The Anatomical Record : New Concepts in Developing Brain Disorder : Autism

vendredi 2 décembre 2011

La revue The Anatomical Record consacre son numéro d’octobre 2011 à l’autisme en lien avec les troubles du développement cérébral.

Les articles sont accessibles sur le site de l’éditeur.


1. Agster KL, Clark BD, Gao W-J, Shumsky JS, Wang HX, Berridge CW, Waterhouse BD. Experimental Strategies for Investigating Psychostimulant Drug Actions and Prefrontal Cortical Function in ADHD and Related Attention Disorders. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1698-1712.

Amphetamine-like psychostimulant drugs have been used for decades to treat a variety of clinical conditions. Methylphenidate (MPH)—RitalinR, a compound that blocks reuptake of synaptically released norepinephrine (NE) and dopamine (DA) in the brain, has been used for more than 30 years in low dose, long-term regimens to treat attention deficit-hyperactive disorder (ADHD) in juveniles, adolescents, and adults. Now, these agents are also becoming increasingly popular among healthy individuals from all walks of life (e.g., military, students) and age groups (teenagers thru senior citizens) to promote wakefulness and improve attention. Although there is agreement regarding the primary biochemical action of MPH, the physiological basis for its efficacy in normal individuals and ADHD patients is lacking. Study of the behavioral and physiological actions of clinically and behaviorally relevant doses of MPH in normal animals provides an opportunity to explore the role of catecholamine transmitters in prefrontal cortical function and attentional processes as they relate to normal operation of brain circuits and ADHD pathology. The goal of ongoing studies has been to : (1) assess the effects of low dose MPH on rodent performance in a well characterized sensory-guided sustained attention task, (2) examine the effects of the same low-dose chronic MPH administration on task-related discharge of prefrontal cortical (PFC) neurons, and (3) investigate the effects of NE and DA on membrane response properties and synaptic transmission in identified subsets of PFC neurons. Combinations of these approaches can be used in adolescent, adult, and aged animals to identify the parameters of cell and neural circuit function that are regulated by MPH and to establish an overarching explanation of how MPH impacts PFC operations from cellular through behavioral functional domains. Anat Rec,, 2011. © 2011 Wiley-Liss, Inc.

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2. Aiello TP, Whitaker-Azmitia PM. Sexual Differentiation and the Neuroendocrine Hypothesis of Autism. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1663-1670.

The phenotypic expression of autism spectrum disorders varies widely in severity and characteristics and it is, therefore, likely that a number of etiological factors are involved. However, one finding which has been found consistently is that there is a greater incidence of autism in boys than girls. Recently, attention has been given to the extreme male hypothesis—that is that autism behaviors are an extreme form of typical male behaviors, including lack of empathy and language deficits but an increase in so-called systemizing behaviors, such as attention to detail and collecting. This points to the possibility that an alteration during sexual differentiation of the brain may occur in autism. During sexual differentiation of the brain, two brain regions are highly sexually dimorphic—the amygdala and the hypothalamus. Both of these regions are also implicated in the neuroendocrine hypothesis of autism, wherein a balance between oxytocin and cortisol may contribute to the disorder. We are thus proposing that the extreme male hypothesis and the neuroendocrine hypothesis are in fact compatible in that sexual differentiation of the brain towards an extreme male phenotype would result in the neuroendocrine changes proposed in autism. We have preliminary data, treating developing rat pups with the differentiating hormone 17-β estradiol during a critical time and showing changes in social behaviors and oxytocin, to support this hypothesis. Further studies should be undertaken to confirm the role of extremes of normal sexual differentiation in producing the neuroendocrine changes associated with autism. Anat Rec, 2011. © 2011 Wiley-Liss, Inc.

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3. Azmitia EC, Singh JS, Hou XP, Wegiel J. Dystrophic Serotonin Axons in Postmortem Brains from Young Autism Patients. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1653-1662.

