Anxious and Hyperactive Phenotype Following Brief Ischemic Episodes in Mice

doi:10.1016/j.biopsych.2005.02.010

Biological Psychiatry

Volume 57, Issue 10, 15 May 2005, Pages 1166-1175

https://doi.org/10.1016/j.biopsych.2005.02.010 Get rights and content

Background

Poststroke emotional and behavioral abnormalities have an impact on outcome but have scarcely been characterized in animal models. We tested whether brief ischemic episodes induce behavioral changes in mice.

Methods

129/Sv mice were subjected to 30-min occlusion of left or right middle cerebral artery (MCAo) followed by reperfusion or sham operation (n = 9 or 10 per group). Eight to ten weeks later, mice were tested for spontaneous locomotor activity, anxiety in the elevated plus maze, and depressive behavior in the modified Porsolt forced swim test. Outcome was correlated to monoamine and amino acid levels and compared with histologic damage at 10 weeks.

Results

Ischemia was associated with increased activity (right MCAo) and anxiety (left MCAo), but not poststroke depression. Noradrenaline increased by 30%–45% in the ischemic striatum and correlated with locomotor activity (r = .48); dopamine and homovanillinic acid were decreased compared with sham. The lesion was confined to the striatum, and scattered neuronal death was observed in a number of remote brain regions.

Conclusion

Brief ischemic episodes in the mouse induce an anxious, hyperactive but not depressive phenotype that may relate to left versus right hemispheric lesion location, alterations in brain monoamine levels, and selective neurodegeneration.

Section snippets

Animals and model of cerebral ischemia

All experimental procedures conformed to institutional and international guidelines. Male 129S6/SvEv wildtype mice (18–20 g, Bundesamt für Gesundheitsschutz, Berlin, Germany) were housed in standard mouse cages in groups of 4–5 mice per cage at 20–21°C with a standard light—dark cycle (8 am–8 pm) with access to food and water ad libitum. Mice were anesthetized with 1.0% isofluorane in 69% N₂O and 30% O₂ using a vaporizer and subjected to left or right filamentous 30-min MCA occlusion or sham

Mild cerebral ischemia and neurologic deficits

129/SV wild-type mice were subjected to 30-min filamentous occlusion of the left or right MCA followed by reperfusion or sham operation (i.e., lMCAo, rMCAo, sham; 10 animals per group). Sensorimotor deficits measured by the Bederson score were ≥ 2 during cerebral ischemia but improved over time (median score at 6 and 10 weeks was 1.0 for both lMCAo and rMCAo; .5 and 1.0 for 25% and 75% confidence intervals, respectively).

Brain monoamine and amino acid levels

Levels of monoamines (NA, DA, and 5-HT), monoamine metabolites (DOPAC,

Discussion

We provide evidence for distinct behavioral changes following brief ischemic episodes in a well-characterized mouse model of mild cerebral ischemia. The most significant finding was that animals with transient lMCAo have evidence of increased anxiety and that mice with rMCAo have increased spontaneous locomotor activity. Monoamine and amino acid levels measured in several brain regions revealed distinct alterations only in the striatum, which is subject to ischemic neuronal cell death. Striatal

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Two of the most common and incapacitating mental health disorders around the world are major depressive disorder (MDD) and post-stroke depression (PSD). MDD is thought to result from abnormal connectivity between the monoaminergic, glutamatergic, GABAergic, and/or cholinergic pathways. Additional factors include the roles of hormonal, immune, ageing, as well as the influence of cellular, molecular, and epigenetics in the development of mood disorders. This complexity of factors has been anticipated by the Swiss psychiatrists Paul Kielholz and Jules Angst who introduced a multimodal treatment of MDD. Depression is the predominant mood disorder, impacting around one-third of individuals who have experienced a stroke. MDD and PSD share common underlying biological mechanisms related to the disruption of monoaminergic pathways. The major contributor to PSD is the stroke lesion location, which can involve the disruption of the serotoninergic, dopaminergic, glutamatergic, GABAergic, or cholinergic pathways. Additionally, various other disorders such as mania, bipolar disorder, anxiety disorder, and apathy might occur post-stroke, although their prevalence is considerably lower. However, there are differences in the onset of MDD among mood disorders. Some mood disorders develop gradually and can persist for a lifetime, potentially culminating in suicide. In contrast, PSD has a rapid onset because of the severe disruption of neural pathways essential for mood behavior caused by the lesion. However, PSD might also spontaneously resolve several months after a stroke, though it is associated with higher mortality. This review also provides a brief overview of the treatments currently available in medical practice.
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Original articleAnxious and Hyperactive Phenotype Following Brief Ischemic Episodes in Mice

Background

Methods

Results

Conclusion

Section snippets

Animals and model of cerebral ischemia

Mild cerebral ischemia and neurologic deficits

Brain monoamine and amino acid levels

Discussion

Lancet

Brain Res

Trends Pharmacol Sci

Neurosci Behav Rev

Biol Psychiatry

Brain Res

Trends Neurosci

Neuroscience

J Pharmacol Sci

J Chromatogr B Biomed Sci Appl

Physiol Behav

Brain Res Bull

Eur J Pharmacol

Biol Psychiatry

Brain Res

Brain Res Brain Res Protoc

2001 Heart and Stroke Statistical Update

Generalized anxiety disorder in stroke patientsA 3-year longitudinal study

Stroke

Direction of handedness linked to hereditary asymmetry of a sensory system

Proc Natl Acad Sci U S A

The crucial role of frontostriatal circuits for depressive disorders in the postacute stage after stroke

Neuropsychiatry Neuropsychol Behav Neurol

Rat middle cerebral artery occlusionEvaluation of the model and development of a neurologic examination

Stroke

Lesion location and poststroke depressionSystematic review of the methodological limitations in the literature

Stroke

Anxiety disorders after strokeResults from the Perth Community Stroke Study

Br J Psychiatry

Prevalence of depression after strokeThe Perth Community Stroke Study

Br J Psychiatry

Clinical correlates of early-onset and late-onset post-stroke generalized anxiety

Am J Psychiatry

Genetics of mouse behaviorInteractions with laboratory environment

Science

Secondary mania with focal cerebrovascular lesions

Am J Psychiatry

Active behaviors in the rat forced swimming test differentially produced by seretonergic and nonadrenergic antidepressants

Psychopharmacology

Attenuation of delayed neuronal cell death after mild focal ischemia by inhibitors of the caspase family

J Cereb Blood Flow Metab

Original article
Anxious and Hyperactive Phenotype Following Brief Ischemic Episodes in Mice