Inhibitory Cell Types Research Articles

Cell-type specific contributions to theta-gamma coupled rhythms in the hippocampus

Abstract Distinct inhibitory cell types participate in cognitively relevant nested brain rhythms, and particular changes in such rhythms are known to occur in disease states. Specifically, the co-expression of theta and gamma rhythms in the hippocampus is believed to represent a general coding scheme, but cellular-based generation mechanisms for these coupled rhythms are currently unclear. We develop a population rate model of the CA1 hippocampus that encompasses circuits of three inhibitory cell types (bistratified cells, parvalbumin (PV)-expressing and cholecystokinin (CCK)-expressing basket cells) and pyramidal cells to examine this. We constrain parameters and perform numerical and theoretical analyses. The theory, in combination with the numerical explorations, predicts circuit motifs and specific cell-type mechanisms that are essential for the co-existence of theta and gamma oscillations. We find that CCK-expressing basket cells initiate the coupled rhythms and regularize theta, and PV-expressing basket cells enhance both theta and gamma rhythms. Pyramidal and bistratified cells govern the generation of theta rhythms, and PV-expressing basket and pyramidal cells play dominant roles in controlling theta frequencies. Our circuit motifs for theta-gamma coupled rhythm generation could be applicable to other brain regions.

Electrophysiological correlates of divergent projections in the avian superior olivary nucleus.

The physiological diversity of inhibitory neurons provides ample opportunity to influence a wide range of computational roles through their varied activity patterns, especially via feedback loops. In the avian auditory brainstem, inhibition originates primarily from the superior olivary nucleus (SON) and so it is critical to understand the intrinsic physiological properties and processing capabilities of these neurons. Neurons in the SON receive ascending input via the cochlear nuclei: directly from the intensity-coding cochlear nucleus angularis (NA) and indirectly via the interaural timing nucleus laminaris (NL), which itself receives input from cochlear nucleus magnocellularis. Two distinct populations of SON neurons provide either inhibitory feedback to ipsilateral NA, NL, and the timing cochlear nucleus NM, or to the contralateral SON. To determine whether these populations correspond to distinct response types, we investigated their electrophysiology in brain stem slices using patch clamp electrophysiology. We identified three phenotypes: single spiking, chattering tonic, and regular tonic neurons. The two tonic phenotypes displayed distinct firing patterns and different membrane properties. Fluctuating "noisy" currents used to probe the capability of SON neurons to encode temporal features showed that each phenotype differed in sensitivity to temporally modulated input. By using cell fills and anatomical reconstructions, we could correlate the firing phenotypes with their axonal projection patterns. We found that SON axons exited via three fiber tracts with each tract composed of specific phenotypes. These results provide a basis for understanding the role of specific inhibitory cell types in auditory function and elucidate the organization of the SON outputs.

Transcriptomic cell-type specificity of local cortical circuits.

Complex neocortical functions rely on networks of diverse excitatory and inhibitory neurons. While local connectivity rules between major neuronal subclasses have been established, the specificity of connections at the level of transcriptomic subtypes remains unclear. We introduce single transcriptome assisted rabies tracing (START), a method combining monosynaptic rabies tracing and single-nuclei RNA sequencing to identify transcriptomic cell types, providing inputs to defined neuron populations. We employ START to transcriptomically characterize inhibitory neurons providing monosynaptic input to 5 different layer-specific excitatory cortical neuron populations in mouse primary visual cortex (V1). At the subclass level, we observe results consistent with findings from prior studies that resolve neuronal subclasses using antibody staining, transgenic mouse lines, and morphological reconstruction. With improved neuronal subtype granularity achieved with START, we demonstrate transcriptomic subtype specificity of inhibitory inputs to various excitatory neuron subclasses. These results establish local connectivity rules at the resolution of transcriptomic inhibitory cell types.

Two-photon imaging of excitatory and inhibitory neural response to infrared neural stimulation.

