Adjacent Neurons Research Articles

Retinal vessel segmentation using simple SPCNN model and line connector

The effective segmentation of retinal blood vessels is essential for the medical diagnosis of ophthalmology diseases. In this paper, a novel approach is presented to segment retinal vessels accurately and efficiently. Firstly, we propose a simple simplified pulse coupled neural network utilizing the similarity of adjacent neurons to acquire the basic structure of blood vessels. Then we apply a line connector to solve the problem of broken vessels occurring in the segmentation, in order to present a complete structure of the blood vessels and improve the accuracy of vessel identification. Experimental analyses on two publicly available databases show that the proposed methods with or without the line connector outperform the most existing methods in terms of average accuracy and have a fast response time. It is of great importance for medical diagnosis with high accuracy and short time consumption. Our methods are practicable either for retinal vessel segmentation, or for other applications of clinical research.

A twisted visual field map in the primate dorsomedial cortex predicted by topographic continuity.

Adjacent neurons in visual cortex have overlapping receptive fields within and across area boundaries, an arrangement theorized to minimize wiring cost. This constraint is traditionally thought to create retinotopic maps of opposing field signs (mirror and nonmirror visual field representations) in adjacent areas, a concept that has become central in current attempts to subdivide the extrastriate cortex. We simulated the formation of retinotopic maps using a model that balances constraints imposed by smoothness in the representation within an area and by congruence between areas. As in the primate cortex, this model usually leads to alternating mirror and nonmirror maps. However, we found that it can also produce a more complex type of map, consisting of sectors with opposing field sign within a single area. Using fully quantitative electrode array recordings, we then demonstrate that this type of inhomogeneous map exists in the controversial dorsomedial region of the primate extrastriate cortex.

L5 Spinal Nerve Axotomy Induces Distinct Electrophysiological Changes in Axotomized L5- and Adjacent L4-Dorsal Root Ganglion Neurons in Rats In Vivo.

Peripheral neuropathic pain (PNP) is a major health problem for which effective drug treatment is lacking. Its underlying neuronal mechanisms are still illusive, but pre-clinical studies using animal models of PNP including the L5-spinal nerve axotomy (L5-SNA) model, suggest that it is partly caused by excitability changes in dorsal root ganglion (DRG) neurons. L5-SNA results in two DRG neuronal groups: (1) axotomized/damaged neurons in L5- plus some in L4-DRGs, and (2) ipsilateral L4-neurons with intact/uninjured fibers intermingling with degenerating L5-fibers. The axotomized neurons are deprived of peripherally derived trophic factors and degenerate causing neuroinflammation, whereas the uninjured L4-neuorns are subject to increased trophic factors and neuroinflammation associated with Wallerian degeneration of axotomized L5-nerve fibers. Whether these two groups of DRG neurons exhibit similar or distinct electrophysiological changes after L5-SNA remains unresolved. Conflicting evidence for this may result from some studies assuming that all L4-fibers are undamaged. Here, we recorded somatic action potentials (APs) intracellularly from C- and A-fiber L4/L5 DRG neurons in vivo, to examine our hypothesis that L5-SNA would induce distinct electrophysiological changes in the two populations of DRG neurons. Consistent with this hypothesis, we found (7 days post-SNA), in SNA rats with established pain hypersensitivity, slower AP kinetics in axotomized L5-neurons and faster AP kinetics in L4-nociceptive neurons including decreased rise time in Aδ-and Aβ-fiber nociceptors, and after-hyperpolarization duration in Aβ-fiber nociceptors. We also found several changes in axotomized L5-neurons but not in L4-nociceptive neurons, and some changes in L4-nociceptive but not L5-neurons. The faster AP kinetics (decreased refractory period) in L4-nociceptive neurons that are consistent with their reported hyperexcitability may lead to repetitive firing and thus provide enhanced afferent input necessary for initiating and/or maintaining PNP development. The changes in axotomized L5-neurons may contribute to the central mechanisms of PNP via enhanced neurotransmitter release in the central nervous system (CNS).

GNAO1 organizes the cytoskeletal remodeling and firing of developing neurons.

