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Nervous systems have evolved to function consistently in the face of the normal environmental fluctuations experienced by animals. The stomatogastric nervous system (STNS) of the crab, Cancer borealis, produces a motor output that has been studied for its remarkable robustness in response to single global perturbations. Changes in environments, however, are often complex and multifactorial. Therefore, we studied the robustness of the pyloric network in the stomatogastric ganglion (STG) in response to simultaneous perturbations of temperature and pH. We compared the effects of elevated temperatures on the pyloric rhythm at control, acid, or base pHs. In each pH recordings were made at 11°C, and then the temperature was increased until the rhythms became disorganized ("crashed"). Pyloric burst frequencies and phase relationships showed minor differences between pH groups until reaching close to the crash temperatures. However, the temperatures at which the rhythms were disrupted were lower in the two extreme pH conditions. This indicates that one environmental stress can make an animal less resilient to a second stressor.NEW & NOTEWORTHY Resilience to environmental fluctuations is important for all animals. It is common that animals encounter multiple stressful events at the same time, the cumulative impacts of which are largely unknown. This study examines the effects of temperature and pH on the nervous system of crabs that live in the fluctuating environments of the Northern Atlantic Ocean. The ranges of tolerance to one perturbation, temperature, are reduced under the influence of a second, pH.
Assuntos
Braquiúros , Piloro , Animais , Temperatura , Piloro/fisiologia , Gânglios dos Invertebrados/fisiologia , Braquiúros/fisiologiaRESUMO
A variety of nonlinear models of biological systems generate complex chaotic behaviors that contrast with biological homeostasis, the observation that many biological systems prove remarkably robust in the face of changing external or internal conditions. Motivated by the subtle dynamics of cell activity in a crustacean central pattern generator (CPG), this paper proposes a refinement of the notion of chaos that reconciles homeostasis and chaos in systems with multiple timescales. We show that systems displaying relaxation cycles while going through chaotic attractors generate chaotic dynamics that are regular at macroscopic timescales and are, thus, consistent with physiological function. We further show that this relative regularity may break down through global bifurcations of chaotic attractors such as crises, beyond which the system may also generate erratic activity at slow timescales. We analyze these phenomena in detail in the chaotic Rulkov map, a classical neuron model known to exhibit a variety of chaotic spike patterns. This leads us to propose that the passage of slow relaxation cycles through a chaotic attractor crisis is a robust, general mechanism for the transition between such dynamics. We validate this numerically in three other models: a simple model of the crustacean CPG neural network, a discrete cubic map, and a continuous flow.
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The MAPK/ERK (mitogen-activated protein kinases/extracellular signal-regulated kinase) pathway is a cardinal regulator of synaptic plasticity, learning, and memory in the hippocampus. One of major endpoints of this signaling cascade is the 5' mRNA cap binding protein eIF4E (eukaryotic Initiation Factor 4E), which is phosphorylated on Ser 209 by MNK (MAPK-interacting protein kinases) and controls mRNA translation. The precise role of phospho-eIF4E in the brain is yet to be determined. Herein, we demonstrate that ablation of eIF4E phosphorylation in male mice (4Eki mice) does not impair long-term spatial or contextual fear memory, or the late phase of LTP. Using unbiased translational profiling in mouse brain, we show that phospho-eIF4E differentially regulates the translation of a subset of mRNAs linked to inflammation, the extracellular matrix, pituitary hormones, and the serotonin pathway. Consequently, 4Eki male mice display exaggerated inflammatory responses and reduced levels of serotonin, concomitant with depression and anxiety-like behaviors. Remarkably, eIF4E phosphorylation is required for the chronic antidepressant action of the selective serotonin reuptake inhibitor fluoxetine. Finally, we propose a novel phospho-eIF4E-dependent translational control mechanism in the brain, via the GAIT complex (gamma IFN activated inhibitor of translation). In summary, our work proposes a novel translational control mechanism involved in the regulation of inflammation and depression, which could be exploited to design novel therapeutics.SIGNIFICANCE STATEMENT We demonstrate that downstream of the MAPK (mitogen-activated protein kinase) pathway, eukaryotic Initiation Factor 4E (eIF4E) Ser209 phosphorylation is not required for classical forms of hippocampal LTP and memory. We reveal a novel role for eIF4E phosphorylation in inflammatory responses and depression-like behaviors. eIF4E phosphorylation is required for the chronic action of antidepressants, such as fluoxetine in mice. These phenotypes are accompanied by selective translation of extracellular matrix, pituitary hormones, and serotonin pathway genes, in eIF4E phospho-mutant mice. We also describe a previously unidentified translational control mechanism in the brain, whereby eIF4E phosphorylation is required for inhibiting the translation of gamma IFN activated inhibitor of translation element-containing mRNAs. These findings can be used to design novel therapeutics for depression.
