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PubMed2006

Prenatal stress suppresses cell proliferation in the early developing brain.

Although prenatal stress has been repeatedly shown to inhibit adult neurogenesis in the dentate gyrus of offspring, its effects on embryonic and early postnatal brain development are not well described. Here, using the cell proliferation marker 5-bromo-2'-deoxyuridine, we examine for the first time the effect of prenatal stress at the embryonic stage on cell proliferation in the hippocampus, nucleus accumbens and amygdala. We show that prenatal stress induces a significant decrease in density of 5-bromo-2'-deoxyuridine-positive cells in the nucleus accumbens (40%) and hippocampus (60%), and a nonsignificant decrease in the amygdala (30%). Taken together, these results demonstrate the adverse effects of prenatal maternal stress on early development in limbic brain regions and the potential mechanisms are discussed.

Animals↗

PubMed1996

Early development of intimal thickening in superficial temporal arteries in patients with moyamoya disease.

BACKGROUND AND PURPOSE: Moyamoya disease is a progressive cerebrovascular occlusive disease that occurs in children. The etiology is unknown. We examined the superficial temporal arteries from patients with moyamoya disease, particularly children, to determine whether the extracranial arteries as well as the intracranial arteries are involved in this disease. METHODS: Small branches of the superficial temporal arteries were obtained from 22 patients with moyamoya disease during indirect arterial bypass surgery. Histological examinations were performed, and the findings were compared with those of arteries from 12 control patients. RESULTS: Intimal thickening was observed in 9 of 17 patients with moyamoya disease younger than 20 years but in none of 7 control patients under the age of 20 years (P < .02, Fisher's exact test). Intimal thickening appeared from age 20 years in control patients. The arteries of moyamoya patients showed fibrocellular intimal thickening with a paucity of lipid. The arteries from moyamoya patients contained strongly stained multilayered elastic fibers in the thickened intima, while those from control patients showed only weakly stained elastic fibers in the intima. CONCLUSIONS: Our findings suggest that moyamoya disease is a systemic vascular disease. The results indicate systemic etiologic factors that may promote the early development of intimal thickening in moyamoya disease.

Adult↗

PubMedDate not supplied

Phyletic patterns of early development in gastropod molluscs.

Cell lineage data for 30 exemplar gastropod taxa representing all major subclades and the outgroup Polyplacophora were examined for phylogenetic signal using cladistic analysis. Most cell lineages show phyletic trends of acceleration or retardation relative to the outgroup and more basal ingroup taxa, and when coded this variation is phylo-genetically informative. PAUP analyses of a cell lineage data set under three sets of character ordering assumptions produced similar tree topologies. The topologies of the strict consensus trees for both ordered and Dollo (near irreversibility of character transformations) character assumptions were similar, whereas the unordered character assumption recovers the least phyletic information. The cell lineage cladograms are also in agreement with the fossil record of the timing and sequence of gastropod subclade origination. A long branch lies between the Patellogastropoda+Vetigastropoda grade and the Neritopsina+Apogastropoda clade. The geological timing of this long branch is correlated with the first large-scale terrestrially derived eutrophication of the near-shore marine habitat, and one possible explanation for this branch may be a developmental shift associated with the evolution of feeding larvae in response to the more productive conditions in the near-shore water column. Although character transformations are highly ordered in this data set, developmental rate characters (like all other morphological and molecular characters) are also subject to homoplasy. Finally, this study further supports the hypothesis that early development of gastropod molluscs has conserved a strong phyletic signal for about half a billion years.

Animals↗

PubMed1997

GATA-2 is a maternal transcription factor present in Xenopus oocytes as a nuclear complex which is maintained throughout early development.

We show that Xenopus oocytes and embryos contain GATA-2, stored in nuclei as a non-chromatin-bound complex. Its binding site specificity is different from that of GATA-1, having a much higher affinity for the motif with a core GATC sequence. This binding site preference was markedly reduced by either release of the factor with deoxycholate or purification on a DNA affinity column, suggesting a role for a cofactor(s). The identity of the maternal GATA factor was established as GATA-2 in two ways: (1) binding to an oligonucleotide probe was abolished by inclusion of either of two GATA-2 monoclonal antibodies, and (2) a protein of correct molecular weight for GATA-2 was detected by immunoblotting with a polyclonal antibody raised against a Xenopus GATA-2-specific peptide. Although predominantly complexed, some of the oocyte GATA-2 is functional as a transcription factor because the transcriptional activity of the chicken betaH-globin promoter injected into oocytes was reduced by mutation of either of two GATA binding sites. This effect was more pronounced when the stronger of the two sites was mutated. Butyrate treatment of oocytes stimulated cap-site initiation by up to 17-fold with both normal promoter and GATA site mutant constructs, showing that the mechanism of butyrate stimulation is not via GATA-2. The possible significance of regulating the availability of maternal GATA-2 during early development is discussed.

