Excitation-inhibition imbalance in medial preoptic area circuits underlies chronic stress-induced depression-like states.

Dysregulation of brain homeostasis is associated with neuropsychiatric conditions such as major depressive disorder. However, underlying neural-circuit mechanisms remain not well-understood. We show in mice that chronic restraint stress (CRS) and social defeat stress (SDS) are both associated with disruption of excitation (E)-inhibition (I) balance, with increased E/I ratios, in medial preoptic area (MPOA) circuits, but through affecting different neuronal types. CRS results in elevated activity in glutamatergic neurons, and their suppression mitigates CRS-induced depressive-like behaviors. Paraventricular hypothalamic input to these neurons contributes to induction but not expression of depressive-like behaviors. Their projections to ventral tegmental area and periaqueductal gray/dorsal raphe suppress midbrain dopaminergic and serotonergic activity, respectively, and mediate expression of divergent depressive-like symptoms. By contrast, SDS results in reduced activity of GABAergic neurons, and their activation alleviates SDS-induced depressive-like behaviors. Thus, E/I imbalance with relatively increased excitation in MPOA circuits may be a general mechanism underlying depression caused by different etiological factors.

Efficient method for modeling large-scale arrays of optical nanoresonators based on the coupling theory of quasinormal mode.

We propose an efficient method for calculating the electromagnetic field of a large-scale array of optical nanoresonators based on the coupling theory of quasinormal mode (QNM). In this method, two approaches of the scattered-field reconstruction and stationary-phase-principle calculated plane-wave expansion are developed to obtain the regularized QNM (RQNM) in different regions. This accurate and efficient calculation of RQNM resolves the far-field divergence issue of QNMs in the QNM-coupling theory, thus enabling a rapid computation of the electromagnetic field of a large-scale array of optical nanoresonators, which is a challenging task for full-wave numerical methods. Using this method, we consider the numerical example of the radiation problem of a single point source in a large-scale periodic array of optical nanoantennas. In comparison to full-wave numerical methods, this method significantly reduces the computation time by 1∼2 orders of magnitude while maintaining accuracy. The high computational efficiency and physical intuitiveness of the method enables to clarify the impact of array size (exceeding 50 × 50 wavelengths), period and field-coupling range (far beyond the tight-binding approximation) on the optical response. The proposed method and results can provide an efficient tool and guidance for the design of large-scale arrays of optical nanoresonators.

The medial preoptic area mediates depressive-like behaviors induced by ovarian hormone withdrawal through distinct GABAergic projections.

Fluctuations in reproductive hormone levels are associated with mood disruptions in women, such as in postpartum and perimenopausal depression. However, the neural circuit mechanisms remain unclear. Here we report that medial preoptic area (MPOA) GABAergic neurons mediate multifaceted depressive-like behaviors in female mice after ovarian hormone withdrawal (HW), which can be attributed to downregulation of activity in Esr1 (estrogen receptor-1)-expressing GABAergic neurons. Enhancing activity of these neurons ameliorates depressive-like behaviors in HW-treated mice, whereas reducing their activity results in expression of these behaviors. Two separate subpopulations mediate different symptoms: a subpopulation projecting to the ventral tegmental area (VTA) mediates anhedonia and another projecting to the periaqueductal gray mediates immobility. These projections enhance activity of dopaminergic neurons in the VTA and serotonergic neurons in the dorsal raphe, respectively, with increased release of dopamine and serotonin, possibly through disinhibition mechanisms. Thus, the MPOA is a hub that mediates depressive-like behaviors resulting from transitions in reproductive hormone levels.

Glutamatergic and GABAergic neurons in pontine central gray mediate opposing valence-specific behaviors through a global network.

Extracting the valence of environmental cues is critical for animals' survival. How valence in sensory signals is encoded and transformed to produce distinct behavioral responses remains not well understood. Here, we report that the mouse pontine central gray (PCG) contributes to encoding both negative and positive valences. PCG glutamatergic neurons were activated selectively by aversive, but not reward, stimuli, whereas its GABAergic neurons were preferentially activated by reward signals. The optogenetic activation of these two populations resulted in avoidance and preference behavior, respectively, and was sufficient to induce conditioned place aversion/preference. Suppression of them reduced sensory-induced aversive and appetitive behaviors, respectively. These two functionally opponent populations, receiving a broad range of inputs from overlapping yet distinct sources, broadcast valence-specific information to a distributed brain network with distinguishable downstream effectors. Thus, PCG serves as a critical hub to process positive and negative valences of incoming sensory signals and drive valence-specific behaviors with distinct circuits.

