Inhibitory Cells Research Articles

Activation of 5-HT7 receptors in the mouse dentate gyrus does not affect theta-burst-induced plasticity at the perforant path synapse.

The study examined the effects of 5-HT7 receptor activation on GABAergic transmission within the dentate gyrus and plasticity at the glutamatergic perforant path input. Immunofluorescence imaging was performed using transverse hippocampal slices from transgenic mice expressing green fluorescent protein (GFP) under the Htr7 promoter. This was followed by whole-cell patch clamp electrophysiological recordings assessing the effects of pharmacologically activating 5-HT7 receptors on spontaneous inhibitory postsynaptic currents recorded from dentate granule cells and hilar mossy cells-two glutamatergic neuron types present in the dentate gyrus. Extracellular recordings of field excitatory postsynaptic potentials were then performed to assess whether 5-HT7 receptor activation influenced theta-burst stimulation-evoked plasticity of the perforant path synaptic input. It was found that parvalbumin and somatostatin interneurons in the dentate gyrus expressed GFP, which suggests they express 5-HT7 receptors. However, activation of 5-HT7 receptors had no effect on GABAergic transmission targeting mossy cells or granule cells. There was also no effect of 5-HT7 receptor activation on perforant path plasticity either with intact or blocked GABAA receptor signaling. The presence of 5-HT7 receptors in a subset of parvalbumin and somatostatin interneurons in the mouse dentate gyrus could mean that they are involved in the inhibitory control of dentate gyrus activity. However, this potential effect was not evident in slice recordings of inhibitory transmission targeting principal cells and did not affect perforant path plasticity. Further experiments are needed to fully elucidate the functional role of these receptors in the dentate gyrus.

Dialectics of perisomatic inhibition—The unity and conflict of opposites

Over the past three decades, a great deal of attention has been paid to the study of perisomatic inhibition and perisomatic inhibitory basket cells. A growing body of experimental evidence points to the leading role of perisomatic inhibitory cells in the generation of oscillatory activity in various frequency ranges. Recently the link between the activity of basket cells and complex behavior has been demonstrated in several laboratories. However, all this is true only for one type of perisomatic inhibitory interneuron—parvalbumin-positive basket cells. Nevertheless, where parvalbumin-positive basket cells are found, there is another type of basket cell, cholecystokinin-positive interneurons. These two types of interneurons share a number of common features: they innervate the same compartments of target neurons and they often receive excitation from the same sources, but they also differ from each other in the synchrony of their GABA release and expression of receptors. The functional role of cholecystokinin-positive basket cells in oscillatory activity is not so obvious. They were thought to be involved in theta oscillations, however recent measurements in free moving animals have put some doubts on this hypothesis. Therefore, an important question is, whether these two types of basket cells work synergistically or perform opposing actions in functional networks? In this mini-review, we attempt to answer this question by putting forward the idea that these two types of basket cells are functionally united as two entities of the same network, and their opposing actions are necessary to maintain rhythmogenesis in a “healthy”, physiological range.

Integration of distinct cortical inputs to primary and higher order inhibitory cells of the thalamus.

The necortex regulates its own sensory input in part through top-down inhibitory mechanisms. Descending corticothalamic projections drive GABAergic neurons of the thalamic reticular nucleus (TRN), which then control thalamocortical cells via inhibition. Neurons in sensory TRN are organized into primary and higher order (HO) subpopulations, with separate intrathalamic connections and distinct genetic and functional properties. Here, we investigated top-down neocortical control over primary and HO neurons of somatosensory TRN. Projections from layer 6 of somatosensory cortex evoked stronger and more state-dependent activity in primary than in HO TRN, driven by more robust synaptic inputs and potent T-type calcium currents. However, HO TRN received additional, physiologically distinct, inputs from layer 5 of S1 and motor cortex. Thus, in a departure from the canonical focused sensory layer 6 innervation characteristic of primary TRN, HO TRN integrates broadly from multiple corticothalamic systems, with unique state-dependence, extending the range of mechanisms for top-down control.

Balancing Tumor Immunotherapy and Immune-Related Adverse Events: Unveiling the Key Regulators.