Developmental and epileptic encephalopathy (DEE) represents a group of neurodevelopmental disorders characterized by infantile-onset intractable seizures and unfavorable prognosis of psychomotor development. To date, hundreds of genes have been linked to the onset of DEE. GNAO1 is a DEE-associated gene encoding the alpha-O1 subunit of guanine nucleotide-binding protein (GαO ). Despite the increasing number of reported children with GNAO1 encephalopathy, the molecular mechanisms underlying their neurodevelopmental phenotypes remain elusive. We herein present that co-immunoprecipitation and mass spectrometry analyses identified another DEE-associated protein, SPTAN1, as an interacting partner of GαO . Silencing of endogenous Gnao1 attenuated the neurite outgrowth and calcium-dependent signaling. Inactivation of GNAO1 in human-induced pluripotent stem cells gave rise to anomalous brain organoids that only weakly expressed SPTAN1 and Ankyrin-G. Furthermore, GNAO1-deficient organoids failed to conduct synchronized firing to adjacent neurons. These data indicate that GαO and other DEE-associated proteins organize the cytoskeletal remodeling and functional polarity of neurons in the developing brain.

Synaptic and metabolic gene expression alterations in neurons that are recipients of proteopathic tau seeds

Recent studies suggest that misfolded tau molecules can be released, and taken up by adjacent neurons, propagating proteopathic seeds across neural systems. Yet critical to understanding whether tau propagation is relevant in pathophysiology of disease would be to learn if it alters neuronal properties. We utilized high resolution multi-color in situ hybridization technology, RNAScope, in a well-established tau transgenic animal, and found that a subset of neurons in the cortex do not appear to express the transgene, but do develop phospho-tau positive inclusions, consistent with having received tau seeds. Recipient neurons show decreases in their expression of synaptophysin, CAMKIIα, and mouse tau in both young and old animals. These results contrast with neurons that develop tau aggregates and also overexpress the transgene, which have few changes in expression of metabolic and synaptic markers. Taken together, these results strongly suggest that tau propagation impacts neuronal functional integrity.

Effects of trigeminal nerve injury on the expression of galanin and its receptors in the rat trigeminal ganglion

In the spinal nervous system, the expression of galanin (GAL) and galanin receptors (GALRs) that play important roles in the transmission and modulation of nociceptive information can be affected by nerve injury. However, in the trigeminal nervous system, the effects of trigeminal nerve injury on the expression of GAL are controversy in the previous studies. Besides, little is known about the effects of trigeminal nerve injury on the expression of GALRs. In the present study, the effects of trigeminal nerve injury on the expression of GAL and GALRs in the rat trigeminal ganglion (TG) were investigated by using quantitative real-time reverse transcription-polymerase chain reaction and immunohistochemistry. To identify the nerve-injured and nerve-uninjured TG neurons, activating transcription factor 3 (ATF3, the nerve-injured neuron marker) was stained by immunofluorescence. The levels of GAL mRNA in the rostral half and caudal half of the TG dramatically increased after transection of infraorbital nerve (ION) and inferior alveolar nerve (IAN), respectively. Immunohistochemical labeling of GAL and ATF3 revealed that GAL level was elevated in both injured and adjacent uninjured small and medium-sized TG neurons after ION/IAN transection. In addition, the levels of GAL2R-like immunoreactivity were reduced in both injured and adjacent uninjured TG neurons after ION/IAN transection, while levels of GAL1R and GAL3R-like immunoreactivity remained unchanged. Furthermore, the number of small to medium-sized TG neurons co-expressing GAL- and GAL1R/GAL2R/GAL3R-like immunoreactivity was significantly increased after ION/IAN transection. In line with previous studies in other spinal neuron systems, these results suggest that GAL and GALRs play functional roles in orofacial neuropathic pain and trigeminal nerve regeneration after trigeminal nerve injury.

Progress in electrochemical detection of neurotransmitters using carbon nanotubes/nanocomposite based materials: A chronological review

AbstractNeurotransmitters (NTs) are chemical compounds that play an important physiological role in the functioning of central nervous, renal, hormonal, and cardiovascular systems. Their function is to regulate neural interactions by reducing the permeability of gap junctions between adjacent neurons of the same type. The abnormal level may lead to diseases, such as Parkinson's disease, Huntington's disease, Alzheimer's diseases, and other neurological diseases. The devastating health hazards associated with the abnormal presence of NTs in biological systems coupled with the demerits of most modern detection methods necessitates the continuous development of novel electrochemical sensors. Carbon nanotube (CNT)‐based sensors, as a result of the large surface area, biocompatibility, and chemical stability supplied by CNTs, have proven to offer massive sensitivity and low limit of detection (LOD). Its significance in sensors applications toward the detection of different group of compounds cannot be overemphasized. There are several review articles on NTs and their determination using different chemically modified electrodes and sensor platform. However, this review highlights the significance of notable NTs and the progress made in the last decade in the design of CNT‐based sensors for the detection of common NTs. Secondly, the review intends to highlight some of the challenges associated with the use of CNT‐modified electrodes for NT detection, quantification, and in real‐life application. Lastly, it will evaluate the future perspective in the use of CNT and its composite modified electrode over other surface modification materials used in sensor fabrication for the determination of NTs.

