Roslyn Holly Fitch

Corpus callosum: region-specific effects of sex, early experience and age

In infancy, rats were provided handling stimulation and compared at 110 and 215 days of age with non-handled controls. Measurements were made of corpus callosum area, perimeter and length; and width measures were taken at 7 points along the longitudinal axis of the callosum. Callosal size was larger in males than in females, even when adjusted for the larger brain weight of the male. At 110 days handling stimulation increased callosal parameters and resulted in a more regular callosum in males, but this effect was no longer apparent by 215 days. Within the callosum, region-specific effects were found, suggesting that certain callosal fiber populations were involved. Handled males have previously been shown to be more lateralized than non-handled males; thus at least in this experimental system, increased callosal size and regularity is associated with greater hemispheric specialization.

A role for ovarian hormones in sexual differentiation of the brain

Historically, studies of the role of endogenous hormones in developmental differentiation of the sexes have suggested that mammalian sexual differentiation is mediated primarily by testicular androgens, and that exposure to androgens in early life leads to a male brain as defined by neuroanatomy and behavior. The female brain has been assumed to develop via a hormonal default mechanism, in the absence of androgen or other hormones. Ovarian hormones have significant effects on the development of a sexually dimorphic cortical structure, the corpus callosum, which is larger in male than in female rats. In the females, removal of the ovaries as late as Day 16 increases the cross-sectional area of the adult corpus callosum. Treatment with low-dose estradiol starting on Day 25 inhibits this effect. Female callosa are also enlarged by a combination of daily postnatal handling and exogenous testosterone administered prior to Day 8. The effects of androgen treatment are expressed early in development, with males and testosterone-treated females having larger callosa than control females as early as Day 30. The effects of ovariectomy do not appear until after Day 55. These findings are more consistent with other evidence of a later sensitive period for ovarian feminization as compared to androgenic masculinization.

Neurobiological Basis of Speech: A Case for the Preeminence of Temporal Processing

In this paper we present evidence supporting the hypothesis that a basic temporal processing impairment in language-impaired children underlies their inability to integrate sensory information that converges in rapid succession in the central nervous system. We provide data showing that this deficit is pansensory; that is, affects processing in multiple sensory modalities, and also affects motor output within the millisecond time frame. We also provide data that links these basic temporal integration deficits to specific patterns of speech perception and speech production deficits in language-impaired children. We suggest that these basic temporal deficits cause a cascade of effects starting with disruption of the normal development of an otherwise effective and efficient phonological system. We propose further that these phonological processing deficits result in subsequent failure to learn to speak and to read normally. That is, both the language and reading problems have their basis in deficiently esta...

Reprint of "Early testosterone modulated sex differences in behavioral outcome following neonatal hypoxia ischemia in rats".

Hypoxia ischemia (HI; reduced blood oxygenation and/or flow to the brain) represents one of the most common injuries for both term and preterm/very low birth weight (VLBW) infants. These children experience elevated incidence of cognitive and/or sensory processing disabilities, including language based learning disabilities. Clinical data also indicate more substantial long‐term deficits for HI injured male babies as compared to HI injured females. Previously, we reported significant deficits in rapid auditory processing and spatial learning in male rats with postnatal day 1 (P1), P7, or P10 HI injury. We also showed sex differences in HI injured animals, with more severe deficits in males as compared to females. Given these findings, combined with extant clinical data, the current study sought to assess a putative role for perinatal testosterone in modulating behavioral outcome following early hypoxic‐ischemic injury in rats. Male, female, and testosterone‐propionate (TP) treated females were subjected to P7 HI or sham surgery, and subsequently (P30+) underwent a battery of auditory testing and water maze assessment. Results confirm previous reports of sex differences following HI, and add new findings of significantly worse performance in TP‐treated HI females compared to vehicle treated HI females. Post mortem anatomic analyses showed consistent effects, with significant brain weight decreases seen in HI male and TP‐treated HI females but not female HI or sham groups. Further neuromorphometric analysis of brain structures showed that HI male animals exhibited increased pathology relative to HI females as reflected in ventricular enlargement. Findings suggest that neonatal testosterone may act to enhance the deleterious consequences of early HI brain injury, as measured by both neuropathology and behavior.

Corpus callosum: ovarian hormones and feminization

The rats corpus callosum is sexually dimorphic with the males being larger. This difference appears to depend in part on the neonatal presence of testosterone in the male and ovarian hormones in the female. To further investigate the possibility that ovarian hormones participate in the differentiation of the rats callosum, females received one of the following treatments on postnatal day 8, 12 or 16: (1) ovariectomy (Ovx); (2) 1 mg of testosterone propionate (TP); or (3) sham surgery. All animals were handled daily from birth until weaning. They were sacrificed at 110 days and a mid-sagittal section of the callosum was obtained. From this section measures of callosal area, perimeter, length, and 99 widths were derived. Widths were averaged into 7 factors as defined by prior factor analysis. Ovariectomy, whether on day 8, 12 or 16, enlarged callosal area and 3 of the callosal width factors. TP had no effect on any callosal variable when administered on day 8, 12 or 16. A comparison of control males and females replicated our prior findings of sexual dimorphism. We conclude that ovarian hormones act to feminize the female callosum, and that their removal results in defeminization. Furthermore, the fact that ovariectomy was effective as late as day 16, while TP treatment on day 8 or later had no effect, suggests that masculinization and feminization of this structure constitute separate processes with distinct sensitive periods.