Pulsed infrared neural stimulation (INS, 1875nm) is an emerging neurostimulation technology that delivers focal pulsed heat to activate functionally specific mesoscale networks and holds promise for clinical application. However, little is known about its effect on excitatory and inhibitory cell types in cerebral cortex. Estimates of summed population neuronal response time courses provide a potential basis for neural and hemodynamic signals described in other studies. Using two-photon calcium imaging in mouse somatosensory cortex, we have examined the effect of INS pulse train application on hSyn neurons and mDlx neurons tagged with GCaMP6s. We find that, in anesthetized mice, each INS pulse train reliably induces robust response in hSyn neurons exhibiting positive going responses. Surprisingly, mDlx neurons exhibit negative going responses. Quantification using the index of correlation illustrates responses are reproducible, intensity-dependent, and focal. Also, a contralateral activation is observed when INS applied. In sum, the population of neurons stimulated by INS includes both hSyn and mDlx neurons; within a range of stimulation intensities, this leads to overall excitation in the stimulated population, leading to the previously observed activations at distant post-synaptic sites.

Distribution of vasoactive intestinal peptide (VIP) immunoreactivity in the rat pallial and subpallial amygdala and colocalization with γ-aminobutyric acid (GABA).

The amygdaloid complex, also known as the amygdala, is a heterogeneous group of distinct nuclear and cortical pallial and subpallial structures. The amygdala plays an important role in several complex functions including emotional behavior and learning. The expression of calcium-binding proteins and peptides in GABAergic neurons located in the pallial and subpallial amygdala is not uniform and is sometimes restricted to specific groups of cells. Vasoactive intestinal polypeptide (VIP) is present in specific subpopulations of GABAergic cells in the amygdala. VIP immunoreactivity has been observed in somatodendritic and axonal profiles of the rat basolateral and central amygdala. However, a comprehensive analysis of the distribution of VIP immunoreactivity in the various pallial and subpallial structures is currently lacking. The present study used immunohistochemical and morphometric techniques to analyze the distribution and the neuronal localization of VIP immunoreactivity in the rat pallial and subpallial amygdala. In the pallial amygdala, VIP-IR neurons are local inhibitory interneurons that presumably directly and indirectly regulate the activity of excitatory pyramidal neurons. In the subpallial amygdala, VIP immunoreactivity is expressed in several inhibitory cell types, presumably acting as projection or local interneurons. The distribution of VIP immunoreactivity is non-homogeneous throughout the different areas of the amygdaloid complex, suggesting a distinct influence of this neuropeptide on local neuronal circuits and, consequently, on the cognitive, emotional, behavioral and endocrine activities mediated by the amygdala.

Postsynaptic cell type and synaptic distance do not determine efficiency of monosynaptic rabies virus spread measured at synaptic resolution.

Retrograde monosynaptic tracing using glycoprotein-deleted rabies virus is an important component of the toolkit for investigation of neural circuit structure and connectivity. It allows for the identification of first-order presynaptic connections to cell populations of interest across both the central and peripheral nervous system, helping to decipher the complex connectivity patterns of neural networks that give rise to brain function. Despite its utility, the factors that influence the probability of transsynaptic rabies spread are not well understood. While it is well established that expression levels of rabies glycoprotein used to trans-complement G-deleted rabies can result in large changes in numbers of inputs labeled per starter cell (convergence index [CI]), it is not known how typical values of CI relate to the proportions of synaptic contacts or input neurons labeled. And it is not known whether inputs to different cell types, or synaptic contacts that are more proximal or distal to the cell body, are labeled with different probabilities. Here, we use a new rabies virus construct that allows for the simultaneous labeling of pre- and postsynaptic specializations to quantify the proportion of synaptic contacts labeled in mouse primary visual cortex. We demonstrate that with typical conditions about 40% of first-order presynaptic excitatory synapses to cortical excitatory and inhibitory neurons are labeled. We show that using matched tracing conditions there are similar proportions of labeled contacts onto L4 excitatory pyramidal, somatostatin (Sst) inhibitory, and vasoactive intestinal peptide (Vip) starter cell types. Furthermore, we find no difference in the proportions of labeled excitatory contacts onto postsynaptic sites at different subcellular locations.

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.

Reciprocal Connections between Parvalbumin-Expressing Cells and Adjacent Pyramidal Cells Are Regulated by Clustered Protocadherin γ.

