Glucocorticoid Receptor Antagonist Mifepristone Does Not Alter Innate Anxiety-Like Behavior in Genetically-Selected Marchigian Sardinian (msP) Rats

Marchigian Sardinian alcohol-preferring (msP) rats serve as a unique model of heightened alcohol preference and anxiety disorders. Their innate enhanced stress and poor stress-coping strategies are driven by a genetic polymorphism of the corticotropin-releasing factor receptor 1 (CRF1) in brain areas involved in glucocorticoid signaling. The activation of glucocorticoid receptors (GRs) regulates the stress response, making GRs a candidate target to treat stress and anxiety. Here, we examined whether mifepristone, a GR antagonist known to reduce alcohol drinking in dependent rats, decreases innate symptoms of anxiety in msPs. Male and female msPs were compared to non-selected Wistar counterparts across three separate behavioral tests. We assessed anxiety-like behavior via the novelty-induced hypophagia (NIH) assay. Since sleep disturbances and hyperarousal are common features of stress-related disorders, we measured sleeping patterns using the comprehensive lab monitoring system (CLAMS) and stress sensitivity using acoustic startle measures. Rats received an acute administration of vehicle or mifepristone (60 mg/kg) 90 min prior to testing on NIH, acoustic startle response, and CLAMS. Our results revealed that both male and female msPs display greater anxiety-like behaviors as well as enhanced acoustic startle responses compared to Wistar counterparts. Male msPs also displayed reduced sleeping bout duration versus Wistars, and female msPs displayed greater acoustic startle responses versus male msPs. Importantly, the enhanced anxiety-like behavior and startle responses were not reduced by mifepristone. Together, these findings suggest that increased expression of stress-related behaviors in msPs are not solely mediated by acute activation of GRs.

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Effects of a postnatal Atrx conditional knockout in neurons on autism-like behaviours in male and female mice

10.1101/2020.02.05.936260 ◽

2020 ◽

Author(s):

Nicole Martin-Kenny ◽

Nathalie G. Bérubé

Keyword(s):

Repeated Measures ◽

Susceptibility Gene ◽

Acoustic Startle ◽

Acoustic Startle Response ◽

Autism Spectrum ◽

Conditional Knockout ◽

Male And Female ◽

Female Mice ◽

Excitatory Neurons ◽

Behavioural Tests

AbstractBackgroundAlpha-thalassemia/mental retardation, X-linked, or ATRX, is an autism susceptibility gene that encodes a chromatin remodeler. Mutations of ATRX result in the ATR-X intellectual disability syndrome and have been identified in autism spectrum disorder (ASD) patients. The mechanisms by which ATRX mutations lead to autism and autistic-like behaviours are not yet known. To address this question, we generated mice with postnatal Atrx inactivation in excitatory neurons of the forebrain and performed a battery of behavioural assays that assess autistic-like behaviours.MethodsMale and female mice with a postnatal conditional knockout of Atrx were tested in a battery of behavioural tests that assess autistic features. We utilized paradigms that measure social behaviour, repetitive and stereotyped behaviours, as well as sensory gating. Statistics were calculated by two-way repeated measures ANOVA with Sidak’s multiple comparison test or unpaired Student’s T-tests as indicated.ResultsThe behaviour tests revealed no significant differences between Atrx-cKO and control mice. We identified sexually dimorphic changes in odor habituation and discrimination; however, these changes did not correlate with social deficits. We additionally observed sex-specific differences in sociability, vertical episodes, and acoustic startle response when results were analyzed by sex.ConclusionThe postnatal knockout of Atrx in forebrain excitatory neurons does not lead to autism-related behaviours in male or female mice.

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Development of the MAM model of schizophrenia in mice: Sex similarities and differences of hippocampal and prefrontal cortical function

10.1101/295741 ◽

2018 ◽

Cited By ~ 1

Author(s):

Kleanthi Chalkiadaki ◽

Aggeliki Velli ◽

Evangelos Kyriazidis ◽

Vasiliky Stavroulaki ◽

Vasilis Vouvoutsis ◽

...

Keyword(s):

