المؤلفون: Mori, Daisuke, Inami, Chihiro, Ikeda, Ryosuke, Sawahata, Masahito, Urata, Shinji, Yamaguchi, Sho, Kobayashi, Yohei, Fujita, Kosuke, Arioka, Yuko, Okumura, Hiroki, Kushima, Itaru, Kodama, Akiko, Hirao, Takashi, Yoshimi, Akira, Sobue, Akira, Ito, Takahiro, Noda, Yukikiro, Mizoguchi, Hiroyuki, Nagai, Taku, Kaibuchi, Kozo, Okabe, Shigeo, Nishiguchi, Koji, Kume, Kazuhiko, Yamada, Kiyofumi, Ozaki, Norio, Suzuki, Toshiaki

المصدر: Translational Psychiatry. 14(1)

مصطلحات موضوعية: Animals, Male, Mice, Behavior, Animal, Bipolar Disorder, Body Temperature, Cadherins, Circadian Rhythm, Disease Models, Animal, Locomotion, Mice, Inbred C57BL, Mice, Knockout, Prepulse Inhibition, Proto-Oncogene Proteins c-fos, Protocadherins

الوصف: Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5xh355t7Test
https://escholarship.org/content/qt5xh355t7/qt5xh355t7.pdfTest

المؤلفون: Okhuarobo, Agbonlahor, Angelo, Maggie, Bolton, Jessica L, Lopez, Catherine, Igbe, Ighodaro, Baram, Tallie Z, Contet, Candice

المصدر: Alcohol Clinical and Experimental Research. 47(2)

مصطلحات موضوعية: Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Basic Behavioral and Social Science, Behavioral and Social Science, Alcoholism, Alcohol Use and Health, Neurosciences, Substance Misuse, Good Health and Well Being, Animals, Female, Mice, Alcohol Drinking, Alcoholism, Ethanol, Mice, Inbred C57BL, Proto-Oncogene Proteins c-fos, Stress, Psychological, early-life stress, hyperkatifeia, pain, resilience, vulnerability, Clinical Sciences, Substance Abuse, Clinical sciences, Biological psychology, Clinical and health psychology

الوصف: BackgroundStressful early-life experiences increase the risk of developing an alcohol use disorder. We previously found that male C57BL/6J mice reared under limited bedding and nesting (LBN) conditions, a model of early-life adversity, escalate their ethanol intake in limited-access two-bottle choice (2BC) sessions faster than control (CTL)-reared counterparts when exposed to chronic intermittent ethanol (CIE) vapor inhalation. However, the alcohol consumption of female littermates was not affected by LBN or CIE. In the present study, we sought to determine whether this phenotype reflected a general insensitivity of female mice to the influence of early-life stress on alcohol responses.MethodsIn a first experiment, CTL and LBN females with a history of 2BC combined or not with CIE were tested in affective and nociceptive assays during withdrawal. In a second group of CTL and LBN females, we examined ethanol-induced antinociception, sedation, plasma clearance, and c-Fos induction.ResultsIn females withdrawn from chronic 2BC, CIE increased digging, reduced grooming, and increased immobility in the tail suspension test regardless of early-life history. In contrast, LBN rearing lowered mechanical nociceptive thresholds regardless of CIE exposure. In females acutely treated with ethanol, LBN rearing facilitated antinociception and delayed the onset of sedation without influencing ethanol clearance rate or c-Fos induction in the paraventricular nucleus of the hypothalamus, paraventricular nucleus of the thalamus, central nucleus of the amygdala, or auditory cortex.ConclusionCIE withdrawal produced multiple indices of negative affect in C57BL/6J females, suggesting that their motivation to consume alcohol may differ from air-exposed counterparts despite equivalent intake. Contrasted with our previous findings in males, LBN-induced mechanical hyperalgesia in chronic alcohol drinkers was specific to females. Lower nociceptive thresholds combined with increased sensitivity to the acute antinociceptive effect of ethanol may contribute to reinforcing ethanol consumption in LBN females but are not sufficient to increase their intake.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/73h137kxTest

