Gain Control With A-Type Potassium Current: IA As A Switch Between Divisive And Subtractive Inhibition

Neurons process and convey information by transforming barrages of synaptic inputs into spiking activity. Synaptic inhibition typically suppresses the output firing activity of a neuron, and is commonly classified as having a subtractive or divisive effect on a neuron’s output firing activity. Subtractive inhibition can narrow the range of inputs that evoke spiking activity by eliminating responses to non-preferred inputs. Divisive inhibition is a form of gain control: it modifies firing rates while preserving the range of inputs that evoke firing activity. Since these two “modes” of inhibition have distinct impacts on neural coding, it is important to understand the biophysical mechanisms that distinguish these response profiles. In this study, we use simulations and mathematical analysis of a neuron model to find the specific conditions (parameter sets) for which inhibitory inputs have subtractive or divisive effects. Significantly, we identify a novel role for the A-type Potassium current (IA). In our model, this fast-activating, slowly-inactivating outward current acts as a switch between subtractive and divisive inhibition. In particular, if IA is strong (large maximal conductance) and fast (activates on a time-scale similar to spike initiation), then inhibition has a subtractive effect on neural firing. In contrast, if IA is weak or insufficiently fast-activating, then inhibition has a divisive effect on neural firing. We explain these findings using dynamical systems methods (plane analysis and fast-slow dissection) to define how a spike threshold condition depends on synaptic inputs and IA. Our findings suggest that neurons can “self-regulate” the gain control effects of inhibition via combinations of synaptic plasticity and/or modulation of the conductance and kinetics of A-type Potassium channels. This novel role for IA would add flexibility to neurons and networks, and may relate to recent observations of divisive inhibitory effects on neurons in the nucleus of the solitary tract

Gain control with A-type potassium current: IA as a switch between divisive and subtractive inhibition

Neurons process information by transforming barrages of synaptic inputs into spiking activity. Synaptic inhibition suppresses the output firing activity of a neuron, and is commonly classified as having a subtractive or divisive effect on a neuron's output firing activity. Subtractive inhibition can narrow the range of inputs that evoke spiking activity by eliminating responses to non-preferred inputs. Divisive inhibition is a form of gain control: it modifies firing rates while preserving the range of inputs that evoke firing activity. Since these two "modes" of inhibition have distinct impacts on neural coding, it is important to understand the biophysical mechanisms that distinguish these response profiles. We use simulations and mathematical analysis of a neuron model to find the specific conditions for which inhibitory inputs have subtractive or divisive effects. We identify a novel role for the A-type Potassium current (IA). In our model, this fast-activating, slowly- inactivating outward current acts as a switch between subtractive and divisive inhibition. If IA is strong (large maximal conductance) and fast (activates on a time-scale similar to spike initiation), then inhibition has a subtractive effect on neural firing. In contrast, if IA is weak or insufficiently fast-activating, then inhibition has a divisive effect on neural firing. We explain these findings using dynamical systems methods to define how a spike threshold condition depends on synaptic inputs and IA. Our findings suggest that neurons can "self-regulate" the gain control effects of inhibition via combinations of synaptic plasticity and/or modulation of the conductance and kinetics of A-type Potassium channels. This novel role for IA would add flexibility to neurons and networks, and may relate to recent observations of divisive inhibitory effects on neurons in the nucleus of the solitary tract.Comment: 20 pages, 11 figure

Platelet-Activating Factor-Induced Reduction in Contact Hypersensitivity Responses Is Mediated by Mast Cells via Cyclooxygenase-2-Dependent Mechanisms

