Cortico-cortical interactions influence binocularity of the primary visual cortex of adult mice.

Electrophysiological studies have revealed that a large proportion of the mouse primary visual cortex (V1) receives input also from the ipsilateral eye. This is surprising as most optic nerve fibers cross at the optic chiasm in mice. Inactivating V1 of one hemisphere has recently demonstrated a strong contribution of one hemisphere's activity on binocularity of single units and visually evoked potentials of V1 in the other hemisphere of young rats and of single units in young adult mice. Here we used intrinsic signal optical imaging to quantitatively study the influence of cortico-cortical connections on the magnitude of neuronal activation in the entire binocular zone of adult mouse V1. We simultaneously measured V1-activity of both hemispheres in adult C57BL/6J mice before and after blocking sensory-driven activity in one hemisphere with muscimol. In V1 contralateral to the inactivation, ipsilateral eye evoked activity was reduced by on average 18% while contralateral eye evoked activity did not change. Our results clearly show that cortico-cortical interactions exert a global amplification of ipsilateral eye evoked activity in adult mouse V1.

Gap prepulse inhibition and auditory brainstem-evoked potentials as objective measures for tinnitus in guinea pigs.

Tinnitus or ringing of the ears is a subjective phantom sensation necessitating behavioral models that objectively demonstrate the existence and quality of the tinnitus sensation. The gap detection test uses the acoustic startle response elicited by loud noise pulses and its gating or suppression by preceding sub-startling prepulses. Gaps in noise bands serve as prepulses, assuming that ongoing tinnitus masks the gap and results in impaired gap detection. This test has shown its reliability in rats, mice, and gerbils. No data exists for the guinea pig so far, although gap detection is similar across mammals and the acoustic startle response is a well-established tool in guinea pig studies of psychiatric disorders and in pharmacological studies. Here we investigated the startle behavior and prepulse inhibition (PPI) of the guinea pig and showed that guinea pigs have a reliable startle response that can be suppressed by 15 ms gaps embedded in narrow noise bands preceding the startle noise pulse. After recovery of auditory brainstem response (ABR) thresholds from a unilateral noise over-exposure centered at 7 kHz, guinea pigs showed diminished gap-induced reduction of the startle response in frequency bands between 8 and 18 kHz. This suggests the development of tinnitus in frequency regions that showed a temporary threshold shift (TTS) after noise over-exposure. Changes in discharge rate and synchrony, two neuronal correlates of tinnitus, should be reflected in altered ABR waveforms, which would be useful to objectively detect tinnitus and its localization to auditory brainstem structures. Therefore, we analyzed latencies and amplitudes of the first five ABR waves at suprathreshold sound intensities and correlated ABR abnormalities with the results of the behavioral tinnitus testing. Early ABR wave amplitudes up to N3 were increased for animals with tinnitus possibly stemming from hyperactivity and hypersynchrony underlying the tinnitus percept. Animals that did not develop tinnitus after noise exposure showed the opposite effect, a decrease in wave amplitudes for the later waves P4-P5. Changes in latencies were only observed in tinnitus animals, which showed increased latencies. Thus, tinnitus-induced changes in the discharge activity of the auditory nerve and central auditory nuclei are represented in the ABR.

Noise overexposure alters long-term somatosensory-auditory processing in the dorsal cochlear nucleus--possible basis for tinnitus-related hyperactivity?

The dorsal cochlear nucleus (DCN) is the first neural site of bimodal auditory-somatosensory integration. Previous studies have shown that stimulation of somatosensory pathways results in immediate suppression or enhancement of subsequent acoustically evoked discharges. In the unimpaired auditory system suppression predominates. However, damage to the auditory input pathway leads to enhancement of excitatory somatosensory inputs to the cochlear nucleus, changing their effects on DCN neurons (Shore et al., 2008; Zeng et al., 2009). Given the well described connection between the somatosensory system and tinnitus in patients we sought to determine whether plastic changes in long-lasting bimodal somatosensory-auditory processing accompany tinnitus. Here we demonstrate for the first time in vivo long-term effects of somatosensory inputs on acoustically evoked discharges of DCN neurons in guinea pigs. The effects of trigeminal nucleus stimulation are compared between normal-hearing animals and animals overexposed with narrow band noise and behaviorally tested for tinnitus. The noise exposure resulted in a temporary threshold shift in auditory brainstem responses but a persistent increase in spontaneous and sound-evoked DCN unit firing rates and increased steepness of rate-level functions. Rate increases were especially prominent in buildup units. The long-term somatosensory enhancement of sound-evoked responses was strengthened while suppressive effects diminished in noise-exposed animals, especially those that developed tinnitus. Damage to the auditory nerve is postulated to trigger compensatory long-term synaptic plasticity of somatosensory inputs that might be an important underlying mechanism for tinnitus generation.

