Dyslexia Research Laboratory and Charles A. Dana Research Institute, Beth Israel Deaconess Medical Center, Division of Behavioral Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston MA 02215 and Harvard Medical School, Boston, MA 02115, USA
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Abstract |
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Introduction |
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In a recent series of experiments, we noted an intriguing sex difference in the behavioral and anatomical consequences of early freezing injury to the neocortex. Male rats with microgyria were found to have difficulties in performing a fast, but not a slow, auditory discrimination task (Fitch et al., 1994, 1997
). In contrast, female littermates with an identical microgyria discrim- inated successfully at both the fast and slow discrimination conditions (Fitch et al., 1997
; Herman et al., 1997
). Further, when the medial geniculate nuclei (MGN) of these animals were examined, male rats with microgyria had more small and fewer large neurons as compared to unlesioned controls. For females, MGN neuronal size distribution did not differ between micro- gyric animals and shams. We suggested that this sex difference in MGN neuronal size distribution, despite comparable microgyria, might account for the disparity between lesioned males and females in the auditory temporal discrimination task.
The observation that changes in the MGN are present in lesioned males but not females, and that males and females show different behavioral effects after comparable injury, merits further investigation. In the current experiment, we tested the hypothesis that the differential response of the MGN to early cortical injury is hormonally mediated. Specifically, neuronal size distribution in the MGN in male and female rats, with or without microgyria, was compared to those in female rats treated perinatally with testosterone propionate (TP). Findings indicate that females treated with TP had MGN neuronal size distribution more similar to males than to untreated females.
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Materials and Methods |
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Time-mated pregnant Wistar rats were obtained from Charles River Laboratories (Wilmington, MA), or females were bred in house from stock acquired from the same source. Embryonic day 1 (E1) corres- ponded to the day sperm was detected on vaginal smear. Pregnant female rats were divided into three groups. Group 1 rats were injected s.c. daily with 2 mg TP suspended within the vehicle (0.1 ml sesame oil) on E16 until E21. Group 2 rats were injected s.c. daily with the vehicle on E16 until E21. Group 3 rats received no injections. On the day after birth (P1), animals were randomly assigned to receive bilateral freezing injuries to the parietal cortex or to a sham condition. Daily treatment was continued on the pups from groups 1 and 2 commencing on P1 and ending on P5. Pups from group 1 were injected with 0.1 mg TP suspended within the vehicle (0.05 ml sesame oil). Pups from group 2 were injected with the vehicle only. At P80, pups were killed, gender classification confirmed by post-mortem examination for testes, and their brains were processed for histological and morphological examination. The male rats from group 1 (TP-treated) were excluded from further analysis. Using stereological techniques, the volumes of the microgyria and the MGN were determined, and neuronal size and number were determined in the MGN.
Induction of Microgyria
Microgyria were induced based on a modification of a technique by Dvorák and colleagues (Dvorák and Feit, 1977; Dvorák et al., 1978
), and reported in detail elsewhere (Humphreys et al., 1991
; Rosen et al., 1992
). Pups were anesthetized with hypothermia, and a small incision was made in the anteroposterior plane of the skin over midline, exposing the skull. A cooled (70°C) 2 mm diameter stainless steel probe was placed on the skull of lesion subjects over one or the other hemisphere for 5 s. The probe, targeted at the presumptive parietal cortex, was placed 1 mm caudal to bregma and 2 mm lateral of the sagittal suture. After placement of the probe, an identical lesion was placed in the opposite hemisphere. The side of the first probe placement was randomly determined. Animals receiving sham surgery were treated identically to those receiving freezing injury except that the probe was maintained at room temperature. Following the second probe placement, the skin was quickly sutured, and subjects were marked with a unique pattern of ink injection to the footpads, warmed under a lamp, and returned to the mother. On P21, litters were weaned and the subjects were housed with littermates (two or three per cage).
Histology
On approximately P80 subjects were anesthetized (87% Ketamine/13% Xylazine; 100 mg/kg i.p.) and were transcardially perfused with 0.9% saline and 10% formalin. The brains were removed, placed in 10% formalin for at least 7 days before being dehydrated in a series of graded alcohols and embedded in 12% celloidin. Serial sections were cut coronally at 30 µm. Series of every fifth section were stained with cresyl violet, mounted on glass slides and coverslipped with Permount.