Functional neural circuits in the cerebral cortex are established through specific neural connections between excitatory and various inhibitory cell types. However, the molecular mechanisms underlying synaptic partner recognition remain unclear. In this study, we examined the impact of clustered protocadherin-γ (cPcdhγ) gene deletion in parvalbumin-positive (PV+) cells on intralaminar and translaminar neural circuits formed between PV+ and pyramidal (Pyr) cells in the primary visual cortex (V1) of male and female mice. First, we used whole-cell recordings and laser-scan photostimulation with caged glutamate to map excitatory inputs from layer 2/3 to layer 6. We found that cPcdhγ-deficient PV+ cells in layer 2/3 received normal translaminar inputs from Pyr cells through layers 2/3-6. Second, to further elucidate the effect on PV+-Pyr microcircuits within intralaminar layer 2/3, we conducted multiple whole-cell recordings. While the overall connection probability of PV+-Pyr cells remained largely unchanged, the connectivity of PV+-Pyr was significantly different between control and PV+-specific cPcdhγ-conditional knock-out (PV-cKO) mice. In control mice, the number of reciprocally connected PV+ cells was significantly higher than PV+ cells connected one way to Pyr cells, a difference that was not significant in PV-cKO mice. Interestingly, the proportion of highly reciprocally connected PV+ cells to Pyr cells with large unitary IPSC (uIPSC) amplitudes was reduced in PV-cKO mice. Conversely, the proportion of middle reciprocally connected PV+ cells to Pyr cells with large uIPSC amplitudes increased compared with control mice. This study demonstrated that cPcdhγ in PV+ cells modulates their reciprocity with Pyr cells in the cortex.

Tonotopic distribution and inferior colliculus projection pattern of inhibitory and excitatory cell types in the lateral superior olive of mice.

The principal neurons (PNs) of the lateral superior olive nucleus (LSO) are an important component of mammalian brainstem circuits that compare activity between the two ears and extract intensity and timing differences used for sound localization. There are two LSO PN transmitter types, glycinergic and glutamatergic, which also have different ascending projection patterns to the inferior colliculus (IC). Glycinergic LSO PNs project ipsilaterally while glutamatergic one's projections vary in laterality by species. In animals with good low-frequency hearing (<3kHz) such as cats and gerbils, glutamatergic LSO PNs have both ipsilateral and contralateral projections; however, rats that lack this ability only have the contralateral pathway. Additionally, in gerbils, the glutamatergic ipsilateral projecting LSO PNs are biased to the low-frequency limb of the LSO suggesting this pathway may be an adaptation for low-frequency hearing. To further test this premise, we examined the distribution and IC projection pattern of LSO PNs in another high-frequency specialized species using mice by combining in situ hybridization and retrograde tracer injections. We observed no overlap between glycinergic and glutamatergic LSO PNs confirming they are distinct cell populations in mice as well. We found that mice also lack the ipsilateral glutamatergic projection from LSO to IC and that their LSO PN types do not exhibit pronounced tonotopic biases. These data provide insights into the cellular organization of the superior olivary complex and its output to higher processing centers that may underlie functional segregation of information.

Target cell-specific synaptic dynamics of excitatory to inhibitory neuron connections in supragranular layers of human neocortex.

Rodent studies have demonstrated that synaptic dynamics from excitatory to inhibitory neuron types are often dependent on the target cell type. However, these target cell-specific properties have not been well investigated in human cortex, where there are major technical challenges in reliably obtaining healthy tissue, conducting multiple patch-clamp recordings on inhibitory cell types, and identifying those cell types. Here, we take advantage of newly developed methods for human neurosurgical tissue analysis with multiple patch-clamp recordings, post-hoc fluorescent in situ hybridization (FISH), machine learning-based cell type classification and prospective GABAergic AAV-based labeling to investigate synaptic properties between pyramidal neurons and PVALB- vs. SST-positive interneurons. We find that there are robust molecular differences in synapse-associated genes between these neuron types, and that individual presynaptic pyramidal neurons evoke postsynaptic responses with heterogeneous synaptic dynamics in different postsynaptic cell types. Using molecular identification with FISH and classifiers based on transcriptomically identified PVALB neurons analyzed by Patch-seq, we find that PVALB neurons typically show depressing synaptic characteristics, whereas other interneuron types including SST-positive neurons show facilitating characteristics. Together, these data support the existence of target cell-specific synaptic properties in human cortex that are similar to rodent, thereby indicating evolutionary conservation of local circuit connectivity motifs from excitatory to inhibitory neurons and their synaptic dynamics.

