Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, New York, USA
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Abstract |
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Introduction |
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Hormone manipulation induced early in postnatal life also appears to have relatively widespread influence on the catecholamine innervation of the cerebral cortex. In male and female rats, perinatal gonadectomy has been shown to affect the tempo of monoamine maturation in cingulate, parietal and occipital cortices (Stewart et al., 1991), and in males imposes lasting decreases in tyrosine hydroxylase (TH)-immunoreactive axon density in somatosensory, motor, premotor and cingulate cortices (Kritzer, 1998
). However, in many neuroendocrine and reproductive brain areas, endpoints of steroid stimulation including effects on neurotransmitters (Herbison and Dye, 1993
) can significantly change and even disappear over the course of the lifespan (Arnold and Gorski, 1984
). There is some evidence that the hormone sensitivity of cortical catecholamines may also vary with maturity. Specifically, whereas long-term effects of perinatal gonadectomy decreased TH-immunoreactive axon density in areas including the cingulate cortex (Kritzer, 1998
), a previous study has shown that there is an increase in innervation density in the right hemifield of this region following adult-stage gonadectomy (Adler et al., 1999
).
Because prior studies in adult animals were limited to the right cingulate cortex (Adler et al., 1999), it is unknown whether the catecholamine innervation of sensorimotor areas which respond vigorously to perinatal gonadectomy (Kritzer, 1998
) retain hormone sensitivity in adulthood. Further, it is unknown whether effects of adult-stage gonadectomy are lateralized, as they can be following perinatal gonadectomy (Kritzer, 1998
). To address these issues, catecholamine innervation was examined in the left and right hemifields of primary somatosensory, primary motor and premotor cortices, and of two prefrontal association areas the anterior cingulate and dorsal anterior insular cortices in adult male rats gonadectomized 4 or 28 days prior to being killed. In the cingulate region, axons in the right hemisphere were reevaluated (Adler et al., 1999
), while those in the left are studied here for the first time. By using immunocytochemistry for TH, axon innervation was qualitatively and quantitatively compared in each of these five areas in gonadectomized animals, gonadectomized subjects supplemented with testosterone proprionate, and in sham-operated controls to explore regional patterns of cortical catecholamine sensitivity to experimentally induced changes in the mature hormonal milieu.
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Materials and Methods |
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Twenty-five adult male SpragueDawley rats (Taconic Farms, Germantown, NY) were used; all animals had served as subjects in a previous study of catecholamine innervation in the right cingulate hemifield (Adler et al., 1999). All procedures involving animals were approved by the Institutional Animal Care and Use Committee, SUNY at Stony Brook, and minimized the use of animals and their discomfort. Animals were housed with food and water freely available under a 12 h light/dark cycle. Five animals were sham-operated (CTRL); the remaining 20 rats were gonadectomized and implanted with pellets containing either biodegradable matrix, i.e. placebo (GDX-pl), or testosterone proprionate (GDX-TP). All animals were killed 4 or 28 days after surgery (see below).
Surgical Procedures
All surgical procedures were performed under aseptic conditions and used a mixture of ketamine (0.09 ml/100 g) and xylazine (0.05 ml/100 g) for anesthesia. For gonadectomies and sham operations, the sac of the scrotum and underlying tunica were incised. For gonadectomies, the vas deferens was ligated bilaterally, the testes were removed and slow-release pellets were implanted (see below). For all surgeries, incisions were closed using 60 silk sutures.
Depending on survival time, gonadectomized animals received either 21 day slow-release pellets (4 day survival) or 60 day slow-release pellets (28 day survival) that contained either TP in biodegradable matrix, or a placebo containing the biodegradable matrix only (cholesterol, microcrystalline cellulose, -lactose, diand tri-calcium phosphate, calcium and magnesium stearate, and stearic acid; Innovative Research of America, Toledo, OH). The TP-containing pellets release ~34 ng of TP/ml blood/day, and have been used successfully in previous investigations to maintain circulating levels of testicular hormones in gonadectomized rats (Carmignac et al., 1994; Collins et al., 1992
).