Morphometry
For all morphological measures of the MGN, sections were coded so that the experimenter would be blind to sex, hormone treatment and surgical group.
Microgyric Volume
Volumes of microgyria were determined from systematic serial sections using point counting and Cavalieri's rule. Images from the sections were projected on a video screen and point counting was performed using NIH Image v. 1.55 interfaced to a Macintosh Centris 650 computer (Apple Computer, Cupertino, CA). Total microgyric volume was determined using Cavalieri's estimation (Gundersen and Jensen, 1987). If the equispaced criteria for Cavalieri's estimator were not met (due to missing or damaged sections), a measurement method involving piecewise parabolic integration was employed (Rosen and Harry, 1990
). The architectonic location of the lesion was quantified by overlaying the topographic location on a normalized flattened map of the neocortex derived from Zilles (1985).
MGN Volume
Volume of the MGN (inclusive of each subnucleus) was determined using the method described above for microgyric volume.
MGN Neuronal Measures
Cross-sectional neuronal areas and cell-packing densities were measured in the MGN of all rats using the three-dimensional counting methods and software of Williams and Rakic (1988). Three fields were measured on each of three slides, sampling from the rostral to the caudal extent and in the dorsal, ventral and medial portions of the nucleus (Winer, 1991) of both hemispheres for a total of 18 fields per brain as described previously (Herman et al., 1997
).
Images taken at 500x on a Zeiss Universal microscope (Carl Zeiss, Inc., Thornwood, NY) were projected onto a Sony GVM 1310 monitor (Sony Corporation, Park Ridge, NJ) that was connected to the Macintosh Centris 650 workstation. A counting square (95 x 85 µm) was overlaid on these images. Movement in the Z-axis was read by a Heidenhain MP-25 photoelectric micrometer (Heidenhain Corporation, Schaumburg, IL) interfaced to a National Instrument NB-GPIB card (National Instruments Corporation, Austin, TX) in the Macintosh. The base of the section was set to a Z-axis reading of zero. A red opaque overlay precluded cell counting below the confines of the optical box. As the plane of focus moved to 5 µm above the base, the screen became transparent. On a digitizing tablet, those neurons whose single nucleoli were in focus were traced. Neurons touching the top and right side of the counting box were omitted. The screen turned green when the fine focus rose above 25 µm, precluding measurement of neurons above the optical box. Thus, a perfect 20 µm thick slab of tissue was measured. Both the neuronal areas and cell packing density (neurons/mm3) were output to the computer. Total neuronal MGN neuronal number for each hemisphere was deter- mined by multiplying the cell-packing density for each hemisphere by its volume.
Analysis
There were two independent measures: `Sex' (Male, Female, Female + TP) and Surgical Group (Lesion and Sham). Anatomically dependent measures included MGN neuronal size, MGN neuronal number, MGN volume and microgyric volume. Statistical analyses of all data were performed using ANOVA and chi-square tests.
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Results |
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Examination of the 50 brains assigned to the lesioned condition showed that ten brains (five females, four androgenized females and one male) had lesions not fully restricted to the parietal region and had to be removed from the analysis. Analysis of the distribution of excluded and included subjects indicated no bias in the dependent variables among the three groups (2 = 2.96, df = 2, NS). Hormone treatment induced masculinization as illustrated by the fact that female rats exposed to androgens had wider ano-genital distances. Subsequent post-mortem examina- tion for the presence of testes confirmed gender identification.
Histology
All subjects receiving the freezing lesion to the cortical plate in the neonatal period exhibited focal cortical malformations resembling four-layered microgyria, and their appearance was identical to that reported in previous work (see Fig. 1). As expected, animals exposed to sham surgery showed no cerebral malformation. The location and mean volume of the microgyria are depicted in Figure 2
. An overall ANOVA demonstrated no difference in volume of lesioned cortex between males, females and TP females [F(2,37) = 1.30, NS]. Further comparisons showed no difference in volume of lesioned cortex between males and females [F(1,25) = 0.47, NS], males and TP-treated females [F(1,26) = 2.56, NS], and females and TP-treated females [F(1,23) = 0.76, NS]. The degree of greatest lesion overlap occurred in Par1 (primary somatosensory cortex) and at the border of Par1 with HL (hindlimb region) and FL (forelimb region, Zilles, 1985
).
