Jennifer F. Linden

Stimulus-Specific Adaptation Occurs in the Auditory Thalamus

Neurons in the primary auditory cortex respond less strongly to a commonly occurring “standard” tone than to the same tone when it is rare or “deviant.” This phenomenon, called “stimulus-specific adaptation” (SSA), has been proposed as a possible single-neuron correlate of the mismatch negativity, a cortical evoked potential associated with stimulus novelty. Previous studies in cat did not observe SSA in single neurons in the auditory thalamus. However, these reports did not differentiate between the auditory thalamic subdivisions and did not examine the effects of changing the stimulus presentation rate. To explore the possibility of thalamic SSA more completely, we recorded extracellularly from 30 single units and 22 multiunit clusters in the ventral, medial, and dorsal subdivisions of the mouse medial geniculate body (MGB), while presenting the anesthetized animals with sequences of standard and deviant tones at interstimulus intervals of 400, 500 and 800 ms. We found SSA in the auditory thalamus at all three stimulus presentation rates, primarily in the medial subdivision but to a lesser degree also in the ventral MGB. Thalamic SSA was evident from the earliest onset of tone-evoked activity, although the latencies of responses to standard and deviant tones were not significantly different. Together with related findings of SSA in neurons of the “belt” regions of the inferior colliculus, these results demonstrate that SSA is present at subcortical levels, primarily in but not restricted to the nonlemniscal auditory pathway.

Nonlinearities and contextual influences in auditory cortical responses modeled with multilinear spectrotemporal methods

The relationship between a sound and its neural representation in the auditory cortex remains elusive. Simple measures such as the frequency response area or frequency tuning curve provide little insight into the function of the auditory cortex in complex sound environments. Spectrotemporal receptive field (STRF) models, despite their descriptive potential, perform poorly when used to predict auditory cortical responses, showing that nonlinear features of cortical response functions, which are not captured by STRFs, are functionally important. We introduce a new approach to the description of auditory cortical responses, using multilinear modeling methods. These descriptions simultaneously account for several nonlinearities in the stimulus–response functions of auditory cortical neurons, including adaptation, spectral interactions, and nonlinear sensitivity to sound level. The models reveal multiple inseparabilities in cortical processing of time lag, frequency, and sound level, and suggest functional mechanisms by which auditory cortical neurons are sensitive to stimulus context. By explicitly modeling these contextual influences, the models are able to predict auditory cortical responses more accurately than are STRF models. In addition, they can explain some forms of stimulus dependence in STRFs that were previously poorly understood.

The Consequences of Response Nonlinearities for Interpretation of Spectrotemporal Receptive Fields

Neurons in the central auditory system are often described by the spectrotemporal receptive field (STRF), conventionally defined as the best linear fit between the spectrogram of a sound and the spike rate it evokes. An STRF is often assumed to provide an estimate of the receptive field of a neuron, i.e., the spectral and temporal range of stimuli that affect the response. However, when the true stimulus–response function is nonlinear, the STRF will be stimulus dependent, and changes in the stimulus properties can alter estimates of the sign and spectrotemporal extent of receptive field components. We demonstrate analytically and in simulations that, even when uncorrelated stimuli are used, interactions between simple neuronal nonlinearities and higher-order structure in the stimulus can produce STRFs that show contributions from time–frequency combinations to which the neuron is actually insensitive. Only when spectrotemporally independent stimuli are used does the STRF reliably indicate features of the underlying receptive field, and even then it provides only a conservative estimate. One consequence of these observations, illustrated using natural stimuli, is that a stimulus-induced change in an STRF could arise from a consistent but nonlinear neuronal response to stimulus ensembles with differing higher-order dependencies. Thus, although the responses of higher auditory neurons may well involve adaptation to the statistics of different stimulus ensembles, stimulus dependence of STRFs alone, or indeed of any overly constrained stimulus–response mapping, cannot demonstrate the nature or magnitude of such effects.

Mouse auditory cortex differs from visual and somatosensory cortices in the laminar distribution of cytochrome oxidase and acetylcholinesterase.

