Direct Anatomical Connections Research Articles

The superior colliculus motor region does not respond to finger tapping movements in humans

Electrophysiological studies in macaques and functional neuroimaging in humans revealed a motor region in the superior colliculus (SC) for upper limb reaching movements. Connectivity studies in macaques reported direct connections between this SC motor region and cortical premotor arm, hand, and finger regions. These findings motivated us to investigate if the human SC is also involved in sequential finger tapping movements. We analyzed fMRI task data of 130 subjects executing finger tapping from the Human Connectome Project. While we found strong signals in the SC for visual cues, we found no signals related to simple finger tapping. In subsequent experimental measurements, we searched for responses in the SC corresponding to complex above simple finger tapping sequences. We observed expected signal increases in cortical motor and premotor regions for complex compared to simple finger tapping, but no signal increases in the motor region of the SC. Despite evidence for direct anatomical connections of the SC motor region and cortical premotor hand and finger areas in macaques, our results suggest that the SC is not involved in simple or complex finger tapping in humans.

Neuroinflammation in Alzheimer's Disease: A Potential Role of Nose-Picking in Pathogen Entry via the Olfactory System?

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and memory impairment. Many possible factors might contribute to the development of AD, including amyloid peptide and tau deposition, but more recent evidence suggests that neuroinflammation may also play an-at least partial-role in its pathogenesis. In recent years, emerging research has explored the possible involvement of external, invading pathogens in starting or accelerating the neuroinflammatory processes in AD. In this narrative review, we advance the hypothesis that neuroinflammation in AD might be partially caused by viral, bacterial, and fungal pathogens entering the brain through the nose and the olfactory system. The olfactory system represents a plausible route for pathogen entry, given its direct anatomical connection to the brain and its involvement in the early stages of AD. We discuss the potential mechanisms through which pathogens may exploit the olfactory pathway to initiate neuroinflammation, one of them being accidental exposure of the olfactory mucosa to hands contaminated with soil and feces when picking one's nose.

Communication of gut microbiota and brain via immune and neuroendocrine signaling.

The gastrointestinal tract of the human is inhabited by about 5 × 1013 bacteria (of about 1,000 species) as well as archaea, fungi, and viruses. Gut microbiota is known to influence the host organism, but the host may also affect the functioning of the microbiota. This bidirectional cooperation occurs in three main inter-organ signaling: immune, neural, and endocrine. Immune communication relies mostly on the cytokines released by the immune cells into circulation. Also, pathogen-associated or damage-associated molecular patterns (PAMPs or DAMPs) may enter circulation and affect the functioning of the internal organs and gut microbiota. Neural communication relies mostly on the direct anatomical connections made by the vagus nerve, or indirect connections via the enteric nervous system. The third pathway, endocrine communication, is the broadest one and includes the hypothalamic-pituitary-adrenal axis. This review focuses on presenting the latest data on the role of the gut microbiota in inter-organ communication with particular emphasis on the role of neurotransmitters (catecholamines, serotonin, gamma-aminobutyric acid), intestinal peptides (cholecystokinin, peptide YY, and glucagon-like peptide 1), and bacterial metabolites (short-chain fatty acids).

Frontopolar cortex shapes brain network structure across prefrontal and posterior cingulate cortex.

Primate frontopolar cortex (FPC), occupied by area 10, sits atop a functional hierarchy of prefrontal cortical regions, yet little is known about its involvement in wider cortical networks. Here we examined resting-state-functional-connectivity (rsfc) in rhesus monkeys with intact or lesioned FPC to identify cortical regions associated with FPC. We present a network of FPC-specific regions of interest (ROIs), whose connectivity was affected by lesion of FPC but not by lesion of neighbouring prefrontal cortex (principal sulcus). This network comprised 'core ROIs' with direct anatomical connections to FPC, located in ventrolateral prefrontal cortex, posterior cingulate cortex, and superior temporal gyrus, and 'peripheral ROIs' well connected to the core network. We further show that the principle effect of a lesion to FPC was to cause a profound disturbance of the functional connectivity of posterior cingulate and ventrolateral prefrontal cortex. We therefore suggest that FPC, posterior cingulate and ventrolateral prefrontal cortex comprise a network of interacting cortical areas whose interactions may be critical for mediating the contribution of FPC to decision making.

Amygdala and hippocampus dialogue with neocortex during human sleep and wakefulness.