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In order to control for the possibility of effect of perinatal manipulation, it was first determined whether there were any differences in morphometric measures between vehicle-injected and control females. As expected, there was no difference in MGN neuronal area, MGN volume or MGN neuronal number between the two groups and their data were pooled for further analysis (F < 1, NS for all comparisons).
In order to analyze the effects of gender and lesion on MGN neuronal size, MGN volume and MGN neuronal number, a series of three two-way ANOVAs were performed. A two-way ANOVA with `Sex' (Male versus TP-treated Female) and Surgical Group (Lesion versus Sham) as the independent measures showed no significant main effects and no interactions for MGN volume and neuronal number. There was a significant main effect of Surgical Group for MGN neuronal size [F(1,58) = 4.24, P < 0.05], indicating that sham animals in both groups had larger neurons than lesioned animals (see Fig. 3). A two-way ANOVA with Sex (Male versus Female) and Surgical Group (Lesion versus Sham) as the independent measures showed no significant main effects or interactions for either MGN neuronal area or number. There was a significant Sex effect for MGN volume [F(1,60) = 4.54, P < 0.05] with males having larger MGN volumes than females. There was also a significant Sex x Surgical Group interaction for this variable [F(1,60) = 4.13, P < 0.05], and a post-hoc analysis indicated that MGN volume was larger in male shams as compared to female shams, but that there was no such difference between males and females with lesions (Table 1
). Finally, a two-way ANOVA with `Sex' (Female versus TP-treated Female) and Surgical Group (Lesion versus Sham) as the independent measures showed no significant main effects or interactions for any variable.
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In order to test the distribution of the MGN neurons in the three subnuclei, the same chi-square analysis described above was performed within each subnucleus of the MGN. There was no difference in MGN neuron size distribution for any region in control females (dorsal 2 = 27.07, ventral
2 = 9.81, medial
2 = 20.59; df = 11, NS). Lesioned males had more small and fewer large neurons in the dorsal, ventral and medial subnuclei of the MGN (dorsal
2 = 54.21, ventral
2 = 47.68, medial
2 = 32.86; df = 11, P < 0.001 for all subnuclei). Lesioned TP-treated females had more small and fewer large neurons in the medial subnucleus of the MGN only (dorsal
2 = 24.76, df = 11, NS; ventral
2 = 23.83, df = 11, NS; medial
2 = 48.30, df = 11, P < 0.001).
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Discussion |
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Gonadal Steroids and Brain Injury
These results, taken together with those reported previously (Herman et al., 1997), suggest that the reaction of the female brain to early injury is different from that of the male. If perinatal exposure to androgens acts to modify the brain's response to early injury, then the question can be asked as to the mechanism for this change. It is well known that exogenous testosterone can affect the central nervous system either directly as testosterone, or through its metabolites estradiol and dihydrotestosterone (cf. MacLusky and Naftolin, 1981
; Pomerantz et al., 1985
). The design of the current experiment does not allow us to distinguish which of these steroids, acting either alone or in some com- bination, are responsible for the effects reported here. Evidence from the literature, however, suggests a number of possibilities.
Gonadal steroids and their metabolites have been shown to play an important role in the reorganization of lesioned neural tissue. Injections of testosterone, estradiol or progesterone attenuate the reactive astrocytic response to penetrating wounds to the parietal cortex and underlying hippocampal structures (Garcia-Estrada et al., 1993). Post-lesion treatment with TP decreased neuronal loss following axotomy of the hypoglossal and facial nerves (Yu, 1989
). Others have shown that proges- terone acts as a neuroprotectant (Roof et al., 1992
, 1993
), and a variety of endogenous and exogenous androgens were shown to attenuate the effects of glutamate toxicity on spinal neurons (Ogata et al., 1993
). Male gerbils display greater postischemic neuronal necrosis than females, perhaps because of an antioxidant effect of endogenous estrogen (Hall et al., 1991
).