Cytochrome oxidase (CYO) and acetylcholinesterase (AChE) staining density varies across the cortical layers in many sensory areas. The laminar variations likely reflect differences between the layers in levels of metabolic activity and cholinergic modulation. The question of whether these laminar variations differ between primary sensory cortices has never been systematically addressed in the same set of animals, since most studies of sensory cortex focus on a single sensory modality. Here, we compared the laminar distribution of CYO and AChE activity in the primary auditory, visual, and somatosensory cortices of the mouse, using Nissl-stained sections to define laminar boundaries. Interestingly, for both CYO and AChE, laminar patterns of enzyme activity were similar in the visual and somatosensory cortices, but differed in the auditory cortex. In the visual and somatosensory areas, staining densities for both enzymes were highest in layers III/IV or IV and in lower layer V. In the auditory cortex, CYO activity showed a reliable peak only at the layer III/IV border, while AChE distribution was relatively homogeneous across layers. These results suggest that laminar patterns of metabolic activity and cholinergic influence are similar in the mouse visual and somatosensory cortices, but differ in the auditory cortex.

Physiological differences between histologically defined subdivisions in the mouse auditory thalamus

The auditory thalamic area includes the medial geniculate body (MGB) and the lateral part of the posterior thalamic nucleus (Pol). The MGB can be subdivided into a ventral subdivision, forming part of the lemniscal (primary) auditory pathway, and medial and dorsal subdivisions, traditionally considered (alongside the Pol) part of the non-lemniscal (secondary) pathway. However, physiological studies of the auditory thalamus have suggested that the Pol may be more appropriately characterised as part of the lemniscal pathway, while the medial MGB may be part of a third (polysensory) pathway, with characteristics of lemniscal and non-lemniscal areas. We document physiological properties of neurons in histologically identified areas of the MGB and Pol in the anaesthetised mouse, and present evidence in favour of a distinctive role for medial MGB in central auditory processing. In particular, medial MGB contains a greater proportion of neurons with short first-spike latencies and high response probabilities than either the ventral or dorsal MGB, despite having low spontaneous rates. Therefore, medial MGB neurons appear to fire more reliably in response to auditory input than neurons in even the lemniscal, ventral subdivision. Additionally, responses in the Pol are more similar to those in the ventral MGB than the dorsal MGB.

Defects in middle ear cavitation cause conductive hearing loss in the Tcof1 mutant mouse

Conductive hearing loss (CHL) is one of the most common forms of human deafness. Despite this observation, a surprising gap in our understanding of the mechanisms underlying CHL remains, particularly with respect to the molecular mechanisms underlying middle ear development and disease. Treacher Collins syndrome (TCS) is an autosomal dominant disorder of facial development that results from mutations in the gene TCOF1. CHL is a common feature of TCS but the causes of the hearing defect have not been studied. In this study, we have utilized Tcof1 mutant mice to dissect the developmental mechanisms underlying CHL. Our results demonstrate that effective cavitation of the middle ear is intimately linked to growth of the auditory bulla, the neural crest cell-derived structure that encapsulates all middle ear components, and that defects in these processes have a profoundly detrimental effect on hearing. This research provides important insights into a poorly characterized cause of human deafness, and provides the first mouse model for the study of middle ear cavity defects, while also being of direct relevance to a human genetic disorder.

Depth-Dependent Temporal Response Properties in Core Auditory Cortex

The computational role of cortical layers within auditory cortex has proven difficult to establish. One hypothesis is that interlaminar cortical processing might be dedicated to analyzing temporal properties of sounds; if so, then there should be systematic depth-dependent changes in cortical sensitivity to the temporal context in which a stimulus occurs. We recorded neural responses simultaneously across cortical depth in primary auditory cortex and anterior auditory field of CBA/Ca mice, and found systematic depth dependencies in responses to second-and-later noise bursts in slow (1–10 bursts/s) trains of noise bursts. At all depths, responses to noise bursts within a train usually decreased with increasing train rate; however, the rolloff with increasing train rate occurred at faster rates in more superficial layers. Moreover, in some recordings from mid-to-superficial layers, responses to noise bursts within a 3–4 bursts/s train were stronger than responses to noise bursts in slower trains. This non-monotonicity with train rate was especially pronounced in more superficial layers of the anterior auditory field, where responses to noise bursts within the context of a slow train were sometimes even stronger than responses to the noise burst at train onset. These findings may reflect depth dependence in suppression and recovery of cortical activity following a stimulus, which we suggest could arise from laminar differences in synaptic depression at feedforward and recurrent synapses.