Euthanasia
Four or 28 days after gonadectomy or sham surgery, rats were deeply anesthetized with an i.m. injection of a mixture of ketamine (0.09 ml/ 100 g) and xylazine (0.05 ml/100 g). After corneal reflexes could no longer be elicited, rats were transcardially perfused with 50100 ml of 0.1 M phosphate buffer (PB) followed by two paraformaldehyde fixative solutions: 4% paraformaldehyde in 0.1 M PB, pH 6.5 (flow rate 30 ml/min, duration 5 min), and then 4% paraformaldehyde, in 0.1 M borate buffer, pH 9.5 (flow rate 35 ml/min, duration 20 min). These parameters were kept constant to maximize comparable preservation of tissue antigens across animals. After perfusion, the brains were removed, blocked and cryoprotected in 0.1 M PB containing 30% sucrose prior to rapid freezing in powdered dry-ice and storage at 80°C. The medial, ventral and lateral bulbocavernosus muscles were also dissected out and weighed at the time of death; mean muscle weights, whole body weights and percent of whole body weight represented in the dissected muscle mass have been published elsewhere (Adler et al., 1999).
Immunocytochemistry
Tissue blocks that included the rostral caudate and septal nuclei were frozen-sectioned at a thickness of 40 µm in the coronal plane; left hemispheres were marked with subcortically placed sectioning artifacts (see Fig. 1). A rostrocaudal series of sections from each animal was then immunoreacted using antibodies recognizing the dopamine-synthesizing enzyme TH. Briefly, sections were rinsed in 0.1 M PB, washed in 1% H2O2 (45 min), treated with 1% sodium borohydride in PB (45 min), and then rinsed in 50 mM Tris-buffered saline (TBS), pH 7.4. Sections were then incubated in blocking solution (50 mM TBS containing 10% normal swine serum, NSS) for 2 h, prior to being placed in anti-TH antibody (23 days, diluted in TBS containing 1% NSS, 4°C). The primary antibody, obtained from Chemicon International Inc. (Temecula, CA) was used at working dilution of 1:1000. The tissue sections were then rinsed in TBS, incubated in biotinylated secondary antibodies (Vector, Burlingame, CA, 2 h, room temperature, working dilution 1:100), rinsed further in TBS, and then placed in avidinbiotin-complexed horseradish peroxidase (ABC, Vector, 2 h, room temperature). After this final incubation, sections were thoroughly rinsed in Tris buffer, pH 7.6, and reacted using 0.07% 3,3'-diaminobenzidine (DAB) as chromagen. As a control, these immunocytochemical labeling procedures were carried out on representative sections with the omission of primary antiserum or secondary antibodies. The specificity of immunolabeling for TH was further supported in parallels in the patterns of cortical labeling obtained with control animals compared to those documented in previous studies of cortical catecholamine innervation in rats (Levitt and Moore, 1978
; Morrison et al., 1978
; Lewis et al., 1979
; Berger et al., 1985
; Van Eden et al., 1987
; Papadapoulos et al., 1989) (see Results).
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The DAB immunoreaction product was intensified using methods of Kitt et al. (Kitt et al., 1988). For this procedure, DAB-reacted, slide-mounted sections were incubated in 1% silver nitrate (pH 7.0, 50 min, 55°C, in the dark), rinsed in running distilled water, placed in 0.2% gold chloride (15 min, room temperature, in the dark), rinsed again in distilled water, and fixed in 5% sodium thiosulfate (10 min, room temperature). The intensified sections were then counterstained with 1% cresyl violet and placed under coverslips. Sections used in control studies (above) were intensified side-by-side with normally immunoreacted slides.
Qualitative Evaluation
Detailed examination of the laminar distribution, orientation, approximate density and the morphology of TH-immunoreactive axons was carried out in representative sections throughout the rostrocaudal extent of the left and right hemifields of the anterior dorsal cingulate cortex (area Cg1), the primary motor cortex (area AgL), primary somatosensory cortex (area Par1), the premotor cortex (area AgM) and the dorsal anterior insular cortex (area AID) (Zilles, 1990; Donoghue and Wise, 1982
) (see Fig. 1
) in each of the five groups of animals. At least two series of sections (immunoreacted on different days) were qualitatively examined from each animal.
