The present proposal will investigate the neural mechanisms of spatial discrimination reversal in developing rats. This research will improve the utility of animal models of developmental disorders such as autism spectrum disorder (ASD) and fetal alcohol spectrum disorder (FASD) in which impaired reversal learning is a prominent feature. Spatial discrimination reversal is operationally simple, is readily administered across ontogeny in both rodents and humans, and is sensitive to a variety of developmental insults. Developmental assessment is important in the study of developmental disorders for several reasons (e.g., Stanton, 1994). It permits analysis of the ontogenetic time course of the disorder which is important for revealing parallels with the human disorder, for understanding mechanisms, and for developing effective therapeutic interventions. It also often increases sensitivity of behavioral assessments (especially in FASD) and can guide interventions at early stages of development when they are more likely to be effective. Although there is some understanding of the neural mechanisms of reversal learning in adults, this understanding is rather limited in developing animals. This proposal will use a preparation for studying T-maze reversal in periweanling and juvenile rats that has been recently established (Pagani, Brown & Stanton, 2005; Watson, Sullivan, Frank & Stanton, 2006) and demonstrated to be sensitive to acute, systemic administration of the noncompetitive NMDA receptor antagonist, MK-801 (Chadman, Watson & Stanton, submitted). It will test the hypothesis that NMDA receptor action in specific regions of the brain is necessary for reversal learning. Acquisition and reversal of a T-maze discrimination will be studied in weanling rats that have been intracranially infused (via bilaterally implanted cannulas) with the competitive NMDA antagonist, AP5 into the dorsal hippocampus (Aim 1); the medial prefrontal cortex (Aim 2), or the dorsomedial striatum (Aim 3). In most Aims, a 2 (Acquisition treatment) x 2 (Reversal treatment) factorial design will be used in which AP5 (or vehicle) will be administered during acquisition, reversal, both or neither. Additional studies may be pursued under each aim to further explore the neural, behavioral, and developmental determinants of effects that are found in these initial experiments. This research will advance the developmental psychobiology of learning and memory and contribute to the development of rodent models that can be applied to the early identification and treatment of developmental disorders, such as FASD and ASD. These goals serve the mission of a variety of NIH agencies (e.g., NICHD, NIMH, NIDA, NIHS, and NIAAA). ? ? ?
| Jablonski, Sarah A; Watson, Deborah J; Stanton, Mark E (2010) Role of medial prefrontal NMDA receptors in spatial delayed alternation in 19-, 26-, and 33-day-old rats. Dev Psychobiol 52:583-91 |
| Watson, Deborah J; Herbert, Mariel R; Stanton, Mark E (2009) NMDA receptor involvement in spatial delayed alternation in developing rats. Behav Neurosci 123:44-53 |
| Watson, Deborah J; Stanton, Mark E (2009) Spatial discrimination reversal learning in weanling rats is impaired by striatal administration of an NMDA-receptor antagonist. Learn Mem 16:564-72 |
| Watson, Deborah J; Stanton, Mark E (2009) Medial prefrontal administration of MK-801 impairs T-maze discrimination reversal learning in weanling rats. Behav Brain Res 205:57-66 |
| Watson, Deborah J; Stanton, Mark E (2009) Intrahippocampal administration of an NMDA-receptor antagonist impairs spatial discrimination reversal learning in weanling rats. Neurobiol Learn Mem 92:89-98 |
