Sex Differences in Behavioral Testing in an Adult Rat Model of Hydrocephalus

Abstract

Hydrocephalus is a developmental disorder that affects children worldwide with an incidence of approximately 1:1000 births. Multiple causes have been implicated, including a dysfunction of the homeostatic mechanisms of cerebrospinal fluid (CSF) secretion from the choroid plexus, a decreased reabsorption from the subarachnoid granules, or a blockage of CSF circulation, leading to excessive accumulation of CSF within the brain ventricles. One animal model of developmental hydrocephalus involves rats carrying a point mutation on the TMEM67 gene. The homozygous form of this mutation causes a ciliopathy that was originally found in rats with polycystic kidney disease (PKD). Rats homozygous for the TMEM67 mutation show severe hydrocephalus and PKD and do not survive beyond postnatal day (P) 18. Recently we identified a TRPV4 antagonist that appears to protect against the ventriculomegaly in preweaning homozygous rats. We propose that this drug has effects directly on the choroid plexus, and since it is administered intraperitoneally, must gain access to the choroid epithelial cells. Animals heterozygous for the TMEM67 mutation develop a milder degree of hydrocephalus, no renal disease, and live past 1 year. The current study tested the hypothesis that treatment of heterozygous adult animals with the TRPV4 antagonist, RN1734, can limit the extent of hydrocephalus thereby protecting against the associated adverse effects on neurobehavioral function. In the current experiments, the behavioral studies assessed exploration of a complex novel environment called the multivariate concentric square field (MCSF), a 100 x 100 cm arena containing multiple defined zones with a large center area, three dimly‐illuminated perimeter corridors, one brightly illuminated slope and bridge, an enclosed dark corner room (DCR), and a corner hurdle. Video recordings of the single 20‐minute session of each rat are scored by two observers blind to group membership, and quantitative measures of behavioral categories (locomotor activity, exploratory activity, shelter seeking, risk assessment, risk taking) are derived from scores of the type, number and duration of activities in the various zones. MRI's were performed on P300 and P331, and the rats were assigned to either RN1734 or vehicle treatment on P301‐P330, and testing on the MCSF occurred on P315. Several interesting and unexpected results emerged from these studies. Regardless of genotype, the proportion of males that developed hydrocephalus was significantly higher than that of females. Regardless of genotype and drug treatment, the females were more active and engaged in less shelter seeking than males. Because of these sex differences the current studies were underpowered to determine effects of genotype and drug treatment on the behavioral activities.Support or Funding InformationHydrocephalus Association and Department of Defense Office of the Congressionally Directed Medical Research Programs (CDMRP)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.