Quantitative Evaluation
Because subtle rostral-to-caudal gradients exist in the density of catecholamine innervation in some of the regions analyzed (Van Eden et al., 1987), a single anteroposterior cortical level, transecting the mid-septal nucleus (Fig. 1
), was selected for quantitative study. Sections at this level contained representations of each of the five cytoarchitectonic fields examined. Tissue sections for these analyses were cut from all animals on the same day and immunoreacted as a group to maximize intersubject consistency in labeling; all slides were coded prior to analysis, and a single observer performed all quantitative analysis for a given cortical region. Quantitative analyses of fiber density and orientation were carried out by first making camera lucida drawings of immunoreactive fibers, visualized under brightfield illumination using a 63x oil immersion objective, in layers II/II and V of the left and right hemifields; section thickness was always measured beforehand (by using roll-focusing from surface-tosurface and the calibrated fine-focus of the microscope, Zeiss Axioskop) to ensure uniformity in section breadth. Individual drawings subtended widths of ~100300 µm (measured parallel to the pial surface), a height dictated by the thickness of the layer, and a depth covering the full thickness of the section. Three non-overlapping drawings were obtained from each cortical layer: from each area of interest, from each hemisphere, from each animal. Per hemisphere, drawings from areas AID, AgM, Cg1 and AgL subtended essentially the entire cytoarchitectonic representation present (Fig. 1
); in area Par1, a subregion that occupied an approximate 3 o'clock position within the hemisphere that lay in radial alignment with a local maxima in cell density of layer IV was analyzed. No other attempts were made to preselect drawing locations. All drawings were then digitized, and measures of mean pixel density from skeletinized images (NIH Image 1. 58) provided fiber density estimates (Kritzer and Kohama, 1998
).
Statistical Analyses
Measures of axon density, and of body weight and bulbocavernosus muscle mass were evaluated using ANOVA, followed by allowed Student NewmanKeuls post-hoc comparisons (Super ANOVA 1.11). Sample sizes of all data sets compared were equal. Prior to analysis of variance, descriptive statistical analyses were performed on each data set (Stat View 4.5) to evaluate sample distribution and variance.
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Results |
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Adult-stage gonadectomy and gonadectomy paired with hormone replacement are established means of experimentally diminishing and maintaining circulating gonadal hormone levels respectively (Collins et al., 1992). The efficacy of these experimental treatments in shaping hormone levels in the animals of this study was evinced by group-specific differences in the weights of the androgen-sensitive bulbocavernosus muscles, which is a proven and highly sensitive index of circulating testicular hormones in rats (Wainman and Shipounoff, 1941
). As anticipated in previous investigations (Collins et al.,. 1992
), bulbocavernosus muscle mass was ~56% and ~32% of normal in rats gonadectomized and placebo-implanted for 4 and 28 days respectively, and 7088% of normal in the gonadectomized animals supplemented with TP for the same amounts of time (Adler et al., 1999
). The reliability of these measures was supported in statistical evaluations. First, an ANOVA identified significant effects of treatment [F(2,21) = 41.76, P < 0.0001] and excluded individual animals as probably sources of variance in the data (P >1.0). The allowed post-hoc comparisons revealed that the reduction in muscle mass in the chronically gonadectomized, placebo-treated group was significant (StudentNewman-Keuls, P < 0.05) (Adler et al., 1999
).
Specificity of TH Immunoreactivity
Tyrosine hydroxylase immunoreactivity was examined in the left and right cerebral hemifields of two prefrontal regions the dorsal anterior cingulate (area Cg1) and dorsal anterior insular (area AID) cortices in the primary somatosensory (area Par1) and primary motor (area AgL) cortices, and in the premotor area (AgM), in hormonally manipulated and control animals. The morphology, distribution and the density of TH-immunoreactive axons has been previously described for these areas in hormonally intact adult rats (Berger et al., 1985; Van Eden et al., 1987
; Papadapoulos et al., 1989). In all regions, the appearance and apparent density of immunolabeling in control animals of this study were highly reminiscent of these descriptions (see below). These parallels with an established literature indicate the specificity of immunolabeling in this study for cortical catecholaminergic fibers, a conclusion also supported by the elimination of any obvious patterned staining upon removal of primary or secondary antibodies from the immunolabeling procedures.
Visual inspection alone revealed clear departures from normal patterns of catecholamine innervation in gonadectomized rats. However, it was also obvious that the effects of acute (4 day) and chronic (28 day) gonadectomy were markedly different from one another. The qualitative and quantitative details of these two outcomes are described separately below.