Animals↗

PubMed1998

Dictyostelium TRFA homologous to yeast Ssn6 is required for normal growth and early development.

The TPR (tetratricopeptide repeat) family became widespread during evolution, having been found from bacteria to mammals. By means of restriction enzyme-mediated integration, we have identified a Dictyostelium gene (trfA) highly homologous to a Saccharomyces cerevisiae gene encoding a TPR protein, Ssn6 (Cyc8), which functions as a global transcriptional repressor for diverse genes. The deduced amino acid sequence of the Dictyostelium gene product, TRFA, contains 10 consecutive TPR units as well as Gln repeats, Asn repeats, and a region rich in Glu, Lys, Ser, and Thr. The sequences of some of the 10 TPR units in TRFA are more than 70% identical to the corresponding units in Ssn6. The trfA- cells produced smooth plaques on a bacterial lawn and failed to aggregate normally when starved on a plain agar plate. Individual trfA- cells also failed to correctly respond to cAMP, although the adenylyl cyclase of trfA- cells was expressed upon starvation and activated by stimulation with cAMP as in the wild-type cells. When cultured in a rich medium in suspension, they grew more slowly and stopped growing at a lower density than the wild-type cells. Furthermore, they divided into cells of various sizes and tended to be much smaller than the wild-type cells. These pleiotropic defects of the trfA- cells suggest the possibility that Dictyostelium TRFA may regulate the transcription of diverse genes required for normal growth and early development.

Amino Acid Sequence↗

PubMed1996

Glycoconjugate expression changes during Rana dalmatina early development.

Glycoconjugates are generally involved in cell adhesion and morphogenetic movements. To investigate their distribution and expression changes during amphibian development, several FITC-or HRP-labeled lectins were used in Rana dalmatina embryos and larvae. During gastrulation, WGA, ConA, HPA, GSA-I, PNA and RCA-I labeled either the envelopes on the perivitelline space-contained substances, while ectodermal cells and/or extracellular matrix were mainly labeled by WGA, GSA-I, DBA and LTA. In these structures fibronectin-like molecules were also found. ConA, HPA, RCA-I, SBA also labeled ectoderm, but with lower affinity. At larval stages, ectodermal derivatives, such as larval skin, central nervous system, eye and ear, were also strongly labeled by WGA, DBA and LTA, while the affinity to ConA, HPA, GSA-I, SBA, appeared less visible; the affinity sites to RCA-I and PNA were totally lacking. Fibronectin-like immunoreactivity was hardly present at the larval stages. These results point out that glycoconjugate expression changes in cell surface and in extracellular matrix might be developmentally regulated. For this reason the different glycoconjugates seem to play stage-specific roles in early development.

Animals↗

PubMed2003

Docosapentaenoic acid does not completely replace DHA in n-3 FA-deficient rats during early development.

The reciprocal replacement of DHA by docosapentaenoic acid (DPAn-6) was studied in rats that consumed an n-3 FA-deficient or n-3 FA-adequate diet. Dams were fed the two experimental diets from weaning and throughout pregnancy and lactation. Their pups were then fed the respective diets after weaning. Cortex FA analysis was performed at various times (0, 5, 10, 20, 50, and 91 d) after birth to determine whether DPAn-6 completely replaced DHA in the n-3-deficient group. Cortical DHA levels were significantly lower (average 86%) in the n-3-deficient rats. DPAn-6 increased significantly in the n-3-deficient rats starting with a 6.5-fold increase at day 0 up to a 54-fold increase at day 91 compared with the n-3-adequate group. However, this significant increase did not completely replace the loss of DHA at postnatal days 5, 10, and 20 in which there was still an 11.5, 10.3, and 8.0% deficit in the sum of DHA and DPAn-6, respectively, in the n-3-deficient group. Once docosatetraenoic (DTA) and arachidonic acids (AA) were included in the sum (DHA + DPAn-6 + DTA + AA), the levels between the two groups were similar. These results suggest that not only DPAn-6 but also other n-6 FA, including DTA and AA, replace DHA in n-3-deficient rats. The lack of total 22-carbon (22C) FA in the brain during the rapid membrane biogenesis that occurs during early development could be a factor in the nervous system functional deficits associated with n-3 FA deficiency.