Tumor immunotherapy has emerged as a promising approach in cancer treatment in recent years, offering vast potential. This method primarily involves targeting and inhibiting the suppressive checkpoints present in different immune cells to enhance their activation, ultimately leading to tumor regression. However, tumor cells exploit the surrounding immune cells and tissues to establish a tumor microenvironment (TME) that supports their survival and growth. Within the TME, the efficacy of effector immune cells is compromised, as tumor cells exploit inhibitory immune cells to suppress their function. Furthermore, certain immune cells can be co-opted by tumor cells to facilitate tumor growth. While significantly enhancing the body's tumor immunity can lead to tumor regression, it can also result in severe toxic side effects and an inflammatory factor storm. As a consequence, patients often discontinue treatment due to immune-related adverse events (irAEs) or, in extreme cases, succumb to toxic side effects before experiencing tumor regression. In this analysis, we examined several remission regimens for irAEs, each with its own drawbacks, including toxic side effects or suppression of tumor immunotherapy, which is undesirable. A recent research study, specifically aimed at downregulating intestinal epithelial barrier permeability, has shown promising results in reducing the severity of inflammatory bowel disease (IBD) while preserving immune function. This approach effectively reduces the severity of IBD without compromising the levels of TNF-α and IFN-γ, which are crucial for maintaining the efficacy of tumor immunotherapy. Based on the substantial similarities between IBD and ICI colitis (combo immune checkpoint inhibitors-induced colitis), this review proposes that targeting epithelial cells represents a crucial research direction for mitigating irAEs in the future.

Co-activation of selective nicotinic acetylcholine receptor subtypes is required to reverse hippocampal network dysfunction and prevent fear memory loss in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia with no known cause and cure. Research suggests that a reduction of GABAergic inhibitory interneurons' activity in the hippocampus by beta-amyloid peptide (Aβ) is a crucial trigger for cognitive impairment in AD via hyperexcitability. Therefore, enhancing hippocampal inhibition is thought to be protective against AD. However, hippocampal inhibitory cells are highly diverse, and these distinct interneuron subtypes differentially regulate hippocampal inhibitory circuits and cognitive processes. Moreover, Aβ unlikely affects all subtypes of inhibitory interneurons in the hippocampus equally. Hence, identifying the affected interneuron subtypes in AD to enhance hippocampal inhibition optimally is conceptually and practically challenging. We have previously found that Aβ selectively binds to two of the three major hippocampal nicotinic acetylcholine receptor (nAChR) subtypes, α7- and α4β2-nAChRs, but not α3β4-nAChRs, and inhibits these two receptors in cultured hippocampal inhibitory interneurons to decrease their activity, leading to hyperexcitation and synaptic dysfunction in excitatory neurons. We have also revealed that co-activation of α7- and α4β2-nAChRs is required to reverse the Aβ-induced adverse effects in hippocampal excitatory neurons. Here, we discover that α7- and α4β2-nAChRs predominantly control the nicotinic cholinergic signaling and neuronal activity in hippocampal parvalbumin-positive (PV+) and somatostatin-positive (SST+) inhibitory interneurons, respectively. Furthermore, we reveal that co-activation of these receptors is necessary to reverse hippocampal network dysfunction and fear memory loss in the amyloid pathology model mice. We thus suggest that co-activation of PV+ and SST+ cells is a novel strategy to reverse hippocampal dysfunction and cognitive decline in AD.

Neurochemical Characterization of Dopaminoceptive Cells in Song Control Nuclei of Canaries and Their Activation During Song Production: A Multiplex Fluorescent In Situ Hybridization Study.

Highly sensitive in situ hybridization procedures (RNAScope) were used to quantify the expression of three dopamine receptors (Drd1, Drd2, and Drd3) in two song control nuclei (HVC and the Area X of the basal ganglia) that are known to receive dopaminergic inputs and in the periaqueductal gray (PAG) of male and female canaries. Both sexes were treated with testosterone to ensure they would sing actively. We also determined the excitatory versus inhibitory phenotype of the cells expressing these receptors as well as their activation following a period of song production. The three receptor types were identified in each brain area, with the exception of Drd3 in Area X. The density of cells expressing each receptor varied as a function of receptor type and brain area. Surprisingly few sex differences were detected; they do not seem to explain the sex differences in testosterone-induced song. Overall, the density of Drd-positive cells was much lower in PAG than in the two song control nuclei. In HVC, the majority of cells expressing the three receptor subtypes were VGlut2-positive, whereas colocalization with Vglut2 occurred in few cells in Area X and in an intermediate proportion of cells in PAG. The number of inhibitory cells expressing dopamine receptors was limited. Most dopaminoceptive cells in Area X did not express either excitatory or inhibitory markers. Finally, cellular activation during singing behavior, as measured by the expression of Egr1, was observed in cells expressing each of the three dopamine receptor subtypes, except Drd3 in the PAG.

