Sex-dependent behavioral effects and morphological changes in the hippocampus after prenatal invasive interventions in rats: implications for animal models of schizophrenia

Abstract

OBJECTIVESAlthough schizophrenia affects both human genders, there are gender-dependent differences with respect to age of onset, clinical characteristics, course and prognosis of the disease.METHODSTo investigate sex-dependent differences in motor coordination and activity as well as in cognitive and social behavior, we repeatedly tested female (n = 14) and male (n = 12) Fisher rats (postnatal days, PD 56–174) that had received intracerebroventricular injections of kainic acid as well as female (n = 15) and male (n = 16) control animals. The hippocampus was examined histologically.RESULTSCompared to male controls, in the alcove test both female controls and female animals with prenatal intervention spent less time in a dark box before entering an unknown illuminated area. Again, animals that received prenatal injection (particularly females) made more perseveration errors in the T-maze alternation task compared to controls. Female rats exhibited a higher degree of activity than males, suggesting these effects to be sex-dependent. Finally, animals that received prenatal intervention maintained longer lasting social contacts. Histological analyses showed pyramidal cells in the hippocampal area CA3 (in both hemispheres) of control animals to be longer than those found in treated animals. Sex-dependent differences were found in the left hippocampi of control animals and animals after prenatal intervention.CONCLUSIONThese results demonstrate important differences between males and females in terms of weight gain, response to fear, working memory and social behavior. We also found sex-dependent differences in the lengths of hippocampal neurons. Further studies on larger sample sets with more detailed analyses of morphological changes are required to confirm our data.

The therapeutic effect of a pulsed electromagnetic field on the reproductive patterns of male Wistar rats exposed to a 2.45-GHz microwave field

“… 32 , 33 The present work supports these findings and others. 41 Von Wilmsdorff et al 42 hypothesized that brain behavioral modifications due to kainic acid treatment cause sex-specific responses via the hypothalamic-pituitary-adrenal-axis. Such effects may be achieved through either a chemical or radiation-based treatment, which suggests that the effects are mediated by the higher brain centers and are transferred to the reproductive system, thereby affecting the testosterone and sperm counts through the endocrine system.…”

Sex differences and left–right asymmetries in expression of insulin and insulin-like growth factor-1 receptors in developing rat hippocampus

“…Together with other mechanisms such as endogenous steroid levels, these differences may also underlie sexual dimorphism and left-right asymmetry in the hippocampus. Nevertheless, the hippocampus implicated in the etiology of several mental health disorders, many of which exhibit some degree of sex difference, and there are also subtle sex differences in hippocampal-associated behaviors such as spatial learning strategies and stress responsivity (Castle and Murray 1991;von Wilmsdorff et al 2010;DeCarolis and Eisch 2010;Exner et al 2008;Frazier et al 2008). Future studies will be needed to determine the possible involvement of IGF-1R and InsR in these gender differences of hippocampal function and dysfunction.…”

A systematic review comparing sex differences in cognitive function in schizophrenia and in rodent models for schizophrenia, implications for improved therapeutic strategies

“…In a different lesion rat model of prenatal hippocampal treatment with kainic acid (0.2 μl; i.c.v; on gestational day 18), significant WM deficits were observed in lesioned female offspring at 12 and 16 weeks of age in the T-maze (von Wilmsdorff et al, 2010). While both sexes had higher levels of perseveration errors, significantly impaired performance was observed in females compared with males, particularly at 12 weeks, corresponding to early adulthood, i.e.…”

“…This is usually the case for several domains of cognition where the tests show intact learning (Barnes maze, Radial maze, Morris Water maze) or performance (Y maze, novel object recognition). A comparison of the experimental group versus the sex-matched control group is mostly used to indirectly highlight a sex difference in rodent models for schizophrenia (Andersen and Pouzet, 2004;Ayhan et al, 2011;Bitanihirwe et al, 2010;Engmann et al, 2011;Hill et al, 2014;Karl et al, 2010;LlorenteBerzal et al, 2012;Markham et al, 2010;Pletnikov et al, 2008;Ryan et al, 2011;Schaevitz et al, 2012;Sircar, 2003;Snigdha et al, 2011;von Wilmsdorff et al, 2010;Wischhof et al, 2015). In all studies we consider, unless otherwise specified, the appropriate control group was used for comparison of the deficit induced by the model in both sexes.…”