Animal Feed↗

PubMed2005

Expression of P2X receptors on rat microglial cells during early development.

We have used single- and double-labeling immunfluorescence and reverse transcription-polymerase chain reaction (RT-PCR) methods to examine expression of P2X receptor subtypes on microglial cells of brain in late embryonic and postnatal rat, in the N9 microglial cell line and primary cultured microglial cells. P2X1, P2X4, and P2X7 receptors were shown on microglial cells from late embryonic day 16. Almost all the microglial cells that were positive for the marker ED1, expressed P2X1 and P2X4 receptors, whereas only about 30% of the cells with ED1-immunoreactivity were found to express the P2X7 receptor. Positive cells were localized mainly in the white matter and around ventricles. From postnatal day 7, many microglial cells with P2X4 receptor-immunoreactivity were seen around the blood vessels. At postnatal day 30, microglial cells with P2X1 receptor-immunoreactivity disappeared and the cells with P2X4 receptor-immunoreactivity were mainly localized around blood vessels and lining the subarachnoid space. From postnatal day 30, the microglial cells with P2X7 receptor-immunoreactivity were found to be distributed widely in the forebrain. Cells with P2X7 receptor-immunoreactivity from P30 were not labeled by ED1, but some were labeled by isolectin B4. The expression of P2X1, P2X4, and P2X7 receptor mRNA and protein on primary cultures of rat microglial cells and on the N9 microglial cell line was demonstrated with immunocytochemistry and RT-PCR. This is the first report that the P2X1 receptor is expressed on microglial cells, at least in early development, before postnatal day 30.

Animals↗

PubMed1994

[Binocular competitive mechanisms in the visual cortex in early developing kittens of monocular deprivation and reverse suture revealed by pattern visual evoked potential].

Using contrast reversing square- wave gratings as stimuli the pattern visual evoked potentials (P-VEP) and pattern electroretinograms (P-ERG) were simultaneously recorded to determine the spatial frequency tuning curves for kittens of monocular deprivation (from 8th to 12th postnatal week) and reverse suture (from 12th to 15th postnatal week), as compared with those of normal kittens of the same age and adult cats. The results showed that in the range from spatial frequency 0.12 to 1.5 c/d the amplitudes of P-VEP responses driven respectively by the left and the right eyes in normal kittens were similar but clearly smaller than those driven binocularly. For kittens with one eye deprived, the P-VEP amplitudes driven by the deprived eye decreased markedly. In contrast, the P-VEP amplitudes driven by the undeprived eye increased significantly, while the P-VEP amplitudes driven by simultaneous stimulation of both eyes were intermediate between the two monocular responses. For the reversely sutured kittens, the P-VEP amplitudes driven by the formally deprived eye recovered to some extent, while the P-VEP amplitudes driven by the reversely sutured eye decreased, and their amplitudes tended to be quite close. The P-VEP amplitude driven by both eyes was the biggest. Neither such shift of spatial frequency tuning curves of the P-VEP in adult cats, nor such functional competition between the two eye in P-ERG responses during early development of kittens of monocular deprivation and reverse suture was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1998

Role of NO and angiotensin II in the early development of endothelial functions impairment and cardiac hypertrophy in deoxycorticosterone acetate-salt hypertension.

This study was designed to investigate the effects of chronic inhibition of NO synthesis as well as chronic angiotensin receptor blockade with losartan in the development of hypertension, on mesenteric arterial bed reactivity as well as on the development of cardiac and kidney hypertrophy in deoxycorticosterone-salt (DOCA) hypertension. Uninephrectomized rats were divided in four experimental groups all receiving saline water to drink and treated or not with losartan over a period of 9 days. Two of these groups were administered DOCA, one of which received also N(G)-nitro-L-arginine-methyl ester (L-NAME) to drink. A third group received only L-NAME, while another group received only saline. Systolic blood pressure was similarly increased in L-NAME, DOCA, DOCA-L-NAME groups. Cardiac and kidney weights were increased in DOCA but significantly reduced in DOCA-L-NAME. Losartan prevented the development of hypertension in all groups and also prevented cardiac and kidney hypertrophy in DOCA. The hyperreactivity of mesenteric arteries to phenylephrine, measured in the presence of indomethacin, was endothelium-dependent in both L-NAME groups but not in DOCA rats. Pretreatment with BQ 123 did not modify these endothelium-dependent responses in L-NAME rats. Chronic losartan prevented endothelium-dependent phenylephrine hyperreactivity only in DOCA, whereas only the removal of the endothelium attenuated the responsiveness in both L-NAME-treated groups. Vasorelaxations to acetylcholine and isoproterenol were attenuated in the three hypertensive groups and were normalized only in DOCA and L-NAME treated with losartan. In summary, in all hypertensive groups, blood pressure was normalized by losartan independently of its effects on endothelial functions. In DOCA, losartan normalized the phenylephrine hyperreactivity through an endothelial-dependent mechanism. However, in L-NAME-treated groups an endothelial-derived contracting factor, other than angiotensin II, endothelin, or vasoconstrictor prostanoids, appears to be activated. Both NO and angiotensin II seem to play a role in the early development of hypertension and organ hypertrophy in DOCA hypertension.

