In recent years, contextual fear conditioning has become a prominent paradigm for studying normal and abnormal development of conjunctive/spatial information processing in rodent models. However, very little is known concerning the neural mechanisms that cause context conditioning to emerge during ontogeny. We propose to use the context pre-exposure facilitation effect (CPFE) for this purpose. The CPFE is a variant of contextual fear conditioning in which learning about the context, consolidation and retrieval of the context memory, associating the context memory with shock, and retrieval of the context-shock association occur during separate phases of the procedure, making them especially amenable to experimental manipulations that can reveal underlying mechanisms. A recent model of the CPFE suggests that these processes depend on interactions between temporal cortical regions, the hippocampus, and the amygdala .. New data from our lab demonstrates the prefrontal cortex is also involved in the CPFE. Furthermore, we have recently shown that the CPFE emerges between Postnatal Day (PD) 17 and PD 24 in the rat and that antagonism of hippocampal NMDA receptors during context preexposure eliminates the effect on PD24 . The present proposal will extend this work by examining the role of immediate early gene (IEG) activation and prefrontal cortex-hippocampus-amygdala interactions in the ontogeny of the CPFE. We have found distinct patterns of expression of the immediate early gene, Egr1, in these brain regions during different phases of the CPFE in juvenile rats (see Significance).
Aim 1 will determine whether changes in these patterns of Egr-1 expression are associated with the early ontogeny of the CPFE.
Aim 2 will use antisense to Egr1 to test a causal role for activation of these IEGs in the ontogeny of the CPFE.
Aim 3 will extend the findings from Aims 1 and 2 to explore mechanisms of impaired cognitive development in an animal model of Fetal Alcohol Spectrum Disorder (FASD). We have recently shown that the CPFE is unusually sensitive to various doses and developmental windows of alcohol exposure in our established rodent model of FASD [49, 50].
Aim 3 will test the hypothesis that impaired IEG expression in the prefrontal cortex, hippocampus and/or amygdala contributes to the severe disruptions of the CPFE produced by developmental alcohol exposure. Taken as a whole, the work in this proposal will advance understanding of the mechanisms of cognitive development in the rat and promote translational applications of this understanding to human developmental learning disorders found in FASD.
This R01 proposal will use a variant of contextual fear conditioning to examine normal and abnormal development of conjunctive/spatial information processing in rodent models. It explores the role of immediate early gene expression in the Context Preexposure Facilitation Effect (CPFE) in normally developing rats and in a rodent model of Fetal Alcohol Spectrum Disorder (FASD). The work will promote translational applications of rodent model research to human developmental learning disorders found in FASD.
|Asok, A; Draper, A; Hoffman, A F et al. (2018) Optogenetic silencing of a corticotropin-releasing factor pathway from the central amygdala to the bed nucleus of the stria terminalis disrupts sustained fear. Mol Psychiatry 23:914-922|
|Heroux, Nicholas A; Osborne, Brittany F; Miller, Lauren A et al. (2018) Differential expression of the immediate early genes c-Fos, Arc, Egr-1, and Npas4 during long-term memory formation in the context preexposure facilitation effect (CPFE). Neurobiol Learn Mem 147:128-138|
|Robinson-Drummer, P A; Chakraborty, T; Heroux, N A et al. (2018) Age and experience dependent changes in Egr-1 expression during the ontogeny of the context preexposure facilitation effect (CPFE). Neurobiol Learn Mem 150:1-12|
|Jablonski, Sarah A; Robinson-Drummer, Patrese A; Schreiber, William B et al. (2018) Impairment of the context preexposure facilitation effect in juvenile rats by neonatal alcohol exposure is associated with decreased Egr-1 mRNA expression in the prefrontal cortex. Behav Neurosci 132:497-511|
|Robinson-Drummer, P A; Heroux, N A; Stanton, M E (2017) Antagonism of muscarinic acetylcholine receptors in medial prefrontal cortex disrupts the context preexposure facilitation effect. Neurobiol Learn Mem 143:27-35|
|Murawski, Nathen J; Asok, Arun (2017) Understanding the contributions of visual stimuli to contextual fear conditioning: A proof-of-concept study using LCD screens. Neurosci Lett 637:80-84|
|Heroux, Nicholas A; Robinson-Drummer, Patrese A; Sanders, Hollie R et al. (2017) Differential involvement of the medial prefrontal cortex across variants of contextual fear conditioning. Learn Mem 24:322-330|
|Ayers, Luke; Agostini, Andrew; Schulkin, Jay et al. (2016) Effects of oxytocin on background anxiety in rats with high or low baseline startle. Psychopharmacology (Berl) 233:2165-2172|
|Robinson-Drummer, Patrese A; Dokovna, Lisa B; Heroux, Nicholas A et al. (2016) Cholinergic mechanisms of the context preexposure facilitation effect in adolescent rats. Behav Neurosci 130:196-205|
|Chakraborty, T; Asok, A; Stanton, M E et al. (2016) Variants of contextual fear conditioning induce differential patterns of Egr-1 activity within the young adult prefrontal cortex. Behav Brain Res 302:122-30|
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