Astrocytes: News about Brain Health and Diseases.

Astrocytes, the most numerous glial cells in the brains of humans and other mammalian animals, have been studied since their discovery over 100 years ago. For many decades, however, astrocytes were believed to operate as a glue, providing only mechanical and metabolic support to adjacent neurons. Starting from a “revolution” initiated about 25 years ago, numerous astrocyte functions have been reconsidered, some previously unknown, others attributed to neurons or other cell types. The knowledge of astrocytes has been continuously growing during the last few years. Based on these considerations, in the present review, different from single or general overviews, focused on six astrocyte functions, chosen due in their relevance in both brain physiology and pathology. Astrocytes, previously believed to be homogeneous, are now recognized to be heterogeneous, composed by types distinct in structure, distribution, and function; their cooperation with microglia is known to govern local neuroinflammation and brain restoration upon traumatic injuries; and astrocyte senescence is relevant for the development of both health and diseases. Knowledge regarding the role of astrocytes in tauopathies and Alzheimer’s disease has grow considerably. The multiple properties emphasized here, relevant for the present state of astrocytes, will be further developed by ongoing and future studies.

Differential Contribution of the Retrotrapezoid Nucleus and C1 Neurons to Active Expiration and Arousal in Rats.

Collectively, the retrotrapezoid nucleus (RTN) and adjacent C1 neurons regulate breathing, circulation and the state of vigilance, but previous methods to manipulate the activity of these neurons have been insufficiently selective to parse out their relative roles. We hypothesize that RTN and C1 neurons regulate distinct aspects of breathing (e.g., frequency, amplitude, active expiration, sighing) and differ in their ability to produce arousal from sleep. Here we use optogenetics and a combination of viral vectors in adult male and female Th-Cre rats to transduce selectively RTN (Phox2b+/Nmb+) or C1 neurons (Phox2b+/Th+) with Channelrhodopsin-2. RTN photostimulation modestly increased the probability of arousal. RTN stimulation robustly increased breathing frequency and amplitude; it also triggered strong active expiration but not sighs. Consistent with these responses, RTN innervates the entire pontomedullary respiratory network, including expiratory premotor neurons in the caudal ventral respiratory group, but RTN has very limited projections to brainstem regions that regulate arousal (locus ceruleus, CGRP+ parabrachial neurons). C1 neuron stimulation produced robust arousals and similar increases in breathing frequency and amplitude compared with RTN stimulation, but sighs were elicited and active expiration was absent. Unlike RTN, C1 neurons innervate the locus ceruleus, CGRP+ processes within the parabrachial complex, and lack projections to caudal ventral respiratory group. In sum, stimulating C1 or RTN activates breathing robustly, but only RTN neuron stimulation produces active expiration, consistent with their role as central respiratory chemoreceptors. Conversely, C1 stimulation strongly stimulates ascending arousal systems and sighs, consistent with their postulated role in acute stress responses.SIGNIFICANCE STATEMENT The C1 neurons and the retrotrapezoid nucleus (RTN) reside in the rostral ventrolateral medulla. Both regulate breathing and the cardiovascular system but in ways that are unclear because of technical limitations (anesthesia, nonselective neuronal actuators). Using optogenetics in unanesthetized rats, we found that selective stimulation of either RTN or C1 neurons activates breathing. However, only RTN triggers active expiration, presumably because RTN, unlike C1, has direct excitatory projections to abdominal premotor neurons. The arousal potential of the C1 neurons is far greater than that of the RTN, however, consistent with C1's projections to brainstem wake-promoting structures. In short, C1 neurons orchestrate cardiorespiratory and arousal responses to somatic stresses, whereas RTN selectively controls lung ventilation and arterial Pco2 stability.

