Michael Wehr

Balanced inhibition underlies tuning and sharpens spike timing in auditory cortex

Neurons in the primary auditory cortex are tuned to the intensity and specific frequencies of sounds, but the synaptic mechanisms underlying this tuning remain uncertain. Inhibition seems to have a functional role in the formation of cortical receptive fields, because stimuli often suppress similar or neighbouring responses, and pharmacological blockade of inhibition broadens tuning curves. Here we use whole-cell recordings in vivo to disentangle the roles of excitatory and inhibitory activity in the tone-evoked responses of single neurons in the auditory cortex. The excitatory and inhibitory receptive fields cover almost exactly the same areas, in contrast to the predictions of classical lateral inhibition models. Thus, although inhibition is typically as strong as excitation, it is not necessary to establish tuning, even in the receptive field surround. However, inhibition and excitation occurred in a precise and stereotyped temporal sequence: an initial barrage of excitatory input was rapidly quenched by inhibition, truncating the spiking response within a few (1–4) milliseconds. Balanced inhibition might thus serve to increase the temporal precision and thereby reduce the randomness of cortical operation, rather than to increase noise as has been proposed previously.

Synaptic Mechanisms of Forward Suppression in Rat Auditory Cortex

In the auditory cortex, brief sounds elicit a powerful suppression of responsiveness that can persist for hundreds of milliseconds. This forward suppression (sometimes also called forward masking) has usually been attributed to synaptic (GABAergic) inhibition. Here we have used whole-cell recordings in vivo to assess the role of synaptic inhibition in forward suppression in auditory cortex. We measured the excitatory and inhibitory synaptic conductances elicited by pairs of brief sounds presented at intervals from tens to hundreds of milliseconds. We find that inhibitory conductances rarely last longer than 50-100 ms, whereas spike responses and synaptic inputs remain suppressed for hundreds of milliseconds. We conclude that postsynaptic inhibition contributes to forward suppression for only the first 50-100 ms after a stimulus and that intracortical contributions to long-lasting suppression must involve other mechanisms, such as synaptic depression.

Parvalbumin-Expressing Inhibitory Interneurons in Auditory Cortex Are Well-Tuned for Frequency

In the auditory cortex, synaptic inhibition is known to be involved in shaping receptive fields, enhancing temporal precision, and regulating gain. Cortical inhibition is provided by local GABAergic interneurons, which comprise 10–20% of the cortical population and can be separated into numerous subclasses. The morphological and physiological diversity of interneurons suggests that these different subclasses have unique roles in sound processing; however, these roles are yet unknown. Understanding the receptive field properties of distinct inhibitory cell types will be critical to elucidating their computational function in cortical circuits. Here we characterized the tuning and response properties of parvalbumin-positive (PV+) interneurons, the largest inhibitory subclass. We used channelrhodopsin-2 (ChR2) as an optogenetic tag to identify PV+ and PV− neurons in vivo in transgenic mice. In contrast to PV+ neurons in mouse visual cortex, which are broadly tuned for orientation, we found that auditory cortical PV+ neurons were well tuned for frequency, although very tightly tuned PV+ cells were uncommon. This suggests that PV+ neurons play a minor role in shaping frequency tuning, and is consistent with the idea that PV+ neurons nonselectively pool input from the local network. PV+ interneurons had shallower response gain and were less intensity-tuned than PV− neurons, suggesting that PV+ neurons provide dynamic gain control and shape intensity tuning in auditory cortex. PV+ neurons also had markedly faster response latencies than PV− neurons, consistent with a computational role in enhancing the temporal precision of cortical responses.

Nonoverlapping Sets of Synapses Drive On Responses and Off Responses in Auditory Cortex

Neurons in visual, somatosensory, and auditory cortex can respond to the termination as well as the onset of a sensory stimulus. In auditory cortex, these off responses may underlie the ability of the auditory system to use sound offsets as cues for perceptual grouping. Off responses have been widely proposed to arise from postinhibitory rebound, but this hypothesis has never been directly tested. We used in vivo whole-cell recordings to measure the synaptic inhibition evoked by sound onset. We find that inhibition is invariably transient, indicating that off responses are not caused by postinhibitory rebound in auditory cortical neurons. Instead, on and off responses appear to be driven by distinct sets of synapses, because they have distinct frequency tuning and different excitatory-inhibitory balance. Furthermore, an on-on sequence causes complete forward suppression, whereas an off-on sequence causes no suppression at all. We conclude that on and off responses are driven by largely nonoverlapping sets of synaptic inputs.

Balanced tone-evoked synaptic excitation and inhibition in mouse auditory cortex

The recent characterization of excitatory and inhibitory synaptic receptive fields in rat auditory cortex laid the basis for further investigation of the roles of synaptic excitation and inhibition in cortical computation and plasticity. The mouse is an increasingly important model system because of the wide range of genetic tools available for it. Here we present the first in vivo whole-cell voltage-clamp measurements of synaptic excitation and inhibition in the mouse cortex. We find that a substantial population of auditory cortical neurons receives balanced synaptic excitation and inhibition, whose amplitude ratios and relative time courses remain approximately constant across tone frequency. We conclude that the synaptic mechanisms underlying tone-evoked auditory cortical responses in mice closely resemble those in rats, supporting the mouse as a suitable model for synaptic processing in auditory cortex.

