Fear Conditioning Test
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The fear conditioning learning and memory model is a method for evaluating trial compounds ability to reverse a drug-induced deficit in memory.
Fear conditioning involves pairing a context and/or cue (conditioning stimuli, CS) to a shock (unconditioned stimulus, US) and later measuring the ‘fear’ response to the CS in the absence of the US. A defensive freezing or immobility response serves as a reliable measure of fear.
Contextual and auditory-cue fear conditioning depend on different neural processes, whereas contextual conditioning is hippocampally driven and cued fear conditioning is not (Kim and Fanselow, 1992; Fendt and Fanselow, 1999).
NMDA-type glutamate receptor antagonists and nicotinic cholinergic receptor antagonists (e.g MK-801) cause amnestic effects in learning and memory tests such as fear conditioning. The compounds are often used to produce deficits in these models. Several classes of drugs reverse learning and memory deficits in the Fear Conditioning Test including acetylcholinesterase inhibitors (Csernansky et al., 2005) and phosphodiesterase type 4 (PDE4; e.g. rolipram) inhibitors (Gong et al. 2004).
Contextual conditioning is considered to require a higher order form of memory involving more cognitive function than cued conditioning. In comparison, cued conditioning involves a simpler, or lower form of memory that is considered to be more reflexive in nature. In Melior’s fear conditioning model context, is established with a number of visual references in the conditioning chamber. Cuing is established with an auditory tone, paired during the training phase.
The study summarized below was designed to establish a dose of MK-801 (an NMDA receptor antagonist) that blocks contextual conditioning but not cued conditioning. Rolipram (a PDE4 inhibitor) restores the deficit created by MK-801.
Csernansky, JG, Martin, M, Shah, R, Bertchume, A, Colvin, J, Dong, H. 2005 Neuropsychopharmacology30:2135-2143.
Kim, JJ, Fanselow, MS. Modality-specific retrograde amnesia of fear. 1992 Science256:675-676.
Fendt, M, Fanselow, MS. The neuroanatomical and neurochemical basis of conditioned fear. 1999 Neurosci Biobehav Reviews23:743-760.
Gong, B, Vitolo, OV, Trinchese, F, Liu, S, Shelanski, M, Arancio, O. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. 2004 J Clin Invest114:1624-1634.