Previous studies have described synchronic electroencephalographic (EEG) patterns of the background activity that is characteristic of several vigilance states. To explore whether the background synchronous activity of the amygdala-hippocampal-neocortical circuit is modified during sleep in the delta, theta, alpha, sigma, beta, and gamma bands characteristic of each sleep state. By simultaneously recording intracranial and noninvasive scalp EEG (10-20 system) in epileptic patients who were candidates for neurosurgery, we explored synchronous activity among the amygdala, hippocampus, and neocortex during wakefulness (W), Non-Rapid Eye Movement (NREM), and Rapid-Eye Movement (REM) sleep. Our findings reveal that hippocampal-cortical synchrony in the sleep spindle frequencies was spread across the cortex and was higher during NREM versus W and REM, whereas the amygdala showed punctual higher synchronization with the temporal lobe. Contrary to expectations, delta synchrony between the amygdala and frontal lobe and between the hippocampus and temporal lobe was higher during REM than NREM. Gamma and alpha showed higher synchrony between limbic structures and the neocortex during wakefulness versus sleep, while synchrony among deep structures showed a mixed pattern. On the one hand, amygdala-hippocampal synchrony resembled cortical activity (i.e. higher gamma and alpha synchrony in W); on the other, it showed its own pattern in slow frequency oscillations. This is the first study to depict diverse patterns of synchronic interaction among the frequency bands during distinct vigilance states in a broad human brain circuit with direct anatomical and functional connections that play a crucial role in emotional processes and memory.

Biocompatibility of ZrO2 vs. Y-TZP Alloys: Influence of Their Composition and Surface Topography.

The osseointegration of implants is defined as the direct anatomical and functional connection between neoformed living bone and the surface of a supporting implant. The biological compatibility of implants depends on various parameters, such as the nature of the material, chemical composition, surface topography, chemistry and loading, surface treatment, and physical and mechanical properties. In this context, the objective of this study is to evaluate the biocompatibility of rough (Ra = 1 µm) and smooth (Ra = 0 µm) surface conditions of yttria–zirconia (Y-TZP) discs compared to pure zirconia (ZrO2) discs by combining a classical toxicological test, morphological observations by SEM, and a transcriptomic analysis on an in vitro model of human Saos-2 bone cells. Similar cell proliferation rates were observed between ZrO2 and Y-TZP discs and control cells, regardless of the surface topography, at up to 96 h of exposure. Dense cell matting was similarly observed on the surfaces of both materials. Interestingly, only 110 transcripts were differentially expressed across the human transcriptome, consistent with the excellent biocompatibility of Y-TZP reported in the literature. These deregulated transcripts are mainly involved in two pathways, the first being related to “mineral uptake” and the second being the “immune response”. These observations suggest that Y-TZP is an interesting candidate for application in implantology.

A Multimodal Multilevel Neuroimaging Model for Investigating Brain Connectome Development

Recent advancements of multimodal neuroimaging such as functional MRI (fMRI) and diffusion MRI (dMRI) offers unprecedented opportunities to understand brain development. Most existing neurodevelopmental studies focus on using a single imaging modality to study microstructure or neural activations in localized brain regions. The developmental changes of brain network architecture in childhood and adolescence are not well understood. Our study made use of dMRI and resting-state fMRI imaging data sets from Philadelphia Neurodevelopmental Cohort (PNC) study to characterize developmental changes in both structural as well as functional brain connectomes. A multimodal multilevel model (MMM) is developed and implemented in PNC study to investigate brain maturation in both white matter structural connection and intrinsic functional connection. MMM addresses several major challenges in multimodal connectivity analysis. First, by using a first-level data generative model for observed measures and a second-level latent network modeling, MMM effectively infers underlying connection states from noisy imaging-based connectivity measurements. Second, MMM models the interplay between the structural and functional connections to capture the relationship between different brain connectomes. Third, MMM incorporates covariate effects in the network modeling to investigate network heterogeneity across subpopoulations. Finally, by using a module-wise parameterization based on brain network topology, MMM is scalable to whole-brain connectomics. MMM analysis of the PNC study generates new insights in neurodevelopment during adolescence including revealing the majority of the white fiber connectivity growth are related to the cognitive networks where the most significant increase is found between the default mode and the executive control network with a 15% increase in the probability of structural connections. We also uncover functional connectome development mainly derived from global functional integration rather than direct anatomical connections. To the best of our knowledge, these findings have not been reported in the literature using multimodal connectomics. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.