المؤلفون: Galer, Erika L, Huang, Ruyi, Madhavan, Meghna, Wang, Emily, Zhou, Yan, Leiter, James C, Lu, Daniel C

المصدر: Journal of Neuroscience. 43(3)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Neurodegenerative, Lung, Neurological, Animals, Female, Male, Rats, Cervical Cord, Electric Stimulation, Neurons, Proto-Oncogene Proteins c-fos, Somatostatin, Spinal Cord, Respiratory Rate, cervical spinal cord, epidural stimulation, somatostatin, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery

الوصف: We tested the hypothesis that dorsal cervical epidural electrical stimulation (CEES) increases respiratory activity in male and female anesthetized rats. Respiratory frequency and minute ventilation were significantly increased when CEES was applied dorsally to the C2-C6 region of the cervical spinal cord. By injecting pseudorabies virus into the diaphragm and using c-Fos activity to identify neurons activated during CEES, we found neurons in the dorsal horn of the cervical spinal cord in which c-Fos and pseudorabies were co-localized, and these neurons expressed somatostatin (SST). Using dual viral infection to express the inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADD), hM4D(Gi), selectively in SST-positive cells, we inhibited SST-expressing neurons by administering Clozapine N-oxide (CNO). During CNO-mediated inhibition of SST-expressing cervical spinal neurons, the respiratory excitation elicited by CEES was diminished. Thus, dorsal cervical epidural stimulation activated SST-expressing neurons in the cervical spinal cord, likely interneurons, that communicated with the respiratory pattern generating network to effect changes in ventilation.SIGNIFICANCE STATEMENT A network of pontomedullary neurons within the brainstem generates respiratory behaviors that are susceptible to modulation by a variety of inputs; spinal sensory and motor circuits modulate and adapt this output to meet the demands placed on the respiratory system. We explored dorsal cervical epidural electrical stimulation (CEES) excitation of spinal circuits to increase ventilation in rats. We identified dorsal somatostatin (SST)-expressing neurons in the cervical spinal cord that were activated (c-Fos-positive) by CEES. CEES no longer stimulated ventilation during inhibition of SST-expressing spinal neuronal activity, thereby demonstrating that spinal SST neurons participate in the activation of respiratory circuits affected by CEES. This work establishes a mechanistic foundation to repurpose a clinically accessible neuromodulatory therapy to activate respiratory circuits and stimulate ventilation.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4d73j4q8Test

المؤلفون: Mayer, Heather, Rosinger, Zachary, Kruithof, Vivian, Mishra, Shambhavi, BlackOwl, Anthony, Stolzenberg, Danielle

مصطلحات موضوعية: Engram, FosTRAP2, Maternal experience, Maternal memory, Targeted recombination in active populations, Animals, Female, Humans, Hypothalamus, Maternal Behavior, Mice, Nucleus Accumbens, Preoptic Area, Proto-Oncogene Proteins c-fos

الوصف: Maternal experience can promote a long-lasting increase in maternal motivation. This maintenance of caregiving behaviors, rather than avoidant or agnostic responses towards young, is advantageous for the survival of subsequent offspring. We have previously reported that maternal motivation is associated with differential immediate early gene expression in central motivation circuits and aversion circuits. Here we ask how these circuits come to differentially respond to infant cues. We used Targeted Recombination in Active Populations (TRAP) to identify cells that respond to pups in maternally hesitant TRAP2;Ai14 virgin female mice. Following an initial 60 min exposure to foster pups, virgin TRAP2;Ai14 mice were injected with 4-hydroxytamoxifen to induce recombination in c-Fos expressing cells and subsequent permanent expression of a red fluorescent reporter. We then examined whether the same cells that encode pup cues are reactivated during maternal memory retrieval two weeks later using c-Fos immunohistochemistry. Whereas initial pup exposure induced c-Fos activation exclusively in the medial preoptic area (MPOA), following repeated experience, c-Fos expression was significantly higher than baseline in multiple regions of maternal and central aversion circuits (e.g., ventral bed nucleus of the stria terminalis, nucleus accumbens, basolateral amygdala, prefrontal cortex, medial amygdala, and ventromedial nucleus of the hypothalamus). Further, cells in many of these sites were significantly reactivated during maternal memory retrieval. These data suggest that cells across both maternal motivation and central aversion circuits are stably responsive to pups and thus may form the cellular representation of maternal memory.

