LFP publications

Harmonicity is a property of complex sounds such as vocalizations or music, but it remains unclear how harmonicity is processed in the auditory cortex (ACtx). Subregions of ACtx are thought to process harmonic stimuli differently. Selective responses to sound features in ACtx emerge hierarchically from primary ACtx (A1) L4 and secondary ACtx (A2) layer (L)2/3, which is believed to be the most responsive to harmonic sounds. Since harmonic stacks can range from 2 to >10 components, being more similar to naturalistic vocalizations, harmonic sensitivity might also arise hierarchically across layers and areas. We studied responses to harmonic stacks of 2–10 frequencies across A1 L4, A1 L2/3, and A2 L2/3 in adult male and female mice using in vivo two-photon microscopy. We found harmonic-sensitive neurons (HNs) responding only to harmonic stacks but not to individual frequencies in all areas at similar proportions. HNs showed highly nonlinear spectral integration of harmonic frequencies that decreased as the harmonic stacks became more complex. Specifically, onset-biased HNs showed greater nonlinearity than offset-biased HNs only in A1 L4. Moreover, HNs in A1 L4 exhibited higher signal correlation than A2 L2/3. Sound-responsive neurons in A1 L4 have the weakest noise correlation compared with A1 L2/3 and A2 L2/3. Together, harmonic sensitivity is not a unique feature of A2 L2/3 but is already established in A1 L4, where neurons robustly encode harmonic sounds through sparse connections.

The thalamocortical pathways exhibit neuroplasticity not only during the critical period but also in adulthood. In this study, we investigated how cholecystokinin (CCK) modulates age-dependent thalamocortical plasticity. Our findings demonstrated that CCK is expressed in thalamocortical neurons and that high-frequency stimulation (HFS) of the thalamocortical pathway triggers the release of CCK in auditory cortex (ACx), as detected by a CCK sensor. HFS of the medial geniculate body (MGB) induced thalamocortical long-term potentiation (LTP) in wild-type young adult mice. However, knockdown of CCK expression in MGB neurons or blockade of the CCK-B receptor (CCKBR) in the ACx abolished HFS-induced LTP. Interestingly, this LTP could not be elicited in juvenile (3-week-old) or aged mice (over 18-month-old) due to distinct mechanisms: the absence of CCKBR in juveniles and the inability to release CCK in aged mice. Notably, exogenous administration of CCK into the ACx rescued LTP in aged mice and significantly improved frequency discrimination. These findings highlight the potential of CCK as a therapeutic intervention for ameliorating neuroplasticity deficits associated with thalamocortical connectivity.

The insular cortex is involved in a wide range of auditory functions in the mammalian brain. We studied the organization and basic response properties of auditory neurons in the insular cortex and adjacent areas by recording responses to sound stimuli in anesthetized female rats. Auditory neurons were present in an insulo-parietal auditory field that spans the boundary between the posterior insula, particularly in the granular insular cortex, and the ventral part of the adjacent nonprimary somatosensory fields. Confirming previous reports, neurons in this field had narrow tuning and were preferentially tuned to relatively low frequencies (<16 kHz). Intriguingly, auditory units in this field displayed shorter minimal latencies than units in the primary auditory cortex, as well as weaker sensitivity to deviance. These results establish the existence of a rapid auditory information stream with distinct properties through the insulo-parietal cortex that may parallel the pathway through the primary and anterior auditory fields.

While evolutionary cortical expansion is thought to underlie the evolution of human cognitive capabilities, excessive developmental expansion can lead to megalencephaly, often found in neurodevelopmental disorders. Still, little is known about how the overproduction of cortical neurons during development affects cortical processing and behavior in later life. Here we show that developmental overproduction of cortical superficial neurons impairs auditory processing in adult mice. We applied XAV939 to overproduce cortical superficial excitatory neurons during development. XAV939-treated adult mice exhibited auditory behavioral deficits and abnormal auditory cortical processing. Furthermore, we found fewer functional monosynaptic connections between cortical putative excitatory neurons. Altogether, our results suggest that abnormal auditory cortical processing contributes to the atypical auditory detectability in XAV939-treated mice. Although the expansion of cortical size is evolutionarily advantageous, an abnormal expansion during development can result in detrimental effects on cortical processing and perceptual behavior in adulthood.

Cortical representations supporting many cognitive abilities emerge from underlying circuits comprised of several different cell types. However, cell type-specific contributions to rate and timing-based cortical coding are not well-understood. Here, we investigated the role of parvalbumin neurons in cortical complex scene analysis. Many complex scenes contain sensory stimuli which are highly dynamic in time and compete with stimuli at other spatial locations. Parvalbumin neurons play a fundamental role in balancing excitation and inhibition in cortex and sculpting cortical temporal dynamics; yet their specific role in encoding complex scenes via timing-based coding, and the robustness of temporal representations to spatial competition, has not been investigated. Here, we address these questions in auditory cortex of mice using a cocktail party-like paradigm, integrating electrophysiology, optogenetic manipulations, and a family of spike-distance metrics, to dissect parvalbumin neurons’ contributions towards rate and timing-based coding. We find that suppressing parvalbumin neurons degrades cortical discrimination of dynamic sounds in a cocktail party-like setting via changes in rapid temporal modulations in rate and spike timing, and over a wide range of time-scales. Our findings suggest that parvalbumin neurons play a critical role in enhancing cortical temporal coding and reducing cortical noise, thereby improving representations of dynamic stimuli in complex scenes.