Angiotensin II↗

PubMed2006

Skewed X chromosome inactivation of blood cells is associated with early development of lung cancer in females.

The skewed X chromosome inactivation (SXCI) was found mainly in adult females. It has been linked to development of ovarian and breast cancers. The present study aimed to describe the relationship between SXCI and development of lung cancer in females. DNA was isolated from blood cells from patients with primary lung cancer (n=148) and reference subjects (n=289). The androgen receptor (AR) gene exon 1 was amplified, with its products from different alleles resolved on denaturing polyacrylamide gels and visualized by silver staining. The corrected ratio (CR) between products from AR alleles after and before HpaII pretreatment was calculated. Occurrence of SXCI was detected in both the patients and reference subjects at similar frequency. However, the phenomenon was more frequent in the patients below 40 years compared to the corresponding reference group, either taking CR >/=3 (25 and 5.8%, respectively; P=0.048) or CR >/=10 as the criterion of SXCI (16.7 and 0.8%, respectively; P=0.022). A higher frequency of SXCI was also found in the patients below 50 years compared to that for the corresponding reference group when CR >/=10 adopted as the criterion (7.9 and 1.2%, respectively; P=0.046). The cancer patients with SXCI were more than 10 years younger in average age than those without SXCI. SXCI of blood cells is associated with early development of lung cancer in females. The X chromosomal inactivation assay, therefore, may be used to screen for females predisposed to malignancies including lung cancer.

Adolescent↗

PubMed2003

Early development of stricturing or penetrating pattern in Crohn's disease is influenced by disease location, number of flares, and smoking but not by NOD2/CARD15 genotype.

BACKGROUND: Crohn's disease is a heterogeneous entity. Disease behaviour, characterised as stricturing, penetrating, or non-stricturing non-penetrating, is a clinically important phenotype as it is associated with complications and need for surgery. It has recently been showed that the behaviour of Crohn's disease changes over the course of the disease. AIM: To assess the association between rapid development of a penetrating or stricturing pattern of Crohn's disease and demographic and clinical characteristics as well as NOD2/CARD15 genotype. PATIENTS AND METHODS: A total of 163 patients with a firm diagnosis of Crohn's disease and who had non-penetrating non-stricturing disease at diagnosis were studied. Various demographic and clinical characteristics as well as antisaccharomyces cerevisiae antibody status and NOD2/CARD15 genotype were documented in these patients. These characteristics were compared in subgroups of patients according to evolution of disease behaviour five years after diagnosis. RESULTS: Five years after diagnosis there were 110 (67.5%) patients with non- structuring non-penetrating disease, 18 (11%) with stricturing disease, and 35 (21.5%) with penetrating disease. In multivariate analysis, only disease location and number of flares per year were significantly discriminant between the three subgroups (p=0.0009 and 0.0001, respectively). Ileal location of the disease was associated with a stricturing pattern while a high number of flares was associated with a penetrating pattern. Active smoking was also associated with a penetrating pattern compared with a non-stricturing non-penetrating pattern only. CONCLUSIONS: Early development of stricturing or penetrating behaviour in Crohn's disease is influenced by disease location, clinical activity of the disease, and smoking habit, but not by NOD2/CARD15 genotype.

Adult↗

PubMed1987

Presence of thyroxine in eggs and changes in its content during early development of chum salmon, Oncorhynchus keta.

