Anxiety-related behavior and densities of glutamate, GABAA, acetylcholine and serotonin receptors in the amygdala of seven inbred mouse strains

Yilmazer-Hanke, Deniz; Roskoden, Thomas; Zilles, Karl; Schwegler, Herbert

doi:10.1016/s0166-4328(03)00107-4

Cited by 88 publications

(70 citation statements)

References 94 publications

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“…The GABA A receptor ␥ subunit is enriched in the basolateral amygdala of both humans and rodents (27)(28)(29)(30)(31). We analyzed GABA A receptor ␥ expression in the amygdala of wild-type and neuroD2ϩ͞Ϫ mice by immunostaining (Fig.…”

Section: Resultsmentioning

confidence: 99%

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

Lin

Hansen

Wang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The amygdala is centrally involved in formation of emotional memory and response to fear or risk. We have demonstrated that the lateral and basolateral amygdala nuclei fail to form in neuroD2 null mice and neuroD2 heterozygotes have fewer neurons in this region. NeuroD2 heterozygous mice show profound deficits in emotional learning as assessed by fear conditioning. Unconditioned fear was also diminished in neuroD2 heterozygotes compared to wild-type controls. Several key molecular regulators of emotional learning were diminished in the brains of neuroD2 heterozygotes including Ulip1, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and GABA A receptor. Thus, neuroD2 is essential for amygdala development and genes involved in amygdala function are altered in neuroD2-deficient mice.basic helix-loop-helix ͉ haploinsufficiency T he amygdala is an almond-shaped brain structure that integrates emotional learning and other emotional responses such as fear perception. The role of the amygdala in fear perception and response was established through lesioning studies in animals and confirmed through positron emission tomography and functional magnetic resonance imaging in normal human subjects and in schizophrenic patients with deficits in fear processing (1-9).We previously reported that neuroD2-null mice on a mixed genetic background are indistinguishable from littermates at birth, but fail to thrive and die within weeks of birth. Before death, nullizygous mice develop ataxia, seizures, cerebellar degeneration, and growth retardation. NeuroD2 heterozygotes appear normal as adults, but have reduced seizure threshold and mild ataxia. We observed aggressive behavior between neuroD2 heterozygotes, which prompted us to evaluate the function and structure of the amygdala and related limbic system brain regions that control aggression, fear, and other emotions. Unconditioned fear (also referred to as anxiety or risk perception) is the response to environmental cues that signal danger. The basolateral amygdala and ventral subiculum of hippocampus are involved in unconditioned fear responses; however, the neuronal circuitry and molecular mechanisms are poorly understood (10).In contrast to unconditioned fear, the neurochemical and molecular basis of emotional learning related to conditioned fear are being elucidated through studies that evaluate fear conditioning in the context of pharmacologic or genetic manipulation of neurotransmitter receptors and second messengers. Fear conditioning involves coupling a neutral conditioned stimulus (CS) such as an audible tone with a noxious unconditioned stimulus (US) such as foot shock and observing that after training and rest periods, that the CS alone is sufficient to elicit behavioral (e.g., freezing) and autonomic responses (11,12). During the training and rest period, the lateral amygdala acquires and consolidates short-and long-term memory that associates the conditioned and unconditioned stimuli through a process known as emotional learning.The acquisition phas...

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Section: Resultsmentioning

confidence: 99%

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

Lin

Hansen

Wang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…LRS thresholds: 9.5 (suggestive), 16.5 (significant), and 26.4 (highly significant). Bouwknecht and Paylor, 2002), free-exploration tests (Kopp et al, 1999;Tang et al, 2002;Yilmazer-Hanke et al, 2003), the novel object test (Tang et al, 2002), and the elevated plus maze (Kim et al, 2002). The A/J mouse strain was selected because these mice: (1) were relatively nonresponsive to citalopram in the TST , (2) showing high levels of anxiety and defecation (Crawley et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