Mouse models of surgical and neuropathic pain produce distinct functional alterations to prodynorphin expressing neurons in the prelimbic cortex

The medial prefrontal cortex (mPFC) consists of a heterogeneous population of neurons that respond to painful stimuli, and our understanding of how different pain models alter these specific mPFC cell types remains incomplete. A distinct subpopulation of mPFC neurons express prodynorphin (Pdyn+), the endogenous peptide agonist for kappa opioid receptors (KORs). Here, we used whole cell patch clamp for studying excitability changes to Pdyn expressing neurons in the prelimbic region of the mPFC (PLPdyn+ neurons) in mouse models of surgical and neuropathic pain. Our recordings revealed that PLPdyn+ neurons consist of both pyramidal and inhibitory cell types. We find that the plantar incision model (PIM) of surgical pain increases intrinsic excitability only in pyramidal PLPdyn+ neurons one day after incision. Following recovery from incision, excitability of pyramidal PLPdyn+ neurons did not differ between male PIM and sham mice, but was decreased in PIM female mice. Moreover, the excitability of inhibitory PLPdyn+ neurons was increased in male PIM mice, but was with no difference between female sham and PIM mice. In the spared nerve injury model (SNI), pyramidal PLPdyn+ neurons were hyperexcitable at both 3 days and 14 days after SNI. However, inhibitory PLPdyn+ neurons were hypoexcitable at 3 days but hyperexcitable at 14 days after SNI. Our findings suggest different subtypes of PLPdyn+ neurons manifest distinct alterations in the development of different pain modalities and are regulated by surgical pain in a sex-specific manner. Our study provides information on a specific neuronal population that is affected by surgical and neuropathic pain.

Neuronal cell types, projections, and spatial organization of the central amygdala.

The central amygdala (CEA) has been richly studied for interpreting function and behavior according to specific cell types and circuits. Such work has typically defined molecular cell types by classical inhibitory marker genes; consequently, whether marker-gene-defined cell types exhaustively cover the CEA and co-vary with connectivity remains unresolved. Here, we combined single-cell RNA sequencing, multiplexed fluorescent in situ hybridization, immunohistochemistry, and long-range projection mapping to derive a "bottom-up" understanding of CEA cell types. In doing so, we identify two major cell types, encompassing one-third of all CEA neurons, that have gone unresolved in previous studies. In spatially mapping these novel types, we identify a non-canonical CEA subdomain associated with Nr2f2 expression and uncover an Isl1-expressing medial cell type that accounts for many long-range CEA projections. Our results reveal new CEA organizational principles across cell types and spatial scales and provide a framework for future work examining cell-type-specific behavior and function.

Organization of Cortical and Thalamic Input to Inhibitory Neurons in Mouse Motor Cortex.

Intracortical inhibition in motor cortex (M1) regulates movement and motor learning. If cortical and thalamic inputs target different inhibitory cell types in different layers, then these afferents may play different roles in regulating M1 output. Using mice of both sexes, we quantified input to two main classes of M1 interneurons, parvalbumin+ (PV+) cells and somatostatin+ (SOM+) cells, using monosynaptic rabies tracing. We then compared anatomic and functional connectivity based on synaptic strength from sensory cortex and thalamus. Functionally, each input innervated M1 interneurons with a unique laminar profile. Different interneuron types were excited in a distinct, complementary manner, suggesting feedforward inhibition proceeds selectively via distinct circuits. Specifically, somatosensory cortex (S1) inputs primarily targeted PV+ neurons in upper layers (L2/3) but SOM+ neurons in middle layers (L5). Somatosensory thalamus [posterior nucleus (PO)] inputs targeted PV+ neurons in middle layers (L5). In contrast to sensory cortical areas, thalamic input to SOM+ neurons was equivalent to that of PV+ neurons. Thus, long-range excitatory inputs target inhibitory neurons in an area and a cell type-specific manner, which contrasts with input to neighboring pyramidal cells. In contrast to feedforward inhibition providing generic inhibitory tone in cortex, circuits are selectively organized to recruit inhibition matched to incoming excitatory circuits.SIGNIFICANCE STATEMENT M1 integrates sensory information and frontal cortical inputs to plan and control movements. Although inputs to excitatory cells are described, the synaptic circuits by which these inputs drive specific types of M1 interneurons are unknown. Anatomical results with rabies tracing and physiological quantification of synaptic strength shows that two main classes of inhibitory cells (PV+ and SOM+ interneurons) both receive substantial cortical and thalamic input, in contrast to interneurons in sensory areas (where thalamic input strongly prefers PV+ interneurons). Further, each input studied targets PV+ and SOM+ interneurons in a different fashion, suggesting that separate, specific circuits exist for recruitment of feedforward inhibition.

