Dopamine modulates auditory responses in the inferior colliculus in a heterogeneous manner.

Perception of complex sounds such as speech is affected by a variety of factors, including attention, expectation of reward, physiological state, and/or disorders, yet the mechanisms underlying this modulation are not well understood. Although dopamine is commonly studied for its role in reward-based learning and in disorders, multiple lines of evidence suggest that dopamine is also involved in modulating auditory processing. In this study, we examined the effects of dopamine application on neuronal response properties in the inferior colliculus (IC) of awake mice. Because the IC contains dopamine receptors and nerve terminals immunoreactive for tyrosine hydroxylase, we predicted that dopamine would modulate auditory responses in the IC. We recorded single-unit responses before, during, and after the iontophoretic application of dopamine using piggyback electrodes. We examined the effects of dopamine on firing rate, timing, and probability of bursting. We found that application of dopamine affected neural responses in a heterogeneous manner. In more than 80 % of the neurons, dopamine either increased (32 %) or decreased (50 %) firing rate, and the effects were similar on spontaneous and sound-evoked activity. Dopamine also either increased or decreased first spike latency and jitter in almost half of the neurons. In 3/28 neurons (11 %), dopamine significantly altered the probability of bursting. The heterogeneous effects of dopamine observed in the IC of awake mice were similar to effects observed in other brain areas. Our findings indicate that dopamine differentially modulates neural activity in the IC and thus may play an important role in auditory processing.

Inhibition shapes response selectivity in the inferior colliculus by gain modulation.

Pharmacological block of inhibition is often used to determine if inhibition contributes to spike selectivity, in which a preferred stimulus evokes more spikes than a null stimulus. When inhibitory block reduces spike selectivity, a common interpretation is that differences between the preferred- and null-evoked inhibitions created the selectivity from less-selective excitatory inputs. In models based on empirical properties of cells from the inferior colliculus (IC) of awake bats, we show that inhibitory differences are not required. Instead, inhibition can enhance spike selectivity by changing the gain, the ratio of output spikes to input current. Within the model, we made preferred stimuli that evoked more spikes than null stimuli using five distinct synaptic mechanisms. In two cases, synaptic selectivity (the differences between the preferred and null inputs) was entirely excitatory, and in two it was entirely inhibitory. In each case, blocking inhibition eliminated spike selectivity. Thus, observing spike rates following inhibitory block did not distinguish among the cases where synaptic selectivity was entirely excitatory or inhibitory. We then did the same modeling experiment using empirical synaptic conductances derived from responses to preferred and null sounds. In most cases, inhibition in the model enhanced spike selectivity mainly by gain modulation and firing rate reduction. Sometimes, inhibition reduced the null gain to zero, eliminating null-evoked spikes. In some cases, inhibition increased the preferred gain more than the null gain, enhancing the difference between the preferred- and null-evoked spikes. Finally, inhibition kept firing rates low. When selectivity is quantified by the selectivity index (SI, the ratio of the difference to the sum of the spikes evoked by the preferred and null stimuli), inhibitory block reduced the SI by increasing overall firing rates. These results are consistent with inhibition shaping spike selectivity by gain control.

FM velocity selectivity in the inferior colliculus is inherited from velocity-selective inputs and enhanced by spike threshold.

Frequency modulation (FM) is computed from the temporal sequence of activated auditory nerve fibers representing different frequencies. Most studies in the inferior colliculus (IC) have inferred from extracellular recordings that the precise timing of nonselective inputs creates selectivity for FM direction and velocity (Andoni S, Li N, Pollak GD. J Neurosci 27: 4882-4893, 2007; Fuzessery ZM, Richardson MD, Coburn MS. J Neurophysiol 96: 1320-1336, 2006; Gordon M, O'Neill WE. Hear Res 122: 97-108, 1998). We recently reported that two additional mechanisms were more important than input timing for directional selectivity in some IC cells: spike threshold and inputs that were already selective (Gittelman JX, Li N, Pollak GD. J Neurosci 29: 13030-13041, 2009). Here, we show that these same mechanisms, selective inputs and spike threshold, underlie selectivity for FM velocity and intensity. From whole cell recordings in awake bats, we recorded spikes and postsynaptic potentials (PSPs) evoked by downward and upward FMs that swept identical frequencies at different velocities and intensities. To determine the synaptic mechanisms underlying PSP selectivity (relative PSP height), we derived sweep-evoked synaptic conductances. Changing FM velocity or intensity changed conductance timing and size. Modeling indicated that excitatory conductance size contributed more to PSP selectivity than conductance timing, indicating that the number of afferent spikes carried more FM information to the IC than precise spike timing. However, excitation alone produced mostly suprathreshold PSPs. Inhibition reduced absolute PSP heights, without necessarily altering PSP selectivity, thereby rendering some PSPs subthreshold. Spike threshold then sharpened selectivity in the spikes by rectifying the smaller PSPs. This indicates the importance of spike threshold, and that inhibition enhances selectivity via a different mechanism than previously proposed.