Corpus callosum: Demasculinization via perinatal anti-androgen

The male rats corpus callosum is significantly larger than the females. This dimorphism depends in part on the early presence of testosterone, since postnatal administration of testosterone to female pups enlarges their callosa in adulthood to the size of males. However, castrating males on day 1 is ineffective in reducing (demasculinizing) the size of their callosa as adults. We then addressed the question as to whether testosterone acts prior to day 1 to enlarge the callosa of males. To investigate this hypothesis pregnant rats were administered a non‐steroidal androgen blocker, flutamide, during the last 5 days of pregnancy, while controls received vehicle only. Male pups from flutamide litters were castrated on day 3 to prevent postnatal recovery following clearance of flutamide, while others received sham surgery. Callosal sex differences were found between males and females of control litters, but not between males and females from flutamide litters. The absence of sex effects among flutamide litters was a consequence of small callosal size in flutamide‐castrated males as compared to control males. We concluded that the prenatal production of testosterone in the male rat pup contributes to sexual dimorphism in the callosa of adult rats.

Corpus callosum : interactive effects of infantile handling and testosterone in the rat

Previous research found that the corpus callosum of male rats is larger than that of females; handling rats in infancy enhances this sex difference; and female rat pups, when handled in infancy and given 1 injection of testosterone propionate (TP) on Day 4 of life, will have callosa as large as those of males. In 2 experiments, male pups were castrated on Day 1 or received sham surgery; female pups were injected with TP on Day 4 or received an oil injection. Litters were handled or nonhandled. The previous finding that females, when handled and given TP in infancy, have a larger callosum was confirmed; however, a TP effect when administered to nonhandled females was not found. Because handling is known to cause a corticosterone release, these findings were interpreted as evidence of a developmental interaction between adrenal and gonadal hormones at the cortical level.

A factor analysis of the rat's corpus callosum*

Previous work from our laboratory (Berrebi et al., Brain Research, 438 (1988) 216-224) demonstrated region-specific sexual dimorphisms in the size of the rats corpus callosum, which are modifiable by extra stimulation in early life. These differences are assumed to reflect regional corticocortical fibers of passage which are altered differentially by gender and our experimental manipulations. In this paper, we report our findings when the original data are reanalyzed using a newly developed computer program. This program not only reproduced, with very high accuracy, the original means, but also permitted us to examine computer generated callosal width scores via a factor analysis procedure. Such a procedure yields useful information concerning the clustering of callosal fibers and thus contributes significantly to our hypothesis that discrete cortical regions are selectively sensitive to experimental variables. Factor analyses of the callosal variables and brain weight of 155 rats found 7 width factors, and an eighth factor which contained the variables of brain weight, callosal length, and callosal perimeter. Callosal area did not load significantly on any of these factors. The percentile locations of the width factors, starting at the anterior (genu) end were: widths 1-5, 6-17, 24-38, 46-57, 62-72, 79-95 and 96-99. Use of these factor scores in analyses of variance revealed that the male callosum is wider than the females, with the differences most pronounced in the genu and the most posterior portion of the splenium. Both age and early handling experience influenced the callosal width factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of X-Linked Inhibitor of Apoptosis with Embelin Differentially Affects Male versus Female Behavioral Outcome following Neonatal Hypoxia-Ischemia in Rats

Hypoxia-ischemia (HI; concurrent oxygen/blood deficiency) and associated encephalopathy represent a common cause of neurological injury in premature/low-birth-weight infants and term infants with birth complications. Resulting behavioral impairments include cognitive and/or sensory processing deficits, as well as language disabilities, and clinical evidence shows that male infants with HI exhibit more severe cognitive deficits compared to females with equivalent injury. Evidence also demonstrates activation of sex-dependent apoptotic pathways following HI events, with males preferentially activating a caspase-independent cascade of cell death and females preferentially activating a caspase-dependent cascade following neonatal hypoxic and/or ischemic insults. Based on these combined data, the ‘female protection’ following HI injury may reflect the endogenous X-linked inhibitor of apoptosis (XIAP), which effectively binds effector caspases and halts downstream cleavage of effector caspases (thus reducing cell death). To test this theory, the current study utilized neonatal injections of vehicle or embelin (a small molecule inhibitor of XIAP) in male and female rats with or without induced HI injury on postnatal day 7 (P7). Subsequent behavioral testing using a clinically relevant task revealed that the inhibition of XIAP exacerbated HI-induced persistent behavioral deficits in females, with no effect on HI males. These results support sex differences in mechanisms of cell death following early HI injuries, and suggest a potential clinical benefit from the development of sex-specific neuroprotectants for the treatment of HI.

Persistent spatial working memory deficits in rats following in utero RNAi of Dyx1c1

Disruptions in the development of the neocortex are associated with cognitive deficits in humans and other mammals. Several genes contribute to neocortical development, and research into the behavioral phenotype associated with specific gene manipulations is advancing rapidly. Findings include evidence that variants in the human gene DYX1C1 may be associated with an increased risk of developmental dyslexia. Concurrent research has shown that the rat homolog for this gene modulates critical parameters of early cortical development, including neuronal migration. Moreover, recent studies have shown auditory processing and spatial learning deficits in rats following in utero transfection of an RNA interference (RNAi) vector of the rat homolog Dyx1c1 gene. The current study examined the effects of in utero RNAi of Dyx1c1 on working memory performance in Sprague–Dawley rats. This task was chosen based on the evidence of short‐term memory deficits in dyslexic populations, as well as more recent evidence of an association between memory deficits and DYX1C1 anomalies in humans. Working memory performance was assessed using a novel match‐to‐place radial water maze task that allows the evaluation of memory for a single brief (∼4–10 seconds) swim to a new goal location each day. A 10‐min retention interval was used, followed by a test trial. Histology revealed migrational abnormalities and laminar disruption in Dyx1c1 RNAi‐treated rats. Dyx1c1 RNAi‐treated rats exhibited a subtle, but significant and persistent impairment in working memory as compared to Shams. These results provide further support for the role of Dyx1c1 in neuronal migration and working memory.