Autism causes neuropathological changes in varied anatomical loci. A coherent neural mechanism to explain the spectrum of autistic symptomatology has not been proposed because most anatomical researchers focus on point-to-point functional neural systems (e.g., auditory and social networks) rather than considering global chemical neural systems. Serotonergic neurons have a global innervation pattern. Disorders Research Program, AS073234, Program Project (JW). Their cell bodies are found in the midbrain but they project their axons throughout the neural axis beginning in the fetal brain. This global system is implicated in autism by animal models and by biochemical, imaging, pharmacological, and genetics studies. However, no anatomical studies of the 5-HT innervation of autistic donors have been reported. Our review presents immunocytochemical evidence of an increase in 5-HT axons in postmortem brain tissue from autism donors aged 2.8–29 years relative to controls. This increase is observed in the principle ascending fiber bundles of the medial and lateral forebrain bundles, and in the innervation density of the amygdala and the piriform, superior temporal, and parahippocampal cortices. In autistic donors 8 years of age and up, several types of dystrophic 5-HT axons were seen in the termination fields. One class of these dystrophic axons, the thick heavily stained axons, was not seen in the brains of patients with neurodegenerative diseases. These findings provide morphological evidence for the involvement of serotonin neurons in the early etiology of autism, and suggest new therapies may be effective to blunt serotonin’s trophic actions during early brain development in children. Anat Rec, 2011. © 2011 Wiley-Liss, Inc.

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4. Blatt GJ, Fatemi SH. Alterations in GABAergic Biomarkers in the Autism Brain : Research Findings and Clinical Implications. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1646-1652.

Autism is a pervasive developmental disorder characterized by repetitive stereotyped behavior, social-emotional deficits, and delayed or absent language abilities. There are known neuropathologies in the autism brain affecting limbic, cerebellar, and cortical structures but the neurochemical profile of affected individuals, revealed in postmortem tissue studies, is only recently emerging. One major component that appears highly impacted in autism is the GABAergic system. It is now apparent that there are widespread significant effects in many distributed regions in the autism brain revealed by histochemical, autoradiographic, and biochemical studies. The key synthesizing enzymes for GABA, glutamic acid decarboxylase type 65 and 67 (GAD65 and GAD67), are decreased in the cerebellum and closer examination of mRNA levels revealed that it is largely due to decreases in Purkinje cells and a subpopulation of larger dentate neurons as measured by in situ hybridization studies. Other cell types had either normal GAD levels (Golgi cells, smaller dentate interneurons, and stellate cells) or increased levels (basket cells). GABA receptor density, number, and protein expression are all decreased in the cerebellum and in select cortical areas. GABAA and GABAB subunit protein expression was significantly reduced in cerebellum, BA 9 and BA 40. Benzodiazepine binding sites were significantly reduced in the hippocampus and anterior cingulate cortex (BA 24). Taken together, data from these studies suggest that there is a marked dysregulation of the inhibitory GABA system in the autism brain affecting particular biomarkers localized to specific cell types and lamina likely influencing circuitry and behavior. Anat Rec, 2011. © 2011 Wiley-Liss, Inc.

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5. Blue ME, Kaufmann WE, Bressler J, Eyring C, O’Driscoll C, Naidu S, Johnston MV. Temporal and Regional Alterations in NMDA Receptor Expression in Mecp2-Null Mice. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1624-1634.

Our previous postmortem study of girls with Rett Syndrome (RTT), a development disorder caused by MECP2 mutations, found increases in the density of N-Methyl-D-aspartate (NMDA) receptors in the prefrontal cortex of 2–8-year-old girls, whereas girls older than 10 years had reductions in NMDA receptors compared with age-matched controls (Blue et al., Ann Neurol 1999b ;45:541–545). Using [3H]-CGP to label NMDA-type glutamate receptors in 2- and 7-week old wild-type (WT), Mecp2-null, and Mecp2-heterozygous (HET) mice (Bird model), we found that frontal areas of the brain also exhibited a bimodal pattern in NMDA expression, with increased densities of NMDA receptors in Mecp2-null mice at 2 weeks of age but decreased densities at 7 weeks of age. Visual cortex showed a similar pattern, while other cortical regions only exhibited changes in NMDA receptor densities at 2 weeks (retrosplenial granular) or 7 weeks (somatosensory). In thalamus of null mice, NMDA receptors were increased at 2 and 7 weeks. No significant differences in density were found between HET and WT mice at both ages. Western blots for NMDAR1 expression in frontal brain showed higher levels of expression in Mecp2-null mice at 2 weeks of age but not at 1 or 7 weeks of age. Our mouse data support the notion that deficient MeCP2 function is the primary cause of the NMDA receptor changes we observed in RTT. Furthermore, the findings of regional and temporal differences in NMDA expression illustrate the importance of age and brain region in evaluating different genotypes of mice. Anat Rec, 2011. © 2011 Wiley-Liss, Inc.

