Selective deficits in spatial working memory in the neonatal ventral hippocampal lesion rat model of schizophrenia

Abstract

The neonatal ventral hippocampal lesion (NVHL) manipulation is a neurodevelopmental animal model of schizophrenia that produces abnormalities in the prefrontal cortex and nucleus accumbens, both efferent targets of the hippocampus, and leads to spatial working memory impairments. To investigate the neuroanatomical basis of spatial working memory in NVHL animals, we assessed performance in two radial arm maze tasks known to be differentially sensitive to the two hippocampal efferent pathways, and measured levels of neuronal activation (Fos immunoreactivity [Fos-IR]) in the prefrontal cortex and nucleus accumbens following task performance. Neonatal rats (postnatal day 6-8) received excitotoxic lesions of the ventral hippocampus (n=25), or a sham procedure (infusions of artificial cerebrospinal fluid; n=22). Upon reaching adulthood, animals were trained in either a non-delayed random foraging task or a spatial delayed win-shift task. NVHL animals were impaired on the spatial delayed win-shift task, which depends on communication between hippocampus and prefrontal cortex, but were unimpaired on the non-delayed random foraging task, which requires connections between hippocampus and nucleus accumbens. Fos-IR in the nucleus accumbens was greater in NVHL animals than in shams following the random foraging task, despite similar levels of performance, while no group differences in Fos-IR in either the nucleus accumbens or prefrontal cortex were observed following win-shift performance. These results suggest that although the NVHL manipulation disrupts development of hippocampal efferents to both the prefrontal cortex and the nucleus accumbens, the disruption of hippocampal-prefrontal pathways has the dominant behavioral effect on spatial performance in NVHL rats.