Multidimensional characterization and differentiation of neurons in the anteroventral cochlear nucleus.

Multiple parallel auditory pathways ascend from the cochlear nucleus. It is generally accepted that the origin of these pathways are distinct groups of neurons differing in their anatomical and physiological properties. In extracellular in vivo recordings these neurons are typically classified on the basis of their peri-stimulus time histogram. In the present study we reconsider the question of classification of neurons in the anteroventral cochlear nucleus (AVCN) by taking a wider range of response properties into account. The study aims at a better understanding of the AVCN's functional organization and its significance as the source of different ascending auditory pathways. The analyses were based on 223 neurons recorded in the AVCN of the Mongolian gerbil. The range of analysed parameters encompassed spontaneous activity, frequency coding, sound level coding, as well as temporal coding. In order to categorize the unit sample without any presumptions as to the relevance of certain response parameters, hierarchical cluster analysis and additional principal component analysis were employed which both allow a classification on the basis of a multitude of parameters simultaneously. Even with the presently considered wider range of parameters, high number of neurons and more advanced analytical methods, no clear boundaries emerged which would separate the neurons based on their physiology. At the current resolution of the analysis, we therefore conclude that the AVCN units more likely constitute a multi-dimensional continuum with different physiological characteristics manifested at different poles. However, more complex stimuli could be useful to uncover physiological differences in future studies.

A 3-d 160-site microelectrode array for cochlear nucleus mapping.

A 3-D application-specific microelectrode array has been developed for physiological studies in guinea pig cochlear nucleus (CN). The batch-fabricated silicon probes contain integrated parylene cables and use a boron etch-stop to define 15µm-thick shanks and limit tissue displacement. Targeting the ventral (three probes) and dorsal (two probes) subnuclei, the custom four-shank 32-site probes are combined in a slotted block platform having a 1.18-mm (2) footprint. The device has permitted, for the first time, high-density 3-D in vivo studies of ventral CN to dorsal CN connections, stimulating with 1000 µm (2) sites in one subnucleus while recording with 177 µm (2) sites in the other. Through these experiments, it has demonstrated the efficacy of bimodal silicon arrays to better understand the central nervous system at the circuit level. The 160 electrode sites also provide a high-density neural interface, which is an essential aspect of auditory prosthesis prototypes.

Transmission of phase-coupling accuracy from the auditory nerve to spherical bushy cells in the Mongolian gerbil.

The phase of low-frequency sinusoids is encoded in phase-coupled discharges of spherical bushy cells (SBCs) of the anteroventral cochlear nucleus and transmitted to the medial superior olive, where binaural input-coincidence is used for processing of sound source localization. SBCs are innervated by auditory nerve fibers through large, excitatory synapses (endbulbs of Held) and by inhibitory inputs, which effectively reduce SBC discharge rates. Here we monitor presynaptic potentials of endbulb-terminals and postsynaptic spikes of SBCs in extracellular single unit recordings in vivo. We compare postsynaptic phase-coupling of SBCs and their presynaptic immediate auditory nerve input. In all but one SBC discharge rates at the characteristic frequency were reduced pre-to-postsynaptically and phase-coupling accuracy was increased in one-third of them. We investigated the contribution of systemic inhibition on spike timing in SBCs by iontophoretic application of glycine- and GABA-receptor antagonists (strychnine, bicuculline). Discharge rate increased in one-third of the units during antagonist application, which was accompanied by a deterioration of phase-coupling accuracy in half of those units. These results suggest that the phase-coupling accuracy is improved in a subpopulation of SBCs during transmission from the auditory nerve to the SBCs by reduction of spike rates.

Dynamic coupling of excitatory and inhibitory responses in the medial nucleus of the trapezoid body.

