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In vivo neuroimaging and behavioral correlates in a rat model of chemotherapy-induced cognitive dysfunction.
Barry RL, Byun NE, Tantawy MN, Mackey CA, Wilson GH, Stark AJ, Flom MP, Gee LC, Quarles CC
(2018) Brain Imaging Behav 12: 87-95
MeSH Terms: Animals, Antineoplastic Agents, Brain, Brain Mapping, Cognitive Dysfunction, Conditioning (Psychology), Disease Models, Animal, Doxorubicin, Fear, Female, Fluorodeoxyglucose F18, Magnetic Resonance Imaging, Neuroimaging, Positron-Emission Tomography, Radiopharmaceuticals, Rats, Sprague-Dawley, Recognition (Psychology), Tomography, X-Ray Computed
Show Abstract · Added March 14, 2018
Adjuvant chemotherapy has been used for decades to treat cancer, and it is well known that disruptions in cognitive function and memory are common chemotherapeutic adverse effects. However, studies using neuropsychological metrics have also reported group differences in cognitive function and memory before or without chemotherapy, suggesting that complex factors obscure the true etiology of chemotherapy-induced cognitive dysfunction (CICD) in humans. Therefore, to better understand possible mechanisms of CICD, we explored the effects of CICD in rats through cognition testing using novel object recognition (NOR) and contextual fear conditioning (CFC), and through metabolic neuroimaging via [F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Cancer-naïve, female Sprague-Dawley rats were administered either saline (1 mL/kg) or doxorubicin (DOX) (1 mg/kg in a volume of 1 mL/kg) weekly for five weeks (total dose = 5 mg/kg), and underwent cognition testing and PET imaging immediately following the treatment regime and 30 days post treatment. We did not observe significant differences with CFC testing post-treatment for either group. However, the chemotherapy group exhibited significantly decreased performance in the NOR test and decreased F-FDG uptake only in the prefrontal cortex 30 days post-treatment. These results suggest that long-term impairment within the prefrontal cortex is a plausible mechanism of CICD in this study, suggesting DOX-induced toxicity in the prefrontal cortex at the dose used.
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18 MeSH Terms
Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M PAM VU6004256.
Grannan MD, Mielnik CA, Moran SP, Gould RW, Ball J, Lu Z, Bubser M, Ramsey AJ, Abe M, Cho HP, Nance KD, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW, Jones CK
(2016) ACS Chem Neurosci 7: 1706-1716
MeSH Terms: Action Potentials, Animals, Cholinergic Agents, Cognition Disorders, Conditioning (Psychology), Disease Models, Animal, Drug Evaluation, Preclinical, Fear, Gene Knockdown Techniques, Heterocyclic Compounds, 4 or More Rings, Long-Term Synaptic Depression, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Nerve Tissue Proteins, Nootropic Agents, Prefrontal Cortex, Pyramidal Cells, Receptors, N-Methyl-D-Aspartate, Recognition (Psychology), Tissue Culture Techniques
Show Abstract · Added April 6, 2017
Abnormalities in the signaling of the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) within cortical and limbic brain regions are thought to underlie many of the complex cognitive and affective symptoms observed in individuals with schizophrenia. The M muscarinic acetylcholine receptor (mAChR) subtype is a closely coupled signaling partner of the NMDAR. Accumulating evidence suggests that development of selective positive allosteric modulators (PAMs) of the M receptor represent an important treatment strategy for the potential normalization of disruptions in NMDAR signaling in patients with schizophrenia. In the present studies, we evaluated the effects of the novel and highly potent M PAM, VU6004256, in ameliorating selective prefrontal cortical (PFC)-mediated physiologic and cognitive abnormalities in a genetic mouse model of global reduction in the NR1 subunit of the NMDAR (NR1 knockdown [KD]). Using slice-based extracellular field potential recordings, deficits in muscarinic agonist-induced long-term depression (LTD) in layer V of the PFC in the NR1 KD mice were normalized with bath application of VU6004256. Systemic administration of VU6004256 also reduced excessive pyramidal neuron firing in layer V PFC neurons in awake, freely moving NR1 KD mice. Moreover, selective potentiation of M by VU6004256 reversed the performance impairments of NR1 KD mice observed in two preclinical models of PFC-mediated learning, specifically the novel object recognition and cue-mediated fear conditioning tasks. VU6004256 also produced a robust, dose-dependent reduction in the hyperlocomotor activity of NR1 KD mice. Taken together, the current findings provide further support for M PAMs as a novel therapeutic approach for the PFC-mediated impairments in schizophrenia.