Tyrosine Hydroxylase Immunoreactivity in Acutely Gonadectomized Rats
The catecholamine innervation of the adult rat cerebrum is characterized by smooth gradients in innervation along its major, e.g. anteroposterior, axes that are interrupted in some cases by more abrupt transitions in axon density or orientation at certain cytoarchitectonic boundaries (Van Eden et al., 1987). These features were clearly recognizable in the TH immunoreactivity of sham-operated control animals. For example, extremely dense accumulations of TH-immunoreactive fibers occupied the cingulate and insular cortices, and more moderate levels of innervation were present in adjacent premotor and somatosensory regions. Innervation also displayed expected regionand layer-specific patterns of axon orientation (Berger et al., 1985
; Febvret et al., 1991
). Whereas axons in areas Cg1 and AID corresponded mainly to short, randomly arranged processes, fibers in motor, premotor and somatosensory areas were most often longer and more radially oriented (Fig. 2A,F
). The TH-immunoreactive axons also corresponded to morphological subtypes similar to those that have been previously described (Berger et al., 1985
; Febvret et al., 1991
), including small populations of thick, straight, smooth axons, greater numbers of medium caliber, beaded fibers, and extremely fine, sparsely varicose immunoreactive axons (Fig. 2A,F
).
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Tyrosine Hydroxylase Immunoreactivity in Chronically Gonadectomized Rats
Immunoreactivity in sham-operated control animals was also compared to immunolabeling in animals that had been gonadectomized and placebo-implanted 28 days prior to being killed (28 day GDX-pl). In contrast to the fairly widespread depletion of immunoreactivity in acutely operated animals, labeling in most of the cortical areas of 28 day GDX-pl animals seemed qualitatively and quantitatively normal. In premotor, motor and somatosensory areas, for example, not only were axon morphology and orientation intact, but normal appearing axon densities were also observed (Fig. 10). Quantitative estimates of axon density substantiated these observations; in area AgM, axon density ranged from 98% (layer V, left hemisphere) to 113% (layer II/III, left hemisphere) of normal (Fig. 5
), in area AgL values were between 92% (layer II/III, right hemisphere) and 104% (layer II/III, left hemisphere) of controls (Fig. 8
), and in area Par1 axon density lay between 89% (layer II/III, right hemisphere) and 123% (layer V, right hemisphere) of values obtained in sham-operated animals (Fig. 9
). Statistical analyses (ANOVA, followed by StudentNewmanKeuls posthoc comparison) showed that none of these axon density measures in any of these areas were statistically different from controls at a P < 0.05 level.
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Qualitative examination of immunoreactivity in both acutely and chronically gonadectomized animals supplemented with testosterone proprionate (GDX-TP) revealed a normal appearance (Fig. 2) and complement of catecholamine axons in all five areas examined (Figs 3, 4, 10, 11
). Quantitative analyses showed that in every area, layer and hemisphere evaluated, axon density estimates in GDX-TP rats were within 25% of normal, and that only in layer V of area Cg1 were measures of axon density obtained significantly different from controls at a P < 0.05 level (Figs 59
).
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Discussion |
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That changes in the levels of circulating hormones were principally responsible for the complex outcomes observed is supported in two lines of evidence. First, all of the longand short-term effects on TH immunoreactivity in gonadectomized rats were essentially absent in gonadectomized animals supplemented with TP; in both acutely and chronically manipulated animals, TP replacement maintained both the mass of the androgen-sensitive bulbocavernosus muscles, and statistically normal levels of TH innervation in all but layer V of area Cg1. In addition, experimental methods were used that minimized variability in axon labeling and analysis (Kritzer, 1998; Adler et al., 1999
) (see Materials and Methods). Consistency in parameters of tissue preservation and concurrent immunoprocessing of tissue samples, for example, provided uniformity in axon labeling, while sampling strategies and assessment of section thickness and axon orientation minimized vagaries that could have been introduced in the extraction of quantitative information from the camera lucida drawings (Kritzer and Kohama, 1998
). These factors combine to support conclusions that catecholamine afferents in the sensorimotor regions examined are either insensitive or only transiently sensitive to changes in the levels of circulating gonadal steroids, whereas the innervation of the two prefrontal cortices assessed was unique for vigorous and sustained responses to changes in the hormonal milieu.