The neuronal representation of acoustic amplitude modulations is an important prerequisite for understanding the processing of natural sounds. We investigated this representation in the medial nucleus of the trapezoid body (MNTB) of the Mongolian gerbil using sinusoidal amplitude modulations (SAM). Depending on the SAM's carrier frequency (f(C)) MNTB cells either increase or decrease their discharge rates, indicating underlying excitatory and inhibitory/suppressive mechanisms. As natural sounds typically are composed of multiple spectral components we investigated how stimuli containing two spectral components are represented in the MNTB, especially when they have opposing effects on the discharge rate. Three conditions were compared: SAM stimuli (1) with rate-increasing f(C), (2) with rate-increasing f(C) and an additional unmodulated rate-decreasing pure tone, and (3) with rate-decreasing f(C) and an unmodulated, rate-increasing pure tone. We found that responses under all three conditions showed comparable strength of phase-locking. Adding a rate-decreasing tone to a rate-increasing SAM increased phase-locking for modulation frequencies (f(AM)) of < or = 600 Hz. A comparison of two possible coding strategies--phase-locking vs. envelope reproduction--indicates that both strategies are realized to different degrees depending on the f(AM). We measured latencies for following modulations in rate-increasing and rate-decreasing SAMs using a modified reverse correlation approach. Although latencies varied between 2.5 and 5 ms between cells, a decrease in rate consistently followed an increase in rate with a delay of about 0.2 ms in each cell. These results suggest a temporally precise representation of rate-increasing and rate-decreasing stimuli at the level of the MNTB during dynamic stimulation.

Interaction of excitation and inhibition in anteroventral cochlear nucleus neurons that receive large endbulb synaptic endings.

Spherical bushy cells (SBCs) of the anteroventral cochlear nucleus (AVCN) receive their main excitatory input from auditory nerve fibers (ANFs) through large synapses, endbulbs of Held. These cells are also the target of inhibitory inputs whose function is not well understood. The present study examines the role of inhibition in the encoding of low-frequency sounds in the gerbil's AVCN. The presynaptic action potentials of endbulb terminals and postsynaptic action potentials of SBCs were monitored simultaneously in extracellular single-unit recordings in vivo. An input-output analysis of presynaptic and postsynaptic activity was performed for both spontaneous and acoustically driven activity. Two-tone stimulation and neuropharmacological experiments allowed the effects of neuronal inhibition and cochlear suppression on SBC activity to be distinguished. Ninety-one percent of SBCs showed significant neuronal inhibition. Inhibitory sidebands enclosed the high- or low-frequency, or both, sides of the excitatory areas of these units; this was reflected as a presynaptic to postsynaptic increase in frequency selectivity of up to one octave. Inhibition also affected the level-dependent responses at the characteristic frequency. Although in all units the presynaptic recordings showed monotonic rate-level functions, this was the case in only half of the postsynaptic recordings. In the other half of SBCs, postsynaptic inhibitory areas overlapped the excitatory areas, resulting in nonmonotonic rate-level functions. The results demonstrate that the sound-evoked spike activity of SBCs reflects the integration of acoustically driven excitatory and inhibitory input. The inhibition specifically affects the processing of the spectral, temporal, and intensity cues of acoustic signals.

Electrophysiological characterization of the superior paraolivary nucleus in the Mongolian gerbil.

The superior paraolivary nucleus (SPN) of the superior olivary complex (SOC) though morphologically well described, has not been characterized physiologically. Here we report the basic response properties of SPN units acquired with extracellular recording techniques under monaural acoustic stimulation in the Mongolian gerbil. Poststimulus-time histograms corresponded to those described earlier for the cat's cochlear nucleus (onset, chopper, primary-like), and partly to those previously acquired in other SOC nuclei (tonic, off/rebound). Two-thirds of the units responded solely to contralateral stimulation (40% excitatory [E], 19% inhibitory [I], 6% mixed [EI]). Most of the remainder responded equally to stimulation from either ear (18% I.I, 9% E.E). Overall, the monaural contralateral input was more effective than the ipsilateral and bilateral input. Characteristic frequencies and response areas covered the entire hearing range of the gerbil and the units mostly showed broad frequency-tuning. In combination, these properties suggest that the SPN might be a constituent of an afferent pathway encoding stimulus features across broad frequency ranges.