The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia

Abstract

Traditionally, animal models of schizophrenia were predominantly pharmacological constructs focused on phenomena linked to dopamine and glutamate neurotransmitter systems, and were created by direct perturbations of these systems. A number of developmental models were subsequently generated that allowed testing of hypotheses about the origin of the disease, mimicked a wider array of clinical and neurobiological features of schizophrenia, and opened new avenues for developing novel treatment strategies. The most thoroughly characterized (approximately 100 primary research articles) is the neonatal ventral hippocampal lesion (NVHL) model, which is the subject of this review. We highlight its advantages and limitations, and how it may offer clues about the extent to which positive, negative, cognitive, and other aspects of schizophrenia, including addiction vulnerability, represent inter-related pathophysiological mechanisms.

Figure 1

Different methods used in schizophrenia research may lead to different conclusions dependent on one’s perspective. This notion is illustrated by a cartoon based on the tale, in which a group of blind men examining different parts of an elephant try to learn what it is like, and draw different conclusions. By generating multiple neurobiological and behavioral “parts” of schizophrenia, the NVHL comprehensively models the “elephant” as a developmental, neurocircuit-based pathophysiological pathway, through which converging genetic and environmental factors produce schizophrenia-spectrum clinical syndromes.

Figure 2

A diagram illustrating major brain circuits thought to be involved in the pathophysiology of schizophrenia [, –5]. They are anatomically and functionally interconnected, and are crucial in determining appropriate decision making outcomes in response to external stimuli [3, 5].

Figure 3

A timeline of the emergence of behavioral changes following the neonatal ventral hippocampal lesion in the rat and a comparison with the emergence of symptoms in schizophrenia in humans. Developmental ventral hippocampal damage produces a number of dopamine-related behavioral abnormalities that emerge late in adolescence and early adulthood, resembling the delayed onset of psychotic symptoms in schizophrenia. Other NVHL-induced behavioral anomalies, such as negative-like symptoms and cognitive deficits [, , –43], occur at both pre- (PD 35) and postpubertal (PD 65) ages, similar to subtle developmental anomalies in humans who later develop schizophrenia, and do not respond to antipsychotic drugs [48].

Figure 4

Photomicrographs depicting the extent of a typical neonatal ventral hippocampal lesion. Coronal Nissl stained sections show the ventral hippocampus of a sham-operated rat (top, SHAM) and a characteristic neonatal ventral hippocampal lesion (bottom, NVHL), characterized by cell loss (arrows), and enlarged ventricles (asterisks).

Figure 5

The development and function of multiple brain systems are affected in the NVHL model, including the frontal and medial temporal lobes, the ventral striatum, and the mesocorticolimbic dopamine system. Early developmental insult of the ventral hippocampus has the unique capacity to change function of a multitude of brain regions and may thus capture the complexity of the disease process of schizophrenia.