Quasinormal Mode Expansion Theory for Mesoscale Plasmonic Nanoresonators: An Analytical Treatment of Nonclassical Electromagnetic Boundary Condition.

Nonclassical quantum effects will significantly affect the optical response of plasmonic nanoresonators with mesoscale feature sizes between about 2 and 20 nm, and can be fully described by the nonclassical electromagnetic boundary condition (NEBC) expressed with the surface-response Feibelman d parameters. In this Letter, a quasinormal mode (QNM) expansion theory under the NEBC is proposed. By adopting the easily solved classical QNMs under the classical electromagnetic boundary condition as a complete set of basis functions, rigorous expansions of the nonclassical source-free QNMs and source-excited electromagnetic field under the nonperturbative NEBC are provided. With the obtained nonclassical QNMs as basis functions, expansions of the nonclassical source-excited field and Green's function tensor are further obtained. These expansions have a fully analytical dependence on the NEBC and classical QNMs, thus transparently unveiling their impact on the nonclassical QNMs and source-excited electromagnetic field. For instance, a new expression of mode volume is proposed for analyzing the nonclassically corrected Purcell factor. The proposed theory is physically intuitive and computationally efficient which is enabled by the dominance of a small set of classical QNMs, thus providing an efficient tool for understanding and designing mesoscale plasmonic nanoresonators.

Chimeric antigen receptor T cells applied to solid tumors.

Chimeric antigen receptor T cell (CAR-T) therapy is novel tumor immunotherapy that enables autologous T to express synthetic receptors to specifically recognize the surface tumor-associated antigens for exerting subsequent antitumor effects, and eliminating the resistance, metastases and recurrence of cancer. Although CAR T cells have exhibited success in eradicating hematologic malignancies, their applications to solid tumors has not yet been achieved due to obstacles such as the immune-suppressor tumor microenvironment and lack of tumor specific target antigens. In this review, we presented advancements in the development of CAR T cell therapy in solid tumors, and offered a brief summary of the challenges, as well as novel engineering and pharmaceutical interventions to overcome these barriers. Looking forward, we discussed the latest studies which are expected to reach the clinicals in the next few years, including CRISPR screens-based CAR modification and CAR T cells driven from progenitor-like T cells. Collectively, this review may inspire researchers and clinicians to develop clinical available strategies of CAR T cell therapies in solid tumor.

A bottom-up reward pathway mediated by somatostatin neurons in the medial septum complex underlying appetitive learning.

Valence detection and processing are essential for the survival of animals and their life quality in complex environments. Neural circuits underlying the transformation of external sensory signals into positive valence coding to generate appropriate behavioral responses remain not well-studied. Here, we report that somatostatin (SOM) subtype of GABAergic neurons in the mouse medial septum complex (MS), but not parvalbumin subtype or glutamatergic neurons, specifically encode reward signals and positive valence. Through an ascending pathway from the nucleus of solitary tract and then parabrachial nucleus, the MS SOM neurons receive rewarding taste signals and suppress the lateral habenula. They contribute essentially to appetitive associative learning via their projections to the lateral habenula: learning enhances their responses to reward-predictive sensory cues, and suppressing their responses to either conditioned or unconditioned stimulus impairs acquisition of reward learning. Thus, MS serves as a critical hub for transforming bottom-up sensory signals to mediate appetitive behaviors.

Transcriptomics and transmission ultrastructural examination reveals the nephrotoxicity of cadmium in laying hens.

