Elsevier

Neuroscience

Volume 194, 27 October 2011, Pages 282-290
Neuroscience

Neurodegeneration, Neuroprotection, and Disease-Oriented Neuroscience
Research Paper
Effects of chronic immobilization stress on anxiety-like behavior and basolateral amygdala morphology in Fmr1 knockout mice

https://doi.org/10.1016/j.neuroscience.2011.06.047Get rights and content

Abstract

Several lines of clinical evidence support the idea that fragile X syndrome (FXS) may involve a dysregulation of hypothalamic-pituitary-adrenal axis function [Wisbeck et al. (2000) J Dev Behav Pediatr 21:278–282; Hessl et al. (2002) Psychoneuroendocrinology 27:855–872]. We had tested this idea in a mouse model of FXS (Fmr1 KO) and found that the hormonal response to acute stress was similar to that of wild-type (WT) mice [Qin and Smith (2008) Psychoneuroendocrinology 33:883–889]. We report here responses to chronic stress (CS) in Fmr1 KO mice. Following restraint for 120 min/d, 10 consecutive days, we assessed dendrite and spine morphology in basolateral amygdala (BLA). We also monitored behavior in an elevated plus maze (EPM) and the hormonal response to this novel spatial environment. After CS, mice of both genotypes underwent adrenal hypertrophy, but effects were greater in WT mice. Behavior in the EPM indicated that only WT mice had the expected increase in anxiety following CS. Serum corticosterone and adrenocorticotropic hormone (ACTH) levels were both increased following the spatial novelty of EPM, and there were no differences between genotypes in the hormonal responses. BLA dendritic branching increased proximal to the soma in WT, but in Fmr1 KO mice branching was unaffected close to the soma and slightly decreased at one point distal to the soma. Similarly, spine density on apical and basal dendrites increased in WT but decreased in Fmr1 KO mice. Spine length on apical and basal dendrites increased in WT but was unaffected in Fmr1 KO mice. These differences in behavioral response and effects on neuron morphology in BLA suggest a diminished adaptive response of Fmr1 KO mice.

Highlights

▶Chronic stress (CS) on anxiety and amygdala dendrites in WT and Fmr1 KO mice. ▶Control Fmr1 KO mice had reduced dendritic arbors and elevated spine densities. ▶ACTH and CORT increased in both genotypes in response to spatial novelty after CS. ▶CS increased anxiety and dendritic branching in WT but not in Fmr1 KO mice. ▶Following CS, spine density increased in WT but decreased in Fmr1 KO mice.

Section snippets

Animals

Male WT and Fmr1 KO offspring were generated by FVB/NJ-Fmr1tm1Cgr breeding pairs (heterozygous females and WT males). We studied male WT and Fmr1 KO mice at 96±1 days of age. Mice with no previous exposure to these or any other stressful conditions were singly housed, beginning one week before the study. Four groups of mice were studied: WT-unstressed control (WT-US) (n=24), Fmr1 KO-US control (n=24), WT-CS (n=19), Fmr1 KO-CS (n=20). All mice were housed in a central facility and maintained

Effects of CS on body weight

We monitored body weight during the 10 days of CS (Fig. 1A). Body weight tended to decrease on Day 3 of CS in both genotypes and continued to decrease in Fmr1 KO mice, while leveling off in WT. The genotype×condition×day of stress interaction was statistically significant (F(4.1,316.8)=2.401, P=0.048). At each time point, we tested for differences between four pairs of groups by means of post hoc t-tests. Results indicate that in US mice, body weights were higher in Fmr1 KO mice compared with

Discussion

The central finding of this study is that stress-induced remodeling of dendritic arbors in murine amygdala is altered in the absence of FMRP. Moreover, Fmr1 KO mice fail to show the increased anxiety induced by CS in rodents. Our findings indicate that these differences in response to CS between WT and Fmr1 KO mice are not the result of a deficiency at the level of circulating stress hormones, because hormone responses are intact in the Fmr1 KO mouse. Results of our study indicate that

Conclusions

Long-term adaptive changes are essential for optimal function of the nervous system. They endow the nervous system with the ability to respond to the environment and make adjustments important for survival. In WT mice, such changes occur in response to CS and are manifest as increased anxiety-like behavior and structural remodeling in the amygdala. Fmr1 KO mice appear to lack this capacity to respond to CS in BLA at least in the time frame that we have studied. Our findings indicate that this

Acknowledgments

We thank Dr. Zhong-Hua Liu for help with the statistical analyses. The research was supported by the Intramural Research Program of the NIMH, NIH and the Fragile X Research Foundation.