The effect of graph connectivity on metastability in a stochastic system of spiking neurons

We consider a continuous-time stochastic model of spiking neurons originally introduced by Ferrari et al. in Ferrari et al. (2018). In this model, we have a finite or countable number of neurons which are vertices in some graph G where the edges indicate the synaptic connection between them. We focus on metastability, understood as the property for the time of extinction of the network to be asymptotically memory-less, and we prove that this model exhibits two different behaviors depending on the nature of the specific underlying graph of interaction G that is chosen. In this model the spiking activity of any given neuron is represented by a point process, whose rate fluctuates between 1 and 0 over time depending on whether the membrane potential is positive or null. The membrane potential of each neuron evolves in time by integrating all the spikes of its adjacent neurons up to the last spike of the said neuron, so that when a neuron spikes, its membrane potential is reset to 0 while the membrane potential of each of its adjacent neurons is increased by one unit. Moreover, each neuron is exposed to a leakage effect, modeled as an abrupt loss of membrane potential which occurs at random times driven by a Poisson process of some fixed rate γ. It was previously proven that when the graph G is the infinite one-dimensional lattice, this model presents a phase transition with respect to the parameter γ. It was also proven that, when γ is small enough, the renormalized time of extinction (the first time at which all neurons have a null membrane potential) of a finite version of the system converges in law toward an exponential random variable when the number of neurons goes to infinity. The present article is divided into two parts. First we prove that, in the finite one-dimensional lattice, this last result does not hold anymore if γ is large enough, and in fact we prove that for γ>1 the renormalized time of extinction is asymptotically deterministic. Then we prove that conversely, if G is the complete graph, the result of metastability holds for any positive γ.

Accurate MR image super-resolution via lightweight lateral inhibition network

In recent years, convolutional neural networks (CNNs) have shown their advantages on MR image super-resolution (SR) tasks. Many current SR models, however, have heavy demands on computation and memory, which are not friendly to magnetic resonance imaging (MRI) where computing resource is usually constrained. On the other hand, a basic consideration in most MRI experiments is how to reduce scanning time to improve patient comfort and reduce motion artifacts. In this work, we ease the problem by presenting an effective and lightweight model that supports fast training and accurate SR inference. The proposed network is inspired by the lateral inhibition mechanism, which assumes that there exist inhibitory effects between adjacent neurons. The backbone of our network consists of several lateral inhibition blocks, where the inhibitory effect is explicitly implemented by a battery of cascaded local inhibition units. When model scale is small, explicitly inhibiting feature activations is expected to further explore model representational capacity. For more effective feature extraction, several parallel dilated convolutions are also used to extract shallow features directly from the input image. Extensive experiments on typical MR images demonstrate that our lateral inhibition network (LIN) achieves better SR performance than other lightweight models with similar model scale.

FPGA-based Experimental Validations of Electrical Activities in Two Adjacent FitzHugh–Nagumo Neurons Coupled by Memristive Electromagnetic Induction

ABSTRACT With the consideration of electromagnetic induction generated by the difference of membrane potentials between two adjacent neurons, a five-dimensional (5-D) memristor-coupled FitzHugh–Nagumo (FHN) bi-neuron model derived from connecting two FHN neurons with the memristive electromagnetic induction is presented. Then, with the 5-D memristor-coupled FHN bi-neuron model, the equilibrium states and their stabilities are explored by theoretical and numerical analyses. It is indicated that the proposed model has two non-zero equilibrium states with the same stability of unstable saddle-focus or unstable saddle point associating to the considered model parameters. The parameter-associated electrical activities of periodic, quasi-periodic, and chaotic behaviors are disclosed by bifurcation plots, dynamical maps, phase plane plots and further confirmed by 0–1 tests. Besides, the phenomena of initial-associated bi-stability with the coexistence of chaotic and periodic behaviors, as well as the riddled attraction basin, are revealed by local attraction basins and phase plane plots. Furthermore, based on field programmable gate array (FPGA), a digitally implemented electronic circuit is made, from which the electrical activities are experimentally captured to verify the numerical ones.

T cell engagement of cross-presenting microglia protects the brain from a nasal virus infection.