The objective of this study was to reveal the effects of cadmium (Cd) on ultrastructural changes, oxidative stress, and transcriptome expression in the kidneys of laying hens. Seventy-two healthy Hy-Line brown laying hens at 41 weeks old were randomly allocated to four treatment groups with six replicates. The control group received a basal diet without additional Cd incorporation, and the other three treatment groups received diets supplemented with 15, 30, or 60 mg Cd /kg of feed. After 6 weeks of exposure, the results show that administration of 60 mg/kg Cd significantly reduced (P < 0.05) eggshell thickness. With an increase in the Cd concentration in feed, the concentrations of renal Zn and Fe also had changed. Renal histopathology and ultrastructure also showed aggravated damage to glomeruli and renal tubules and the deformation of nuclei and mitochondria in all Cd treatment groups. With an increase in Cd in feed, the activity of glutathione peroxide (GPX) and catalase (CAT) was significantly reduced (P < 0.05), while the activity of total antioxidant capacity (T -AOC) was decreased (P < 0.05) only in the 60 mg/kg Cd group. RNA-seq analysis revealed that 410 genes displayed differential expression (≥ 1.5-fold) in the 60 mg/kg supplementation group, compared to the control group. GO and KEGG pathway analysis results showed that Cd affected many genes involved in mitochondria and ion transport. In conclusion, this study elaborates the mechanisms underlying renal toxicity caused by Cd, which might provide target candidate genes for alleviating Cd poisoning in laying hens.

Inhibition of Aß peptide aggregation by ruthenium(II) polypyridyl complexes through copper chelation.

Alzheimer's disease (AD) is known as a complex multifactorial syndrome and both metal chelators and amyloid ß peptide (Aß) inhibitors show promise against AD. Herein, four small hybrid compounds have been designed and synthesized utilizing 8-hydroxyquinoline, pyridine or imidazole as chelators and benzimidazole as the recognition moiety for AD treatment. These conjugates can capture Cu2+ from Aß and become dimers upon Cu2+ coordination and show high efficiency for both Cu2+ elimination and Aß assembly inhibition. Besides, these designed complexes can inhibit the production of Aß-induced reactive oxygen species (ROS), protect mitochondria from damage, and improve the survival rate of neuron cells. Our work provides a new strategy to combine hydrophobic interaction and metal ion chelation to design amyloid inhibitors.

Efficient method for the calculation of the optical force of a single nanoparticle based on the quasinormal mode expansion.

An efficient method for the calculation of the optical force of a single nanoparticle is proposed based on the expansion of quasinormal modes (QNMs), which are eigensolutions of source-free Maxwell's equations with complex eigenfrequencies. In this method, the optical force is calculated by integrating the Maxwell stress tensor (MST) over a closed surface encompassing the nanoparticle. The electromagnetic (EM) field required for evaluating the MST is computed by a rigorous modal analysis, in which the EM field is expanded onto a small set of QNMs. Once the QNMs of the nanoparticle are solved, their excitation coefficients are obtained analytically. This means that additional full-wave computations are not required if the nanoparticle's location and the wavelength or distribution of the excitation field vary. Comparisons with full-wave numerical calculations of optical force evidence the high efficiency and accuracy of our formalism.

Mitochondria-targeted cyclometalated rhodium(III) complexes: synthesis, characterization and anticancer research.

Over the past few decades, the landscape of inorganic medicinal chemistry has been dominated by investigations on platinum or ruthenium, while the research based on other metal centers such as rhodium has been relatively insufficient. In this work, a series of cyclometalated rhodium(iii) complexes with imidazo[4,5-f][1,10]phenanthroline containing different aromatic rings were synthesized and characterized. Notably, all the complexes displayed stronger anticancer activity against various cancer cells compared with cisplatin. A mechanism study revealed that the rhodium complexes accumulated in the mitochondria, elevated the levels of mitochondrial reactive oxygen species (ROS) and released cytochrome c, indicating severe mitochondrial damage during the anticancer activity. Further studies illustrated that the rhodium complexes caused cell cycle arrest at the G2/M phase, upregulated the expression of p53 and reduced the ratio of B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated x (Bax), which ultimately resulted in cellular apoptosis. Overall, through mitochondrial pathways, these Rh(iii) complexes could induce cellular apoptosis to a larger extent than cisplatin and should be paid close attention as promising chemotherapeutic drugs in anticancer research.

Mitochondrial targeted rhodium(III) complexes: Synthesis, characterized and antitumor mechanism investigation.

