 20 Hz in vivo. The results of this study suggest that the SPON is particularly well suited to encode rhythmic sound patterns. Such temporal periodicity information is likely important for detection of communication cues, such as the acoustic envelopes of animal vocalizations and speech signals.

Fitting Neuron Models to Spike Trains

Computational modeling is increasingly used to understand the function of neural circuits in systems neuroscience. These studies require models of individual neurons with realistic input–output properties. Recently, it was found that spiking models can accurately predict the precisely timed spike trains produced by cortical neurons in response to somatically injected currents, if properly fitted. This requires fitting techniques that are efficient and flexible enough to easily test different candidate models. We present a generic solution, based on the Brian simulator (a neural network simulator in Python), which allows the user to define and fit arbitrary neuron models to electrophysiological recordings. It relies on vectorization and parallel computing techniques to achieve efficiency. We demonstrate its use on neural recordings in the barrel cortex and in the auditory brainstem, and confirm that simple adaptive spiking models can accurately predict the response of cortical neurons. Finally, we show how a complex multicompartmental model can be reduced to a simple effective spiking model.

Sensitivity of Noisy Neurons to Coincident Inputs

How do neurons compute? Two main theories compete: neurons could temporally integrate noisy inputs (rate-based theories) or they could detect coincident input spikes (spike timing-based theories). Correlations at fine timescales have been observed in many areas of the nervous system, but they might have a minor impact. To address this issue, we used a probabilistic approach to quantify the impact of coincidences on neuronal response in the presence of fluctuating synaptic activity. We found that when excitation and inhibition are balanced, as in the sensory cortex in vivo, synchrony in a very small proportion of inputs results in dramatic increases in output firing rate. Our theory was experimentally validated with in vitro recordings of cortical neurons of mice. We conclude that not only are noisy neurons well equipped to detect coincidences, but they are so sensitive to fine correlations that a rate-based description of neural computation is unlikely to be accurate in general.

Early compensation of vestibulo-oculomotor symptoms after unilateral vestibular loss in rats is related to GABAB receptor function

The horizontal vestibulo-oculomotor reflex was studied in pigmented rats during the first 5 days after a unilateral chemical or surgical vestibular deafferentation. Spontaneous eye movements in darkness and slow phase velocity gain of compensatory eye movements during horizontal sinusoidal rotation were evaluated. The most evident vestibulo-oculomotor symptom immediately after a unilateral vestibular loss was a spontaneous nystagmus, which gradually abated during the following days. Further, an asymmetry between ipsi- and contra-lesional gains was evident during sinusoidal vestibular stimulation. Single systemic doses of the GABA(B) receptor antagonist [3-[1-(S)-[[3-(cyclohexylmethyl)-hydroxyphosphinoyl]-2-(S)-hydroxypropyl]amino]ethyl]-benzoic acid (CGP 56433A), the agonist baclofen, or the GABA(A) receptor agonist (4,5,6,7-tetrahydroisoxazolo-[5,4-c]-pyridin-3-ol (THIP) were given at different intervals after unilateral vestibular deafferentation. CGP 56433A highly aggravated the vestibulo-oculomotor symptoms, observed as an increase in spontaneous nystagmus and slow phase velocity gain asymmetry. This effect was most pronounced during the first 2 days after unilateral vestibular loss, when CGP 56433A even decompensated the vestibular system to the extent that all vestibular responses were abolished. Baclofen caused no effect during the first days after unilateral vestibular loss, but in parallel with the abatement of spontaneous nystagmus, the drug equilibrated or even reversed the remaining spontaneous nystagmus with corresponding effects on the slow-phase velocity gain asymmetry. The effects of baclofen were very similar after both chemical and surgical deafferentation. THIP caused a slight depression of all vestibular responses. All single dose effects of the drugs were transient. Altogether these results reveal that endogenous stimulation of GABA(B) receptors in GABA-ergic vestibulo-oculomotor circuits are important for reducing the vestibular asymmetry during the early period after unilateral vestibular deafferentation. A possible role for GABA(B) receptors in the reciprocal inhibitory commissural pathways in the vestibular nuclei is suggested.