Platelet-activating factor (PAF) stimulates numerous cell types via activation of the G protein-coupled PAF receptor (PAFR). PAFR activation not only induces acute proinflammatory responses, but it also induces delayed systemic immunosuppressive effects by modulating host immunity. Although enzymatic synthesis and degradation of PAF are tightly regulated, oxidative stressors, such as UVB, chemotherapy, and cigarette smoke, can generate PAF and PAF-like molecules in an unregulated fashion via the oxidation of membrane phospholipids. Recent studies have demonstrated the relevance of the mast cell (MC) PAFR in PAFR-induced systemic immunosuppression. The current study was designed to determine the exact mechanisms and mediators involved in MC PAFR-mediated systemic immunosuppression. By using a contact hypersensitivity model, the MC PAFR was not only found to be necessary, but also sufficient to mediate the immunosuppressive effects of systemic PAF. Furthermore, activation of the MC PAFR induces MC-derived histamine and PGE2 release. Importantly, PAFR-mediated systemic immunosuppression was defective in mice that lacked MCs, or in MC-deficient mice transplanted with histidine decarboxylase- or cyclooxygenase-2-deficient MCs. Lastly, it was found that PGs could modulate MC migration to draining lymph nodes. These results support the hypothesis that MC PAFR activation promotes the immunosuppressive effects of PAF in part through histamine- and PGE2-dependent mechanisms

Platelet-Activating Factor-Receptor and Tumor Immunity

First described in 1972 by Benveniste and colleagues, platelet-activating factor (PAF) remains one of the potent phospholipid known to date. The role of PAF produced enzymatically in mediating diverse biological and pathophysiological processes including inflammatory and allergic diseases and cancers in response to various stimuli has been extensively studied. However, little is known about the role of non-enzymatically-generated PAF-like lipids produced in response to pro-oxidative stressors, particularly in modulating the host immune responses to tumor immunity, which is the focus of this review

The IUPUI Signature Center for Atopic Dermatitis

poster abstractAtopic dermatitis is a chronic inflammatory skin disease characterized by dry skin, hypersensitivity to irritants and allergens, and significant pruritus. Atopic dermatitis is commonly associated with other atopic diseases including asthma, allergic rhinitis, and gastrointestinal disorders including eosinophilic esophagitis. Though a very common disease, there exists much misinformation and controversy/conflict in both the lay and medical communities about its pathogenesis and treatment, resulting in suboptimal care for the atopic dermatitis patient. Thus, education of both clinicians and lay public is needed. Inasmuch as atopic dermatitis is considered a systemic disorder, the optimal management should entail a multidisciplinary approach. Finally, research into the mechanisms by which atopic dermatitis occurs is needed to improve treatment of this common and quite debilitating disorder. The objective of the IUPUI Signature Center for Atopic Dermatitis is to provide optimal patient care, education and research in atopic dermatitis for the citizens of the state of Indiana. The Atopic Dermatitis has three separate components. First, we have developed an Atopic Dermatitis Working Group (ADWG) consisting of clinicians and scientists who meet on a monthly basis to disseminate information about research ideas/trials, and discuss topics and present difficult patients. Second, we have developed a monthly multidisciplinary AD clinic which has attracted the most challenging AD patients. Finally, we have developed infrastructure to assist in clinical and basic science research projects involving AD. Altogether, the IUPUI Signature Center for AD has been very successful as measured by the numbers of clinicians, researchers and patients who have been impacted by its presence

Memory, learning and language in autism spectrum disorder

Background and aims: The ‘dual-systems’ model of language acquisition has been used by Ullman and colleagues to explain patterns of strength and weakness in the language of higher-functioning people with autism spectrum disorder (ASD). Specifically, intact declarative/explicit learning is argued to compensate for a deficit in non-declarative/implicit procedural learning, constituting an example of the so-called ‘see-saw’ effect. Ullman and Pullman (2015) extended their argument concerning a see-saw effect on language in ASD to cover other perceived anomalies of behaviour, including impaired acquisition of social skills. The aim of this paper is to present a critique of Ullman and colleagues’ claims, and to propose an alternative model of links between memory systems and language in ASD. Main contribution: We argue that a 4-systems model of learning, in which intact semantic and procedural memory are used to compensate for weaknesses in episodic memory and perceptual learning, can better explain patterns of language ability across the autistic spectrum. We also argue that attempts to generalise the ‘impaired implicit learning/spared declarative learning’ theory to other behaviours in ASD are unsustainable. Conclusions: Clinically significant language impairments in ASD are under-researched, despite their impact on everyday functioning and quality of life. The relative paucity of research findings in this area lays it open to speculative interpretation which may be misleading. Implications: More research is need into links between memory/learning systems and language impairments across the spectrum. Improved understanding should inform therapeutic intervention, and contribute to investigation of the causes of language impairment in ASD with potential implications for prevention

