Cognitive Effects of Neonatal Hippocampal Lesions in a Rat Model of Schizophrenia

Abstract

Lesioning the ventral hippocampus of neonatal rats has been proposed as an experimental model of schizophrenia. This lesion causes a syndrome of hyperresponsivity to the stimulant effects of amphetamine, impaired grooming and disrupted social interactions, effects that emerge during adolescence, much like schizophrenia. Persisting cognitive effects of neonatal ventral hippocampal lesions were assessed in the current study, because the hippocampus is critically important for a variety of cognitive functions and cognitive impairment and because it is an important feature of schizophrenia. Spatial learning and working memory were assessed in the radial-arm maze, which is sensitive to the adverse effects of hippocampal lesions made in adults. Lesioned rats showed pronounced deficits in radial-arm maze choice accuracy that persisted throughout training. Deficits were seen during the prepubertal period as well as in adulthood. Even though the lesioned rats performed more poorly, they were significantly less sensitive to the amnestic effects of the nicotinic antagonist mecamylamine and the muscarinic antagonist scopolamine. No significant effects of nicotine or amphetamine were seen in either the lesioned or control groups. The long-lasting deficits in spatial learning and working memory resulting from neonatal ventral hippocampal lesions show that, unlike frontal cortical lesions during the same age, the effects of hippocampal lesions are not overcome during development. The resistance to the amnestic effects of nicotinic and muscarinic acetylcholine (ACh) antagonists suggests that the hippocampus is a critical site for the action of these drugs. Neonatal hippocampal lesions may provide a good model of the cognitive impairments of schizophrenia and may be useful to assess novel drug effects to counteract the cognitive deficits in schizophrenia.

Neonatal Damage of the Ventral Hippocampus Impairs Working Memory in the Rat

“…These findings are consistent with previous reports that temporolimbic development affects the ontogeny of working memory Stanton 1991, 1992;Green and Stanton 1989), and that the neonatal hippocampal lesions may have widespread and lasting adverse effects in the interconnected areas implicated in certain cognitive processes (Van Praag et al 1998;Khaing et al 2000;Chambers et al 1996;Le Pen et al 2000).…”

“…Previous studies assessed learning and working memory of animals with this neonatal lesion using a radial-arm maze and Morris water maze, tests strongly dependent on spatial recognition (Chambers et al 1996, Le Pen et al 2000. In both tests, the neonatally lesioned rats showed pronounced impairments; deficits in choice accuracy in a radial-arm maze test were apparent prepuberty, persisted into adulthood and were evident in both female and male rats with the neonatal hippocampal lesion (Chambers et al 1996).…”

“…Previous studies assessed learning and working memory of animals with this neonatal lesion using a radial-arm maze and Morris water maze, tests strongly dependent on spatial recognition (Chambers et al 1996, Le Pen et al 2000. In both tests, the neonatally lesioned rats showed pronounced impairments; deficits in choice accuracy in a radial-arm maze test were apparent prepuberty, persisted into adulthood and were evident in both female and male rats with the neonatal hippocampal lesion (Chambers et al 1996). In the present study, we examined the effect of the neonatal lesion on performance in two related working memory tasks: (1) the continuous delayed alternation (Brito et al 1982); (2) the discrete paired-trial delayed alternation (Aultman and Moghaddam 2001), the relatively non-spatial tests because high walls of the maze in our tests reduced external cues.…”

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

“…Similarly, to the extent that total durations of magazine entries over conditioning may reflect motivated effort or non-specific seeking behavior for the water reward, the absence of lesion effects on this measure, or on the proportional durations of magazine entries during the water presentation (UCS phase), do not support an interpretation whereby lesion effects on the CS or INA measures resulted from significant differences in reward motivation per se. However, since NVHL rats show profound deficits in working memory performance measured by food reward seeking on a radial arm maze (Chambers et al 1996), but increased lever pressing for food reward on a fixed-ratio 3 schedule (Chambers and Self 2002), the present results may reflect abnormal functioning of neural systems that integrate cognitive with motivational processes. NVHLs may compromise efficient reward acquisition requiring more complex learned associations (e.g., CS-UCS associations), while increasing motivational responding under more simple contingencies (e.g., achieving increasing proportions of UCS-targeted approaches via greater proportions of indiscriminate INA phase approaches).…”

“…NVHL rats have been studied by several groups as a comprehensive animal model of schizophrenia. NVHL rats show post-adolescent onset of neurolepticresponsive, positive-like symptoms, such as hyper-responsivity of dopamine-mediated behaviors (Lipska et al 1993;Lipska and Weinberger 1994) accompanied by a number of schizophrenia-related cognitive and negative-like symptoms Chambers et al 1996;Grecksch et al 1999;Lipska et al 1995). In applying this animal model toward understanding increased substance use disorder (SUD) comorbidity in schizophrenia, NVHL rats show increased vulnerability to developing an addicted phenotype in acquisition, maintenance and post-withdrawal phases of COC self-administration (Chambers and Self 2002).…”