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23 MeSH Terms
2-arachidonoylglycerol signaling impairs short-term fear extinction.
Hartley ND, Gunduz-Cinar O, Halladay L, Bukalo O, Holmes A, Patel S
(2016) Transl Psychiatry 6: e749
MeSH Terms: Animals, Arachidonic Acids, Behavior, Animal, Cannabinoid Receptor Agonists, Endocannabinoids, Extinction, Psychological, Fear, Glycerides, Male, Mice, Mice, Inbred C57BL, Signal Transduction
Show Abstract · Added March 14, 2018
Impairments in fear extinction are thought to be central to the psychopathology of posttraumatic stress disorder, and endocannabinoid (eCB) signaling has been strongly implicated in extinction learning. Here we utilized the monoacylglycerol lipase inhibitor JZL184 to selectively augment brain 2-AG levels combined with an auditory cue fear-conditioning paradigm to test the hypothesis that 2-AG-mediated eCB signaling modulates short-term fear extinction learning in mice. We show that systemic JZL184 impairs short-term extinction learning in a CB1 receptor-dependent manner without affecting non-specific freezing behavior or the acquisition of conditioned fear. This effect was also observed in over-conditioned mice environmentally manipulated to re-acquire fear extinction. Cumulatively, the effects of JZL184 appear to be partly due to augmentation of 2-AG signaling in the basolateral nucleus of the amygdala (BLA), as direct microinfusion of JZL184 into the BLA produced similar results. Moreover, we elucidate a short ~3-day temporal window during which 2-AG augmentation impairs extinction behavior, suggesting a preferential role for 2-AG-mediated eCB signaling in the modulation of short-term behavioral sequelae to acute traumatic stress exposure.
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12 MeSH Terms
Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids.
Gunduz-Cinar O, Flynn S, Brockway E, Kaugars K, Baldi R, Ramikie TS, Cinar R, Kunos G, Patel S, Holmes A
(2016) Neuropsychopharmacology 41: 1598-609
MeSH Terms: Amidohydrolases, Amygdala, Animals, Anti-Anxiety Agents, Arachidonic Acids, Endocannabinoids, Extinction, Psychological, Fear, Fluoxetine, Male, Mice, Mice, Inbred Strains, Polyunsaturated Alkamides
Show Abstract · Added March 14, 2018
Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders.
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13 MeSH Terms
Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes.
Brown JA, Ramikie TS, Schmidt MJ, Báldi R, Garbett K, Everheart MG, Warren LE, Gellért L, Horváth S, Patel S, Mirnics K
(2015) Mol Psychiatry 20: 1499-507
MeSH Terms: Animals, Behavior, Animal, Brain, Disease Models, Animal, Electrophysiology, Exploratory Behavior, Fear, Gene Silencing, Glutamate Decarboxylase, Interneurons, Ketamine, Male, Mice, Mice, Inbred C3H, Mice, Transgenic, Parvalbumins, Receptors, N-Methyl-D-Aspartate, Schizophrenia, Sensory Gating, Synaptic Transmission
Show Abstract · Added February 12, 2015
Reduced expression of the Gad1 gene-encoded 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of schizophrenia. GAD67 downregulation occurs in multiple interneuronal sub-populations, including the parvalbumin-positive (PVALB+) cells. To investigate the role of the PV-positive GABAergic interneurons in behavioral and molecular processes, we knocked down the Gad1 transcript using a microRNA engineered to target specifically Gad1 mRNA under the control of Pvalb bacterial artificial chromosome. Verification of construct expression was performed by immunohistochemistry. Follow-up electrophysiological studies revealed a significant reduction in γ-aminobutyric acid (GABA) release probability without alterations in postsynaptic membrane properties or changes in glutamatergic release probability in the prefrontal cortex pyramidal neurons. Behavioral characterization of our transgenic (Tg) mice uncovered that the Pvalb/Gad1 Tg mice have pronounced sensorimotor gating deficits, increased novelty-seeking and reduced fear extinction. Furthermore, NMDA (N-methyl-d-aspartate) receptor antagonism by ketamine had an opposing dose-dependent effect, suggesting that the differential dosage of ketamine might have divergent effects on behavioral processes. All behavioral studies were validated using a second cohort of animals. Our results suggest that reduction of GABAergic transmission from PVALB+ interneurons primarily impacts behavioral domains related to fear and novelty seeking and that these alterations might be related to the behavioral phenotype observed in schizophrenia.
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20 MeSH Terms
Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction.