Sparse representation of neurons for encoding complex sounds in the auditory cortex

Listening in complex sound environments requires rapid segregation of different sound sources, e.g., having a conversation with multiple speakers or other environmental sounds. Efficient processing requires fast encoding of inputs to adapt to target sounds and identify relevant information from past experiences. This adaptation process represents an early phase of implicit learning of the sound statistics to form auditory memory. The auditory cortex (ACtx) plays a crucial role in this implicit learning process, but the underlying circuits are unknown. In awake mice, we recorded neuronal responses in different ACtx subfields using in vivo 2-photon imaging of excitatory and inhibitory (parvalbumin; PV) neurons. We used a paradigm adapted from human studies that induced rapid implicit learning from passively presented complex sounds and imaged A1 Layer 4 (L4), A1 L2/3, and A2 L2/3. In this paradigm, a frozen spectro-temporally complex ‘Target’ sound randomly re-occurred within a stream of other random complex sounds. All ACtx subregions contained distinct groups of cells specifically responsive to complex acoustic sequences, indicating that even thalamocortical input layers (A1 L4) respond to complex sounds. Subgroups of excitatory and inhibitory cells in all subfields showed decreased responses for re-occurring Target sounds, indicating that ACtx is highly involved in the early implicit learning phase. At the population level, activity was more decorrelated to Target sounds independent of the duration of frozen token, subregions, and cell type. These findings suggest that ACtx and its input layers contribute to the early phase of auditory memory for complex sounds, suggesting a parallel strategy across ACtx areas and between excitatory and inhibitory neurons.

Dendritic cell-based biomimetic nanoparticles for foot-and-mouth disease induce robust cellular immunity

Foot-and-mouth disease (FMD) is a highly contagious and economically devastating viral disease of ruminants and swine, badly affecting the livestock industry worldwide. In clinical practice, vaccination is a frequently employed strategy to prevent foot-and-mouth disease (FMDV). However, commercial inactivated vaccines for FMD mainly rely on humoral immunity, exhibiting poor cellular immune responses and causing adverse reactions. Here, we use the double emulsion method to prepare poly (lactic-co-glycolic acid) nanoparticles (PLGA-NP) encapsulated with IL-2 cytokines, wrap the dendritic cell (DC) membrane carrying FMDV antigen information on the surface of the nanoparticles, obtaining a biomimetic nanoparticle vaccine Biom@DC with uniform size. This vaccine can effortlessly move through lymph nodes due to its nanoscale size advantage. It also possesses DC ability to present antigens, and antigen presentation can be made more effective with high biocompatibility. The sustained release of IL-2 encapsulated in the core of PLGA-NP in vivo can effectively promote the body's cellular immune response. Immune tests on mice have shown that Biom@DC may greatly increase T cell activation and proliferation both in vivo and in vitro, while also significantly reducing the fraction of inhibitory Treg cells. Furthermore, in the micro serum neutralization assay for FMDV, it has been demonstrated that the group vaccinated with Biom@DC exhibits a clear neutralizing effect. Given its strong immunogenicity, Biom@DC has the potential to develop into a novel, potent anti-FMDV vaccination.

Dysregulation of parvalbumin expression and neurotransmitter imbalance in the auditory cortex of the BTBR mouse model of autism spectrum disorder.