Crowley

Brodkin

Blendy

et al. 2006

Neuropsychopharmacol

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The identification of genetic variants regulating antidepressant response in human patients would allow for more individualized, rational, and successful drug treatments. We have previously identified the BALB/cJ inbred mouse strain as highly responsive to the selective serotonin reuptake inhibitor (SSRI) citalopram in the tail suspension test (TST), a widely used and well-established screening paradigm for detecting compounds with antidepressant activity. In contrast, A/J mice did not show a significant response to citalopram in this test despite exposure to equivalent plasma levels of the drug. To identify genetic determinants of this differential response, 506 F 2 mice from an intercross between BALB/cJ and A/J mice were phenotyped. Composite interval mapping of 92 mice from the phenotypic extremes revealed three loci on chromosomes 7, 12, and 19 affecting citalopram response in the TST. The quantitative trait locus (QTL) at the telomeric end of chromosome 19 showed the greatest level of significance. Three candidate genes residing in this locus include those for vesicular monoamine transporter 2 (VMAT2, slc18a2), alpha 2A adrenergic receptor (adra2a), and beta 1 adrenergic receptor (adrb1). The protein coding regions of these three genes in BALB/cJ and A/J mice were sequenced and two polymorphisms were found in VMAT2 (Leu117Pro and Ser505Pro), while the transcribed regions of adra2a and adrb1 were of identical sequence between strains. Follow-up studies are needed to determine if the VMAT2 polymorphisms are functional and if they could explain the chromosome 19 QTL. The present quantitative trait study suggests possible candidate genes for human pharmacogenetic studies of therapeutic responses to SSRIs such as citalopram.

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“…The BALB/c strain has been shown to be highly emotional, or anxious, relative to other strains in many classical approach/avoidance paradigms including the open field test (Kim et al, 2002), the light/dark test (Griebel et al, 2000;Bouwknecht and Paylor, 2002), free-exploration tests (Kopp et al, 1999;Tang et al, 2002), and the novel object test (Tang et al, 2002). BALB/c mice are also comparatively anxious when evaluated for ethological measures, such as stretch-attend postures and defecation in a novel environment (Kim et al, 2002;Yilmazer-Hanke et al, 2003). The DBA2J strain is also highly anxious in a number of paradigms, including the plus maze (Yilmazer-Hanke et al, 2003) and hole-board tests (Ohl et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…BALB/c mice are also comparatively anxious when evaluated for ethological measures, such as stretch-attend postures and defecation in a novel environment (Kim et al, 2002;Yilmazer-Hanke et al, 2003). The DBA2J strain is also highly anxious in a number of paradigms, including the plus maze (Yilmazer-Hanke et al, 2003) and hole-board tests (Ohl et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Effects of Chronic Fluoxetine in Animal Models of Anxiety and Depression

Dulawa

Holick

Gundersen

et al. 2004

Neuropsychopharmacol

609

485

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The onset of the therapeutic response to antidepressant treatment exhibits a characteristic delay. Animal models sensitive to chronic, but not acute, antidepressant treatment are greatly needed for studying antidepressant mechanisms. We initially assessed four inbred mouse strains for their behavioral response to chronic treatment with the selective-serotonin reuptake inhibitor fluoxetine (0, 5, 10 mg/kg/day in drinking water), which is used for the treatment of mood and anxiety disorders. Only the highly anxious BALB/c strain exhibited sensitivity to fluoxetine in the forced swim test. Additionally, fluoxetine reduced locomotion in C57BL/6 and 129SvEv, but not BALB/c and DBA/2, strains. We then evaluated the effects of subchronic (B4 days) and chronic (B24 days) fluoxetine treatment (0, 10, 18, 25 mg/kg/day) on measures of anxiety and depression in BALB/c mice. Anxiety measures were obtained using the open field and noveltyinduced hypophagia tests. Antidepressant effects were evaluated using the forced swim test. We found 18 mg/kg/day of chronic fluoxetine to be active in all three paradigms; subchronic treatment had no effect. Anxiety-related measures were reduced by 18 mg/kg/ day. In the forced swim test, 10 and 18 mg/kg/day increased swimming and reduced immobility. Here we present several novel effects of chronic, but not subchronic, antidepressant treatment.

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Anxiety-related behavior and densities of glutamate, GABAA, acetylcholine and serotonin receptors in the amygdala of seven inbred mouse strains

Cited by 88 publications

References 94 publications

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

Effects of Chronic Fluoxetine in Animal Models of Anxiety and Depression

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