Walker AG, Wenthur CJ, Xiang Z, Rook JM, Emmitte KA, Niswender CM, Lindsley CW, Conn PJ
(2015) Proc Natl Acad Sci U S A 112: 1196-201
MeSH Terms: Animals, Behavior, Animal, Cognition, Fear, HEK293 Cells, Humans, Long-Term Synaptic Depression, Mice, Mice, Inbred ICR, Mice, Knockout, Prefrontal Cortex, Rats, Receptors, Metabotropic Glutamate
Show Abstract · Added January 20, 2015
Clinical studies have revealed that genetic variations in metabotropic glutamate receptor 3 (mGlu3) affect performance on cognitive tasks dependent upon the prefrontal cortex (PFC) and may be linked to psychiatric conditions such as schizophrenia, bipolar disorder, and addiction. We have performed a series of studies aimed at understanding how mGlu3 influences PFC function and cognitive behaviors. In the present study, we found that activation of mGlu3 can induce long-term depression in the mouse medial PFC (mPFC) in vitro. Furthermore, in vivo administration of a selective mGlu3 negative allosteric modulator impaired learning in the mPFC-dependent fear extinction task. The results of these studies implicate mGlu3 as a major regulator of PFC function and cognition. Additionally, potentiators of mGlu3 may be useful in alleviating prefrontal impairments associated with several CNS disorders.
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13 MeSH Terms
Development and validation of a questionnaire to assess fear of kidney failure following living donation.
Rodrigue JR, Fleishman A, Vishnevsky T, Whiting J, Vella JP, Garrison K, Moore D, Kayler L, Baliga P, Chavin KD, Karp S, Mandelbrot DA
(2014) Transpl Int 27: 570-5
MeSH Terms: Adult, Age Factors, Anxiety, Cross-Sectional Studies, Fear, Female, Humans, Incidence, Kidney Transplantation, Living Donors, Male, Middle Aged, Nephrectomy, Odds Ratio, Psychometrics, Reference Values, Renal Insufficiency, Reproducibility of Results, Risk Assessment, Self Report, Sex Factors, Stress, Psychological, Surveys and Questionnaires
Show Abstract · Added May 22, 2014
Living kidney donors (LKDs) may feel more anxious about kidney failure now that they have only one kidney and the security of a second kidney is gone. The aim of this cross-sectional study was to develop and empirically validate a self-report scale for assessing fear of kidney failure in former LKDs. Participants were 364 former LKDs within the past 10 years at five US transplant centers and 219 healthy nondonor controls recruited through Mechanical Turk who completed several questionnaires. Analyses revealed a unidimensional factor structure, excellent internal consistency (α = 0.88), and good convergent validity for the Fear of Kidney Failure questionnaire. Only 13% of former donors reported moderate to high fear of kidney failure. Nonwhite race (OR = 2.9, P = 0.01), genetic relationship with the recipient (OR = 2.46, P = 0.04), and low satisfaction with the donation experience (OR = 0.49, P = 0.002) were significant predictors of higher fear of kidney failure. We conclude that while mild anxiety about kidney failure is common, high anxiety about future renal failure among former LKDs is uncommon. The Fear of Kidney Failure questionnaire is reliable, valid, and easy to use in the clinical setting.
© 2014 Steunstichting ESOT.
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23 MeSH Terms
Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100.
Byun NE, Grannan M, Bubser M, Barry RL, Thompson A, Rosanelli J, Gowrishankar R, Kelm ND, Damon S, Bridges TM, Melancon BJ, Tarr JC, Brogan JT, Avison MJ, Deutch AY, Wess J, Wood MR, Lindsley CW, Gore JC, Conn PJ, Jones CK
(2014) Neuropsychopharmacology 39: 1578-93
MeSH Terms: Amphetamine, Animals, Antipsychotic Agents, Blood Pressure, Brain, Cell Line, Transformed, Central Nervous System Stimulants, Disease Models, Animal, Dopamine Plasma Membrane Transport Proteins, Fear, Heart Rate, Humans, Hyperkinesis, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Motor Activity, Protein Binding, Pyridines, Rats, Rats, Sprague-Dawley, Receptor, Muscarinic M4, Reflex, Startle, Thiophenes
Show Abstract · Added March 27, 2014
Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.
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25 MeSH Terms
Early postoperative fear of movement predicts pain, disability, and physical health six months after spinal surgery for degenerative conditions.