Individuals diagnosed with autism spectrum disorder (ASD) frequently exhibit abnormalities in auditory perception, a phenomenon potentially attributed to alterations in the excitatory and inhibitory cells constituting cortical circuits. However, the exact genetic factors and cell types affected by ASD remain unclear. The present study investigated the balance of excitatory and inhibitory activity in the auditory cortex using BTBR T+ Itpr3tf/J (BTBR) mice, a well-established model for autism research. Our investigation unveiled a reduction in parvalbumin-positive (PV+) neurons within the AC of BTBR mice. Remarkably, in vivo magnetic resonance spectroscopy studies disclosed an elevation in glutamate (Glu) levels alongside a decrement in γ-aminobutyric acid (GABA) levels in this cortical region. Additionally, transcriptomic analysis of the mouse model facilitated the classification of several ASD-associated genes based on their cellular function and pathways. By comparing autism risk genes with RNA transcriptome sequencing data from the ASD mouse model, we identified the recurrent target gene Scn1a and performed validation. Intriguingly, we uncovered the specific expression of Scn1a in cortical inhibitory neurons. These findings hold significant value for understanding the underlying neural mechanisms of abnormal sensory perception in animal models of ASD.

Local synthesis of estradiol in the rostral ventromedial medulla protects against widespread muscle pain in male mice.

Animal studies consistently demonstrate that testosterone is protective against pain in multiple models, including an animal model of activity-induced muscle pain. In this model, females develop widespread muscle hyperalgesia, and reducing testosterone levels in males results in widespread muscle hyperalgesia. Widespread pain is believed to be mediated by changes in the central nervous system, including the rostral ventromedial medulla (RVM). The enzyme that converts testosterone to estradiol, aromatase, is highly expressed in the RVM. Therefore, we hypothesized that testosterone is converted by aromatase to estradiol locally in the RVM to prevent development of widespread muscle hyperalgesia in male mice. This was tested through pharmacological inhibition of estrogen receptors (ER), aromatase, or ER-α in the RVM which resulted in contralateral hyperalgesia in male mice (C57BL/6J). ER inhibition in the RVM had no effect on hyperalgesia in female mice. As prior studies show modulation of estradiol signaling alters GABA receptor and transporter expression, we examined if removal of testosterone in males would decrease mRNA expression of GABA receptor subunits and vesicular GABA transporter (VGAT). However, there were no differences in mRNA expression of GABA receptor subunits of VGAT between gonadectomized and sham control males. Lastly, we used RNAscope to determine expression of ER-α in the RVM and show expression in inhibitory (VGAT+), serotonergic (tryptophan hydroxylase 2+), and μ-opioid receptor expressing (MOR+) cells. In conclusion, testosterone protects males from development of widespread hyperalgesia through aromatization to estradiol and activation of ER-α which is widely expressed in multiple cell types in the RVM.Significance Statement This study's findings reveal, for the first time, that testosterone protects males from development of widespread muscle hyperalgesia through aromatization to estradiol and activation of ER-α within the RVM. The findings also show, for the first time, ER-α expression in the RVM in male mice, and the distribution patterns of this expression among multiple cell types. Thus, together our data suggest a unique endogenous mechanism in the RVM for protection against widespread pain in males only.

Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy

CD4+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses1–5, other CD4+ T cells have recently been implicated in inhibiting this response6,7. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified them as type 1 regulatory T (Tr1) cells expressing IL-10, granzyme B, perforin, CCL5 and LILRB4. Tumour-specific Tr1 cells suppressed tumour rejection induced by anti-PD1, LDVax or adoptively transferred tumour-specific effector T cells. Mechanistically, HDVax-induced Tr1 cells selectively killed MHC-II tumour antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in tumours. We then documented modalities to overcome this inhibition, specifically via anti-LILRB4 blockade, using a CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. Collectively, these data show that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumour responses and thereby function to impede immune control of cancer.

Insights into Immune Exhaustion in Chronic Hepatitis B: A Review of Checkpoint Receptor Expression.

Hepatitis B, caused by the hepatitis B virus (HBV), often progresses to chronic infection, leading to severe complications, such as cirrhosis, liver failure, and hepatocellular carcinoma. Chronic HBV infection is characterized by a complex interplay between the virus and the host immune system, resulting in immune cell exhaustion, a phenomenon commonly observed in chronic viral infections and cancer. This state of exhaustion involves elevated levels of inhibitory molecules, cells, and cell surface receptors, as opposed to stimulatory counterparts. This review aims to elucidate the expression patterns of various co-inhibitory and co-stimulatory receptors on immune cells isolated from chronic hepatitis B (CHB) patients. By analyzing existing data, the review conducts comparisons between CHB patients and healthy adults, explores the differences between HBV-specific and total T cells in CHB patients, and examines variations between intrahepatic and peripheral immune cells in CHB patients. Understanding the mechanisms underlying immune exhaustion in CHB is crucial for developing novel immunotherapeutic approaches. This detailed analysis sheds light on the immune exhaustion observed in CHB and lays the groundwork for future combined immunotherapy strategies aimed at leveraging checkpoint receptors to restore immune function and improve clinical outcomes.