Immunosuppressive effects of vascular endothelial growth factor (Review)

Vascular endothelial growth factor (VEGF) serves a critical role in vasculogenesis, angiogenesis, tumor, inflammatory angiogenesis and lymphangiogenesis. Since 2004, bevacizumab (Avastin), a humanized anti-VEGFA monoclonal antibody, has been approved for the treatment of non-small cell lung, breast, kidney and ovarian cancer in combination with standard chemotherapy. VEGF has been demonstrated to be important in the clinic as a therapeutic target in the anti-angiogenic approach to cancer therapy. The targeting of VEGF, together with immunotherapy, has been reported to be able to reverse the immunosuppressive effects of VEGF. A positive correlation between VEGF expression and the reduced survival rates of patients with cancer has also been demonstrated. Furthermore, increased VEGF expression can lead to immune suppression via the inhibition of dendritic cell maturation, the reduction of T-cell tumor infiltration and the promotion of inhibitory cell types in the tumor microenvironment.

Histone deacetylase 4 inhibition ameliorates the social deficits induced by Ephrin-B2 mutation

Deterioration of inhibitory synapse may be an essential neurological basis underlying abnormal social behaviours. Manipulations that regulate GABAergic transmission are associated with improved behavioural phenotypes in sociability. The synaptic protein, Ephrin-B2 (EB2), plays an important role in the maintenance and reconfiguration of inhibitory synapses in the medial prefrontal cortex (mPFC). However, the inhibitory cell-type specific role of EB2 in the pathophysiology and treatment of social deficits remains unknown. As expected, we revealed that tdTomato-expressing cells were only found in GABAergic neurons instead of excitatory neurons in transgenic EB2-vGATCre mice. This result indicated that depletion of EB2 would occur in those neurons, which further contribute to social deficits. In addition, specific over-expression of mPFC EB2 restored the defective social behaviour abnormalities. These results suggest that the effect of EB2 on social deficits is anatomically and cell-type specific. More importantly, the global upregulation of HDAC4 expression was found in EB2-vGATCre mice. Significant subcellular nuclear shuttling of HDAC4 in vGAT+ neurons was examined and quantified, suggesting a role of nuclear HDAC4 in mediating the mechanism underlying EB2 impairment in vGAT+ neurons. Treatment with LMK235 led to a remarkable rescue of social deficits, thus our data revealed a new domain for the potential utility of HDAC targeting agents to treat social deficits. In conclusion, these results not only revealed a novel molecular mechanism underlying the pathophysiology of social deficits, but also suggested a potential intervention avenue for the treatment of social deficits.

Propranolol Administration Modulates Neural Activity in the Hippocampal Hilus During Fear Retrieval.