Scale-free networks with tunable degree distribution exponents

We propose and study a model of scale-free growing networks that gives a degree distribution dominated by a power-law behavior with a model-dependent, hence tunable, exponent. The model represents a hybrid of the growing networks based on popularity-driven and fitness-driven preferential attachments. As the network grows, a newly added node establishes $m$ new links to existing nodes with a probability $p$ based on popularity of the existing nodes and a probability $1-p$ based on fitness of the existing nodes. An explicit form of the degree distribution $P(p,k)$ is derived within a mean field approach. For reasonably large $k$, $P(p,k) \sim k^{-\gamma(p)}{\cal F}(k,p)$, where the function ${\cal F}$ is dominated by the behavior of $1/\ln(k/m)$ for small values of $p$ and becomes $k$-independent as $p \to 1$, and $\gamma(p)$ is a model-dependent exponent. The degree distribution and the exponent $\gamma(p)$ are found to be in good agreement with results obtained by extensive numerical simulations.Comment: 12 pages, 2 figures, submitted to PR

Insulin-like Growth Factor 1 Receptor Signaling Is Required for Optimal ATR-CHK1 Kinase Signaling in Ultraviolet B (UVB)-irradiated Human Keratinocytes

UVB wavelengths of light induce the formation of photoproducts in DNA that are potentially mutagenic if not properly removed by the nucleotide excision repair machinery. As an additional mechanism to minimize the risk of mutagenesis, UVB-irradiated cells also activate a checkpoint signaling cascade mediated by the ATM and Rad3-related (ATR) and checkpoint kinase 1 (CHK1) kinases to transiently suppress DNA synthesis and cell cycle progression. Given that keratinocytes in geriatric skin display reduced activation of the insulin-like growth factor 1 receptor (IGF-1R) and alterations in DNA repair rate, apoptosis, and senescence following UVB exposure, here we used cultured human keratinocytes in vitro and skin explants ex vivo to examine how IGF-1R activation status affects ATR-CHK1 kinase signaling and the inhibition of DNA replication following UVB irradiation. We find that disruption of IGF-1R signaling with small-molecule inhibitors or IGF-1 withdrawal partially abrogates both the phosphorylation and activation of CHK1 by ATR and the accompanying inhibition of chromosomal DNA synthesis in UVB-irradiated keratinocytes. A critical protein factor that mediates both ATR-CHK1 signaling and nucleotide excision repair is replication protein A, and we find that its accumulation on UVB-damaged chromatin is partially attenuated in cells with an inactive IGF-1R. These results indicate that mutagenesis and skin carcinogenesis in IGF-1-deficient geriatric skin may be caused by defects in multiple cellular responses to UVB-induced DNA damage, including through a failure to properly suppress DNA synthesis on UVB-damaged DNA templates

Detection of HC11N in the Cold Dust Cloud TMC-1

Two consecutive rotational transitions of the long cyanopolyyne HC11N, J=39-38, and J=38-37, have been detected in the cold dust cloud TMC-1 at the frequencies expected from recent laboratory measurements by Travers et al. (1996), and at about the expected intensities. The astronomical lines have a mean radial velocity of 5.8(1) km/s, in good agreement with the shorter cyanopolyynes HC7N and HC9N observed in this very sharp-lined source [5.82(5) and 5.83(5) km/s, respectively]. The column density of HC11N is calculated to be 2.8x10^(11) cm^(-2). The abundance of the cyanopolyynes decreases smoothly with length to HC11N, the decrement from one to the next being about 6 for the longer carbon chains.Comment: plain tex 10 pages plus 3 ps fig file