Recently, rhodium complexes have received intensive attentions due to their tunable chemical and biological properties as well as attractive antitumor activity. In this work, two imidazole triphenylamino rhodium complexes [Rh(ppy)2L1]PF6 (Rh1) and [Rh(ppy)2L2]PF6 (Rh2) (ppy = 2-phenylpyridine, L1 = 4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-N,N-diphenylaniline, L2 = N-(4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenyl)-4-methyl-N-(p-tolyl)aniline) have been synthesized and characterized. Both complexes display stronger anticancer activity against a various of cancer cells than cisplatin and they can effectively localize to mitochondria. Further mechanism studies show that Rh1 induce caspase-dependent apoptosis through mitochondrial damage, down-regulate the expression of B-cell lymphoma-2 (Bcl-2)/Bcl2-associated x (Bax) and reactive oxygen species (ROS) elevation. Our work provides a strategy for the construction of highly effective anticancer agents targeting mitochondrial metabolism through rational modification of rhodium complexes.

Medial preoptic area antagonistically mediates stress-induced anxiety and parental behavior.

Anxiety is a negative emotional state that is overly displayed in anxiety disorders and depression. Although anxiety is known to be controlled by distributed brain networks, key components for its initiation, maintenance and coordination with behavioral state remain poorly understood. Here, we report that anxiogenic stressors elicit acute and prolonged responses in glutamatergic neurons of the mouse medial preoptic area (mPOA). These neurons encode extremely negative valence and mediate the induction and expression of anxiety-like behaviors. Conversely, mPOA GABA-containing neurons encode positive valence and produce anxiolytic effects. Such opposing roles are mediated by competing local interactions and long-range projections of neurons to the periaqueductal gray. The two neuronal populations antagonistically regulate anxiety-like and parental behaviors: anxiety is reduced, while parenting is enhanced and vice versa. Thus, by evaluating negative and positive valences through distinct but interacting circuits, the mPOA coordinates emotional state and social behavior.

Effects of dietary cadmium supplementation on production performance, cadmium residue in eggs, and hepatic damage in laying hens.

This study was conducted to investigate the adverse effects of cadmium (Cd) on the production performance, serum biochemistry, liver antioxidant status, histopathology, and egg residue in laying hens. A total of 72 healthy Hy-Line brown laying hens at 40-week-old were randomly assigned to four diets containing 0 (control diet), 15, 30, or 60 mg/kg Cd for 6 weeks. Laying hens exposed to 60 mg/kg Cd had lower egg production rate and worse feed to egg ratio (P < 0.05). Dietary Cd exposure (≥ 15 mg/kg) significantly decreased hepatic glutathione peroxide (GPX) activities, while increasing malondialdehyde (MDA) (P < 0.05). Hepatic histopathology and ultrastructure also showed damage and the symptoms were exacerbated in a dose-dependent manner. The residue of Cd in the yolk was increased with increasing dietary Cd concentration. The mRNA expression levels of mt4L, mt3, sod1, sod2, gpx1, gpx3, and gpx4 in the liver of laying hens exposed to 60 mg Cd/kg feed were significantly decreased (P < 0.05). In conclusion, dietary Cd exposure at ≥ 15 mg/kg induced hepatic damage in laying hens, indicating that the content of Cd in feed must be critically controlled.

Heavy Metal Content in Feedstuffs and Feeds in Hubei Province, China.

ABSTRACT: Heavy metal pollution threatens the health and life of animals and humans through the food chain. This study was performed to survey the heavy metal contamination in feedstuffs and feeds in Hubei Province, People's Republic of China, from 2012 to 2016. Samples were analyzed for cadmium (306 samples), mercury (117 samples), chromium (149 samples), and arsenic (4,358 samples) using atomic absorption spectrometry or atomic fluorescence spectrometry. The incidence rates of cadmium, mercury, chromium, and arsenic contamination of feedstuffs and feeds were high, and feeds were most often contaminated with chromium, followed by arsenic, cadmium, and mercury. The concentrations of heavy metals in samples positive for cadmium, mercury, chromium, and arsenic ranged from 0.001 to 1.200, 0.002 to 6.540, 0.060 to 8737.000, and 0.070 to 33.000 mg/kg, respectively. The mineral and additive samples had higher concentrations of heavy metals. The present study findings highlight the importance of monitoring heavy metals in feedstuffs and feeds and implementing feed management and bioremediation strategies to reduce heavy metal exposure.