Altered fear learning is a strong behavioral component of anxiety disorders such as post-traumatic stress disorder (PTSD). Recent efforts have attempted to combine exposure therapies with drugs that target fear memory retrieval and memory reconsolidation, in order to improve treatment efficacy. The noradrenergic (NA) signaling system is of particular interest, due to its role in regulating the stress response and its involvement in fear and learning processes. Importantly, propranolol (P), a non-selective β-adrenergic antagonist, has shown the potential in decreasing exaggerated fear in both humans and animal models. In a previous study, we utilized an activity-dependent tagging murine model to determine the neural mechanisms by which propranolol attenuates learned fear. We found that propranolol acutely decreased memory trace reactivation specifically in the dorsal dentate gyrus (dDG), but not in CA3 or CA1. Here, we extended our previous study by investigating whether propranolol additionally altered activity in the hilus, a polymorphic layer that consists of neurons, mossy cells, and GABAergic interneurons. We found that propranolol acutely reduced overall hilar activity in both the dorsal and ventral hilus. Moreover, we report that propranolol significantly altered the activity of parvalbumin (PV)+ cells in the ventral (vDG), but not dorsal DG (dDG). Together, these results suggest that a β-adrenergic blockade may affect the activity of excitatory and inhibitory cell types in the hilar layer of the DG, and that these alterations may contribute to manipulating fear memory traces.

Abstract 2829: Non-viral precision genome engineering enables personalized adoptive neoTCR T cell therapy for cancer including multiple additional edits that improve the activity of neoTCR T cells by enhancing CD4 T cell antigen sensitivity and conferring resistance to TGFβ

Abstract Personalized autologous TCR-T cell therapies targeting neoepitopes (neoE) derived from tumor-specific mutations are a compelling approach for the treatment of patients with solid tumors. Using the ultra-sensitive imPACT Isolation Technology®, antigen-experienced, neoE-specific CD8 T cells are captured from the blood of patients with solid cancers followed by cloning of the cognate, neoE-specific, MHC class I-restricted T cell receptors (neoTCRs). DNA-mediated (non-viral) precision genome engineering technology is then used to engineer autologous CD8 and CD4 T cells to express the neoTCR. We have further built upon this platform to modify neoTCR-T cells to address potential sources for tumor immune evasion. The versatility of this single-step gene editing platform is demonstrated here by the presentation of a neoTCR T cell product with knockout of endogenous TCRα and TCRβ and the simultaneous expression of a neoTCR with CD8 co-receptor (CD8coR) from the same expression cassette along with knockout of TGFβ receptor 2 (TGFBR2). We have previously shown that CD8coR expression augments the activity of CD4 T cells engineered to express MHC class I restricted neoTCRs, by increasing CD4 neoTCR T cell helper and effector function. TGFβ is known to promote tumor growth, metastasis, and epithelial to mesenchymal transition (EMT) and to inhibit effector immune responses while promoting fibrosis and the differentiation of inhibitory cell types such as regulatory T cells. TGFβ is expressed by many tumor types and high TGFβ expression is associated with worse prognosis for several cancer subtypes including colorectal, lung and glioblastoma. TGFBR2 is a critical mediator of TGFβ signaling, resulting in potent, inhibitory effects on T cell function. Our data show that simultaneous ablation of TGFBR2 signaling and expression of CD8coR was achieved with high efficiency, resulting in fully functional CD8 and CD4 neoTCR-T cells. Deletion of TGFBR2 with or without CD8coR expression, together with the expression of a neoE-targeted TCR preserved T cell effector function in the presence of inhibitory concentrations of TGFβ. Importantly, the combination of TGFBR2 knockout and CD8coR expression resulted in additive benefits, providing proof-of-concept for modifying two orthogonal features to improve neoTCR T cell function. Altogether, these results demonstrate the applicability of this versatile, precision genome engineering platform technology to yield enhanced, next-generation neoTCR-T cell therapies to expand the potential for clinical benefit in persons with solid cancers. Citation Format: Charles W. Tran, Kayla Lee, Bhamini Purandare, James Byers, Michael M. Dubreuil, William Lu, Michal Mass, Kyle Jacoby, Stefanie J. Mandl, Barbara Sennino. Non-viral precision genome engineering enables personalized adoptive neoTCR T cell therapy for cancer including multiple additional edits that improve the activity of neoTCR T cells by enhancing CD4 T cell antigen sensitivity and conferring resistance to TGFβ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2829.

Descending Axonal Projections from the Inferior Colliculus Target Nearly All Excitatory and Inhibitory Cell Types of the Dorsal Cochlear Nucleus.