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6. Daza JD, Diogo R, Johnston P, Abdala V. Jaw Adductor Muscles across Lepidosaurs : A Reappraisal. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1765-1782.

The exact homologies of tetrapod jaw muscles remain unresolved, and this provides a barrier for phylogenetic analysis and tracing character evolution. Here, lepidosaur jaw muscles are surveyed using direct examination of species from 23 families and published descriptions of species from 10 families. A revised nomenclature is applied according to proposed homologies with Latimeria. Among lepidosaurs, variation was found in many aspects of jaw muscle anatomy. The superficial layers mm. levator and retractor anguli oris (LAO and RAO) are present in Sphenodon but not all squamates. The external jaw adductor muscles universally present in lepidosaurs are homologous with the main adductor muscle, A2, of Latimeria and include four layers : superficialis (A2-SUP), medialis (A2-M), profundus (A2-PRO), and posterior (A2-PVM). The A2-SUP appears divided in Agamidae, Gekkota, Xantusiidae, and Varanidae. The A2-M is layered lateromedial in lizards but anteroposterior in snakes. The names pseudotemporalis (PS) and pterygomandibularis (PTM) are recommended for subdivisions of the internal adductors of reptiles and amphibians, because the homology of this muscle with the A3′ and A3 ″ of Latimeria remains inconclusive. The intramandibularis of lepidosaurs and Latimeria (A-ω) are homologous. The distribution of six jaw muscle characters was found to plot more parsimoniously on phylogenies based on morphological rather than and molecular data. Character mapping indicates that Squamata presents reduction in the divisions of the A2-M, Scincoidea presents reduction or loss of LAO, and two apomorphic features are found for the Gekkota. Anat Rec, 2011. © 2011 Wiley-Liss, Inc.

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7. Fairless AH, Shah RY, Guthrie AJ, Li H, Brodkin ES. Deconstructing Sociability, An Autism-Relevant Phenotype, in Mouse Models. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1713-1725.

Reduced sociability is a core feature of autism spectrum disorders (ASD) and is highly disabling, poorly understood, and treatment refractory. To elucidate the biological basis of reduced sociability, multiple laboratories are developing ASD-relevant mouse models in which sociability is commonly assessed using the Social Choice Test. However, various measurements included in that test sometimes support different conclusions. Specifically, measurements of time the “test” mouse spends near a confined “stimulus” mouse (chamber scores) sometimes support different conclusions from measurements of time the test mouse sniffs the cylinder containing the stimulus mouse (cylinder scores). This raises the question of which type of measurements are best for assessing sociability. We assessed the test-retest reliability and ecological validity of chamber and cylinder scores. Compared with chamber scores, cylinder scores showed higher correlations between test and retest measurements, and cylinder scores showed higher correlations with time spent in social interaction in a more naturalistic phase of the test. This suggests that cylinder scores are more reliable and valid measures of sociability in mouse models. Cylinder scores are reported less commonly than chamber scores, perhaps because little work has been done to establish automated software systems for measuring the former. In this study, we found that a particular automated software system performed at least as well as human raters at measuring cylinder scores. Our data indicate that cylinder scores are more reliable and valid than chamber scores, and that the former can be measured very accurately using an automated video analysis system in ASD-relevant models. Anat Rec, 2011. © 2011 Wiley-Liss, Inc.

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8. Fatemi SH, Folsom TD, Kneeland RE, Liesch SB. Metabotropic Glutamate Receptor 5 Upregulation in Children with Autism is Associated with Underexpression of Both Fragile X Mental Retardation Protein and GABAA Receptor Beta 3 in Adults with Autism. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1635-1645.

