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The neonatal ventral hippocampal lesion model (NVHL) was originally developed by Lipska and Weinberger. It was reviewed by Tseng and colleagues (2009) and has been validated by a large number of studies. It is important because it demonstrates how a single neurobiological defect early in life can be responsible for producing later physiological and behavioral abnormalities reminiscent of the complex syndrome of schizophrenia, including some positive, negative, and cognitive symptoms. It involves lesioning the ventral hippocampus of rodents at postnatal day 7, a time corresponding to the human second trimester, a period of fetal hippocampal vulnerability. Although the young animals at day 35 behave normally, the lesion apparently alters the trajectory of brain development such that those same animals during post-adolescence (day 56) show significantly greater hyperactivity in response to stimuli such as mild stress, novelty, amphetamine, and apomorphine. The fact that these stimuli cause DA efflux suggests that the early lesion may produce an increased mesolimbic DA response as the animals mature—an effect supportive of the DA hypothesis of schizophrenia. Haloperidol and other antipsychotic drugs that block DA receptors can prevent the emergence of hyperactivity. Other parallels to the positive symptoms of the disorder, such as abnormal PPI and increased sensitivity to glutamate antagonists, also appear at this time.
It is especially interesting that those animals that did not show DA hyperresponsivity until day 56 did display analogs of negative symptoms at day 35 as well as day 56. Among the deficits is reduced social interaction, a hallmark feature of schizophrenia that occurs much earlier than the positive symptoms. Cognitive impairments are also evident in the animals, as demonstrated by deficits in the Morris water maze and tests of working memory. These deficits occur both early and later, and some may be analogous to the subtle impairments that schizophrenic individuals show before the onset of psychosis. It is significant that injecting tetrodotoxin, which prevents action potentials by blocking voltage-gated sodium channels, into the hippocampus at day 7 produces a similar phenotype and timing of deficit onset without causing a lesion. These results suggest that even temporary interruption of hippocampal function, if it occurs at a critical time of development, impairs further development of associated neural circuits. A timeline for the appearance of behavioral deficits is provided in Figure 1. Particularly fascinating is the observation that, just as symptoms vary among patients with schizophrenia, the effects of lesions of the same size in various rat strains produce different phenotypes and differences in age at onset of the behavioral deficits. Of additional interest is that brief social isolation of young NVHL rats exaggerates the neurochemical, behavioral, and physiological outcomes. Other forms of stress produce similar enhancement.
Figure 1 Timeline of the behavioral syndrome of the NVHL model. The upper timeline shows the emergence of behavioral changes in rats following neonatal ventral hippocampal lesioning in comparison with the occurrence of symptoms in schizophrenic individuals (lower timeline). As in human patients, negative-like symptoms and cognitive deficits appear early in rodents, whereas positive-like symptoms occur at a time corresponding to late human adolescence or early adulthood. (After Tseng et al., 2009.)
A fascinating line of research has also shown that early hippocampal lesions affect the development of several other brain areas implicated in schizophrenia, including the prefrontal cortex, medial temporal lobe, and nucleus accumbens. For instance, it is suspected that loss of hippocampal input to PFC is responsible for the decreased dendritic length and spine density that are characteristic of NVHL animals. A developmentally delayed change in the balance of dopamine–glutamate interactions also has been seen in the PFC of these animals, which might be expected to contribute to hypofrontality in patients (see textbook Chapter 19).
For an update of the research evaluating this model, see Mattei and coworkers (2015).
References
Mattei, D., Schweibold, R., and Wolf, S. A. (2015). Brain in flames: Animal models of psychosis: Utility and limitations. Neuropsychiat. Dis. Treat., 11, 1313–1329.
Tseng, K. Y., Chambers, R. A., and Lipska, B. K. (2009). The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia. Behav. Brain Res., 204, 295–305.