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Transient Inactivation of the Neonatal Ventral Hippocampus Disrupts Mesolimbic Regulation of Prefrontal Glutamate Release

出版	Ohio State University, 2012
URL	http://books.google.com.hk/books?id=m6HkmgEACAAJ&hl=&source=gbs_api

註釋Abstract: Cognitive control deficits in schizophrenia (SZ) reflect maturational disruptions within a distributed neural system that includes the hippocampus, nucleus accumbens (NAC), basal forebrain, and prefrontal cortex (PFC). The ventral hippocampus (VH) sends glutamatergic projections to both the PFC and NAC, thus contributing to the development of these target regions. The VH of schizophrenics exhibits cytoarchitectural disorganization, implicating the developing VH in the cognitive deficits seen in patients with SZ. Lesions of the neonatal VH of rodents have been considered a model of the cognitive symptoms of SZ. While animals with such lesions exhibit several cognitive deficits that correspond with those seen in SZ (i.e. impairments in sensory gating, set-shifting, and working memory), the extensive tissue loss produced by such lesions is considered a major challenge to the face validity of the model. Therefore, we and others have developed a related, yet more refined model in which the development of the VH and its targets is disrupted transiently by inactivating VH impulse flow as a result of infusions of tetrodotoxin (TTX) into this region. This model reproduces cognitive deficits seen in other models and in the disease itself, including impairments in latent inhibition and cognitive flexibility. Neurochemically, we reported that adult rats treated with TTX on PD7, but not on PD32, lose the normal mesolimbic regulation of prefrontal ACh release (Brooks et al., 2011). Given that ACh, via alpha7 nicotinic acetylcholine receptors, regulates glutamate release in PFC (Konradsson et al., 2009; Bortz et al., in press), we determined the ability of mesolimbic activation to evoke phasic prefrontal glutamate release in intact adult rats, and then rats that had received saline or TTX as neonates (PD7) or during adolescence (PD32). NAC outflow was activated by infusing NMDA (0.05-0.30 μg/0.4 μL) into the shell of this region. Basal and evoked glutamate levels were measured amperometrically, using a glutamate-sensitive microelectrode array. There were no differences in basal glutamate levels (overall mean: 1.70 uM) between any of the groups tested. However, intra-NAC infusion of NMDA evoked prefrontal glutamate release in PD7 TTX rats that was significantly reduced when compared to intact and PD7 Sham rats. In contrast to this effect, infusions of TTX during adolescence (PD32) did not alter the increases in glutamate release caused by intra-NAC NMDA infusions. These age-related differences parallel impairments in set-shifting performance in PD7 but not PD32 TTX rats (Brooks et al., 2012), a task that requires intact glutamatergic transmission in PFC. Collectively, these findings support the significance and usefulness of PD7 VH TTX infusions as an animal model of neurochemical and cognitive impairments in SZ.