It should be pointed out, however, that the studies cited above investigated the efficacy of gonadal steroids as potential neuro- protective agents in the mature nervous system. The current study, in contrast, introduced exogenous testosterone and induced microgyria during the perinatal period. We found that there was no difference in lesion size between males and females, but rather in secondary changes in the thalamus. Thus, the findings suggest that the sex differences in MGN neuronal size distribution could not be the result of sex differences in lesion size. Rather, the lack of a local neuroprotective effect (e.g. Rosen et al., 1995a; Fitch et al., 1997
) by circulating androgens in this developmental brain injury model lends support to the hypothesis that the male/female differences reported here, as well as possibly the sex differences in the behavioral con- sequences of this type of induced cortical malformation, are the result of the effects of androgens on the reorganization of neuronal connectivity and trophic activity following early injury rather than on the modulation of the size or severity of the brain injury itself.
Connectivity, Early Brain Injury and Testosterone
Early damage to the developing brain can result in profound changes in connectivity. In hamsters, neonatal lesions of the superior colliculus result in altered retinal projections (Schneider, 1979, 1981
; Finlay et al., 1979
). Maintenance of otherwise transient projections follows the induction of micro- gyria in cats (Innocenti and Berbel, 1991a
,b
), and unilateral removal of facial whiskers in newborn rats results in the maintenance of a normally transient cross-modal projection between the MGN and somatosensory cortex (Nicolelis et al., 1991
). Neonatal ischemia results in an excess of callosal projections from visual areas 17 and 18 in cats (Miller et al., 1993
), and an increase in callosal connectivity has been noted in a microgyric rat (Rosen et al., 1989
).
We had previously hypothesized that the changes in MGN neuronal size distribution in male rats with microgyria resulted from changes in connectivity following induction of microgyria (Herman et al., 1997). If perinatal gonadal steroids mediate these post-injury changes in connectivity, then there are a number of potential mechanisms by which they could do so. It could be, as discussed above, that there is a protective effect of endogenous androgens in the females. Alternatively, exposure to testosterone might enhance the process of normal plasticity, thereby encouraging extraordinary restructuring of connectivity. Still further, some combination of these two factors could be at play. In the human, Raz et al., (1995) reported that the cognitive sequelae of perinatal intracranial hemorrhage was greater in males than in females, thus supporting the notion of a greater vulnerability of the male brain to the effects of early injury. In rats, Kolb and Stewart (1995) found that neonatal TP treatment of females reduced the brain's ability to recover from the trauma of early prefrontal cortex lesions. In non-human primates, early damage to orbital prefrontal cortex had differential effects on the two sexes (Goldman et al., 1974
) that appeared to be mediated by gonadal steroids (Clark and Goldman-Rakic, 1989
). Speci- fically, lesioned males performed worse than unlesioned males on an object discrimination task, whereas there was no differ- ence between lesioned and unlesioned females. Treating females postnatally with testosterone masculinized their behavior (Clark and Goldman-Rakic, 1989
).
There are several possibilities that may explain how gonadal steroids may modulate neuronal plasticity during normal and pathological conditions. One mechanism might be the effect of gonadal steroids on the formation and/or the elimination of synaptic contacts by modulation of the number of pre- and post-synaptic neurons (Garcia-Segura et al., 1994). The effects of gonadal steroids on glial cells may also be important in neuronal remodeling, as described above (Garcia-Estrada et al., 1993
). Alternatively, sex steroids may mediate changes in the formation, growth and shape of dendrites, dendritic spines and axons. Thus, studies of organotypic cultures of the developing rodent hypothalamus, preoptic area and cerebral cortex reveal that estrogen elicits a striking enhancement of neurite growth, involving both axons and dendrites (Toran-Allerand, 1991
). Gonadal steroids may, therefore, promote extensive remodeling of neuronal tissue after a brain insult, and not only in neuroendocrine regions of the brain (e.g. Nichizuka and Arai, 1982
; Hammer and Jacobson, 1984
; Ferreira and Caceres, 1991
).