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الوصول الحر: https://escholarship.org/uc/item/4hs867p3Test

المؤلفون: Cross, Sarah J, Leslie, Frances M

المصدر: Behavioural Pharmacology. 32(4)

مصطلحات موضوعية: Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Alcoholism, Alcohol Use and Health, Tobacco, Substance Misuse, Neurosciences, Basic Behavioral and Social Science, Tobacco Smoke and Health, Pediatric, Behavioral and Social Science, Mental health, Good Health and Well Being, Age Factors, Animals, Anxiety, Central Nervous System Depressants, Ethanol, Ganglionic Stimulants, Gene Expression Regulation, Developmental, Injections, Intravenous, Male, Models, Animal, Motivation, Motor Activity, Nicotine, Proto-Oncogene Proteins c-fos, Rats, Ventral Tegmental Area, adolescence, alcohol, anxiety, functional connectivity, stress, tobacco, Neurology & Neurosurgery, Pharmacology and pharmaceutical sciences, Biological psychology

الوصف: Use of alcohol (EtOH) and nicotine (Nic) typically begins during adolescence. Smoking and drinking often occur together and lead to a higher consumption of alcohol. Although we have shown that Nic+EtOH is reinforcing in self-administration tests in adolescent male rats, whether Nic+EtOH affects other behaviors or neuronal activity in an age-dependent manner is unknown. To address this, adolescent and adult male rats were given intravenous injections of Nic (30 µg/kg)+EtOH (4 mg/kg) and evaluated for locomotor and anxiety-like behaviors. Regional neuronal activity, assessed by cFos mRNA expression, was measured and used to evaluate functional connectivity in limbic regions associated with anxiety and motivation. Nic+EtOH increased locomotor activity and was anxiolytic in adolescents, but not adults. The posterior ventral tegmental area (pVTA), a critical regulator of drug reward, was selectively activated by Nic+EtOH in adults, while activity in its target region, the NAc-shell, was decreased. Drug-induced alterations in functional connectivity were more extensive in adults than adolescents and may act to inhibit behavioral responses to Nic+EtOH that are seen in adolescence. Overall, our findings suggest that brief, low-dose exposure to Nic+EtOH produces marked, age-dependent changes in brain and behavior and that there may be an ongoing maturation of the pVTA during adolescence that allows increased sensitivity to Nic+EtOH's reinforcing, hyperlocomotor, and anxiolytic effects. Furthermore, this work provides a potential mechanism for high rates of co-use of nicotine and alcohol by teenagers: this drug combination is anxiolytic and recruits functional networks that are unique from protective, inhibitory networks recruited in the mature and adult brain.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5vk2d4j0Test

المؤلفون: Leake, Jessica, Zinn, Raphael, Corbit, Laura H, Fanselow, Michael S, Vissel, Bryce

المصدر: Journal of Neuroscience. 41(18)

مصطلحات موضوعية: Basic Behavioral and Social Science, Mental Health, Neurosciences, Behavioral and Social Science, 1.2 Psychological and socioeconomic processes, Underpinning research, Mental health, Neurological, Good Health and Well Being, Animals, Conditioning, Classical, Dentate Gyrus, Discrimination, Psychological, Estrogen Antagonists, Fear, Hippocampus, Learning, Male, Memory, Mice, Mice, Inbred C57BL, Models, Psychological, Neurons, Proto-Oncogene Proteins c-fos, Tamoxifen, c-fos, context, engram, fear conditioning, hippocampus, memory, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery

الوصف: Memories are rarely acquired under ideal conditions, rendering them vulnerable to profound omissions, errors, and ambiguities. Consistent with this, recent work using context fear conditioning has shown that memories formed after inadequate learning time display a variety of maladaptive properties, including overgeneralization to similar contexts. However, the neuronal basis of such poor learning and memory imprecision remains unknown. Using c-fos to track neuronal activity in male mice, we examined how these learning-dependent changes in context fear memory precision are encoded in hippocampal ensembles. We found that the total number of c-fos-encoding cells did not correspond with learning history but instead more closely reflected the length of the session immediately preceding c-fos measurement. However, using a c-fos-driven tagging method (TRAP2 mouse line), we found that the degree of learning and memory specificity corresponded with neuronal activity in a subset of dentate gyrus cells that were active during both learning and recall. Comprehensive memories acquired after longer learning intervals were associated with more double-labeled cells. These were preferentially reactivated in the conditioning context compared with a similar context, paralleling behavioral discrimination. Conversely, impoverished memories acquired after shorter learning intervals were associated with fewer double-labeled cells. These were reactivated equally in both contexts, corresponding with overgeneralization. Together, these findings provide two surprising conclusions. First, engram size varies with learning. Second, larger engrams support better neuronal and behavioral discrimination. These findings are incorporated into a model that describes how neuronal activity is influenced by previous learning and present experience, thus driving behavior.SIGNIFICANCE STATEMENT Memories are not always formed under ideal circumstances. This is especially true in traumatic situations, such as car accidents, where individuals have insufficient time to process what happened around them. Such memories have the potential to overgeneralize to irrelevant situations, producing inappropriate fear and contributing to disorders, such as post-traumatic stress disorder. However, it is unknown how such poorly formed fear memories are encoded within the brain. We find that restricting learning time results in fear memories that are encoded by fewer hippocampal cells. Moreover, these fewer cells are inappropriately reactivated in both dangerous and safe contexts. These findings suggest that fear memories formed at brief periods overgeneralize because they lack the detail-rich information necessary to support neuronal discrimination.

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الوصول الحر: https://escholarship.org/uc/item/8nj131pvTest

المؤلفون: Hokenson, Rachael E, Short, Annabel K, Chen, Yuncai, Pham, Aidan L, Adams, Emily T, Bolton, Jessica L, Swarup, Vivek, Gall, Christine M, Baram, Tallie Z

المصدر: Journal of Neuroscience. 41(4)

مصطلحات موضوعية: Behavioral and Social Science, Mental Health, Neurosciences, Estrogen, Basic Behavioral and Social Science, Underpinning research, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Aetiology, Mental health, Animals, Brain, CA1 Region, Hippocampal, Dendritic Spines, Estrogens, Estrous Cycle, Estrus, Female, Male, Maze Learning, Memory Disorders, Mice, Mice, Inbred C57BL, Nerve Net, Proto-Oncogene Proteins c-fos, Spatial Memory, Stress, Psychological, Uterus, estrogen, hippocampus, memory, sex differences, stress, synapses, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery

الوصف: Stress may promote emotional and cognitive disturbances, which differ by sex. Adverse outcomes, including memory disturbances, are typically observed following chronic stress, but are now being recognized also after short events, including mass shootings, assault, or natural disasters, events that consist of concurrent multiple acute stresses (MAS). Prior work has established profound and enduring effects of MAS on memory in males. Here we examined the effects of MAS on female mice and probed the role of hormonal fluctuations during the estrous cycle on MAS-induced memory problems and the underlying brain network and cellular mechanisms. Female mice were impacted by MAS in an estrous cycle-dependent manner: MAS impaired hippocampus-dependent spatial memory in early-proestrous mice, characterized by high levels of estradiol, whereas memory of mice stressed during estrus (low estradiol) was spared. As spatial memory requires an intact dorsal hippocampal CA1, we examined synaptic integrity in mice stressed at different cycle phases and found a congruence of dendritic spine density and spatial memory deficits, with reduced spine density only in mice stressed during high estradiol cycle phases. Assessing MAS-induced activation of brain networks interconnected with hippocampus, we identified differential estrous cycle-dependent activation of memory- and stress-related regions, including the amygdala. Network analyses of the cross-correlation of fos expression among these regions uncovered functional connectivity that differentiated impaired mice from those not impaired by MAS. In conclusion, the estrous cycle modulates the impact of MAS on spatial memory, and fluctuating physiological levels of sex hormones may contribute to this effect.SIGNIFICANCE STATEMENT: Effects of stress on brain functions, including memory, are profound and sex-dependent. Acute stressors occurring simultaneously result in spatial memory impairments in males, but effects on females are unknown. Here we identified estrous cycle-dependent effects of such stresses on memory in females. Surprisingly, females with higher physiological estradiol experienced stress-induced memory impairment and a loss of underlying synapses. Memory- and stress-responsive brain regions interconnected with hippocampus were differentially activated across high and low estradiol mice, and predicted memory impairment. Thus, at functional, network, and cellular levels, physiological estradiol influences the effects of stress on memory in females, providing insight into mechanisms of prominent sex differences in stress-related memory disorders, such as post-traumatic stress disorder.

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الوصول الحر: https://escholarship.org/uc/item/0wt5w8dkTest

المؤلفون: Li, Liang, Yang, Ming, Shrestha, Saroj Kumar, Kim, Hyoungsu, Gerwick, William H, Soh, Yunjo

المصدر: International Journal of Molecular Sciences. 22(5)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biological Sciences, Medicinal and Biomolecular Chemistry, Chemical Sciences, Microbiology, Osteoporosis, Aetiology, Underpinning research, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Musculoskeletal, Actins, Animals, Bone Density, Bone Resorption, Cathepsin K, Cell Survival, Inflammation, Janus Kinases, Lipids, Lipopolysaccharides, Lyngbya, MAP Kinase Signaling System, Macrophage Colony-Stimulating Factor, Macrophages, Male, Matrix Metalloproteinase 9, Membrane Proteins, Mice, Mice, Inbred ICR, NFATC Transcription Factors, Nerve Tissue Proteins, Osteoclasts, Osteogenesis, Phosphorylation, Proto-Oncogene Proteins c-fos, RANK Ligand, Tartrate-Resistant Acid Phosphatase, Thiazoles, kalkitoxin, marine natural product, osteoclast, inflammation, bone loss, Other Chemical Sciences, Genetics, Other Biological Sciences, Chemical Physics, Biochemistry and cell biology, Medicinal and biomolecular chemistry

الوصف: Osteoclasts, bone-specified multinucleated cells produced by monocyte/macrophage, are involved in numerous bone destructive diseases such as arthritis, osteoporosis, and inflammation-induced bone loss. The osteoclast differentiation mechanism suggests a possible strategy to treat bone diseases. In this regard, we recently examined the in vivo impact of kalkitoxin (KT), a marine product obtained from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), on the macrophage colony-stimulating factor (M-CSF) and on the receptor activator of nuclear factor κB ligand (RANKL)-stimulated in vitro osteoclastogenesis and inflammation-mediated bone loss. We have now examined the molecular mechanism of KT in greater detail. KT decreased RANKL-induced bone marrow-derived macrophages (BMMs) tartrate-resistant acid phosphatase (TRAP)-multinucleated cells at a late stage. Likewise, KT suppressed RANKL-induced pit area and actin ring formation in BMM cells. Additionally, KT inhibited several RANKL-induced genes such as cathepsin K, matrix metalloproteinase (MMP-9), TRAP, and dendritic cell-specific transmembrane protein (DC-STAMP). In line with these results, RANKL stimulated both genes and protein expression of c-Fos and nuclear factor of activated T cells (NFATc1), and this was also suppressed by KT. Moreover, KT markedly decreased RANKL-induced p-ERK1/2 and p-JNK pathways at different time points. As a result, KT prevented inflammatory bone loss in mice, such as bone mineral density (BMD) and osteoclast differentiation markers. These experiments demonstrated that KT markedly inhibited osteoclast formation and inflammatory bone loss through NFATc1 and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, KT may have potential as a treatment for destructive bone diseases.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8r24r062Test