Disruption of Balanced Cortical Excitation and Inhibition by Acoustic Trauma

Sensory deafferentation results in rapid shifts in the receptive fields of cortical neurons, but the synaptic mechanisms underlying these changes remain unknown. The rapidity of these shifts has led to the suggestion that subthreshold inputs may be unmasked by a selective loss of inhibition. To study this, we used in vivo whole cell recordings to directly measure tone-evoked excitatory and inhibitory synaptic inputs in auditory cortical neurons before and after acoustic trauma. Here we report that acute acoustic trauma disrupted the balance of excitation and inhibition by selectively increasing and reducing the strength of inhibition at different positions within the receptive field. Inhibition was abolished for frequencies far below the trauma-tone frequency but was markedly enhanced near the edges of the region of elevated peripheral threshold. These changes occurred for relatively high-level tones. These changes in inhibition led to an expansion of receptive fields but not by a simple unmasking process. Rather, membrane potential responses were delayed and prolonged throughout the receptive field by distinct interactions between synaptic excitation and inhibition. Far below the trauma-tone frequency, decreased inhibition combined with prolonged excitation led to increased responses. Near the edges of the region of elevated peripheral threshold, increased inhibition served to delay rather than abolish responses, which were driven by prolonged excitation. These results show that the rapid receptive field shifts caused by acoustic trauma are caused by distinct mechanisms at different positions within the receptive field, which depend on differential disruption of excitation and inhibition.

Simultaneous paired intracellular and tetrode recordings for evaluating the performance of spike sorting algorithms

Objective evaluation of spike sorting algorithms such as those used to decompose tetrode recordings into distinct spike trains requires a priori knowledge of the correct classification for a given recording. Intracellular recording can unambiguously assign spikes to a single neuron, and thus provide correct classification if signals from that neuron concurrently appear in a tetrode recording. Simultaneous single or paired intracellular and tetrode recordings are used here to evaluate a contemporary spike sorting algorithm for isolated as well as overlapped events. These data are also used to demonstrate that overlapping extracellular spikes combine additively, and to introduce a means for quantifying variability in action potential shape.

Level dependence of contextual modulation in auditory cortex.

Responses of cortical neurons to sensory stimuli within their receptive fields can be profoundly altered by the stimulus context. In visual and somatosensory cortex, contextual interactions have been shown to change sign from facilitation to suppression depending on stimulus strength. Contextual modulation of high-contrast stimuli tends to be suppressive, but for low-contrast stimuli tends to be facilitative. This trade-off may optimize contextual integration by cortical cells and has been suggested to be a general feature of cortical processing, but it remains unknown whether a similar phenomenon occurs in auditory cortex. Here we used whole cell and single-unit recordings to investigate how contextual interactions in auditory cortical neurons depend on the relative intensity of masker and probe stimuli in a two-tone stimulus paradigm. We tested the hypothesis that relatively low-level probes should show facilitation, whereas relatively high-level probes should show suppression. We found that contextual interactions were primarily suppressive across all probe levels, and that relatively low-level probes were subject to stronger suppression than high-level probes. These results were virtually identical for spiking and subthreshold responses. This suggests that, unlike visual cortical neurons, auditory cortical neurons show maximal suppression rather than facilitation for relatively weak stimuli.

Vision Drives Accurate Approach Behavior during Prey Capture in Laboratory Mice

The ability to genetically identify and manipulate neural circuits in the mouse is rapidly advancing our understanding of visual processing in the mammalian brain [1, 2]. However, studies investigating the circuitry that underlies complex ethologically relevant visual behaviors in the mouse have been primarily restricted to fear responses [3-5]. Here, we show that a laboratory strain of mouse (Mus musculus, C57BL/6J) robustly pursues, captures, and consumes live insect prey and that vision is necessary for mice to perform the accurate orienting and approach behaviors leading to capture. Specifically, we differentially perturbed visual or auditory input in mice and determined that visual input is required for accurate approach, allowing maintenance of bearing to within 11° of the target on average during pursuit. While mice were able to capture prey without vision, the accuracy of their approaches and capture rate dramatically declined. To better explore the contribution of vision to this behavior, we developed a simple assay that isolated visual cues and simplified analysis of the visually guided approach. Together, our results demonstrate that laboratory mice are capable of exhibiting dynamic and accurate visually guided approach behaviors and provide a means to estimate the visual features that drive behavior within an ethological context.

Neural Dynamics, Oscillatory Synchronisation, and Odour Codes

Years of productive research examining insect olfaction have revealed numerous important functional and organisational features of the antennal lobe (AL), as described throughout this volume. Recent advances in techniques for simultaneously monitoring the activities of multiple neurons have revealed another important fact about the AL, that its dynamics act to coordinate large numbers of olfactory interneurons so that, when processing odorants, many of them oscillate in synchrony. The effect of this coherent neural activity is surprisingly powerful: it enables the AL to encode odour information in time. We will summarise here experimental results suggesting that, in insects, essential information about odour quality is indeed conveyed not only by the identity of activated neurons (a spatial pattern), but also by the temporal patterns of their odour responses relative to a common time base, the oscillatory ensemble activity.