Cognitive Function ◽

Acoustic Startle ◽

Long Term Potentiation ◽

Female Offspring ◽

Nmda Receptor Antagonist ◽

Acoustic Startle Reflex ◽

Acute Administration ◽

Cortical Function ◽

Male And Female ◽

Prefrontal Cortical

AbstractSchizophrenia is a debilitating disorder with complex and unclarified etiological factors. Sex differences have been observed in humans but animal models have only focused on male subjects. In this study, we report the establishment of the neurodevelopmental MAM model of schizophrenia in mice and compare the schizotypic-like characteristics and cognitive function in both sexes. Pregnant mice were injected with 26mg/kg(i.p.) of Methylazoxy-methanol acetate (MAM) or saline (5ml/kg) on gestational day (GD) 16 (MAM-16) or 17 (MAM-17). Behavioral, histological and electrophysiological and mass spectrometry-based comparative proteomic techniques were employed to assess the schizotypic-like characteristics and cognitive function of adult male and female offspring (MAM- or saline-treated). Female MAM-16, but not MAM-17 treated mice exhibited enhanced hyperlocomotion after acute administration of the NMDA receptor antagonist, MK-801, compared to saline treated mice. Male MAM-16, but not MAM-17 treated mice showed decreased pre-pulse inhibition of the acoustic startle reflex. Both male and female MAM-16 and MAM-17 treated mice exhibited reduced hippocampal (HPC) size and thinning of the prefrontal cortex (PFC), but only male MAM-16 treated mice showed decreased parvalbumin expression in HPC and PFC. Similarly, both male and female MAM-16 treated mice displayed impaired contextual fear memory, while only male MAM-16 treated mice exhibited deficits in the delayed alternation task. The neurophysiological mechanisms that underlie these cognitive functions were further investigated. Both male and female MAM-16 treated mice had significantly reduced long-term potentiation (LTP) in the HPC CA1 synapses, while only male MAM-16 treated mice exhibited decreased LTP in the PFC. Proteomic analyses of PFC lysates further showed significant MAM- and sex-dependent differences in regulation of protein expression. Our results demonstrate that while both male and female mice, prenatally exposed to MAM on GD16, display several core schizophrenia-like deficits and impairments in the hippocampus, only male MAM-treated mice have PFC-dependent cognitive deficits.

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Food-Restriction Lowers the Acoustic Startle Response in both Male and Female Rats, and, in Combination with Acute Ghrelin Injection, Abolishes the Expression of Fear-Potentiated Startle in Male Rats

Journal of Neuroendocrinology ◽

10.1111/jne.12436 ◽

2016 ◽

Vol 28 (11) ◽

Cited By ~ 1

Author(s):

D. J. Toufexis ◽

O. Lipatova ◽

A. C. Johnson ◽

A. Abizaid

Keyword(s):

Startle Response ◽

Food Restriction ◽

Acoustic Startle ◽

Acoustic Startle Response ◽

Female Rats ◽

Male Rats ◽

Male And Female ◽

Male And Female Rats ◽

Fear Potentiated Startle

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The Acoustic Startle Response and Disruption of Aiming. 2. Modulation by Forewarning and Preliminary Stimuli

10.21236/ada217105 ◽

1989 ◽

Author(s):

John A. Foss ◽

James R. Ison ◽

James P. Torre ◽

Wansack Jr ◽

Samuel

Keyword(s):

Startle Response ◽

Acoustic Startle ◽

Acoustic Startle Response

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Sexual dimorphic role of the glucocorticoid receptor in chronic muscle pain produced by early-life stress

Molecular Pain ◽

10.1177/17448069211011313 ◽

2021 ◽

Vol 17 ◽

pp. 174480692110113

Author(s):

Paul G Green ◽

Pedro Alvarez ◽

Jon D Levine

Keyword(s):

Glucocorticoid Receptor ◽

Adult Male ◽

Life Stress ◽

Early Life ◽

Glucocorticoid Receptors ◽

Early Life Stress ◽

Nociceptive Threshold ◽

Male And Female ◽

Mechanical Nociceptive Threshold

Fibromyalgia and other chronic musculoskeletal pain syndromes are associated with stressful early life events, which can produce a persistent dysregulation in the hypothalamic-pituitary adrenal (HPA) stress axis function, associated with elevated plasm levels of corticosterone in adults. To determine the contribution of the HPA axis to persistent muscle hyperalgesia in adult rats that had experienced neonatal limited bedding (NLB), a form of early-life stress, we evaluated the role of glucocorticoid receptors on muscle nociceptors in adult NLB rats. In adult male and female NLB rats, mechanical nociceptive threshold in skeletal muscle was significantly lower than in adult control (neonatal standard bedding) rats. Furthermore, adult males and females that received exogenous corticosterone (via dams’ milk) during postnatal days 2–9, displayed a similar lowered mechanical nociceptive threshold. To test the hypothesis that persistent glucocorticoid receptor signaling in the adult contributes to muscle hyperalgesia in NLB rats, nociceptor expression of glucocorticoid receptor (GR) was attenuated by spinal intrathecal administration of an oligodeoxynucleotide (ODN) antisense to GR mRNA. In adult NLB rats, GR antisense markedly attenuated muscle hyperalgesia in males, but not in females. These findings indicate that increased corticosterone levels during a critical developmental period (postnatal days 2–9) produced by NLB stress induces chronic mechanical hyperalgesia in male and female rats that persists in adulthood, and that this chronic muscle hyperalgesia is mediated, at least in part, by persistent stimulation of glucocorticoid receptors on sensory neurons, in the adult male, but not female rat.

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