The role of the pre-commissural fornix in episodic autobiographical memory and simulation

Neuropsychological and functional magnetic resonance imaging evidence suggests that the ability to vividly remember our personal past, and imagine future scenarios, involves two closely connected regions: the hippocampus and ventromedial prefrontal cortex (vmPFC). Despite evidence of a direct anatomical connection from hippocampus to vmPFC, it is unknown whether hippocampal-vmPFC structural connectivity supports both past- and future-oriented episodic thinking. To address this, we applied a novel deterministic tractography protocol to diffusion-weighted magnetic resonance imaging (dMRI) data from a group of healthy young adult humans who undertook an adapted past-future autobiographical interview (portions of this data were published in Hodgetts et al., 2017a). This tractography protocol enabled distinct subdivisions of the fornix, detected previously in axonal tracer studies, to be reconstructed in vivo, namely the pre-commissural (connecting the hippocampus to vmPFC) and post-commissural (linking the hippocampus and medial diencephalon) fornix. As predicted, we found that inter-individual differences in pre-commissural - but not post-commissural - fornix microstructure (fractional anisotropy) were significantly correlated with the episodic richness of both past and future autobiographical narratives. Notably, these results held when controlling for non-episodic narrative content, verbal fluency, and grey matter volumes of the hippocampus and vmPFC. This study provides novel evidence that reconstructing events from one's personal past, and constructing possible future events, involves a distinct, structurally-instantiated hippocampal-vmPFC pathway.

The Connectome Predicts Resting State Functional Connectivity Across the Drosophila Brain

Connectomic datasets have emerged as invaluable tools for understanding neural circuits in many systems. What constraints does the connectome place on information processing and routing in a large scale neural circuit? For mesoscale brain networks, the relationship between cell and synaptic level connectivity and brain function is not well understood. Here, we use data from the Drosophila connectome in conjunction with whole-brain \textit{in vivo} imaging to relate structural and functional connectivity in the central brain. We find that functional connectivity is strongly associated with the strength of both direct and indirect anatomical pathways. We also show that some brain regions, including the mushroom body and central complex, show considerably higher functional connectivity to other brain regions than is predicted based on their direct anatomical connections. We find several key topological similarities between mesoscale brain networks in flies and mammals, revealing conserved principles relating brain structure and function.

Transnasal Delivery of the Peptide Agonist Specific to Neuromedin-U Receptor 2 to the Brain for the Treatment of Obesity.

Obesity and metabolic syndrome are threats to the health of large population worldwide as they are associated with high mortality, mainly linked to cardiovascular diseases. Recently, CPN-116 (CPN), which is an agonist peptide specific to neuromedin-U receptor 2 (NMUR2) that is expressed predominantly in the brain, has been developed as a new therapeutic candidate for the treatment of obesity and metabolic syndrome. However, treatment with CPN poses a challenge due to the limited delivery of CPN to the brain. Recent studies have clarified that the direct anatomical connection of the nasal cavity with brain allows delivery of several drugs to the brain. In this study, we confirm the nasal cavity as a promising CPN delivery route to the brain for the treatment of obesity and metabolic syndrome. According to the pharmacokinetic study, the clearance of CPN from the blood was very rapid with a half-life of 3 min. In vitro study on its stability in the serum and cerebrospinal fluid (CSF) indicates that CPN was more stable in the CSF than in the blood. The concentration of CPN in the brain was higher after nasal administration, despite its lower concentrations in the plasma than that after intravenous administration. The study on its pharmacological potency suggests the effective suppression of increased body weight in mice in a dose-dependent manner due to the direct activation of NMUR2 by CPN. This results from the higher concentration of corticosterone in blood after nasal administration of CPN as compared to nasal application of saline. In conclusion, the above findings indicate that the nasal cavity is a promising CPN delivery route to the brain to treat obesity and metabolic syndrome.