The neuroepithelium is a nasal barrier surface populated by olfactory sensory neurons that detect odorants in the airway and convey this information directly to the brain via axon fibers. This barrier surface is especially vulnerable to infection, yet respiratory infections rarely cause fatal encephalitis, suggesting a highly evolved immunological defense. Here, using a mouse model, we sought to understand the mechanism by which innate and adaptive immune cells thwart neuroinvasion by vesicular stomatitis virus (VSV), a potentially lethal virus that uses olfactory sensory neurons to enter the brain after nasal infection. Fate-mapping studies demonstrated that infected central nervous system (CNS) neurons were cleared noncytolytically, yet specific deletion of major histocompatibility complex class I (MHC I) from these neurons unexpectedly had no effect on viral control. Intravital imaging studies of calcium signaling in virus-specific CD8+ T cells revealed instead that brain-resident microglia were the relevant source of viral peptide-MHC I complexes. Microglia were not infected by the virus but were found to cross-present antigen after acquisition from adjacent neurons. Microglia depletion interfered with T cell calcium signaling and antiviral control in the brain after nasal infection. Collectively, these data demonstrate that microglia provide a front-line defense against a neuroinvasive nasal infection by cross-presenting antigen to antiviral T cells that noncytolytically cleanse neurons. Disruptions in this innate defense likely render the brain susceptible to neurotropic viruses like VSV that attempt to enter the CNS via the nose.

Initial Sensitive Dynamics in Memristor Synapse-coupled Hopfield Neural Network

The initial sensitive dynamics in a Hopfield Neural Network (HNN) with three neurons under the action of electromagnetic induction current is reported. A simple 4-D memristive HNN is constructed by using a non-ideal memristor synapse to imitate the electromagnetic induction current caused by membrane potential difference between two adjacent neurons. By means of theoretical analyses and numerical simulations, the complex dynamical behaviors under different coupling strengths of the memristor synapse are researched, and special phenomena closely related to the initial values are revealed. Finally, the analog equivalent realization circuit of the memristive HNN model is designed, and the correctness of MATLAB numerical simulation is verified by PSIM circuit simulations.

A disintegrin and metalloproteinase domain 17-epidermal growth factor receptor signaling contributes to oral cancer pain.

Cancer cells secrete pronociceptive mediators that sensitize adjacent sensory neurons and cause pain. Identification and characterization of these mediators could pinpoint novel targets for cancer pain treatment. In this study, we identified candidate genes in cancer cell lines that encode for secreted or cell surface proteins that may drive nociception. To undertake this work, we used an acute cancer pain mouse model, transcriptomic analysis of publicly available human tumor-derived cell line data, and a literature review. Cancer cell line supernatants were assigned a phenotype based on evoked nociceptive behavior in an acute cancer pain mouse model. We compared gene expression data from nociceptive and nonnociceptive cell lines. Our analyses revealed differentially expressed genes and pathways; many of the identified genes were not previously associated with cancer pain signaling. Epidermal growth factor receptor (EGFR) and disintegrin metalloprotease domain 17 (ADAM17) were identified as potential targets among the differentially expressed genes. We found that the nociceptive cell lines contained significantly more ADAM17 protein in the cell culture supernatant compared to nonnociceptive cell lines. Cytoplasmic EGFR was present in almost all (>90%) tongue primary afferent neurons in mice. Monoclonal antibody against EGFR, cetuximab, inhibited cell line supernatant-induced nociceptive behavior in an acute oral cancer pain mouse model. We infer from these data that ADAM17-EGFR signaling is involved in cancer mediator-induced nociception. The differentially expressed genes and their secreted protein products may serve as candidate therapeutic targets for oral cancer pain and warrant further evaluation.

A Central Amygdala-Ventrolateral Periaqueductal Gray Matter Pathway for Pain in a Mouse Model of Depression-like Behavior.

The mechanisms underlying depression-associated pain remain poorly understood. Using a mouse model of depression, the authors hypothesized that the central amygdala-periaqueductal gray circuitry is involved in pathologic nociception associated with depressive states. The authors used chronic restraint stress to create a mouse model of nociception with depressive-like behaviors. They then used retrograde tracing strategies to dissect the pathway from the central nucleus of the amygdala to the ventrolateral periaqueductal gray. The authors performed optogenetic and chemogenetic experiments to manipulate the activity of this pathway to explore its roles for nociception. The authors found that γ-aminobutyric acid-mediated (GABAergic) neurons from the central amygdala project onto GABAergic neurons of the ventrolateral periaqueductal gray, which, in turn, locally innervate their adjacent glutamatergic neurons. After chronic restraint stress, male mice displayed reliable nociception (control, mean ± SD: 0.34 ± 0.11 g, n = 7 mice; chronic restraint stress, 0.18 ± 0.11 g, n = 9 mice, P = 0.011). Comparable nociception phenotypes were observed in female mice. After chronic restraint stress, increased circuit activity was generated by disinhibition of glutamatergic neurons of the ventrolateral periaqueductal gray by local GABAergic interneurons via receiving enhanced central amygdala GABAergic inputs. Inhibition of this circuit increased nociception in chronic restraint stress mice (median [25th, 75th percentiles]: 0.16 [0.16, 0.16] g to 0.07 [0.04, 0.16] g, n = 7 mice per group, P < 0.001). In contrast, activation of this pathway reduced nociception (mean ± SD: 0.16 ± 0.08 g to 0.34 ± 0.13 g, n = 7 mice per group, P < 0.001). These findings indicate that the central amygdala-ventrolateral periaqueductal gray pathway may mediate some aspects of pain symptoms under depression conditions.