The expression of ERAP1 is favorable for the prognosis and immunotherapy in colorectal cancer: a study based on the bioinformatic and immunohistochemical analysis.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an emerging pharmacological target in cancer immunotherapy. This study was set out to examine the expression profiles and implications for prognosis and immunotherapy of ERAP1 in CRC. Based on bioinformatics and immunohistochemical analysis, we analyzed ERAP1 for potential diagnostic and prognostic significance in CRC. Functional enrichment analysis was conducted to detect the pathways associated with ERAP1, thus determining possible mechanisms. ESTIMATE, TIMER, and CIBESORT probed the links between ERAP1 and tumor-infiltrating immune cells. Lastly, we examined how ERAP1 expression correlated with the sensitivity to immunotherapy. Tumor tissues had decreased levels of ERAP1 expression relative to normal tissues. Patients whose ERAP1 expression was low suffered a worse chance of survival. Besides, it was shown that ERAP1 expression was associated with the advanced M stage and pathologic stage. Survival analysis revealed that low ERAP1 expression, age, pathologic stage, T stage, and M stage were independent indicators for unfavorable CRC patients' prognoses. The 1-, 3-, and 5-year OS calibration curves all fit well with the ideal model, suggesting that the age-ERAP1-T-stage-M-stage nomogram is a reliable predictor of OS. Additionally, we discovered that ERAP1 expression was associated with immune response and infiltration of various immune cells, such as down-regulated inhibitory immune cells and up-regulated stimulating immune cells. Sensitivity to PD-1 and CTLA4 inhibitors was associated with high ERAP1 levels. In summary, ERAP1 has potential as a diagnostic and prognostic biological marker, highlighting new insights into the study of CRC and the design of effective therapies.

Differential isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 mutation-related landscape in intrahepatic cholangiocarcinoma.

Patients with intrahepatic cholangiocarcinoma (ICC) are prone to recurrence and poor survival. Targeted therapy related to isocitrate dehydrogenase (IDH) is an extremely important treatment. IDH1 and IDH2 mutations are generally thought to have similar effects on the tumor landscape. However, it is doubtful whether these 2 mutations have exactly the same effects on tumor cells and the tumor microenvironment. All collected tumor samples were subjected to simultaneous whole-exon sequencing and proteome sequencing. IDH1 mutations accounted for 12.2%, and IDH2 mutations accounted for 5.5%, all missense mutations. Tumors with IDH mutations had lower proportions of KRAS and TP53 mutations. Mutated genes were obviously enriched in the kinase pathway in the tumors with IDH2 mutations. The signaling pathways were mainly enriched in the activation of cellular metabolic activities and an increase of inhibitory immune cells in the tumors with IDH mutations. Moreover, tumors had unique enrichment in DNA repair in IDH1 mutants and secretion of biological molecules in IDH2 mutants. Inhibitory immune cells might be more prominent in IDH2 mutants, and the expression of immune checkpoints PVR and HLA-DQB1 was more prominent in IDH1 mutants. IDH mutants were more related to metabolism-related and inflammation-immune response clusters, and some belonged to the DNA replication and repair cluster. These results revealed the differential IDH1 and IDH2 mutation-related landscapes, and we have provided an important reference database to guide ICC treatment.

Cell-type-specific effects of age and sex on human cortical neurons

Altered transcriptional and epigenetic regulation of brain cell types may contribute to cognitive changes withadvanced age. Using single-nucleus multi-omic DNA methylation and transcriptome sequencing (snmCT-seq) in frontal cortex from young adult and aged donors, we found widespread age- and sex-related variation in specific neuron types. The proportion of inhibitory SST- and VIP-expressing neurons was reduced in aged donors. Excitatory neurons had more profound age-related changes in their gene expression and DNA methylation than inhibitory cells. Hundreds of genes involved in synaptic activity, including EGR1, were less expressed in aged adults. Genes located in subtelomeric regions increased their expression with age and correlated with reduced telomere length. We further mapped cell-type-specific sex differences in gene expression and X-inactivation escape genes. Multi-omic single-nucleus epigenomes and transcriptomes provide new insight into the effects of age and sex on human neurons.

