Injections of NGF into neonatal frontal cortex decrease social interaction as adults: a rat model of schizophrenia

Abstract

Background: Injection of nerve growth factor (NGF) into the developing frontal cortex (FC) has been shown to produce adult-onset subcortical dopaminergic hyperactivity, impaired prepulse inhibition of the acoustic startle response, and several neuropathological features of schizophrenia. The present study was to determine whether such lesions would lead to impaired social interaction, a prominent negative feature of schizophrenia.

Methods: Rat pups received daily injections of human recombinant NGF into the developing FC on postnatal days 1 and 2 to partially lesion subplate neurons. Lesioned rats were tested in similar-treatment pairings lasting 23.5 hours using the EthoVision behavioral monitoring system at 6 and 14 weeks of age. Brains were then perfusion fixed for histological analysis.

Results: Lesioned rats showed significantly increased movement, relative to controls, during the light phase at 6 weeks of age. At 14 weeks, they maintained a significantly greater mean distance apart from one another, and engaged in significantly less approach and avoidance behavior during the dark phase, relative to controls. Histological changes were consistent with those described previously in this animal model.

Conclusion: Results indicate that injections of NGF into the developing FC of neonatal rats result in reduced social interaction, which is consistent with behaviors observed in human schizophrenia patients.

Fig. 1.

Calculation of the relative movement measures. EthoVision detects whether Rat B is moving toward or away from Rat A by comparing the trajectory of Rat B with the midpoint of the trajectory of Rat A (M). The distance from M to B₁ is less than the distance from M to B₂; therefore, Rat B is avoiding Rat A. The distance from M to B₁ is greater than the distance from M to B₃; therefore, Rat B is approaching Rat A. (Figure and caption adapted from Noldus Information Technology, 2003.)

Fig. 2.

Bright-field images of neutral red-stained coronal sections of adult rats that received neonatal infusions of saline (A, C) or NGF (B, D) showing the thickness of cingulate cortex (Cg1, Cg2) (A, B) and the size of lateral ventricles (C, D). Sections A and B, and C and D were taken through the same rostrocaudal plane. Note that the thickness of Cg1 and Cg2 areas appears smaller in NGF-lesioned rat (B) compared with the control rat (A). The surface area of the lateral ventricle in NGF-lesioned rat (D) appears larger than that of the control (C); cc, corpus callosum, CP, caudate-putamen, LS, lateral septum (bar, A, B = 650 μm; C, D = 300 μm).

Fig. 3.

Percent time moving at 6 weeks of age. There was a significant group difference during the light phase, in which NGF rats engaged in greater movement. Data points represent group mean percent of time moving analyzed for time bins of 2 hours, except for bin 12, which is 1.5 hours in duration. Error bars in all figures represent ± 1 standard error of the mean.

Fig. 4.

Percent time moving at 14 weeks of age. There was no significant treatment effect in either the dark or the light phases. Data points represent groups mean percent of time moving analyzed for time bins of 2 hours, except for bin 12, which is 1.5 hours in duration.

Fig. 5.

Mean distance apart at 14 weeks of age. There was a significant treatment effect during the dark phase, in which NGF rats maintained a greater mean distance apart. Data points represent group mean distance apart in centimeter averaged for time bins of 2 hours, except for bin 12, which is 1.5 hours in duration.

Fig. 6.

Mean distance apart during the light phase at 14 weeks. There is a significant treatment effect during the first 4 hours of the light phase (bins 25–32), in which NGF rats maintain a greater mean distance apart. There are no significant treatment effects during the second 4 hours or the last 3.5 hours. Data points represent group mean distance apart in centimeter averaged for time bins of 30 minutes.

Fig. 7.

Digitized movement paths of control and NGF rat pairs for time bins 25–32. Each time bin represents 30 minutes. The rat pairs whose data appear in this figure are those whose mean distance apart data for time bins 25–32 were closest to the mean values of their respective groups. The squares embedded in the paths represent the most common position of the rats for each time bin. The squares are indicated by arrows for clarity.

Fig. 8.

Approach behavior at 14 weeks of age. There was a significant effect of treatment during the dark cycle, in which NGF rats engaged in less approach behavior. Data points represent group mean distance apart in centimeter averaged for time bins of 2 hours, except for bin 12, which is 1.5 hours in duration.

Fig. 9.

Avoidance behavior at 14 weeks of age. There was a significant treatment effect during the dark cycle, in which NGF rats engaged in less avoidance behavior. Data points represent group mean distance apart in centimeter averaged for time bins of 2 hours, except for bin 12, which is 1.5 hours in duration.