Maximized lateral inhibition in paired magnetic domain wall racetracks for neuromorphic computing

Lateral inhibition is an important functionality in neuromorphic computing, modeled after the biological neuron behavior that a firing neuron deactivates its neighbors belonging to the same layer and prevents them from firing. In most neuromorphic hardware platforms lateral inhibition is implemented by external circuitry, thereby decreasing the energy efficiency and increasing the area overhead of such systems. Recently, the domain wall—magnetic tunnel junction (DW-MTJ) artificial neuron is demonstrated in modeling to be intrinsically inhibitory. Without peripheral circuitry, lateral inhibition in DW-MTJ neurons results from magnetostatic interaction between neighboring neuron cells. However, the lateral inhibition mechanism in DW-MTJ neurons has not been studied thoroughly, leading to weak inhibition only in very closely-spaced devices. This work approaches these problems by modeling current- and field- driven DW motion in a pair of adjacent DW-MTJ neurons. We maximize the magnitude of lateral inhibition by tuning the magnetic interaction between the neurons. The results are explained by current-driven DW velocity characteristics in response to an external magnetic field and quantified by an analytical model. Dependence of lateral inhibition strength on device parameters is also studied. Finally, lateral inhibition behavior in an array of 1000 DW-MTJ neurons is demonstrated. Our results provide a guideline for the optimization of lateral inhibition implementation in DW-MTJ neurons. With strong lateral inhibition achieved, a path towards competitive learning algorithms such as the winner-take-all are made possible on such neuromorphic devices.

Molecularly Defined Hippocampal Inputs Regulate Population Dynamics in the Prelimbic Cortex to Suppress Context Fear Memory Retrieval

BackgroundContext fear memory dysregulation is a hallmark symptom of several neuropsychiatric disorders, including generalized anxiety disorder and posttraumatic stress disorder. The hippocampus (HC) and prelimbic (PrL) subregion of the medial prefrontal cortex have been linked with context fear memory retrieval in rodents, but the mechanisms by which HC-PrL circuitry regulates this process remain poorly understood. MethodsSpatial and genetic targeting of HC-PrL circuitry was used for RNA sequencing (n = 31), chemogenetic stimulation (n = 44), in vivo calcium imaging (n = 20), ex vivo electrophysiology (n = 8), and molecular regulation of plasticity cascades during fear behavior (context fear retrieval) (n = 16). ResultsWe showed that ventral HC (vHC) neurons with projections to the PrL cortex (vHC-PrL projectors) are a transcriptomically distinct subpopulation compared with adjacent nonprojecting neurons, and we showed complementary enrichment for diverse neuronal processes and central nervous system–related clinical gene sets. We further showed that stimulation of this population of vHC-PrL projectors suppresses context fear memory retrieval and impairs the ability of PrL neurons to dynamically distinguish between distinct phases of fear learning. Using transgenic and circuit-specific molecular targeting approaches, we demonstrated that unique patterns of activity-dependent gene transcription associated with brain-derived neurotrophic factor signaling within vHC-PrL projectors causally regulated activity in excitatory and inhibitory PrL neurons during context fear memory retrieval. ConclusionsTogether, our data show that activity-dependent brain-derived neurotrophic factor release from molecularly distinct vHC-PrL projection neurons modulates postsynaptic signaling in both inhibitory and excitatory PrL neurons, modifying activity in discrete populations of PrL neurons to suppress freezing during context fear memory retrieval.