In order to examine the role of thyroid hormones during salmonid development, techniques were developed for quantitative extraction of thyroxine from eggs, whole embryos, and alevins of chum salmon (Oncorhynchus keta) at various stages of development. Frozen eggs, embryos, alevins, or fry were homogenized in ice-cold methanol. The homogenate was centrifuged, and the supernatant was washed with a mixture of chloroform and 0.05% CaCl2. The aqueous layer was lyophilized, and the residue was redissolved in barbital buffer for thyroxine radioimmunoassay (RIA). Serial dilutions of the egg or tissue extracts gave inhibition slopes that were parallel to that of the thyroxine standard in the RIA. Immunoreactivity of the extracts coeluted with thyroxine standard in reverse-phase HPLC on an ODS column. Recovery of thyroxine from egg and tissue extracts was estimated from the recovery of 125I-labeled thyroxine added to the initial homogenates. Thyroxine content of eggs just after fertilization was 4-5 ng/egg, and this level was maintained until hatching. A decrease in thyroxine content was seen during yolk absorption. Total thyroxine increased to about 10 ng/fish, a level higher than that in the unfertilized egg, at the time of complete yolk absorption, and decreased within 10 days to a low level of 1 ng/fish. These findings are discussed in relation to the role of maternal thyroid hormones during early development and also to the onset of larval thyroid function.

Animals↗

PubMed1998

Pituitary expression of protein kinase C isotypes during early development.

Protein kinase C (PKC) is a critical regulator of signal transduction and cell function in many tissues, including pituitary. Although PKC influences pituitary hormone secretion in adults, its role in determining characteristic perinatal patterns of hormone secretion and synthesis is not known, and the expression of major PKC isotypes in perinatal pituitary is poorly defined. We therefore determined the developmental, cell-specific expression of the major PKC isotypes, using Western analysis and double label immunohistochemistry, in pituitaries of perinatal and mature rats. Expression of specific PKC isotypes was strikingly age-dependent. Pituitary expression of PKC alpha was particularly high in neonates and declined significantly with age, with levels in adult rats approximately half those of neonates as assessed by Western analysis. Similarly, immunohistochemistry indicated that PKC alpha was less abundant in adult than in neonatal pituitaries; the most intensely staining cells of both age groups were identified as somatotrophs and gonadotrophs. In contrast to PKC alpha, pituitary expression of PKC epsilon increased approximately two-fold with advancing age as assessed by Western analysis; this age-dependent pattern was confirmed by immunohistochemistry. Perinatal pituitaries expressed PKC epsilon in some somatotrophs and in all gonadotrophs, whereas PKC epsilon expression was limited to gonadotrophs in the mature pituitary. Pituitary expression of PKC betaII, delta, and zeta did not differ with age, and PKC gamma was not detected in pituitaries of any age group. These results indicate that expression of PKC isotypes within the pituitary is developmentally regulated in a cell-specific and isotype-specific manner, and are consistent with the concept that PKC contributes to the regulation of pituitary function during early development.

Aging↗

PubMed2004

Effect of food deprivation during early development on cognition and neurogenesis in the rat.

Food deprivation has been recognized as having pronounced beneficial effects in adult animals, increasing longevity, reducing seizure susceptibility, and enhancing resistance to neurotoxins. It is not known whether food deprivation in developing animals is neuroprotective or harmful. To evaluate the effects of food deprivation on brain development, we evaluated visual-spatial learning and memory and neurogenesis in the dentate gyrus of the hippocampus in food-deprived (FD) and well-fed (WF) rats. To induce food deprivation, pups were removed from their dams for 12 hours per day from Postnatal Day (P) 2 to P19. FD and WF rat pups were then subjected to status epilepticus (SE) induced by lithium-pilocarpine at P20. After SE, neurogenesis was measured, while in another group of P38 rats, learning and memory were evaluated using the Morris water maze. Food deprivation was found to reduce neurogenesis when assessed after the period of food deprivation. Although SE reduced neurogenesis in the WF animals, it had little effect additional to food deprivation on neurogenesis in the FD rats. Compared with the WF group, FD rats had a mild impairment in memory in the water maze testing after SE. Our study demonstrates that food deprivation during the neonatal period in rats is associated with a decrease in neurogenesis and mild impairment of visual-spatial memory. Although SE decreased neurogenesis in the WF group, in FD animals, SE did not reduce neurogenesis more than what was seen with food deprivation alone. Our results suggest that although food deprivation during early development reduces dentate gyrus neurogenesis, the reduced neurogenesis is not a major factor in cognitive impairment after SE in FD rats.

Age Factors↗

PubMed1986

Localization of fodrin during fertilization and early development of sea urchins and mice.