Background: Auditory hallucinations (which occur when the distinction between thoughts and perceptions is blurred) are common in psychotic disorders. The orbitofrontal cortex (OFC) may be implicated, because it receives multiple inputs, including sound and affective value via the amygdala, orchestrating complex emotional responses. We aimed to elucidate the circuit and neuromodulatory mechanisms that underlie the processing of emotionally salient auditory stimuli in the OFC — mechanisms that may be involved in auditory hallucinations. Methods: We identified the cortico-cortical connectivity conveying auditory information to the mouse OFC; its sensitivity to neuromodulators involved in psychosis and postpartum depression, such as dopamine and neurosteroids; and its sensitivity to sensory gating (defective in dysexecutive syndromes). Results: Retrograde tracers in OFC revealed input cells in all auditory cortices. Acoustic responses were abolished by pharmacological and chemogenetic inactivation of the above-identified pathway. Acoustic responses in the OFC were reduced by local dopaminergic agonists and neurosteroids. Noticeably, apomorphine action lasted longer in the OFC than in auditory areas, and its effect was modality-specific (augmentation for visual responses), whereas neurosteroid action was sex-specific. Finally, acoustic responses in the OFC reverberated to the auditory association cortex via feedback connections and displayed sensory gating, a phenomenon of local origin, given that it was not detectable in input auditory cortices. Limitations: Although our findings were for mice, connectivity and sensitivity to neuromodulation are conserved across mammals. Conclusion: The corticocortical loop from the auditory association cortex to the OFC is dramatically sensitive to dopamine and neurosteroids. This suggests a clinically testable circuit behind auditory hallucinations. The function of OFC input–output circuits can be studied in mice with targeted and clinically relevant mutations related to their response to emotionally salient sounds.

Introduction It is known that an interruption of acoustic input in early life will result in abnormal development of the auditory system. Here, we further show that this negative impact actually spans beyond the auditory system to the hippocampus, a system critical for spatial memory. Methods We induced a temporary conductive hearing loss (TCHL) in P14 rats by perforating the eardrum and allowing it to heal. The Morris water maze and Y‐maze tests were deployed to evaluate spatial memory of the rats. Electrophysiological recordings and anatomical analysis were made to evaluate functional and structural changes in the hippocampus following TCHL. Results The rats with the TCHL had nearly normal hearing at P42, but had a decreased performance with the Morris water maze and Y‐maze tests compared with the control group. A functional deficit in the hippocampus of the rats with the TCHL was found as revealed by the depressed long‐term potentiation and the reduced NMDA receptor‐mediated postsynaptic current. A structural deficit in the hippocampus of those animals was also found as revealed the abnormal expression of the NMDA receptors, the decreased number of dendritic spines, the reduced postsynaptic density and the reduced level of neurogenesis. Conclusions Our study demonstrates that even temporary auditory sensory deprivation in early life of rats results in abnormal development of the hippocampus and consequently impairs spatial memory in adulthood.

Nicotine enhances sensory and cognitive processing via actions at nicotinic acetylcholine receptors (nAChRs), yet the precise circuit- and systems-level mechanisms remain unclear. In sensory cortex, nicotinic modulation of receptive fields (RFs) provides a model to probe mechanisms by which nAChRs regulate cortical circuits. Here, we examine RF modulation in mouse primary auditory cortex (A1) using a novel electrophysiological approach: current-source density (CSD) analysis of responses to tone-in-notched-noise (TINN) acoustic stimuli. TINN stimuli consist of a tone at the characteristic frequency (CF) of the recording site embedded within a white noise stimulus filtered to create a spectral “notch” of variable width centered on CF. Systemic nicotine (2.1 mg/kg) enhanced responses to the CF tone and to narrow-notch stimuli, yet reduced the response to wider-notch stimuli, indicating increased response gain within a narrowed RF. Subsequent manipulations showed that modulation of cortical RFs by systemic nicotine reflected effects at several levels in the auditory pathway: nicotine suppressed responses in the auditory midbrain and thalamus, with suppression increasing with spectral distance from CF so that RFs became narrower, and facilitated responses in the thalamocortical pathway, while nicotinic actions within A1 further contributed to both suppression and facilitation. Thus, multiple effects of systemic nicotine integrate along the ascending auditory pathway. These actions at nAChRs in cortical and subcortical circuits, which mimic effects of auditory attention, likely contribute to nicotinic enhancement of sensory and cognitive processing.

The primary auditory cortex (A1) is organized tonotopically, with neurons sensitive to high and low frequencies arranged in a rostro-caudal gradient. We used laser scanning photostimulation in acute slices to study the organization of local excitatory connections onto layers 2 and 3 (L2/3) of the mouse A1. Consistent with the organization of other cortical regions, synaptic inputs along the isofrequency axis (orthogonal to the tonotopic axis) arose predominantly within a column. By contrast, we found that local connections along the tonotopic axis differed from those along the isofrequency axis: some input pathways to L3 (but not L2) arose predominantly out-of-column. In vivo cell-attached recordings revealed differences between the sound-responsiveness of neurons in L2 and L3. Our results are consistent with the hypothesis that auditory cortical microcircuitry is specialized to the one-dimensional representation of frequency in the auditory cortex.