Effective Regulation of Auditory Processing by Parvalbumin Interneurons in the Tail of the Striatum.

Parvalbumin (PV) interneurons in the auditory cortex (AC) play a crucial role in shaping auditory processing, including receptive field formation, temporal precision enhancement, and gain regulation. PV interneurons are also the primary inhibitory neurons in the tail of the striatum (TS), which is one of the major descending brain regions in the auditory nervous system. However, the specific roles of TS-PV interneurons in auditory processing remain elusive. In this study, morphological and slice recording experiments in both male and female mice revealed that TS-PV interneurons, compared with AC-PV interneurons, were present in fewer numbers but exhibited longer projection distances, which enabled them to provide sufficient inhibitory inputs to spiny projection neurons (SPNs). Furthermore, TS-PV interneurons received dense auditory input from both the AC and medial geniculate body (MGB), particularly from the MGB, which rendered their auditory responses comparable to those of AC-PV interneurons. Optogenetic manipulation experiments demonstrated that TS-PV interneurons were capable of bidirectionally regulating the auditory responses of SPNs. Our findings suggest that PV interneurons can effectively modulate auditory processing in the TS and may play a critical role in auditory-related behaviors.

Spatial Distribution of Inhibitory Innervations of Excitatory Pyramidal Cells by Major Interneuron Subtypes in the Auditory Cortex.

Mental disorders, characterized by the National Institute of Mental Health as disruptions in neural circuitry, currently account for 13% of the global incidence of such disorders. An increasing number of studies suggest that imbalances between excitatory and inhibitory neurons in neural networks may be a crucial mechanism underlying mental disorders. However, the spatial distribution of inhibitory interneurons in the auditory cortex (ACx) and their relationship with excitatory pyramidal cells (PCs) remain elusive. In this study, we employed a combination of optogenetics, transgenic mice, and patch-clamp recording on brain slices to investigate the microcircuit characteristics of different interneurons (PV, SOM, and VIP) and the spatial pattern of inhibitory inhibition across layers 2/3 to 6 in the ACx. Our findings revealed that PV interneurons provide the strongest and most localized inhibition with no cross-layer innervation or layer specificity. Conversely, SOM and VIP interneurons weakly regulate PC activity over a broader range, exhibiting distinct spatial inhibitory preferences. Specifically, SOM inhibitions are preferentially found in deep infragranular layers, while VIP inhibitions predominantly occur in upper supragranular layers. PV inhibitions are evenly distributed across all layers. These results suggest that the input from inhibitory interneurons to PCs manifests in unique ways, ensuring that both strong and weak inhibitory inputs are evenly dispersed throughout the ACx, thereby maintaining a dynamic excitation-inhibition balance. Our findings contribute to understanding the spatial inhibitory characteristics of PCs and inhibitory interneurons in the ACx at the circuit level, which holds significant clinical implications for identifying and targeting abnormal circuits in auditory system diseases.

The activated synaptic terminals beyond the light illumination range affect the results of optogenetics.

OBJECTIVES: Optogenetics is widely applied to study complex brain networks. However, recent studies have found that light alone can produce effects that are unrelated to optogenetics, and it is still unclear whether this can affect the results of optogenetic experiments. METHODS: We explored the characteristics of projection of interneurons to excitatory neurons in the auditory cortex with optogenetics, transgenic mice and patch-clamp recording. RESULTS: We discovered that postsynaptic responses can be induced when we stimulated a blank area adjacent to the edge of brain slice. Similar results can be observed after blocking the polysynaptic responses by drugs. Together with the results of control experiments, we found that the false response is caused by activating the synaptic terminals beyond the range of the blue light (470 nm). Also, there was a linear relationship between the response and the stimulus distance for all data, which suggested that these false responses may be related to other factors, such as light scattering. CONCLUSIONS: The LED-light-evoked response cannot reflect microcircuit of the recorded neuron and the activated neurons within the illumination range accurately. Together, these results confirm that light alone can affect neural activity, but this can be unrelated to the genuine 'optogenetic effect'.

Cross-Modality Sharpening of Visual Cortical Processing through Layer-1-Mediated Inhibition and Disinhibition.

Cross-modality interaction in sensory perception is advantageous for animals' survival. How cortical sensory processing is cross-modally modulated and what are the underlying neural circuits remain poorly understood. In mouse primary visual cortex (V1), we discovered that orientation selectivity of layer (L)2/3, but not L4, excitatory neurons was sharpened in the presence of sound or optogenetic activation of projections from primary auditory cortex (A1) to V1. The effect was manifested by decreased average visual responses yet increased responses at the preferred orientation. It was more pronounced at lower visual contrast and was diminished by suppressing L1 activity. L1 neurons were strongly innervated by A1-V1 axons and excited by sound, while visual responses of L2/L3 vasoactive intestinal peptide (VIP) neurons were suppressed by sound, both preferentially at the cell's preferred orientation. These results suggest that the cross-modality modulation is achieved primarily through L1 neuron- and L2/L3 VIP-cell-mediated inhibitory and disinhibitory circuits.

Thalamocortical Innervation Pattern in Mouse Auditory and Visual Cortex: Laminar and Cell-Type Specificity.

