Animal models of anxiety in mice

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PRECLINICAL ANIMAL MODELS OF ANXIETY Michel Bourin University of Nantes

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ANXIETY Fear is an adaptive component of the acute ‘stress’ response to potentially-dangerous stimuli which threaten to perturb homeostasis

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From Dinan, 1997

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MAJOR DIVISIONS AND CONNECTIONS OF THE AMYGDALA

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ANIMAL MODELS Experimental preparations developed in one species for the purpose of studying phenomena occurring in another species

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Face validity Predictive validity Construct validity VALIDATION OF ANIMAL MODELS

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TRAIT ANXIETY MODELS Long term anxious states genetic models: transgenic and knock-out mice chronic exposure to fear-provoking stimuli rodent strains displaying high or low anxiety inter-individual differences within a defined strain

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STATE ANXIETY MODELS Acute anxious states Conditioned (learned) fear Unconditioned (spontaneous) fear

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CLASSIFICATION OF ANXIETY MODELS

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GELLER-SEIFTER TESTGeller and Seifter 1960 Alternation of punished and non-punished components Responding is suppressed during the punished component (0.6 mA, 0.5s) Anxiolytics increase punished responding

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VOGEL CONFLICT TESTVogel et al., 1971 Water Deprivation Drinking punished during test session with an electric shock via bottle spout (0.5 mA, 1 s) number of shocks accepted throughout a 5-min experimental session is recorded.

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ULTRASONIC VOCALISATION (USV)Paalzow and Paalzow, 1975 UV emitted (22 and 50 kHz) as response to aversive stimuli Inescapable footshocks First test session: rats receive four 1.0-mA inescapable footshocks, (10-s duration) with an intershock interval of 5 s. Remain in test cages for 6 min after the last shock. The same shock regimen was followed on test days. Recording of USV starts 1 min after the last shock, for 5 min.

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DEFENSIVE BURYING (DB)Pinel and Treit, 1978 Refers to displacing bedding material directed towards a variety of noxious stimuli Electrified shock-prod/probe Active (i.e. burying) or passive (i.e. freezing) forms of responding Latency to first shock Latency to burying initiation

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FOUR PLATE TEST (FPT) (Aron et al 1971) Punished suppression of exploration [electric footshocks (0.6 mA; 0.5 s)] 15 s habituation period Electric shock when crossing from one plate to another. PARAMETERS MEASURED: - number of crossed punishments (60s)

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SOCIAL INTERACTION (SI)File and Hyde, 1978 Time spent by a pair of rats in SI (e.g. sniffing, following or grooming the partner) Test conditions are manipulated LF, generating the lowest level of anxiety HF and LU, generating moderate levels of anxiety HU, generating the highest level of anxiety

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ELEVATED PLUS MAZE (EPM) (Pellow et al 1985, Lister 1987) Curiosity/exploration, locomotion Vertigo PARAMETERS MEASURED: - time spent on arms - number of entries onto arms - risk assessment behaviour

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LIGHT/DARK EXPLORATION (L/D) (Crawley et al 1981) (Hascoët and Bourin 1998) Brightness New environment PARAMETERS MEASURED: - locomotion / movement in each zone - time spent in each zone - latency of the first crossing from one compartment to the other - shuttle crossings between both compartments

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FACTORS INFLUENCING ANXIETY MODELS

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MODULATORS OF ANXIETY Monoamines GABA Glutamate Neuropeptides Neurotrophins Hormones Adenosine Cannabinoids Cytokines

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SITES OF ACTION OF NEUROTRANSMITTERS From Millan, 2003

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SITES OF ACTION OF NEUROPEPTIDES From Millan, 2003

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DRUG EFFECTS IN ANIMAL MODELS OF ANXIETY 5-HT receptor ligands Animal BZD 5-HT1A 5-HT2 5-HT2 5-HT3 NPY1 CCK4 SSRIs CRF models ag. ag. ag. ant. ant. ag. ag. ant. EPM ++ +/- +/0 +/0 +/0 + - -/0 +/0 L/D ++ +/0 0 0 ++ ND - +/0 +/0 SI ++ +/0 +/- +/0 +/0 + 0 - + GS ++ +/0 + + 0 + 0 -/0 + Vogel ++ + +/0 +/0 +/0 +/0 -/0 -/0 + DB ++ +/0 + + 0 ND ND + ND USV ++ +/0 0 0 0 ++ - ++ +/0 FPT ++ + ++ 0 ND ++ 0 ++ + ++: potent anxiolytic-like effect; +: anxiolytic-like effect, -: anxiogenic effect, 0: no effect, ND: Not Determined

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SEROTONINERGIC MODEL OF ANXIETY (Graeff et al 1996) + - + + Amygdala Dorsal Raphe nucleus Periaqueductal grey Frontal Cortex Ascending pathway facilitates conditoned fear DRN – periaqueductal pathway inhibits inborn unconditioned fear

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WHAT LINKS ANIMAL MODELS AND ANXIETY DISORDERS IN HUMANS ? Different models measure different anxiety disorders

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OTHER TARGETS Long-term administration Rebound, withdrawal anxiety Switching of medicines Test-retest models

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CONCLUSION Several animal models have proven effective in the detection of the anxiolytic activity of certain novel compounds A combination strategy may result in a more robust anxiolytic profile

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	michel.bourin@univ-nantes.fr 5 Years ago.



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