Fodrin, a spectrin-like protein, is localized in gametes, zygotes, and embryos from sea urchins and mice. Mammalian fodrin comprises two polypeptides with molecular weights of approximately 240 kDa (alpha) and 235 kDa (beta). An antibody specific for mammalian alpha-fodrin cross-reacted with a 240-kDa polypeptide from sea urchin egg extracts. This indicates that sea urchins contain a protein of similar electrophoretic mobility and immunological properties to mammalian alpha-fodrin. When this antibody was used to stain the sea urchin gametes with indirect immunofluorescence, fodrin-specific fluorescence was localized to the acrosome of the sperm and was distributed over the entire egg near the surface in a punctate pattern similar to the distribution of polymeric actin. During sperm incorporation, the fodrin-specific fluorescence is found at the site of sperm incorporation, in the fertilization cone. After fertilization, the intensity of fodrin fluorescence increases. During mitosis and cytokinesis in sea urchins, the entire surface of the egg remains stained; the cleavage furrow also was stained but no more intensely than was the rest of the egg surface. Antibody labeling with colloidal gold followed by electron microscopy showed that fodrin was loated in the cytoplasm immediately beneath the plasma membrane. In unfertilized mouse oocytes, both actin and fodrin were stained most intensely beneath the membrane adjacent to the meiotic spindle. After insemination, the cell surfaces of the pronucleate egg and the second polar body were stained; however, the actin matrix surrounding the apposed pronuclei did not bind the fodrin antibody. During cytokinesis in the mouse, the cleavage furrow stained more intensely than did the rest of the egg cortex, and in embryos the cell borders were delineated. These results indicate that organisms as unrelated to mammals as sea urchins have fodrin-like proteins; the rearrangements of such proteins suggest that they participate in the actin-mediated events at the cell surface during fertilization and early development in both mice and sea urchins.

Actins↗

PubMed1990

Origin and early development of female germ cells in Eoleptestheria ticinensis Balsamo-Crivelli, 1859 (Crustacea, Branchiopoda, Conchostraca).

We have studied the early stages of the development of the female germ cells in the Conchostraca Eoleptestheria ticinensis Balsamo-Crivelli, 1859. The gametes originate in a scattered way throughout the tubular units of the gonad, with no development gradient recognizable. The female germ cells arise from successive karyokineses not followed by cytokinesis, within an unorganised area in which a sort of plasmodium is formed. Each primordial nucleus of this germarium develops and then forms an individual plasmic membrane. Subsequently, the usual organules differentiate in the cytoplasm. The presence of synaptinemal complexes and the beginning of the endogenous vitellogenesis by the rough endoplasmic reticulum and the Golgi apparatus qualify the previtellogenesis. The general characteristics of this early development phase of the gametes, as well as several substantial differences in the gametogenesis with respect to the other Phyllopoda studied, lead us to suggest the systematic positioning of the Leptestheriidae.

Animals↗

PubMed1983

Effects of experimental suppression of active (REM) sleep during early development upon adult brain and behavior in the rat.

In order to test the hypothesis that active sleep (AS) is important for the normal development of the central nervous system, 3 different deprivation methods were applied to male Wistar rat pups during the first month of life. Daily injection of clomipramine from 8 to 21 days of age reduced the high level of AS to less than the adult value throughout most of the experimental period. Administration of clonidine from 8 to 21 days of life induced an almost total suppression of AS. Instrumental deprivation, using the 'pendulum' method, led to a significant (but less severe) AS reduction during 2-4 weeks of postnatal age. Open-field behavior testing in adulthood revealed a higher than normal level of ambulation in all 3 experimental groups. Masculine sexual responses were deficient, due to a low level of both mounts and ejaculations, in both clomipramine- and clonidine-treated animals. Neither passive avoidance learning nor dark preference tests revealed any differences between the experimental and control rats. Sleep observations showed that there was an abnormally high incidence of large myoclonic jerks during AS in both clomipramine- and clonidine-treated rats. Subsequent measurement of regional brain weights showed a significant reduction in the cerebral cortex and medulla oblongata, as compared with the respective control groups, in both the clomipramine- and the clonidine-treated rats. In addition, DNA and protein determination in the affected brain areas showed a proportional reduction in the cortex and in the medulla. These results demonstrate that interference with normal functioning either of AS per se or of specific monoaminergic transmitter systems during early development can produce long-lasting behavioral as well as brain morphological and biochemical abnormalities in later life.

Animals↗