Despite many previous studies, the functional innervation pattern of thalamic axons and their target specificity remains to be investigated thoroughly. Here, in primary auditory cortical slices, we examined thalamic innervation patterns for excitatory and different types of inhibitory neurons across laminae, by optogenetically stimulating axons from the medial geniculate body. We found that excitatory cells and parvalbumin (PV)-expressing inhibitory neurons across layer 2/3 (L2/3) to L6 are directly innervated by thalamic projections, with the strongest innervation occurring in L4. The innervation of PV neurons is stronger than that of excitatory neurons in the same layer, with a relatively constant ratio between their innervation strengths across layers. For somatostatin and vasoactive intestinal peptide inhibitory neurons, essentially only L4 neurons were innervated by thalamic axons and the innervation was much weaker compared with excitatory and PV cells. In addition, more than half of inhibitory neurons in L1 were innervated, relatively strongly, by thalamic axons. Similar innervation patterns were also observed in the primary visual cortex. Thus, thalamic information can be processed independently and differentially by different cortical layers, in addition to the generally thought hierarchical processing starting from L4. This parallel processing is likely shaped by feedforward inhibition from PV neurons in each individual lamina, and may extend the computation power of sensory cortices.

Auditory cortex controls sound-driven innate defense behaviour through corticofugal projections to inferior colliculus.

Defense against environmental threats is essential for animal survival. However, the neural circuits responsible for transforming unconditioned sensory stimuli and generating defensive behaviours remain largely unclear. Here, we show that corticofugal neurons in the auditory cortex (ACx) targeting the inferior colliculus (IC) mediate an innate, sound-induced flight behaviour. Optogenetic activation of these neurons, or their projection terminals in the IC, is sufficient for initiating flight responses, while the inhibition of these projections reduces sound-induced flight responses. Corticocollicular axons monosynaptically innervate neurons in the cortex of the IC (ICx), and optogenetic activation of the projections from the ICx to the dorsal periaqueductal gray is sufficient for provoking flight behaviours. Our results suggest that ACx can both amplify innate acoustic-motor responses and directly drive flight behaviours in the absence of sound input through corticocollicular projections to ICx. Such corticofugal control may be a general feature of innate defense circuits across sensory modalities.

Sensory Cortical Control of a Visually Induced Arrest Behavior via Corticotectal Projections.

Innate defense behaviors (IDBs) evoked by threatening sensory stimuli are essential for animal survival. Although subcortical circuits are implicated in IDBs, it remains largely unclear whether sensory cortex modulates IDBs and what the underlying neural pathways are. Here, we show that optogenetic silencing of corticotectal projections from layer 5 (L5) of the mouse primary visual cortex (V1) to the superior colliculus (SC) significantly reduces an SC-dependent innate behavior (i.e., temporary suspension of locomotion upon a sudden flash of light as short as milliseconds). Surprisingly, optogenetic activation of SC-projecting neurons in V1 or their axon terminals in SC sufficiently elicits the behavior, in contrast to other major L5 corticofugal projections. Thus, via the same corticofugal projection, visual cortex not only modulates the light-induced arrest behavior, but also can directly drive the behavior. Our results suggest that sensory cortex may play a previously unrecognized role in the top-down initiation of sensory-motor behaviors.

A feedforward inhibitory circuit mediates lateral refinement of sensory representation in upper layer 2/3 of mouse primary auditory cortex.

Sensory information undergoes ordered and coordinated processing across cortical layers. Whereas cortical layer (L) 4 faithfully acquires thalamic information, the superficial layers appear well staged for more refined processing of L4-relayed signals to generate corticocortical outputs. However, the specific role of superficial layer processing and how it is specified by local synaptic circuits remains not well understood. Here, in the mouse primary auditory cortex, we showed that upper L2/3 circuits play a crucial role in refining functional selectivity of excitatory neurons by sharpening auditory tonal receptive fields and enhancing contrast of frequency representation. This refinement is mediated by synaptic inhibition being more broadly recruited than excitation, with the inhibition predominantly originating from interneurons in the same cortical layer. By comparing the onsets of synaptic inputs as well as of spiking responses of different types of neuron, we found that the broadly tuned, fast responding inhibition observed in excitatory cells can be primarily attributed to feedforward inhibition originating from parvalbumin (PV)-positive neurons, whereas somatostatin (SOM)-positive interneurons respond much later compared with the onset of inhibitory inputs to excitatory neurons. We propose that the feedforward circuit-mediated inhibition from PV neurons, which has an analogous function to lateral inhibition, enables upper L2/3 excitatory neurons to rapidly refine auditory representation.

Electrostatic interaction between inactivation ball and T1-S1 linker region of Kv1.4 channel.

Inactivation of potassium channels plays an important role in shaping the electrical signaling properties of nerve and muscle cells. The rapid inactivation of Kv1.4 has been assumed to be controlled by a "ball and chain" inactivation mechanism. Besides hydrophobic interaction between inactivation ball and the channel's inner pore, the electrostatic interaction has also been proved to participate in the "ball and chain" inactivation process of Kv1.4 channel. Based on the crystal structure of Kv1.2 channel, the acidic T1-S1 linker is indicated to be a candidate interacting with the positively charged hydrophilic region of the inactivation domain. In this study, through mutating the charged residues to amino acids of opposite polar, we identified the electrostatic interaction between the inactivation ball and the T1-S1 linker region of Kv1.4 channel. Inserting negatively charged peptide at the amino terminal of Kv1.4 channel further confirmed the electrostatic interaction between the two regions.