High-Yield Methods for Accurate Two-Alternative Visual Psychophysics in Head-Fixed Mice

Summary Research in neuroscience increasingly relies on the mouse, a mammalian species that affords unparalleled genetic tractability and brain atlases. Here, we introduce high-yield methods for probing mouse visual decisions. Mice are head-fixed, facilitating repeatable visual stimulation, eye tracking, and brain access. They turn a steering wheel to make two alternative choices, forced or unforced. Learning is rapid thanks to intuitive coupling of stimuli to wheel position. The mouse decisions deliver high-quality psychometric curves for detection and discrimination and conform to the predictions of a simple probabilistic observer model. The task is readily paired with two-photon imaging of cortical activity. Optogenetic inactivation reveals that the task requires mice to use their visual cortex. Mice are motivated to perform the task by fluid reward or optogenetic stimulation of dopamine neurons. This stimulation elicits a larger number of trials and faster learning. These methods provide a platform to accurately probe mouse vision and its neural basis.

Hearing loss in a mouse model of 22q11.2 deletion syndrome

22q11.2 Deletion Syndrome (22q11DS) arises from an interstitial chromosomal microdeletion encompassing at least 30 genes. This disorder is one of the most significant known cytogenetic risk factors for schizophrenia, and can also cause heart abnormalities, cognitive deficits, hearing difficulties, and a variety of other medical problems. The Df1/+ hemizygous knockout mouse, a model for human 22q11DS, recapitulates many of the deficits observed in the human syndrome including heart defects, impaired memory, and abnormal auditory sensorimotor gating. Here we show that Df1/+ mice, like human 22q11DS patients, have substantial rates of hearing loss arising from chronic middle ear infection. Auditory brainstem response (ABR) measurements revealed significant elevation of click-response thresholds in 48% of Df1/+ mice, often in only one ear. Anatomical and histological analysis of the middle ear demonstrated no gross structural abnormalities, but frequent signs of otitis media (OM, chronic inflammation of the middle ear), including excessive effusion and thickened mucosa. In mice for which both in vivo ABR thresholds and post mortem middle-ear histology were obtained, the severity of signs of OM correlated directly with the level of hearing impairment. These results suggest that abnormal auditory sensorimotor gating previously reported in mouse models of 22q11DS could arise from abnormalities in auditory processing. Furthermore, the findings indicate that Df1/+ mice are an excellent model for increased risk of OM in human 22q11DS patients. Given the frequently monaural nature of OM in Df1/+ mice, these animals could also be a powerful tool for investigating the interplay between genetic and environmental causes of OM.

Input-Specific Gain Modulation by Local Sensory Context Shapes Cortical and Thalamic Responses to Complex Sounds

Summary Sensory neurons are customarily characterized by one or more linearly weighted receptive fields describing sensitivity in sensory space and time. We show that in auditory cortical and thalamic neurons, the weight of each receptive field element depends on the pattern of sound falling within a local neighborhood surrounding it in time and frequency. Accounting for this change in effective receptive field with spectrotemporal context improves predictions of both cortical and thalamic responses to stationary complex sounds. Although context dependence varies among neurons and across brain areas, there are strong shared qualitative characteristics. In a spectrotemporally rich soundscape, sound elements modulate neuronal responsiveness more effectively when they coincide with sounds at other frequencies, and less effectively when they are preceded by sounds at similar frequencies. This local-context-driven lability in the representation of complex sounds—a modulation of “input-specific gain” rather than “output gain”—may be a widespread motif in sensory processing.