Archer KR, Seebach CL, Mathis SL, Riley LH, Wegener ST
(2014) Spine J 14: 759-67
MeSH Terms: Adult, Aged, Aged, 80 and over, Cervical Vertebrae, Depression, Disability Evaluation, Disabled Persons, Fear, Female, Health Status, Humans, Lumbar Vertebrae, Male, Middle Aged, Movement, Multivariate Analysis, Outcome Assessment (Health Care), Pain Measurement, Pain, Postoperative, Phobic Disorders, Postoperative Period, Prospective Studies, Spinal Diseases, Young Adult
Show Abstract · Added February 19, 2015
BACKGROUND CONTEXT - The fear-avoidance model offers a promising framework for understanding the development of chronic postoperative pain and disability. However, limited research has examined this model in patients undergoing spinal surgery.
PURPOSE - To determine whether preoperative and early postoperative fear of movement predicts pain, disability, and physical health at 6 months following spinal surgery for degenerative conditions, after controlling for depressive symptoms and other potential confounding variables.
STUDY DESIGN/SETTING - A prospective cohort study conducted at an academic outpatient clinic.
PATIENT SAMPLE - One hundred forty-one patients undergoing surgery for lumbar or cervical degenerative conditions.
OUTCOME MEASURES - Self-reported pain and disability were measured with the Brief Pain Inventory and the Oswestry Disability Index/Neck Disability Index, respectively. The physical composite scale of the 12-Item Short-Form Health Survey (SF-12) measured physical health.
METHODS - Data collection occurred preoperatively and at 6 weeks and 6 months following surgery. Fear of movement was measured with the Tampa Scale for Kinesiophobia and depression with the Prime-MD PHQ-9.
RESULTS - One hundred and twenty patients (85% follow-up) completed the 6-month postoperative assessment. Multivariable mixed-method linear regression analyses found that early postoperative fear of movement (6 weeks) predicted pain intensity, pain interference, disability, and physical health at 6-month follow-up (p<.05). Preoperative and early postoperative depression predicted pain interference, disability, and physical health.
CONCLUSION - Results provide support for the fear-avoidance model in a postsurgical spine population. Early postoperative screening for fear of movement and depressive symptoms that do not acutely improve following surgical intervention appears warranted. Cognitive and behavioral strategies may be beneficial for postsurgical patients with high fear of movement and/or depressive symptoms.
Copyright © 2014 Elsevier Inc. All rights reserved.
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24 MeSH Terms
Cognitive-behavioral-based physical therapy to improve surgical spine outcomes: a case series.
Archer KR, Motzny N, Abraham CM, Yaffe D, Seebach CL, Devin CJ, Spengler DM, McGirt MJ, Aaronson OS, Cheng JS, Wegener ST
(2013) Phys Ther 93: 1130-9
MeSH Terms: Adult, Aged, Cognitive Behavioral Therapy, Disability Evaluation, Fear, Female, Humans, Lumbar Vertebrae, Male, Middle Aged, Pain Measurement, Physical Therapy Modalities, Quality of Life, Reproducibility of Results, Risk Factors, Spinal Diseases, Surveys and Questionnaires, Treatment Outcome
Show Abstract · Added February 19, 2015
BACKGROUND AND PURPOSE - Fear of movement is a risk factor for poor postoperative outcomes in patients following spine surgery. The purposes of this case series were: (1) to describe the effects of a cognitive-behavioral-based physical therapy (CBPT) intervention in patients with high fear of movement following lumbar spine surgery and (2) to assess the feasibility of physical therapists delivering cognitive-behavioral techniques over the telephone.
CASE DESCRIPTION - Eight patients who underwent surgery for a lumbar degenerative condition completed the 6-session CBPT intervention. The intervention included empirically supported behavioral self-management, problem solving, and cognitive restructuring and relaxation strategies and was conducted in person and then weekly over the phone. Patient-reported outcomes of pain and disability were assessed at baseline (6 weeks after surgery), postintervention (3 months after surgery), and at follow-up (6 months after surgery). Performance-based outcomes were tested at baseline and postintervention. The outcome measures were the Brief Pain Inventory, Oswestry Disability Index, 5-Chair Stand Test, and 10-Meter Walk Test.
OUTCOMES - Seven of the patients demonstrated a clinically significant reduction in pain, and all 8 of the patients had a clinically significant reduction in disability at 6-month follow-up. Improvement on the performance-based tests also was noted postintervention, with 5 patients demonstrating clinically meaningful change on the 10-Meter Walk Test.
DISCUSSION - The findings suggest that physical therapists can feasibly implement cognitive-behavioral skills over the telephone and may positively affect outcomes after spine surgery. However, a randomized clinical trial is needed to confirm the results of this case series and the efficacy of the CBPT intervention. Clinical implications include broadening the availability of well-accepted cognitive-behavioral strategies by expanding implementation to physical therapists and through a telephone delivery model.
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18 MeSH Terms