Excitotoxic Lesions of the Rat Medial Prefrontal Cortex Effects on Abnormal Behaviors Associated with Neonatal Hippocampal Damage

Abstract

excitotoxic damage of the ventral hippocampus (VH) is a heuristic model of schizophrenia. We investigated whether: (1) neonatal damage of the medial prefrontal cortex (mPFC) has effects similar to the neonatal VH lesion; and (2) intrinsic mPFC neurons contribute to the abnormal behaviors associated with VH lesions. Neonatal rats were lesioned in the mPFC. In adulthood, they showed attenuated locomotion in response to novelty, amphetamine, and Structural neurodevelopmental abnormalities in the temporolimbic cortex, dysfunction of the prefrontal cortex (PFC), and dysregulation of dopamine and glutamate systems are implicated in the pathophysiology of schizophrenia (Weinberger 1987;Robbins 1990;Grace 1991;Mittleman et al. 1993;Weinberger and Lipska 1995). In an attempt to recreate these neuropathological features in an animal, we previously investigated the consequences of neonatal excitotoxic damage of the ventral hippocampal formation in the rat on behaviors related to dopamine and glutamate function (Lipska et al. , 1995a Weinberger 1993, 1994; AlAmin et al. 1997). The results of these studies indicate that the neonatally lesioned rats display a constellation of behavioral abnormalities indicative of hyperdopaminergic subcortical activity and hyperresponsivity to glutamate antagonists and that the appearance of these behaviors is delayed until early adult life. Our results and subsequent reports from other laboratories (Flores et al. 1996a;Black et al. 1996;Wan et al. 1996;Wan and Corbett 1997) suggest that this lesion reproduces a constellation of core phenomena associated with schizophrenia, and may thus be used as an animal model of this disorder. Such neonatally lesioned rats also express Received January 5, 1998; revised April 16, 1998; accepted April 30, 1998. 452 B.K. Lipska et al. N EUROPSYCHOPHARMACOLOGY 1998 -VOL . 19 , NO . 6 behaviors that implicate dysfunction of the PFC (Chambers et al. 1996;Sams-Dodd et al. 1997), possibly because neonatal damage of the ventral hippocampus disrupts neuronal development of the PFC, with which the hippocampus is closely interconnected (Swanson 1981;Ferino et al. 1987;Jay et al. 1989;Laroche et al. 1990;Jay et al. 1992;Carr and Sesack 1996). Because PFC dysfunction has been shown in rodents (Adler 1961;Lynch et al. 1969;Iversen 1971;Pycock et al. 1980;Kolb 1984;Reibaud et al. 1984;Louilot et al. 1989;Jaskiw et al. 1991;Vezina et al. 1991;Deutch 1992;Jaskiw and Weinberger 1992;King and Finlay 1995;Taber et al. 1995;Karreman and Moghaddam 1996) and in primates (Kolachana et al. 1995;Roberts et al. 1994) to affect subcortical dopamine activity, the effect of the VH lesion on dopamine function might be indirectly mediated by an alteration at the level of the mPFC.The current study addresses the question of whether direct excitotoxic damage of the prefrontal cortex induced in neonatal rats affects glutamatergic and subcortical dopaminergic function in a manner similar to that observed in animals with the neonatal ventral hippocampal lesion. The lesion was inten...

Alterations in Behavioral Responses to a Cholinergic Agonist in Post-Pubertal Rats with Neonatal Ventral Hippocampal Lesions: Relationship to Changes in Muscarinic Receptor Levels

“…For example, alterations in the PFC are believed to be primarily responsible for the emergence of behavioral and physiological abnormalities observed in the NVH lesioned rats (Lipska et al, 1998;O'Donnell et al, 2002). Anatomical evidence from rats and monkeys demonstrated that some PFC neurons project to several brain areas notably the striatum, thalamus, hypothalamus, and brainstem, notably to the nucleus of solitary tract (Chiba et al, 2001;Van Eden and Buijs, 2000;Vertes, 2004).…”

Natural reward-related learning in rats with neonatal ventral hippocampal lesions and prior cocaine exposure

“…Correlated with these molecular and cellular alterations are neurophysiological changes: NVHL rats show abnormal patterns and elevations of neuronal firing in medial PfC pyramidal neurons produced by VTA stimulation that is mirrored by similar abnormalities in firing in medium spiny neurons in the NAc (Goto and O'Donnell 2002). Notably, a medial PfC uncorrupted by direct lesioning in NVHL rats is required for both the expression of hyperlocomotive responses to novelty and psychostimulants (Lipska et al 1998), and the VTA-stimulation-induced increases in NAc neuronal firing (Goto and O'Donnell 2004). Taken together, these studies point to the involvement of both gross developmental injury in the ventral hippocampus and more subtle secondary changes in PfC regions that project directly into reward-responsive subcortical circuits including the NAc and VTA, in the impulsive style of natural reward approach observed in the current study.…”

A review of MRI findings in schizophrenia

“…A potential model for such phenomena is also supported by animal studies. More specifically, rat pups with hippocampi lesioned early in development show delayed aberrant behavior occurring during adolescence (Lipska et al, 1993(Lipska et al, , 1995(Lipska et al, , 1998. These findings suggest that a neurodevelopmental lesion in a critical area, such as the hippocampus, may have delayed manifestations.…”