المؤلفون: Löken, Line S, Braz, Joao M, Etlin, Alexander, Sadeghi, Mahsa, Bernstein, Mollie, Jewell, Madison, Steyert, Marilyn, Kuhn, Julia, Hamel, Katherine, Llewellyn-Smith, Ida J, Basbaum, Allan

مصطلحات موضوعية: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Peripheral Neuropathy, Chronic Pain, Neurodegenerative, Pain Research, Physical Injury - Accidents and Adverse Effects, 2.1 Biological and endogenous factors, Aetiology, Neurological, Animals, Behavior, Animal, Calcitonin Gene-Related Peptide, Disease Models, Animal, Hyperalgesia, Interneurons, Mechanotransduction, Cellular, Mice, Inbred C57BL, Mice, Transgenic, Neural Inhibition, Pain Threshold, Peripheral Nerve Injuries, Physical Stimulation, Posterior Horn Cells, Proto-Oncogene Proteins c-fos, Vesicular Glutamate Transport Protein 1, Mice, CGRP, interneurons, mechanical sensitivity, mouse, neuroscience, pain, spinal cord, touch, Biochemistry and Cell Biology, Biological sciences, Biomedical and clinical sciences, Health sciences

الوصف: Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible CalcaCreER transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally directed, dendrites, and ventrally directed axons. As under resting conditions, CGRP interneurons are under tonic inhibitory control, neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive Aβ primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. On the other hand, chemogenetic activation of the neurons produced a mechanical hypersensitivity in response to von Frey stimulation, whereas their caspase-mediated ablation led to mechanical hyposensitivity. Finally, after partial peripheral nerve injury, innocuous stimulation (brush) induced significant Fos expression in the CGRP interneurons. These findings suggest that CGRP interneurons become hyperexcitable and contribute either to ascending circuits originating in deep dorsal horn or to the reflex circuits in baseline conditions, but not in the setting of nerve injury.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1sj0862bTest
https://escholarship.org/content/qt1sj0862b/qt1sj0862b.pdfTest

المؤلفون: Ravindran, Pavithran T, Wilson, Maxwell Z, Jena, Siddhartha G, Toettcher, Jared E

المصدر: Communications biology. 3(1)

مصطلحات موضوعية: NIH 3T3 Cells, Animals, Mice, DNA Damage, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins c-fos, Mitogens, Genetic Engineering, Signal Transduction, Transcription, Genetic, Gene Expression Regulation, Kinetics, Genes, Immediate-Early, Genes, Synthetic

الوصف: Many cell- and tissue-level functions are coordinated by intracellular signaling pathways that trigger the expression of context-specific target genes. Yet the input-output relationships that link pathways to the genes they activate are incompletely understood. Mapping the pathway-decoding logic of natural target genes could also provide a basis for engineering novel signal-decoding circuits. Here we report the construction of synthetic immediate-early genes (SynIEGs), target genes of Erk signaling that implement complex, user-defined regulation and can be monitored by using live-cell biosensors to track their transcription and translation. We demonstrate the power of this approach by confirming Erk duration-sensing by FOS, elucidating how the BTG2 gene is differentially regulated by external stimuli, and designing a synthetic immediate-early gene that selectively responds to the combination of growth factor and DNA damage stimuli. SynIEGs pave the way toward engineering molecular circuits that decode signaling dynamics and combinations across a broad range of cellular contexts.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4z49t3fkTest