Excitatory effects of the primary auditory cortex on the sound-evoked responses in the ipsilateral anterior auditory field in rat.

In the neocortex, interaction and cooperation between different areas are important for information processing, which also applies to different areas within one sensory modality. In the temporal cortex of rodents and cats, both the primary auditory cortex (A1) and the anterior auditory field (AAF) have tonotopicity but with a mirrored frequency gradient. However, whether and how A1 modulates the responses in AAF is largely unknown. Here, we functionally identified the locations of A1 and AAF in rats and used an optogenetic approach to manipulate the activity of A1 in vivo. We found that activation of A1 axon terminals in AAF did not change AAF responses, but activating A1 neuronal cell bodies could increase the sound-evoked responses in AAF, as well as decrease the intensity threshold and broaden the frequency bandwidth, while suppressing A1 could cause the opposite effects. Our results suggested that A1 could modulate the general excitability of AAF through indirect pathways, which provides a potential relationship between these two parallel auditory ascending pathways.

Diversity in Excitation-Inhibition Mismatch Underlies Local Functional Heterogeneity in the Rat Auditory Cortex.

Cortical neurons are heterogeneous in their functional properties. This heterogeneity is fundamental for the processing of different features of sensory information. However, functional diversity within a local group of neurons is poorly understood. Here, we demonstrate that neighboring cortical neurons in layer 5 but not those of layer 4 of the rat anterior auditory field (AAF) exhibited a surprisingly high level of diversity in tonal receptive fields. In vivo whole-cell voltage-clamp recordings revealed that the diversity of frequency representation was due to a spectral mismatch between synaptic excitation and inhibition to varying degrees. The spectral distribution of excitation was skewed at different levels, whereas inhibition was homogeneous and non-skewed, similar to the summed spiking activity of local neuronal ensembles, which further enhanced diversity. Our results indicate that AAF in the auditory cortex is involved in processing auditory information in a highly refined manner that is important for complex pattern recognition.

Bidirectional Shifting Effects of the Sound Intensity on the Best Frequency in the Rat Auditory Cortex.

Frequency and intensity are two independent attributes of sound stimuli. Psychoacoustic studies have found that the sound intensity can affect the perception of frequency; however, the underlying neuronal mechanism remains largely unknown. To investigate if and how the sound level affects the frequency coding for auditory cortical neurons, we recorded the activities of neuronal ensembles and single neurons, as well as the synaptic input evoked by pure tones of different frequency and intensity combinations, in layer 4 of the rat primary auditory cortex. We found that the best frequency (BF) shifted bidirectionally with the increases in intensity. Specifically, the BF of neurons with a low characteristic frequency (CF) shifted lower, whereas the BF of neurons with a higher CF shifted higher. Meanwhile, we found that these shifts in the BF can lead to the expansion of high- and low-frequency areas in the tonotopic map, increasing the evenness of the BF distribution at high intensities. Our results revealed that the frequency tuning can bidirectionally shift with an increase in the sound intensity at both the cellular and population level. This finding is consistent with the perceptual illusions observed in humans and could provide a potential mechanism for this psychoacoustic effect.

Unbalanced synaptic inputs underlying multi-peaked frequency selectivity in rat auditory cortex.

By measuring the frequency selectivity at different intensities in the primary auditory cortex of adult rats, we found that a small group of cortical neurons can exhibit relatively weak but robust selectivity at multiple frequencies that are different from the most preferred frequency. Both in vivo multi-unit recordings (26/93 recordings) and single-unit recordings (16/137 neurons) confirmed that the preferred frequencies are periodic and have an averaged bandwidth (BW) of 0.3-0.4 octaves, which leads to multi-peaked frequency selectivity. Interestingly, the averaged bandwidth of the ripple in the frequency response tuning curve was invariant with the sound intensity. An investigation of the synaptic currents in vivo also revealed similar multi-peaked frequency selectivity for both excitation and inhibition. While the excitatory and inhibitory inputs were relatively balanced for most frequencies, the ratio between excitation and inhibition at the peak and valley of each ripple was highly unbalanced. Since this multi-peaked frequency selectivity can be observed at the synaptic, single-cell, and population levels, our results reveal a potential mechanism underlying the multi-peaked pattern of frequency selectivity in the primary auditory cortex.