Selective Functional Interaction Between the Lateral Habenula and Hippocampus During Different Tests of Response Flexibility

The lateral habenula (LHb) has been shown to play critical roles in a variety of appetitive tasks (e.g., spatial memory and object recognition) that require animals to flexibly respond to changing task conditions. These types of tasks are known to be dependent on hippocampus (HPC) and/or medial prefrontal cortex (mPFC), suggesting that the LHb contributes to the limbic memory circuit. Here we provide new evidence that the LHb and HPC play distinct but complimentary roles in tasks that require flexible responding to changing task conditions. Experiment 1 tested whether the LHb is needed for the performance of a HPC-dependent maze-based spatial delayed alternation task. The importance of interactions between the LHb and HPC to accomplish the same spatial delayed alternation task was tested in Experiment 2 where the LHb and HPC were disconnected both ipsilaterally and contralaterally. Experiment 3 tested LHb’s involvement in a standard behavioral economic task that requires flexible responding (maze-based delayed discounting), a task previously shown to rely on HPC. Results of Experiment 1, revealed that LHb inactivation impairs spatial delayed alternation during asymptotic performance but not during initial learning. Importantly, working memory did not appear to be affected as performance remained above chance levels both during initial learning and asymptotic testing. Experiment 2 showed that ipsilateral and contralateral disconnection of the LHb and HPC led to impaired performance on the spatial delayed alternation task. Impairments were not observed after unilateral inactivation of only one structure. Results of Experiment 3 were similar to our previous report of the effects of HPC inactivation: LHb inactivation impaired delayed discounting. All effects could not be accounted for by changes in reward magnitude discrimination, reward location per se, or sex of the animal. These findings, combined with other recent publications confirms and extends our working hypothesis that the LHb enables adaptive and flexible responding, particularly when established rules must be flexibly applied on a trial by trial basis. Since there are no known direct anatomical connections between LHb and HPC, future research is needed to understand how these structures communicate to enable flexible and rapid responding.

Anatomical connections underlying personally-familiar face processing.

Familiar face processing involves face specific regions (the core face system) as well as other non-specific areas related to processing of person-related information (the extended face system). The connections between core and extended face system areas must be critical for face recognition. Some studies have explored the connectivity pattern of unfamiliar face responding area, but none have explored those areas related to face familiarity processing in the extended system. To study these connections, diffusion weighted imaging with probabilistic tractography was used to estimate the white-matter pathways between core and extended system regions, which were defined from functional magnetic resonance imaging responses to personally-familiar faces. Strong white matter connections were found between occipitotemporal face areas (OFA/FFA) with superior temporal sulcus and insula suggesting the possible existence of direct anatomical connections from face-specific areas to frontal nodes that could underlay the processing of emotional information associated to familiar faces.

Disruption of splenic nerve‐to‐spleen neurotransmission worsens disease outcome in a murine model of systemic lupus erythematosus

Aberrant chronic inflammation can usually be counteracted by endogenous mechanisms; however, such mechanisms may be impaired in the development of hypertension and renal injury. These anti‐inflammatory pathways involve the autonomic nervous system but it is unclear which branch is primarily responsible for quelling inflammation in chronic inflammatory conditions. The cholinergic anti‐inflammatory pathway is a compensatory mechanism thought to include a direct anatomical connection between the parasympathetic vagus and the sympathetic splenic nerve. Although this route of neurotransmission is controversial, we have evidence that stimulation of both of these nerves individually results in a decrease in the production and release of pro‐inflammatory cytokines from splenic immune cells. Our preliminary findings also indicate that chemical splenic denervation may disrupt anti‐inflammatory mechanisms, suggesting an important sympathetic component. In order to confirm this we removed the spleen from mice with systemic lupus erythematosus (SLE), a model of chronic inflammation, hypertension and renal injury, and hypothesized that splenectomy would further disrupt sympathetic neurotransmission within the cholinergic anti‐inflammatory pathway and result in worsened disease outcome. Female SLE mice were subjected to splenectomy or sham surgery (n = 10–12/group) at 31 weeks of age before being implanted with arterial catheters, blood pressure measurement and subsequently euthanization 4 weeks later. Anti‐double‐stranded autoantibodies, the hallmark of SLE, were not different amongst sham and splenectomized mice (4.8e5 ± 8.1e4 vs. 4.6e5 ± 5.4e4 activity units; p = 0.857), and neither was body weight (41.6 ± 2.0 vs. 40.1 ± 1.1 g; p = 0.497). However the incidence of albuminuria [> 300 mg/dL; 42% (5 out of 12) vs. 33% (3 out of 9)] and leukocytes in the urine [50% (6 out of 12) vs. 33% (3 out of 9)] was elevated in splenectomized SLE mice compared to sham‐operated SLE mice. Although blood pressure was not different between sham‐operated and splenectomized SLE mice (131 ± 2 vs. 134 ± 7 mmHg; p = 0.815), there was an increase in mortality following splenectomy [33% (4 out of 12) vs. 10% (1 out of 10)]. In summary, although further studies are needed to confirm the effect splenectomy on inflammation in SLE mice we found that splenectomy exacerbated the progression of SLE disease. This suggests that the sympathetic component of the cholinergic anti‐inflammatory pathway may be important in combating the inflammation in SLE. Taken together, our studies on vagus nerve stimulation, splenic nerve stimulation and denervation and splenectomy in SLE mice suggest critical interactions between autonomic branches that may be impaired during chronic inflammation. Future studies may use technology like direct vagal stimulation via central injections and designer receptors exclusively activated by designer drugs (DREADDs) to further characterize the importance of these autonomic nervous system‐mediated pathways.Support or Funding InformationFunded by NIH 1K01HL139869 and the Lupus Research Alliance Novel Disease GrantThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain.

