Kaolin‐induced ventriculomegaly at weaning produces long‐term learning, memory, and motor deficits in rats

Abstract

Ventriculomegaly occurs when there is imbalance between creation and absorption of cerebrospinal fluid (CSF); even when treated, long-term behavioral changes occur. Kaolin injection in the cisterna magna of rats produces an obstruction of CSF outflow and models one type of hydrocephalus. Previous research with this model shows that neonatal onset has mixed effects on Morris water maze (MWM) and motoric performance; we hypothesized that this might be because the severity of ventricular enlargement was not taken into consideration. In the present experiment, rats were injected with kaolin or saline on postnatal day (P)21 and analyzed in subgroups based on Evan's ratios (ER) of the severity of ventricular enlargement at the end of testing to create 4 subgroups from least to most severe: ER0.4–0.5, ER0.51-0.6, ER0.61-0.7, and ER0.71-0.82, respectively. Locomotor activity (dry land and swimming), acoustic startle with prepulse inhibition (PPI), and MWM performance were tested starting on P28 (122 cm maze) and again on P42 (244 cm maze). Kaolin-treated animals weighed significantly less than controls at all times. Differences in locomotor activity were seen at P42 but not P28. On P28 there was an increase in PPI for all but the least severe kaolin-treated group, but no difference at P42 compared with controls. In the MWM at P28, all kaolin-treated groups had longer path lengths than controls, but comparable swim speeds. With the exception of the least severe group, probe trial performance was worse in the kaolin-treated animals. On P42, only the most severely affected kaolin-treated group showed deficits compared with control animals. This group showed no MWM learning and no memory for the platform position during probe trial testing. Swim speed was unaffected, indicating motor deficits were not responsible for impaired learning and memory. These findings indicate that kaolin-induced ventriculomegaly in rats interferes with cognition regardless of the final enlargement of the cerebral ventricles, but final size critically determines whether lasting locomotor, learning, and memory impairments occur.

Hydrocephalus compacted cortex and hippocampus and altered their output neurons in association with spatial learning and memory deficits in rats

“…These cannot be attributed to difference in swimming ability between animals ( Figure 1B) (35,70). Our findings that hydrocephalus impaired rats' spatial learning and memory are consistent with earlier study testing the animals' performance with multiple day MWM task (15,70) as well. Our findings that hydrocephalus impaired rats' spatial learning and memory are consistent with earlier study testing the animals' performance with multiple day MWM task (15,70) as well.…”

“…Like earlier studies, kaolin-induced hydrocephalic rats showed slower body weight gain (15,44,70). Acute hydrocephalic rats showed increased escape latency starting from the second trial block of the single-day MWM task while chronic animals (a different batch of animals, first exposure to the task) took longer to find the underwater platform than their age-matched controls starting in the first trail block of the day.…”

“…Previous studies in the same animal model found a positive correlation only in the most severe cases of ventriculomegaly (52,70). This prevented us from checking whether changes in ventricle sizes and thicknesses of the cerebral cortex and corpus callosum were correlated with the animals' performance in Morris water maze task.…”

“…Kaolin was injected at postnatal day 21 to correlate with human infancy (55) when hydrocephalus most commonly develops clinically. Hydrocephalic rats were studied 1 and 5 weeks post-induction to represent the acute and chronic hydrocephalic stages, respectively, because the ventriculomegaly reached maximum and remained stable 3 weeks following kaolin injection (18,70). Cognitive changes and anatomic and biochemical alterations in the primary somatosensory cortex and dorsal hippocampus were explored.…”

Current Topics in Postnatal Behavioral Testing

“…Adapted from Williams et al 33 deficit persists using back-to-back phases, it would also remain for spaced phases. 34 Therefore, we think this is an appropriate way to monitor changes in learning and memory over time. For specific details, see Vorhees and Williams.…”