The Effects of Perinatal versus Adult-stage Gonadectomy
A characteristic common to many hormone-sensitive structures in brain and spinal cord is that they are not always nor equally responsive to gonadal steroid stimulation; at an extreme are critical periods of hormone sensitivity discrete windows of time when and only when a given structure or endpoint is influenced by gonadal steroid exposure (Arnold and Gorski, 1984). Although the data do not speak to critical periods of hormone sensitivity in the cerebrum, comparison of the current findings with previously described effects of perinatal gonadectomy (Kritzer, 1998
) does suggest significant change in the hormone sensitivity of cortical TH axons before and after puberty. For example, perinatal gonadectomy produces lasting, highly lateralized decrements in TH innervation in primary somatosensory and motor cortices (Kritzer, 1998
), whereas the same manipulation in adult animals only transiently diminished catecholamine afferents in these fields. Even more striking, however, was that while perinatal gonadectomy affects axon density in sensory, motor and association areas similarly (Kritzer, 1998
), catecholamine axons in the two prefrontal cortices examined were much more sensitive to acute and chronic gonadectomy performed in adulthood than afferents in sensory and motor regions. Four days after surgery, for example, decrements in axon density in cingulate and insular cortices were proportionately nearly twice those observed in somatosensory and motor areas, and by 28 days, it was only in prefrontal regions that aberrant patterns of innervation persisted. In further contradistinction, the enduring elevations in TH immunoreactivity that were observed in the cingulate cortex (Adler et al., 1999
) provide a striking contrast to the chronic depression of axon density in this region that follows perinatal gonadectomy (Kritzer, 1998
).
There are also some subtle differences in the degree to which TP replacement attenuates the effects of perinatal versus adult-stage gonadectomy. Specifically, the nearly pan-cortical effectiveness of the slow-release TP pellets implanted in animals gonadectomized as adults in stimulating normal levels of catecholamine innervation contrasts with the more regionally selective ability of daily injections of TP (adjusted weekly for changes in body weight) to sustain innervation in perinatally gonadectomized rats (Kritzer, 1998). Although both methods achieve near physiological levels of circulating testicular hormones (Sodersten, 1984
; Collins et al., 1992
; Carmignac et al., 1993
), these differences could be related to methods of hormone supplementation. However, they may also reflect a greater degree of similarity between the square pulses of experimentally introduced steroids and the native hormonal milieu of postpubescent male rat brain. In contrast to the series of conspicuous, stereotyped surges in circulating hormones that mark prepubertal life stages, the adult brain is exposed to more consistent levels of gonadal steroids (Resko et al., 1968
). Because these relatively unchanging hormone levels are likely to be more closely approximated by the levels of testicular hormones introduced by either daily injections and slow-release pellets, an end result of a more effective means of stimulating normal cortical catecholamine innervation in the adult brain may not be surprising.
Possible Underlying Mechanisms
As developmental mitogens and in their capacity as neurotransmitters, the catecholamines provide a functionally critical, lifelong influence to the cerebral cortex. The present study suggests that testicular hormones may provide regulatory influence over these important afferents in the adult brain. Although not directly examined in this study, some speculation about mechanisms that could underlie this influence may be forthcoming. For example, the fact that changes in catecholamine axons are region-specific suggests that hormone effects on TH-immunoreactive axons are somehow targeted rather than occurring secondarily to non-specific, perhaps diffuse metabolic changes. This in turn brings to mind intracellular estrogen receptors (ER) and androgen receptors (AR), whose cortical distributions show intriguing parallels with patterns of TH-immunoreactive axon responsiveness. Thus, whereas the widespread distribution of classical ERs (ERs) and ARs (Shughrue et al., 1990
; Simerly et al., 1990
), and the left/right differences in ER
s in neonatal rat cortex (Sandhu et al., 1986
) are consonant with the broadly cast and sometimes lateralized effects of perinatal gonadectomy (Kritzer, 1998
), the relative confinement of AR and ER
binding (Shughrue et al., 1990
; Miranda and Toran-Allerand, 1992
) and/or mRNAs (Simerly et al., 1990
) to medial and perirhinal cortices in the adult brain parallels the particular vulnerability of TH immunoreactivity in these regions to changes induced by adult-stage gonadectomy. There may also be correspondence with the distribution of the more recently described beta ERs, where in situ hybridization studies in adult rats have shown that mRNAs for this receptor subtype are present throughout the cortex but are particularly abundant in perirhinal cortex (Shughrue et al., 1997
).