We have exploited whole brain microscopy to map the progressive deposition of hyperphosphorylated tau in intact, cleared mouse brain. We found that the three-dimensional spreading pattern of hyperphosphorylated tau in the brain of an aging Tau.P301L mouse model did not resemble that observed in AD patients. Injection of synthetic or patient-derived tau fibrils in the CA1 region resulted in a more faithful spreading pattern. Atlas-guided volumetric analysis showed a connectome-dependent spreading from the injection site and also revealed hyperphosphorylated tau deposits beyond the direct anatomical connections. In fibril-injected brains, we also detected a persistent subpopulation of rod-like and swollen microglia. Furthermore, we showed that the hyperphosphorylated tau load could be reduced by intracranial co-administration of, and to a lesser extent, by repeated systemic dosing with an antibody targeting the microtubule-binding domain of tau. Thus, the combination of targeted seeding and in toto staging of tau pathology allowed assessing regional vulnerability in a comprehensive manner, and holds potential as a preclinical drug validation tool.

Wisdom Tooth's Revenge: Retropharyngeal Abscess and Mediastinitis after Molar Tooth Extraction

Retropharyngeal abscess is potentially associated with high morbidity and mortality as a result of its direct anatomical connection with the mediastinum. Therefore, knowledge of the relevant anatomy is essential for recognizing the presence and extent of disease in a timely manner. In this case report, we aim to review the pertinent anatomy and patterns of spread of infection from a full blown deep neck space infection to result in mediastinitis and empyema.

Intrinsic connectivity networks in posterior cortical atrophy: A role for the pulvinar?

BackgroundPosterior cortical atrophy (PCA) is a clinical variant of Alzheimer's disease (AD) that presents with progressive visuospatial symptoms. While amnestic AD is characterized by disrupted default mode network (DMN) connectivity with corresponding increases in salience network (SN) connectivity, a visuospatial network appears to be disrupted early in PCA. Based on PCA patients' clinical features, we hypothesized that, in addition to early decreased integrity within the visuospatial network, patients with PCA would show increases in SN connectivity despite relative preservation of DMN. As the lateral pulvinar nucleus of the thalamus has direct anatomical connections with striate and extrastriate cortex and DMN, and the medial pulvinar is anatomically interconnected with SN, we further hypothesized that lateral and medial pulvinar nuclei might be implicated in intrinsic connectivity changes in PCA.Methods26 patients with PCA and 64 matched controls were recruited through UCSF Memory and Aging Center research programs. Each completed a standardized neuropsychological battery, structural MRI, and task-free fMRI. Seed-based functional correlations were used to probe networks of interest, including those seeded by the medial and lateral pulvinar thalamic nuclei, across the whole brain, and functional data analyses were adjusted for brain atrophy.ResultsPatients with PCA showed disproportionate deficits in the visuospatial domain; they also showed preserved social sensitivity and endorsed more depressive symptoms than HCs. PCA patients had significant parietooccipital atrophy accompanied by widespread connectivity decreases within the visuospatial network, enhanced connectivity between some structures in SN, and enhanced connectivity between key nodes of the DMN compared to controls. Increased SN connectivity correlated with a measure of social sensitivity, and increased DMN connectivity correlated with short-term memory performance. Medial pulvinar connectivity increases in PCA were topographically similar to SN (anterior insula) connectivity increases, while lateral pulvinar connectivity increases were similar to DMN (posterior cingulate) connectivity increases.ConclusionsPCA is characterized by preserved to heightened connectivity in the SN and DMN despite decreased visuospatial network connectivity. The spatial similarity of medial and lateral pulvinar connectivity changes to those seen in the SN and DMN suggests a role for the pulvinar in intrinsic connectivity network changes in PCA.