It's about time: how input timing is used and not used to create emergent properties in the auditory system.

The hypothesis for directional selectivity of frequency modulations (FMs) invokes a mechanism with an honored tradition in sensory neurobiology, the relative timing of excitation and inhibition. The proposal is that the timing disparity is created by asymmetrical locations of excitatory tuning and inhibitory sidebands. Thus, cells in which the inhibitory sidebands are tuned to frequencies lower than the excitatory tuning are selective for downward sweeping FMs, because frequencies first generate excitation followed by inhibition. Upward sweeping FMs, in contrast, first evoke inhibition that either leads or is coincident with the excitation and prevents discharges. Here we evaluated FM directional selectivity with in vivo whole-cell recordings from the inferior colliculus of awake bats. From the whole-cell recordings, we derived synaptic conductance waveforms evoked by downward and upward FMs. We then tested the effects of shifting inhibition relative to excitation in a model and found that latency shifts had only minor effects on EPSP amplitudes that were often <1.0 mV/ms shift. However, when the PSPs peaked close to spike threshold, even small changes in latency could cause some cells to fire more strongly to a particular FM direction and thus change its directional selectivity. Furthermore, the effect of shifting inhibition depended strongly on initial latency differences and the shapes of the conductance waveforms. We conclude that "timing" is more than latency differences between excitation and inhibition, and response selectivity depends on a complex interaction between the timing, the shapes, and magnitudes of the excitatory and inhibitory conductances and spike threshold.

Inhibitory projections from the ventral nucleus of the lateral lemniscus and superior paraolivary nucleus create directional selectivity of frequency modulations in the inferior colliculus: a comparison of bats with other mammals.

This review considers four auditory brainstem nuclear groups and shows how studies of both bats and other mammals have provided insights into their response properties and the impact of their convergence in the inferior colliculus (IC). The four groups are octopus cells in the cochlear nucleus, their connections with the ventral nucleus of the lateral lemniscus (VNLL) and the superior paraolivary nucleus (SPON), and the connections of the VNLL and SPON with the IC. The theme is that the response properties of neurons in the SPON and VNLL map closely onto the synaptic response features of a unique subpopulation of cells in the IC of bats whose inputs are dominated by inhibition. We propose that the convergence of VNLL and SPON inputs generates the tuning of these IC cells, their unique temporal responses to tones, and their directional selectivities for frequency modulated (FM) sweeps. Other IC neurons form directional properties in other ways, showing that selective response properties are formed in multiple ways. In the final section we discuss why multiple formations of common response properties could amplify differences in population activity patterns evoked by signals that have similar spectrotemporal features.

The dominance of inhibition in the inferior colliculus.

Almost all of the processing that occurs in the various lower auditory nuclei converges upon a common target in the central nucleus of the inferior colliculus (ICc) thus making the ICc the nexus of the auditory system. A variety of new response properties are formed in the ICc through the interactions among the excitatory and inhibitory inputs that converge upon it. Here we review studies that illustrate the dominant role inhibition plays in the ICc. We begin by reviewing studies of tuning curves and show how inhibition shapes the variety of tuning curves in the ICc through sideband inhibition. We then show how inhibition shapes selective response properties for complex signals, focusing on selectivity for the sweep direction of frequency modulations (FM). In the final section we consider results from in vivo whole-cell recordings that show how parameters of the incoming excitation and inhibition interact to shape directional selectivity. We show that post-synaptic potentials (PSPs) evoked by different signals can be similar but evoke markedly different spike-counts. In these cases, spike threshold acts as a non-linear amplifier that converts small differences in PSPs into large differences in spike output. Such differences between the inputs to a cell compared to the outputs from the same cell suggest that highly selective discharge properties can be created by only minor adjustments in the synaptic strengths evoked by one or both signals. These findings also suggest that plasticity of response features may be achieved with far less modifications in circuitry than previously supposed.