The striking differences in the effects of acute versus chronic gonadectomy on cortical immunoreactivity, however, may also have parallels to the hormone regulation of TH mRNA levels and transcription in ERand AR-containing cells of the hypothalamus. In the anteroventral periventricular nucleus, for example, TH mRNA levels have been shown to be conspicuously elevated 7 days after gonadectomy in both male and female rats, but indistinguishable from controls 10 weeks after surgery (Simerly, 1989). Similarly, nuclear run-on assays in the arcuate nucleus have identified acute but not chronic effects of estrogen treatment on the rate of TH mRNA transcription in ovariectomized rats (Blum et al., 1987
). It is possible that the changes in cortical TH immunoreactivity, which are either transient or change significantly in the acute and chronic condition, may be endproducts of similar hormone receptor-mediated transcriptional regulation of TH mRNA in cortical catecholaminergic cells of origin. Consistent with this possibility are findings that subsets of noradrenergic cells in the locus coeruleus and dopaminergic cells in the substantia nigra, ventral tegmental area, and in the retrorubral fields contain ER and AR (Heritage et al., 1981
; Kritzer, 1997
; Shughrue et al., 1997
). Further, there is a particularly good match between the distribution of ERß, AR and prefrontally projecting midbrain dopamine neurons (Kritzer, 1997
; Shughrue et al., 1997
).
While supporting arguments can be mounted for mechanisms involving either cortical or midbrain/brainstem hormone receptors, additional possibilities must also be considered, including transneuronal and even non-genomic routes of hormone influence (see McEwen, 1991). It may also be significant that the behavior of gonadectomized animals in open field testing differs from hormonally intact animals (Adler et al., 1999) and that these changes in behavior somehow effect cortical catecholamines. An important requisite to distinguishing among these and other possible mechanisms is to clarify whether the observed effects involve dopaminergic or noradrenergic afferents, or both. This was not possible in the present study because catecholamine axons were assessed using immunoreactivity for TH, a biosynthetic enzyme common to dopaminergic, noradrenergic and adrenergic axons. It has, however, been argued that this marker has some selectivity for dopamine axons in the prefrontal regions of the rat cortex (Lewis et al., 1979
; Berger et al., 1985
). Further, previous analyses of homogenates of rat cortex indicate that adult-stage gonadectomy increases dopamine and its major metabolites, but has no significant effect on noradrenalin (Battaner et al., 1987
). Thus, the results of this study may specifically reflect sensitivity of the dopamine innervation of rat cortex. This question is being pursued in studies of the effects of gonadectomy on cortical dopamine ß-hydroxylase immunoreactivity, an enzyme marker of adrenergic axons.
Whether the axons involved are dopaminergic, noradrenergic or both, there is clear evidence for exquisite, regionally selective hormone stimulation of cortical catecholamine innervation in the adult rat brain. The present data further suggest that with maturation, the initially widespread long-term consequences of perinatal gonadectomy for sensory, motor and prefrontal (cingulate) areas (Kritzer, 1998) are replaced by an especial and perhaps selective disruption of catecholamine innervation in the two prefrontal cortices studied. Given the reliance of prefrontal cortical operations on their catecholamine inputs (Brozoski et al., 1979
; Stam et al., 1989
; Wilcott and Xuemei, 1990
), this enduring responsiveness to changes in the hormonal milieu could have relevance for observed relationships between cognitive information processing and circulating hormone levels in adult men and women (Hampson, 1990
). Further, that one outcome of the hormone manipulation paradigms used was a higher than normal catecholamine innervation in deep layers of these prefrontal cortices may also be of interest in relation to schizophrenia a disorder in which hypodopaminergia in prefrontal cortex has been implicated in its negative symptoms [e.g. anhedonia, poor planning and motivation (Davis et al., 1991
; Goldman-Rakic, 1991
)] which are also those that tend to be most frequent and most resilient to pharmacological treatment in males (Seeman and Lang, 1990).
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Notes |
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Address correspondence to: Mary Kritzer, Department of Neurobiology and Behavior, SUNY at Stony Brook, Stony Brook, NY 11794-5230, USA. Email: mkritzer{at}neurobio.sunysb.edu.
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