The combined activity of a variety of endogenous neuro- trophic agents also regulates neuronal development, survival and repair after an injury (Barde, 1989, 1990
). The forebrain regions of both sexes are potential targets for neurotrophins and estrogen, as well as sites of neurotrophin and estrogen synthesis (Toran-Allerand, 1996
). Estrogen receptors co-localize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain (Toran-Allerand et al., 1992
). In addition, there is evidence for co-expression of mRNAs for both estrogen and neurotrophin receptors (Miranda et al., 1993b
), as well as evidence that estrogen target neurons in the developing rodent forebrain co-localize the mRNAs for the neurotrophins and their receptors (Miranda et al., 1993a
). Thus, working either in combination or cooperatively, estrogen and neurotrophins play crucial roles in neuronal development, survival and plas- ticity (Toran-Allerand, 1996
).
Considering the current results in the light of these findings then, it could be that high levels of circulating androgens in the developing male brain may render it `hyper-reactive', so that it responds to injury with extensive neuronal remodeling that is ultimately detrimental. One would predict, therefore, that any changes in connectivity associated with induction of microgyria would be greater in males than in females, and this hypothesis is currently being investigated. On the other hand, an argument could be made that circulating androgens in the male brain accelerate the process of connectional formation in such a way that it no longer responds to injury and is, in contrast to the hypothesis above, `hypo-reactive'. If these neonatal rats were indeed hypo-plastic, then one would posit that they would have formed their adult patterns of connectivity prior to the lesion, and that the effects of neonatal lesions in these rats on MGN neuronal size would be identical to those following lesions in adulthood. While we consider this possibility to be unlikely, it cannot be excluded until the effects of adult lesions to the parietal cortex on cell size of the MGN are investigated.
Alternatively, it could be argued that estradiol in physiological doses may act as a neuroprotectant. As discussed above, we have no evidence that endogenous estrogens affect the freezing injury itself the size of the microgyria is no different between males and females. Thus, any neuroprotective effect would have to occur during the purported connectional reorganization that follows the original injury. Future research aimed at eliminating endogenous estrogens without the introduction of exogenous testosterone will enable us to answer this question definitively.
An additional alternative is the possibility that the effects of androgens on the distribution of neuronal sizes in the MGN are activational rather than organizational. In this scenario, the cyclic ovarian hormone release post-pubertally in females would act to `rescue' the neurons of the MGN from a change in distribution in reaction to the freezing lesion. Although there is evidence that exogenous treatment with TP in gonadectomized ferrets enlarges the soma of hypothalamic neurons (Cherry et al., 1992), there is no evidence that estrogen or progesterone in physiological dosages affect neuronal size activationally. While we think that the effects of circulating androgens acting activationally is unlikely, it cannot be excluded until the current experiment is replicated with the addition of pre-pubertal gonadectomies for all groups.
Summary and Conclusions
Previous investigation had indicated that freezing injury to the neocortex of neonatal male rats induces cerebrocortical microgyria and was associated with defects in fast auditory processing and a shift toward smaller neuronal sizes in the MGN (Herman et al., 1997). No difference was observed in the MGN neuronal size distribution in microgyric females. The current study replicates these results and demonstrates that gonadal steroid hormones play a role in modulating the effects of freezing injury to the cortical plate on MGN neuronal size distribution. Specifically, early administration of TP to female rats eliminates the aforementioned sex difference in MGN neuronal size distribution. These findings suggest that the presence of circu- lating androgens in the developing male brain permits sex differences in the reorganization of the thalamus in response to cortical injury as compared to the female. While the current experiment cannot directly address the issue of mechanism underlying this gonadal steroid-mediated difference, we hypo- thesize that the presence of circulating androgens in the developing male brain may generate a `hyper-plastic' condition such that there is more extensive neuronal remodeling after injury than in the female brain. Additional investigations will be required to delineate further how gonadal steroids modulate the brain response to early injury.
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Notes |
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Address correspondence to Glenn D. Rosen, Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. Email: glenn_rosen{at}bidmc.harvard.edu.
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