Recent work has demonstrated the impact of dysfunction of the GABAergic signaling system in brain and the resultant behavioral pathologies in subjects with autism. In animal models, altered expression of Fragile X mental retardation protein (FMRP) has been linked to downregulation of GABA receptors. Interestingly, the autistic phenotype is also observed in individuals with Fragile X syndrome. This study was undertaken to test previous theories relating abnormalities in levels of FMRP to GABAA receptor underexpression. We observed a significant reduction in levels of FMRP in the vermis of adults with autism. Additionally, we found that levels of metabotropic glutamate receptor 5 (mGluR5) protein were significantly increased in vermis of children with autism versus age and postmortem interval matched controls. There was also a significant decrease in level of GABAA receptor beta 3 (GABRβ3) protein in vermis of adult subjects with autism. Finally, we found significant increases in glial fibrillary acidic protein in vermis of both children and adults with autism when compared with controls. Taken together, our results provide further evidence that altered FMRP expression and increased mGluR5 protein production potentially lead to altered expression of GABAA receptors. Anat Rec,, 2011. © 2011 Wiley-Liss, Inc.

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9. Lin RCS. Special Issue : New Concepts in Developing Brain Disorders—Autism. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1613-1614.

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10. Moran MM, Nummela S, Thewissen JGM. Development of the Skull of the Pantropical Spotted Dolphin (Stenella attenuata). The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1743-1756.

We describe the bony and cartilaginous structures of five fetal skulls of Stenella attenuata (pantropical spotted dolphin) specimens. The specimens represent early fetal life as suggested by the presence of rostral tactile hairs and the beginnings of skin pigmentation. These specimens exhibit the developmental order of ossification of the intramembranous and endochondral elements of the cranium as well as the functional and morphological development of specific cetacean anatomical adaptations. Detailed observations are presented on telescoping, nasal anatomy, and middle ear anatomy. The development of the middle ear ossicles, ectotympanic bone, and median nasal cartilage is of interest because in the adult these structures are morphologically different from those in land mammals. We follow specific cetacean morphological characteristics through fetal development to provide insight into the form and function of the cetacean body plan. Combining these data with fossil evidence, it is possible to overlie ontogenetic patterns and discern evolutionary patterns of the cetacean skull. Anat Rec, 2011. © 2011 Wiley-Liss, Inc.

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11. Page DT. A Candidate Circuit Approach to Investigating Autism. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1671-1684.

A major problem in understanding mechanisms of pathogenesis in autism spectrum disorder (ASD) is deciphering how risk factors act via the brain to influence the behavioral symptoms of this disorder. We may start to bridge this gap in our understanding by systematically examining the structure and function of cell types that make up circuits underlying behavioral endophenotypes in animal models for ASD. A confluence of advances in basic behavioral neurobiology, in ASD mechanisms and animal models, and in genetic tools for imaging and manipulating brain circuits will make this possible. Through a process of elimination of candidates and comparison across models, we may hope to understand how ASD risk factors influence the development and function of neural circuitry at the level of genetically defined cell types. As an example of how this candidate circuit approach may be applied to investigating ASD, here I focus on social behavior as an endophenotype, and I discuss recent findings regarding the development and function of the oxytocin system, which is implicated in both normal social behavior and ASD pathogenesis. I stress the importance of a collaborative, multidisciplinary approach to probing candidate cell types and circuits across mouse models of ASD. Anat Rec,, 2011. © 2011 Wiley-Liss, Inc.

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12. Rodriguez-Porcel F, Green D, Khatri N, Harris SS, May WL, Lin RCS, Paul IA. Neonatal Exposure of Rats to Antidepressants Affects Behavioral Reactions to Novelty and Social Interactions in a Manner Analogous to Autistic Spectrum Disorders. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1726-1735.

We have demonstrated that neonatal exposure to selective serotonin reuptake inhibitors has lasting effects on behavior and serotonergic neurons in Long Evans rats. Hyperserotoninemia and altered sensory processing are reported in autistic spectrum disorders (ASD). We hypothesized that early life exposure to SSRIs alters sensory processing, disrupts responses to novelty, and impairs social interactions in a manner similar to that observed in ASD. Male and female Long-Evans rat pups were administered citalopram, buproprion, fluoxetine, or saline from postnatal day (P) 8–21. Rats were tested for response to a novel tone before weaning (P25). Later, rats were tested 2× for response to a novel object (P39), and to a novel conspecific (P78, P101). In addition, rats were assessed for juvenile play behaviors (P32–P34) and later, we assessed sexual response to an estrus female in male rats (P153–184). Antidepressant exposure increased freezing after tone, diminished novel object exploration, and reduced conspecific interaction up to 3× compared to saline exposed rats. Juvenile play was profoundly reduced in antidepressant-exposed males when compared to saline exposed groups. Exposure to the SSRIs, but not bupropion disrupted male sexual behaviors. Moreover, specific male responses to female proceptive behaviors were disrupted in SSRI, but not bupropion exposed rats. We conclude that neonatal exposure to antidepressants in rats results in sensory and social abnormalities that parallel many of those reported in ASD. Anat Rec,, 2011. © 2011 Wiley-Liss, Inc.