Differential IDH1 and IDH2 mutation-related landscape in intrahepatic cholangiocarcinoma.

e16224 Background: Patients with intrahepatic cholangiocarcinoma (ICC) are prone to recurrence and poor survival. Targeted therapy related to isocitrate dehydrogenase (IDH) is an extremely important treatment. IDH1 and IDH2 mutations are generally thought to have similar effects on the tumor landscape. However, it is doubtful whether these two mutations have exactly the same effects on tumor cells and the tumor microenvironment. Methods: All collected tumor samples were subjected to simultaneous whole-exon sequencing and proteome sequencing. Results: IDH1 mutations accounted for 12.2%, and IDH2 mutations accounted for 5.5%, all missense mutations. Tumors with IDH mutations had lower proportions of KRAS and TP53 mutations. Mutated genes were obviously enriched in the kinase pathway in the tumors with IDH2 mutations. The signaling pathways were mainly enriched in the activation of cellular metabolic activities and an increase of inhibitory immune cells in the tumors with IDH mutations. Moreover, tumors had unique enrichment in DNA repair in IDH1 mutants and secretion of biological molecules in IDH2 mutants. Inhibitory immune cells might be more prominent in IDH2 mutants, and the expression of immune checkpoints PVR and HLA-DQB1 were more prominent in IDH1 mutants. IDH mutations were more related to metabolism-related and inflammation-immune response clusters, and some belonged to the DNA replication cluster. Conclusions: These results revealed the differential IDH1 and IDH2 mutation-related landscapes, and we have provided an important reference database to guide ICC treatment.

The role of MDSCs in the development of bone marrow fibrosis.

e18532 Background: Myelofibrosis is a type of myeloproliferative disorder, and research indicates that the immunosuppressive tumor microenvironment plays a significant role in the pathogenesis of myelofibrosis, with myeloid-derived suppressor cells (MDSC) being the primary inhibitory cells involved in shaping the tumor immune microenvironment. In this study, we used flow cytometry to detect the number of MDSC in the bone marrow of myelofibrosis patients, and the concentration of CCL2 in the supernatant of bone marrow MDSC cells of patients with myelofibrosis was detected by Elisa technique. Methods: In this study, we utilized flow cytometry to identify the number of Lin-HLA-DR-CD33+ labeled MDSC in the bone marrow of 109 myelofibrosis patients and 20 healthy individuals. Subsequently, we detected the CCL2 concentration in the cell culture supernatant of bone marrow MDSC cells from 42 patients with bone marrow fibrosis after stable culture using ELISA technique. Results: The results of flow cytometry revealed a significant increase in the percentage of MDSC in the bone marrow of myelofibrosis patients (15.16±6.25%) compared to healthy individuals (1.72±0.88%) (p<0.0001). Among them, the MDSC counts were 20.86±6.17% in PMF patients, 18.10±4.77% in post-ET MF patients, and 15.58±3.65% in post-PV MF patients, with no significant statistical difference in MDSC counts among the three groups.And them, the CCL2 concentration in the supernatant was 13.67±1.68 pg/ml for patients with MDSC count <5% (n=6), 36.36±11.88 pg/ml for patients with MDSC count between 5% and 10% (n=16), 55.12±9.71 pg/ml for patients with MDSC count between 10% and 20% (n=14), and 83.19±14.01 pg/ml for patients with MDSC count >20% (n=6). Conclusions: Research has shown that the number of MDSCs is elevated in patients with myelofibrosis compared to healthy individuals. We also found that as the MDSC count increased, the CCL2 concentration in the cell culture supernatant increased accordingly, suggesting that CCL2 may be involved in the proliferation and activation of MDSCs.