The dorsal cochlear nucleus (DCN) integrates auditory nerve input with nonauditory sensory signals and is proposed to function in sound source localization and suppression of self-generated sounds. The DCN also integrates activity from descending auditory pathways, including a particularly large feedback projection from the inferior colliculus (IC), the main ascending target of the DCN. Understanding how these descending feedback signals are integrated into the DCN circuit and what role they play in hearing requires knowing the targeted DCN cell types and their postsynaptic responses. In order to explore these questions, neurons in the DCN that received descending synaptic input from the IC were labeled with a trans-synaptic viral approach in male and female mice, which allowed them to be targeted for whole-cell recording in acute brain slices. We tested their synaptic responses to optogenetic activation of the descending IC projection. Every cell type in the granule cell domain received monosynaptic, glutamatergic input from the IC, indicating that this region, considered an integrator of nonauditory sensory inputs, processes auditory input as well and may have complex and underappreciated roles in hearing. Additionally, we found that DCN cell types outside the granule cell regions also receive descending IC signals, including the principal projection neurons, as well as the neurons that inhibit them, leading to a circuit that may sharpen tuning through feedback excitation and lateral inhibition.SIGNIFICANCE STATEMENT Auditory processing starts in the cochlea and ascends through the dorsal cochlear nucleus (DCN) to the inferior colliculus (IC) and beyond. Here, we investigated the feedback projection from IC to DCN, whose synaptic targets and roles in auditory processing are unclear. We found that all cell types in the granule cell regions, which process multisensory feedback, also process this descending auditory feedback. Surprisingly, all except one cell type in the entire DCN receive IC input. The IC-DCN projection may therefore modulate the multisensory pathway as well as sharpen tuning and gate auditory signals that are sent to downstream areas. This excitatory feedback loop from DCN to IC and back to DCN could underlie hyperexcitability in DCN, widely considered an etiology of tinnitus.

Single Circuit in V1 Capable of Switching Contexts During Movement Using an Inhibitory Population as a Switch.

As animals adapt to their environments, their brains are tasked with processing stimuli in different sensory contexts. Whether these computations are context dependent or independent, they are all implemented in the same neural tissue. A crucial question is what neural architectures can respond flexibly to a range of stimulus conditions and switch between them. This is a particular case of flexible architecture that permits multiple related computations within a single circuit. Here, we address this question in the specific case of the visual system circuitry, focusing on context integration, defined as the integration of feedforward and surround information across visual space. We show that a biologically inspired microcircuit with multiple inhibitory cell types can switch between visual processing of the static context and the moving context. In our model, the VIP population acts as the switch and modulates the visual circuit through a disinhibitory motif. Moreover, the VIP population is efficient, requiring only a relatively small number of neurons to switch contexts. This circuit eliminates noise in videos by using appropriate lateral connections for contextual spatiotemporal surround modulation, having superior denoising performance compared to circuits where only one context is learned. Our findings shed light on a minimally complex architecture that is capable of switching between two naturalistic contexts using few switching units.

Contributions of Distinct Auditory Cortical Inhibitory Neuron Types to the Detection of Sounds in Background Noise.

The ability to separate background noise from relevant acoustic signals is essential for appropriate sound-driven behavior in natural environments. Examples of this separation are apparent in the auditory system, where neural responses to behaviorally relevant stimuli become increasingly noise invariant along the ascending auditory pathway. However, the mechanisms that underlie this reduction in responses to background noise are not well understood. To address this gap in knowledge, we first evaluated the effects of auditory cortical inactivation on mice of both sexes trained to perform a simple auditory signal-in-noise detection task and found that outputs from the auditory cortex are important for the detection of auditory stimuli in noisy environments. Next, we evaluated the contributions of the two most common cortical inhibitory cell types, parvalbumin-expressing (PV+) and somatostatin-expressing (SOM+) interneurons, to the perception of masked auditory stimuli. We found that inactivation of either PV+ or SOM+ cells resulted in a reduction in the ability of mice to determine the presence of auditory stimuli masked by noise. These results indicate that a disruption of auditory cortical network dynamics by either of these two types of inhibitory cells is sufficient to impair the ability to separate acoustic signals from noise.