Development of on-off spiking in Superior Paraolivary Nucleus neurons of the mouse

The superior paraolivary nucleus (SPON) is a prominent cell group in the auditory brain stem that has been increasingly implicated in representing temporal sound structure. Although SPON neurons selectively respond to acoustic signals important for sound periodicity, the underlying physiological specializations enabling these responses are poorly understood. We used in vitro and in vivo recordings to investigate how SPON neurons develop intrinsic cellular properties that make them well suited for encoding temporal sound features. In addition to their hallmark rebound spiking at the stimulus offset, SPON neurons were characterized by spiking patterns termed onset, adapting, and burst in response to depolarizing stimuli in vitro. Cells with burst spiking had some morphological differences compared with other SPON neurons and were localized to the dorsolateral region of the nucleus. Both membrane and spiking properties underwent strong developmental regulation, becoming more temporally precise with age for both onset and offset spiking. Single-unit recordings obtained in young mice demonstrated that SPON neurons respond with temporally precise onset spiking upon tone stimulation in vivo, in addition to the typical offset spiking. Taken together, the results of the present study demonstrate that SPON neurons develop sharp on-off spiking, which may confer sensitivity to sound amplitude modulations or abrupt sound transients. These findings are consistent with the proposed involvement of the SPON in the processing of temporal sound structure, relevant for encoding communication cues.

Effects of toluene on tonic firing and membrane properties of rat medial vestibular nucleus neurones in vitro

The effects of toluene on discharge rate and membrane properties of tonically active medial vestibular nucleus (MVN) neurones were investigated in an in vitro slice preparation of the dorsal brainstem of the rat. The majority of the cells (50/56) were inhibited in a dose-dependent manner by toluene. The inhibitory effects of toluene persisted after blockade of synaptic transmission. Complementary patch-clamp recordings showed that toluene caused a hyperpolarisation of 2-5 mV associated with an increase in membrane conductance. These findings indicate that toluene might interfere with specific ion channels or the receptors regulating them along the cell membrane. The effective toluene concentrations used in this experiment are comparable to the concentrations producing vestibulo-ocular disturbances in vivo.

Surface protein patterns govern morphology, proliferation, and expression of cellular markers but have no effect on physiological properties of cortical precursor cells

The ability to differentiate and give rise to neurons, astrocytes, and oligodendrocytes is an inherent feature of neural stem cells, which raises hopes for cell‐based therapies of neurodegenerative diseases. However, there are many hurdles to cross before such regimens can be applied clinically. A considerable challenge is to elucidate the factors that contribute to neural differentiation. In this study, we evaluated the possibility of steering neuronal maturation by growing cortical precursor cells on microscale surface patterns of extracellular matrix (ECM) proteins. When the cells were encouraged to extend processes along lines of ECM proteins, they displayed a much more mature morphology, less proliferation capacity, and greater expression of a neuronal marker in comparison with cells grown in clusters on ECM dots. This implied that the growth pattern alone could play a crucial role for neural differentiation. However, in spite of the strikingly different morphology, when performing whole‐cell patch‐clamp experiments, we never observed any differences in the functional properties between cells grown on the two patterns. These results clearly demonstrate that morphological appearances are not representative measures of the functional phenotype or grade of neuronal maturation, stressing the importance of complementary electrophysiological evidence. To develop successful transplantation therapies, increased cell survival is critical. Because process‐bearing neurons are sensitive and break easily, it would be of clinical interest to explore further the differentiating capacity of the cells cultured on the ECM dot pattern, described in this article, which are devoid of processes but display the same functional properties as neurons with mature morphology.

Persistence of Past Stimulations: Storing Sounds within the Inner Ear

Tones cause vibrations within the hearing organ. Conventionally, these vibrations are thought to reflect the input and therefore end with the stimulus. However, previous recordings of otoacoustic emissions and cochlear microphonic potentials suggest that the organ of Corti does continue to move after the end of a tone. These after-vibrations are characterized here through recordings of basilar membrane motion and hair cell extracellular receptor potentials in living anesthetized guinea pigs. We show that after-vibrations depend on the level and frequency of the stimulus, as well as on the sensitivity of the ear. Even a minor loss of hearing sensitivity caused a sharp reduction in after-vibration amplitude and duration. Mathematical models suggest that after-vibrations are driven by energy added into organ of Corti motion after the end of an acoustic stimulus. The possible importance of after-vibrations for psychophysical phenomena such as forward masking and gap detection are discussed.