Intracellular recordings reveal novel features of neurons that code interaural intensity disparities in the inferior colliculus.

Many cells in the inferior colliculus (IC) are excited by contralateral and inhibited by ipsilateral stimulation and are thought to be important for sound localization. These excitatory-inhibitory (EI) cells comprise a diverse group, even though they exhibit a common binaural response property. Previous extracellular studies showed the diversity results from different circuits that generate the same EI property among the IC population, where some inherit the property from a lower nucleus, some are formed de novo in the IC, and others inherit EI features that are modified by inhibitory circuits. Here we evaluated the differential circuitry by recording inputs (postsynaptic potentials) and outputs (spikes) with in vivo whole-cell recordings from the IC of awake Mexican free-tailed bats. We show that in a minority of EI cells, either they inherited their binaural property from a lower binaural nucleus or the EI property was created in the IC via inhibitory projections from the ipsilateral ear, features consistent with those observed in extracellular studies. However, in a majority of EI cells, ipsilateral signals evoked subthreshold EPSPs that behaved paradoxically in that EPSP amplitudes increased with intensity, even though binaural signals with the same ipsilateral intensities generated progressively greater spike suppressions. We propose circuitry that can account for the responses we observed and suggest that the ipsilaterally evoked EPSPs could influence the responsiveness of IC cells to dynamic signals with interaural intensity disparities that change over time, such as moving sound sources or multiple sounds that occur in complex acoustic environments.

Mechanisms underlying directional selectivity for frequency-modulated sweeps in the inferior colliculus revealed by in vivo whole-cell recordings.

Auditory neurons in the inferior colliculus (IC) show remarkable selectively in that they can distinguish between complex sounds that have identical spectral energy but different temporal structure, such as frequency modulations (FMs) that sweep either upward or downward. Extracellular recordings show that blocking inhibition locally reduces or eliminates response selectivity, suggesting that selectivity is created de novo in the IC, with inhibition playing a prominent role. However, these studies can only infer underlying mechanisms based on spike counts. Using in vivo whole-cell recordings, we examine the mechanisms underlying FM directional selectivity in the IC. We first report that spike threshold can strongly amplify directional selectivity in that the spike directionality was on average more than twice as large as the directionality of the postsynaptic potentials (PSPs). We then show that, in our sample of IC cells, PSP directional selectivity is not created de novo. Rather, we found that the preferred and null FMs evoked synaptic conductances of different magnitudes, indicating that the presynaptic neurons were directionally selective. Combining conductance data with modeling, we show that directionally dependent magnitude differences, not temporal differences, underlie PSP directionality. Modeling also shows that our results are consistent with extracellular studies in which blocking inhibition reduces or eliminates directionality. Our findings suggest that some IC cells use a rate code in their inputs rather than a time code and that highly selective discharge properties can be created by only minor adjustments in the synaptic strengths evoked by different signals.

Rethinking tuning: in vivo whole-cell recordings of the inferior colliculus in awake bats.