Blindsight relies on a functional connection between hMT+ and the lateral geniculate nucleus, not the pulvinar.

When the primary visual cortex (V1) is damaged, the principal visual pathway is lost, causing a loss of vision in the opposite visual field. While conscious vision is impaired, patients can still respond to certain images; this is known as ‘blindsight’. Recently, a direct anatomical connection between the lateral geniculate nucleus (LGN) and human motion area hMT+ has been implicated in blindsight. However, a functional connection between these structures has not been demonstrated. We quantified functional MRI responses to motion in 14 patients with unilateral V1 damage (with and without blindsight). Patients with blindsight showed significant activity and a preserved sensitivity to speed in motion area hMT+, which was absent in patients without blindsight. We then compared functional connectivity between motion area hMT+ and a number of structures implicated in blindsight, including the ventral pulvinar. Only patients with blindsight showed an intact functional connection with the LGN but not the other structures, supporting a specific functional role for the LGN in blindsight.

Splenic 6‐hydroxydopamine Worsens Renal Inflammation and Injury in a Murine Model of Systemic Lupus Erythematosus

Renal inflammation is prevalent in the chronic autoimmune disease systemic lupus erythematosus (SLE) and drives the progression of kidney injury, which contributes to the morbidity and mortality. Inflammation in SLE results from a loss of self‐tolerance and the production of autoantibodies against nuclear antigens (e.g., anti‐double‐stranded (ds) DNA autoantibodies); however, other immunoregulatory mechanisms such as the cholinergic anti‐inflammatory pathway may also be dysregulated and contribute to aberrant systemic and renal inflammation in the disease. The cholinergic anti‐inflammatory pathway is a protective, neuroimmune mechanism thought to involve neurotransmission between the parasympathetic vagus and the sympathetic splenic nerves. Although a direct anatomical connection between the vagus and the splenic nerve is controversial, stimulation of these nerves results in a decrease in the production and release of pro‐inflammatory cytokines from splenic immune cells. In order to confirm the importance of the splenic nerve in this pathway, others have used 6‐hydroxydopamine (6OHDA), a neurotoxin that depletes catecholamines, to chemically denervate the spleen and thereby dampen the sympathetic component of the cholinergic anti‐inflammatory pathway. We hypothesized that splenic injection of 6OHDA would further disrupt the cholinergic anti‐inflammatory pathway in a mouse model of SLE and result in increased renal inflammation and worsened disease severity, which would highlight the importance of the splenic nerve in quelling renal inflammation. In the current study, female SLE and control mice were injected with 6OHDA (120 μg in 60 μl saline) or vehicle directly into the spleen at 33 weeks of age (n = 6/group). To confirm splenic denervation with 6OHDA, we utilized the glyoxylic acid condensation reaction on 12 μm spleen sections of representative animals and verified that catecholamine histofluorescence was diminished in 6OHDA‐treated mice (205 vs. 111 histofluorescent foci). Renal cortical TNF‐α (normalized to total protein) was increased in SLE mice compared to controls (3.1e6 ± 1.2e5 vs. 7.8e5 ± 1.6e4 intensity units; p = 0.029), and 6OHDA exacerbated this pro‐inflammatory cytokine in SLE mice (7.6e6 ± 2.4 intensity units; p = 0.048) with no effect in controls (1.8e6 ± 7.0e5 intensity units; p = 0.697). Anti‐dsDNA autoantibodies were elevated in SLE mice compared to controls (2.1e4 ± 5.7e3 vs. 1.0e4 ± 4.7e3 activity units; p = 0.013), but 6OHDA did not alter this measure of disease severity in SLE mice (1.8e4 ± 5.2e3 activity units; p = 0.692). Albumin excretion rate (AER) was elevated in SLE mice compared to controls (160.7 ± 28.0 vs. 2.7 ± 2.7 mg/dL; p < 0.001). 6OHDA accentuated the increase in AER in SLE mice (454.2 ± 150.2 mg/dL; p = 0.010) but had no effect in controls (27.5 ± 17.0 mg/dL; p = 0.754). In summary, 6OHDA aggravated renal inflammation and injury in SLE mice indicated by heightened renal cortical TNF‐α and AER. This suggests that chemical splenic denervation may disrupt endogenous, sympathetically‐mediated anti‐inflammatory mechanisms. Further studies are needed to confirm the role of the splenic nerve in regulating renal inflammation.Support or Funding InformationFunded by AHA grants 14SDG18320033 (KWM), 16PRE29910012 (GSP), and UNTHSC Intramural FundingThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Adipocytes promote nicotine-induced injury of endothelial cells via the NF-κB pathway