Angiotensin AT2 receptors in the solitary tract nucleus lower blood pressure via inhibition of GABA signaling

Chronic CNS administration of angiotensin AT2 receptor (AT2R) agonists lowers blood pressure (BP) in normal and hypertensive rodents, but the location(s) and mechanism(s) of action are unknown. One locus may be the intermediate solitary tract nucleus (intNTS). Our previous studies demonstrated a high density of AT2R located on GABA neurons in the intNTS (de Kloet et al, Brain Struct. Func., 2016, 22:891–912), and decades of research have established increased GABA signaling in the intNTS as a pathophysiological mechanism contributing to increased BP and hypertension. These studies reveal that reductions in BP (~8 mmHg) induced by 2‐week intracerebroventricular (icv) infusion of the AT2R agonist C21 (7.5 ng/kg/h) in normotensive mice is associated with significant decreases in gene expression of GABA synthetic enzymes (GAD‐1 &amp; GAD‐2) in the intNTS. Based on this, we developed the hypothesis that the depressor action of C21 is mediated through AT2R located on intNTS GABA neurons and a reduction of GABA signaling. To test this, we engineered a novel mouse line that has Cre‐recombinase expression directed to the AT2R gene (AT2R‐Cre), and demonstrated that Cre recombinase activity mirrors AT2R mRNA expression within the NTS. Next, we used the Cre‐LoxP system and virally (AAV)‐mediated gene transfer to direct expression of the light‐sensitive excitatory opsin channelrhodopsin‐2 (ChR2) and/or eYFP specifically to neurons in the intNTS that synthesize AT2R. Using these mice, we performed electrophysiological‐ or cardiovascular recordings during optogenetic manipulations (blue light) that selectively excite AT2R‐expressing neurons in the intNTS. For the electrophysiological studies, optical stimulation produced a strong inward current in voltage clamp (611.80 ± 78.55 pA; n=9), and robust frequency dependent firing of action potentials in current‐clamp, validating functional opsin expression within AT2R‐expressing neurons. Optical activation of the Chr2/eYFP‐containing AT2R‐expressing neurons in brain slices resulted in activation of adjacent (non‐eYFP‐labeled) neurons, as indicated by light‐evoked currents (n=31), an effect blocked by GABA receptor antagonists (PTX and CGP). Cardiovascular studies revealed that (i) Optogenetic stimulation of the AT2R intNTS neurons expressing ChR2 in isoflurane anesthetized mice elicited significant elevations in BP compared with control mice that express only eYFP; (ii) The AT2R‐containing neurons that were activated by light stimulation are GABAergic, as indicated by increased expression and co‐localization of c‐Fos mRNA with GAD‐1 mRNA and eYFP; (iii) Chronic icv infusion of C21 as above significantly blunted the light‐induced increases in BP, an effect that persisted across all patterns of optical stimulation. Collectively, these data indicate that AT2R‐mediated decreases in BP involve a blunting of GABA signaling in the intNTS, and suggest that neurons expressing AT2R in the intNTS may be an access point for cardiovascular control.Support or Funding InformationNIH grants HL‐125805 (AdK), HL‐145028 (AdK), HL‐136595 (EGK/CS)

Activation Complexity: A Cognitive Impairment Tool for Characterizing Neuro-isolation

Electroencephalography (EEG) is a method for recording electrical activity, indicative of cortical brain activity from the scalp. EEG has been used to diagnose neurological diseases and to characterize impaired cognitive states. When the electrical activity of neurons are temporally synchronized, the likelihood to reach their threshold potential for the signal to propagate to the next neuron, increases. This phenomenon is typically analyzed as the spectral intensity increasing from the summation of these neurons firing. Non-linear analysis methods (e.g., entropy) have been explored to characterize neuronal firings, but only analyze temporal information and not the frequency spectrum. By examining temporal and spectral entropic relationships simultaneously, we can better characterize how neurons are isolated, (the signal’s inability to propagate to adjacent neurons), an indicator of impairment. A novel time-frequency entropic analysis method, referred to as Activation Complexity (AC), was designed to quantify these dynamics from key EEG frequency bands. The data was collected during a cognitive impairment study at NASA Langley Research Center, involving hypoxia induction in 49 human test subjects. AC demonstrated significant changes in EEG firing patterns characterize within explanatory (p < 0.05) and predictive models (10% increase in accuracy). The proposed work sets the methodological foundation for quantifying neuronal isolation and introduces new potential technique to understand human cognitive impairment for a range of neurological diseases and insults.