References (44)

  • Y.S. Mineur et al.

    Social behavior deficits in the Fmr1 mutant mouse

    Behav Brain Res

    (2006)
  • K.Y. Miyashiro et al.

    RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice

    Neuron

    (2003)
  • W. Paradee et al.

    Fragile X mouse: strain effects of knockout phenotype and evidence suggesting deficient amygdala function

    Neuroscience

    (1999)
  • M. Qin et al.

    A mouse model of the fragile X premutation: effects on behavior, dendrite morphology, and regional rates of cerebral protein synthesis

    Neurobiol Dis

    (2011)
  • M. Qin et al.

    Unaltered hormonal response to stress in a mouse model of fragile X syndrome

    Psychoneuroendocrinology

    (2008)
  • A. Vyas et al.

    Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala

    Neuroscience

    (2006)
  • A. Vyas et al.

    Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior

    Neuroscience

    (2004)
  • P. Campolongo et al.

    Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory

    Proc Natl Acad Sci U S A

    (2009)
  • D. Gothelf et al.

    Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP)

    Ann Neurol

    (2008)
  • R.B. Harris et al.

    Weight loss in rats exposed to repeated acute restraint stress is independent of energy or leptin status

    Am J Physiol Regul Integr Comp Physiol

    (2002)
  • A.S. Kling et al.

    The amygdala and social behavior

  • J. LeDoux

    The emotional brain, fear, and the amygdala

    Cell Mol Neurobiol

    (2003)
  • Cited by (64)

    • High Environmental Temperature: Insights into Behavioural, Neurodevelopmental and Gut Microbiome Changes Following Gestational Exposure in Rats

      2022, Neuroscience
      Citation Excerpt :

      It is possible that thermal stress alters this tightly controlled mechanism, with deleterious effects. Similar result was documented by Qin et al. (2011), following immobilization stress in WT mice. Myelin-related defects have been implicated in several stress-induced disorders, neurological diseases, and may well contribute to neuropsychiatric disorders (Franklin and Ffrench-Constant, 2017; Oberoi et al., 2019).

    • Chronic restraint stress induces anxiety-like behavior and remodeling of dendritic spines in the central nucleus of the amygdala

      2022, Behavioural Brain Research
      Citation Excerpt :

      It is presently believed that fear and anxiety arising from stressful life events are mediated by alterations in dendritic and synaptic structure in stress-responsive brain regions, including the hippocampus, the medial prefrontal cortex (mPFC) and the amygdala [7,8]. Interestingly, it has been documented that chronic restraint or immobilization stress consistently induce dendritic atrophy in hippocampal CA3 [9–11] and mPFC pyramidal neurons [12], and that the same stress paradigms increase dendritic arborization and spine density in pyramidal neurons of the basolateral amygdala (BLA) concomitant with increased anxiety-like behavior in rodents [10,13,14]. In keeping with these observations, chronic immobilization stress increased the complexity of dendritic arbors in the bed nucleus of stria terminalis (BNST) in the extended amygdala, but it had no trophic effects on pyramidal neurons of the central nucleus of the amygdala (CeA) [15].

    • How stress physically re-shapes the brain: Impact on brain cell shapes, numbers and connections in psychiatric disorders

      2021, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      When compared with fMRI data from humans that indicate the centrality of the PFC and hippocampus is reduced in response to stress (Wheelock et al., 2018), cytoarchitectural evidence suggests that the communication in pyramidal excitatory circuits in these regions is similarly inhibited, particularly in response to chronic stress. In the amygdala, chronic stress (immobilisation, social defeat) in adult rodents (rats and mice) has been repeatedly shown to increase dendritic spine density, particularly in the BLA (Suvrathan et al., 2014; Qin et al., 2011; Hill et al., 2013; Vyas et al., 2006; Mitra et al., 2005; Patel et al., 2018). Similarly, chronic corticosterone administration over a 20 day period in adult mice also induces increases in spine density, although these increases return to normal after a washout period (Gourley et al., 2013).

    View all citing articles on Scopus
    View full text