Cigarette smoking is one of the most important risk factors of atherosclerosis, which can induce endothelial injury. Meanwhile, adipocytes are the main cell type of perivascular adipose tissue (PVAT), the largest endocrine and paracrine organ and direct anatomical connection to adventitia, which may play a key role in the injury of endothelial cells. We used nicotine to induce dysfunctional HUVECs and adipocytes. In addition, we used a novel model to co-culture HUVECs and adipocytes in vitro by the transwell co-culture system to determine the effect of adipocytes on endothelial injury. Cell apoptosis was detected by Annexin V-FITC. Genes and proteins involved in the nuclear factor kappa B (NF-κB) signaling pathway were detected by qRT-PCR and western blot analysis, respectively. We also investigated the nuclear translocation of NF-κB p65 using immunofluorescence staining. Our results showed that nicotine dose-dependently induces the apoptosis of HUVECs and adipocytes and is associated with increased IKKβ and NF-κB p65 expression and with IkBα degradation. Meanwhile through the co-culture system, adipocytes promoted the expression of IKKβ and NF-κB p65, as well as the translocation of NF-κB p65, and they accelerated the degradation of IkBα, resulting in increased apoptosis of HUVECs compared with that of the single cultured system. In conclusion, adipocytes could promote endothelial injury via the NF-κB pathway. Moreover, the NF-κB pathway plays pivotal roles in nicotine-induced vascular injury.

Structural Basis of Large-Scale Functional Connectivity in the Mouse.

Translational neuroimaging requires approaches and techniques that can bridge between multiple different species and disease states. One candidate method that offers insights into the brain's functional connectivity (FC) is resting-state fMRI (rs-fMRI). In both humans and nonhuman primates, patterns of FC (often referred to as the functional connectome) have been related to the underlying structural connectivity (SC; also called the structural connectome). Given the recent rise in preclinical neuroimaging of mouse models, it is an important question whether the mouse functional connectome conforms to the underlying SC. Here, we compared FC derived from rs-fMRI in female mice with the underlying monosynaptic structural connectome as provided by the Allen Brain Connectivity Atlas. We show that FC between interhemispheric homotopic cortical and hippocampal areas, as well as in cortico-striatal pathways, emerges primarily via monosynaptic structural connections. In particular, we demonstrate that the striatum (STR) can be segregated according to differential rs-fMRI connectivity patterns that mirror monosynaptic connectivity with isocortex. In contrast, for certain subcortical networks, FC emerges along polysynaptic pathways as shown for left and right STR, which do not share direct anatomical connections, but high FC is putatively driven by a top-down cortical control. Finally, we show that FC involving cortico-thalamic pathways is limited, possibly confounded by the effect of anesthesia, small regional size, and tracer injection volume. These findings provide a critical foundation for using rs-fMRI connectivity as a translational tool to study complex brain circuitry interactions and their pathology due to neurological or psychiatric diseases across species.SIGNIFICANCE STATEMENT A comprehensive understanding of how the anatomical architecture of the brain, often referred to as the "connectome," corresponds to its function is arguably one of the biggest challenges for understanding the brain and its pathologies. Here, we use the mouse as a model for comparing functional connectivity (FC) derived from resting-state fMRI with gold standard structural connectivity measures based on tracer injections. In particular, we demonstrate high correspondence between FC measurements of cortico-cortical and cortico-striatal regions and their anatomical underpinnings. This work provides a critical foundation for studying the pathology of these circuits across mouse models and human patients.