Tuning curves were recorded with patch electrodes from the inferior colliculus (IC) of awake bats to evaluate the tuning of the inputs to IC neurons, reflected in their synaptic tuning, compared with the tuning of their outputs, expressed in their discharge tuning. A number of unexpected features were revealed with whole-cell recordings. Among these was that most neurons responded to tones with inhibition and/or subthreshold excitation over a surprisingly broad frequency range. The synaptic tuning in many cells was at least 1.5-2.0 octaves wide and, on average, was more than twice as wide as the frequency range that evoked discharges even after inhibition was blocked. In most cells, tones evoked complex synaptic response configurations that varied with frequency, suggesting that these cells were not innervated by congruent excitatory and inhibitory projections. Synaptic tuning was not only wide but was also diverse, in which some cells were dominated by excitation (n = 20), others were dominated by excitation with sideband inhibition (n = 21), but most were dominated by inhibition with little evidence of excitation (n = 31). Another unexpected finding was that some cells responded with inhibition to the onset and offset of tones over a wide frequency range, in which the patterns of synaptic responses changed markedly with frequency. These cells never fired to tones at 50 dB sound pressure level but fired to frequency-modulated sweeps at that intensity and were directionally selective. Thus, the features revealed by whole-cell recordings show that the processing in many IC cells results from inputs spectrally broader and more complex than previously believed.

Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons.

Genes Kcna1 and Kcna2 code for the voltage-dependent potassium channel subunits Kv1.1 and Kv1.2, which are coexpressed in large axons and commonly present within the same tetramers. Both contribute to the low-voltage-activated potassium current I Kv1, which powerfully limits excitability and facilitates temporally precise transmission of information, e.g., in auditory neurons of the medial nucleus of the trapezoid body (MNTB). Kcna1-null mice lacking Kv1.1 exhibited seizure susceptibility and hyperexcitability in axons and MNTB neurons, which also had reduced I Kv1. To explore whether a lack of Kv1.2 would cause a similar phenotype, we created and characterized Kcna2-null mice (-/-). The -/- mice exhibited increased seizure susceptibility compared with their +/+ and +/- littermates, as early as P14. The mRNA for Kv1.1 and Kv1.2 increased strongly in +/+ brain stems between P7 and P14, suggesting the increasing importance of these subunits for limiting excitability. Surprisingly, MNTB neurons in brain stem slices from -/- and +/- mice were hypoexcitable despite their Kcna2 deficit, and voltage-clamped -/- MNTB neurons had enlarged I Kv1. This contrasts strikingly with the Kcna1-null MNTB phenotype. Toxin block experiments on MNTB neurons suggested Kv1.2 was present in every +/+ Kv1 channel, about 60% of +/- Kv1 channels, and no -/- Kv1 channels. Kv1 channels lacking Kv1.2 activated at abnormally negative potentials, which may explain why MNTB neurons with larger proportions of such channels had larger I Kv1. If channel voltage dependence is determined by how many Kv1.2 subunits each contains, neurons might be able to fine-tune their excitability by adjusting the Kv1.1:Kv1.2 balance rather than altering Kv1 channel density.

Kv1.1-containing channels are critical for temporal precision during spike initiation.

Low threshold, voltage-gated potassium currents (Ikl) are widely expressed in auditory neurons that can fire temporally precise action potentials (APs). In the medial nucleus of the trapezoid body (MNTB), channels containing the Kv1.1 subunit (encoded by the Kcna1 gene) underlie Ikl. Using pharmacology, genetics and whole cell patch-clamp recordings in mouse brain slices, we tested the role of Ikl in limiting AP latency-variability (jitter) in response to trains of single inputs at moderate to high stimulation rates. With dendrotoxin-K (DTX-K, a selective blocker of Kv1.1-containing channels), we blocked Ikl maximally (approximately 80% with 100 nM DTX-K) or partially (approximately 50% with 1-h incubation in 3 nM DTX-K). Ikl was similar in 3 nM DTX-K-treated cells and cells from Kcna1(-/-) mice, allowing a comparison of these two different methods of Ikl reduction. In response to current injection, Ikl reduction increased the temporal window for AP initiation and increased jitter in response to the smallest currents that were able to drive APs. While 100 nM DTX-K caused the largest increases, latency and jitter in Kcna1(-/-) cells and in 3 nM DTX-K-treated cells were similar to each other but increased compared with +/+. The near-phenocopy of the Kcna1(-/-) cells with 3 nM DTX-K shows that acute blockade of a subset of the Kv1.1-containing channels is functionally similar to the chronic elimination of all Kv1.1 subunits. During rapid stimulation (100-500 Hz), Ikl reduction increased jitter in response to both large and small inputs. These data show that Ikl is critical for maintaining AP temporal precision at physiologically relevant firing rates.