Distinct feedforward and feedback pathways for cell-type specific attention effects

Selective attention is thought to depend on enhanced firing activity in extrastriate areas. Theories suggest that this enhancement depends on selective inter-areal communication via gamma (30-80Hz) phase-locking. To test this, we simultaneously recorded from different cell types and cortical layers of macaque V1 and V4. We find that while V1-V4 gamma phase-locking between local field potentials increases with attention, the V1 gamma rhythm does not engage V4 excitatory-neurons, but only fast-spiking interneurons in L4 of V4. By contrast, attention enhances V4 spike-rates in both excitatory and inhibitory cells, most strongly in L2/3. The rate increase in L2/3 of V4 precedes V1 in time. These findings suggest enhanced signal transmission with attention does not depend on inter-areal gamma phase-locking and show that the endogenous gamma rhythm has cell-type- and layer-specific effects on downstream target areas. Similar findings were made in the mouse visual system, based on opto-tagging of identified interneurons.

A Morphologically Distinct Subclass of Somatostatin-expressing Interneurons in the Somatosensory Cortex are Strongly Recruited by Input from the Motor Cortex

The motor cortex (M1) and somatosensory cortex (S1) are strongly interconnected regions, and their interactions are essential for sensory perception and motor execution. However, the mechanisms by which M1 activity modulates sensory processing within S1 are poorly understood. In particular, M1 recruitment of distinct GABAergic inhibitory cells could impact S1 responsiveness. Preliminary work in our lab identified a subpopulation of somatostatin (SOM) expressing inhibitory interneurons in layer 6 (L6) of S1 that are strongly recruited by M1 input. We hypothesize these M1-responding L6 SOM cells are an electrophysiological and morphologically distinct subclass that express the enzyme neuronal nitric oxide synthase (nNOS). To stimulate the M1 to S1 pathway and test this hypothesis, we injected adeno-associated virus (AAV) encoding the light-sensitive cation channel, channelrhodopsin-2 (ChR2), in M1 of postnatal day 21 (+/-1) mice in vivo. After three weeks of expression, we prepared acute coronal brain slices for targeted loose-patch recordings and selective optical stimulation of M1 terminals. We found two groups of L6 SOM cells based on their spiking behavior during photostimulation: responsive (15%) and non-responsive (85%). Whole-cell recordings and neurobiotin injections into responsive and non-responsive SOM cells revealed robust electrophysiological and morphological differences. Initial anatomical reconstructions indicate that the non-responsive SOM cells (n=12) exhibit both Martinotti (with an L1 axonal projection) and non-Martinotti (no L1 axonal projection) morphologies, whereas the responsive SOM cells had axonal arborizations projecting toward the underlying white matter (n=10). The responsive SOM cells had quasi-fast-spiking electrophysiological properties (n=10) and were negative for nNOS (n=9), whereas the non-responsive SOM cells exhibited non-adaptive spiking behavior. Importantly, responsive SOM cells were negative for parvalbumin (PV), a marker for a distinct class of fast-spiking interneurons in the cortex, indicating these cells were not mislabeled PV cells due to the known off-target recombination in the SOM-IRES-Cre mouse line (n=4). In summary, our data show that input from M1 strongly recruits a previously unknown SOM-expressing interneuron in lower L6 with distinct morphological and electrophysiological features that could influence sensory responsiveness in S1. Future studies will focus on the mechanisms of this selective activation and identifying the postsynaptic targets of these cells to further our understanding of this sensorimotor circuit. NIH R01NS117636 (SRC); APS SURF (MKS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Two inhibitory neuronal classes govern acquisition and recall of spinal sensorimotor adaptation.

Spinal circuits are central to movement adaptation, yet the mechanisms within the spinal cord responsible for acquiring and retaining behavior upon experience remain unclear. Using a simple conditioning paradigm, we found that dorsal inhibitory neurons are indispensable for adapting protective limb-withdrawal behavior by regulating the transmission of a specific set of somatosensory information to enhance the saliency of conditioning cues associated with limb position. By contrast, maintaining previously acquired motor adaptation required the ventral inhibitory Renshaw cells. Manipulating Renshaw cells does not affect the adaptation itself but flexibly alters the expression of adaptive behavior. These findings identify a circuit basis involving two distinct populations of spinal inhibitory neurons, which enables lasting sensorimotor adaptation independently from the brain.