Assuntos
Depressão/metabolismo , Fator de Iniciação 4E em Eucariotos/metabolismo , Inflamação/metabolismo , Biossíntese de Proteínas/fisiologia , Animais , Depressão/fisiopatologia , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , FosforilaçãoRESUMO
Neuronal activity and energy supply must maintain a fine balance for neuronal fitness. Various channels of communication between the two could impact network output in different ways. Sulfonylurea receptors (SURs) are a modification of ATP-binding cassette proteins (ABCs) that confer ATP-dependent gating on their associated ion channels. They are widely expressed and link metabolic states directly to neuronal activity. The role they play varies in different circuits, both enabling bursting and inhibiting activity in pathological conditions. The crab, Cancer borealis, has central patterns generators (CPGs) that fire in rhythmic bursts nearly constantly and it is unknown how energy availability influences these networks. The pyloric network of the stomatogastric ganglion (STG) and cardiac ganglion (GC) control rhythmic contractions of the foregut and heart respectively. Pharmacological manipulation of SURs results in opposite effects in the two CPGs. Neuronal firing completely stops in the STG when SUR-associated channels are open, and firing increases when the channels are closed. This results from a decrease in the excitability of pyloric dilator (PD) neurons, which are a part of the pacemaker kernel. The neurons of the CG, paradoxically, increase firing within bursts when SUR-associated channels are opened, and bursting slows when SUR-associated channels are closed. The channel permeability and sensitivities analyses present novel SUR-conductance biophysics, which nevertheless change activity in ways reminiscent of the predominantly studied mammalian receptor/channels. We suggest that SUR-associated conductances allow different neurons to respond to energy states in different ways through a common mechanism.
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In many animals, the daily cycling of light is a key environmental cue, encoded in part by specialized light-sensitive neurons without visual functions. We serendipitously discovered innate light-responsiveness while imaging the extensively studied stomatogastric ganglion (STG) of the crab, Cancer borealis. The STG houses a motor circuit that controls the rhythmic contractions of the foregut, and the system has facilitated deep understanding of circuit function and neuromodulation. We illuminated the crab STG in vitro with different wavelengths and amplitudes of light and found a dose-dependent increase in neuronal activity upon exposure to blue light (λ460-500 nm). The response was elevated in the absence of neuromodulatory inputs to the STG. The pacemaker kernel that drives the network rhythm was responsive to light when synaptically isolated, and light shifted the threshold for slow wave and spike activity in the hyperpolarized direction, accounting for the increased activity patterns. Cryptochromes are evolutionarily conserved blue-light photoreceptors that are involved in circadian behaviors.1 Their activation by light can lead to enhanced neuronal activity.2 We identified cryptochrome sequences in the C. borealis transcriptome as potential mediators of this response and confirmed their expression in pyloric dilator (PD) neurons, which are part of the pacemaker kernel, by single-cell RNA-seq analysis.
Assuntos
Braquiúros , Neoplasias , Animais , Braquiúros/fisiologia , Gânglios , Gânglios dos Invertebrados/metabolismo , Neoplasias/metabolismo , Neurônios/fisiologia , PeriodicidadeRESUMO
Small rhythmic circuits, such as those found in invertebrates, have provided fundamental insights into how circuit dynamics depend on individual neuronal and synaptic properties. Degenerate circuits are those with different network parameters and similar behavior. New work on degenerate circuits and their modulation illustrates some of the rules that help maintain stable and robust circuit function despite environmental perturbations. Advances in neuropeptide isolation and identification provide enhanced understanding of the neuromodulation of circuits for behavior. The advent of molecular studies of mRNA expression provides new insight into animal-to-animal variability and the homeostatic regulation of excitability in neurons and networks.
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Rede Nervosa , Neurônios , Animais , Homeostase/fisiologia , Invertebrados , Rede Nervosa/fisiologia , Neurônios/fisiologia , RNA MensageiroRESUMO
BACKGROUND: Anemia is the commonest nutritional deficiency disorder in the world, particularly in developing countries. Though anemia is easily treatable and largely preventable disease if timely detected, it still continues to be significantly prevalent among pregnant women. AIM: The aim of this study was to measure the extent of anemia in pregnancy and to assess the association of risk factors with anemia. STUDY DESIGN: Hospital-based cross-sectional descriptive study. MATERIALS AND METHODS: A total of 200 women were selected among pregnant women attending antenatal clinic. Sampling was done by selecting every fifth woman visiting antenatal clinic within the duration of two months on alternate days. Data were collected using a predesigned, pretested semi-structured schedule. Hemoglobin concentrations were also recorded for each patient. Data were analyzed using Chi-square test and 'T' test of significance. A value of P < 0.05 was considered significant. RESULTS: We found overall prevalence of anemia to be 90% among pregnant women. Most of the anemic patients (60.5%) belong to moderate severity according to the World Health Organization classification. Three factors namely socioeconomic status, gravida and time of 1st antenatal visit were significantly associated with prevalence of anemia in pregnancy (P < 0.05). CONCLUSION: In this study, a high prevalence of anemia was found in pregnant women. Low socioeconomic status, multigravida and delayed visit to antenatal clinic were significantly associated with anemia in pregnancy. So, awareness and education programs should be generated to make people come to know about anemia, its complications during pregnancy and ways to prevent it.
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Fragile X syndrome (FXS), a commonly inherited form of autism and intellectual disability, is associated with emotional symptoms that implicate dysfunction of the amygdala. However, current understanding of the pathogenesis of the disease is based primarily on studies in the hippocampus and neocortex, where FXS defects have been corrected by inhibiting group I metabotropic glutamate receptors (mGluRs). Here, we observe that activation, rather than inhibition, of mGluRs in the basolateral amygdala reverses impairments in a rat model of FXS. FXS rats exhibit deficient recall of auditory conditioned fear, which is accompanied by a range of in vitro and in vivo deficits in synaptic transmission and plasticity. We find presynaptic mGluR5 in the amygdala, activation of which reverses deficient synaptic transmission and plasticity, thereby restoring normal fear learning in FXS rats. This highlights the importance of modifying the prevailing mGluR-based framework for therapeutic strategies to include circuit-specific differences in FXS pathophysiology.
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Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Comportamento Animal , Medo , Síndrome do Cromossomo X Frágil/fisiopatologia , Rememoração Mental , Plasticidade Neuronal , Transmissão Sináptica , Animais , Complexo Nuclear Basolateral da Amígdala/metabolismo , Modelos Animais de Doenças , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/psicologia , Masculino , Ratos Sprague-Dawley , Ratos Transgênicos , Receptor de Glutamato Metabotrópico 5/metabolismoRESUMO
Although mGluR5-antagonists prevent fear and anxiety, little is known about how the same receptor in the amygdala gives rise to both. Combining in vitro and in vivo activation of mGluR5 in rats, we identify specific changes in intrinsic excitability and synaptic plasticity in basolateral amygdala neurons that give rise to temporally distinct and mutually exclusive effects on fear-related behaviors. The immediate impact of mGluR5 activation is to produce anxiety manifested as indiscriminate fear of both tone and context. Surprisingly, this state does not interfere with the proper encoding of tone-shock associations that eventually lead to enhanced cue-specific fear. These results provide a new framework for dissecting the functional impact of amygdalar mGluR-plasticity on fear versus anxiety in health and disease.
Assuntos
Tonsila do Cerebelo/fisiologia , Ansiedade , Medo , Receptores de Ácido Caínico/agonistas , Animais , Comportamento Animal , RatosRESUMO
A majority of rodent studies characterizing the anxiogenic effects of stress have utilized exploration-based models, such as the elevated plus-maze. An alternative strategy has relied on ethologically natural behavior such as defensive burying. One such paradigm, marble burying, has proven to be an effective behavioral assay of the anxiolytic effects of pharmacological manipulations, and of genetically modified mouse models. Relatively little, however, is known about the sensitivity of this test in assessing the anxiogenic effects of stress. Most of the earlier reports have examined the immediate, but not more long-term, effects of pharmacological or environmental manipulations in mice. Hence, we used the marble burying test to examine if acute immobilization stress leads to enhanced anxiety-like behavior in C57Bl/6 mice if the test is employed with a significant time delay. We find this test to be sensitive enough to detect the anxiogenic effects even 10 days after a single episode of 2-h immobilization stress. Our results suggest that the marble burying test could serve as a useful behavioral paradigm for not only estimating the gradual progression of the anxiogenic impact of stress over time, but also raises the possibility of using the temporal delay after stress to test the potential efficacy of post-stress interventions with anxiolytic drugs.