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13. Silva-Junior GO, Aguila MB, Mandarim-de-Lacerda CA. Insights Into Coronary Artery Development in Model of Maternal Protein Restriction in Mice. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1757-1764.

Programming of fetal development is considered to be an important risk factor for noncommunicable diseases of adulthood, including coronary heart disease (CHD). Aiming to investigate the association between maternal nutrition and the development of the coronary arteries (CAs) in staged mice embryos, C57BL/6 mice embryos from Stages 16 to 23 were taken from mothers fed a normal protein (NP) or low protein (LP) diet, and the CA were studied. Although the LP embryos had lower masses, they had faster heart growth rates when compared with the NP embryos. The subepicardial plexuses were observed earlier in the NP embryos (Stage 20) than in the LP ones (Stage 22 ; P < 0.01). Apoptotic nuclei were seen around the aortic peritruncal ring beginning at Stage 18 in the NP and LP embryos. FLK1+ (fetal liver kinase 1 = VEGF-r2 or vascular endothelial growth factor receptor 2) cells had a homogeneous distribution in the NP embryos as early as Stage 18, whereas a similar distribution in the LP embryos was only seen at Stages 22 and 23. Maternal protein restriction in mice leads to a delay in the growth of the heart in the embryonic period modifying the development of the subepicardial peritruncal plexus and the apoptosis in the future coronary orifice region. Anat Rec, 2011. © 2011 Wiley-Liss, Inc.

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14. Tanaka K, Hayakawa T, Maeda S, Kuwahara-Otani S, Seki M. Distribution and Ultrastructure of Afferent Fibers in the Parietal Peritoneum of the Rat. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1736-1742.

The distribution and the ultrastructure of afferent fibers innervating the parietal peritoneum in the rat was studied with immunohistochemistry using an antiserum against the neuronal marker protein gene product 9.5. The immunoreactive fibers were distributed throughout the peritoneum. They generally ran straight and parallel to the intercostal nerves running in the abdominal muscles underlying the peritoneum. They sometimes branched and terminated by forming club-like endings. The number of nerve endings on the peritoneal surface was 3.25 ± 1.66 mm−2. Electron microscopic observations revealed both unmyelinated and myelinated nerve fibers. The unmyelinated fibers were thin and about 1 μm in diameter. Their endings formed slight swellings located just inside the peritoneal cell layer. The myelinated fibers often formed a bundle that was composed of two or three nerve fibers. Each myelinated fiber kept in contact with a Shwann cell and projected toward the peritoneal cavity. Finally, they penetrated the peritoneal cell layer to reach the peritoneal cavity. These fibers then made contacts with the peritoneal cells and became free from the myelin sheath. The ending had a club-like shape covered with collagen fibers, and contained many neurofilaments, a few mitochondria, but no synaptic vesicles. These results suggest that since the sensory endings are exposed at the peritoneal cavity, the sensory fibers are highly sensitive to somatic or nociceptive stimuli. Anat Rec, 2011. © 2011 Wiley-Liss, Inc.

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15. Trowbridge S, Narboux-Nême N, Gaspar P. Genetic Models of Serotonin (5-HT) Depletion : What do They Tell Us About the Developmental Role of 5-HT ?. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1615-1623.

A large number of hyposerotonergic genetic models have been generated over the past few years. Serotonin (5-HT) depletion has been obtained via targeting of genes involved in 5-HT synthesis (Tph1 and Tph2), specification and determination of the 5-HT phenotype during development (GATA3, Pet1, and Lmx1b), and 5-HT storage or clearance (Vmat2 and SERT). Here we review these various models from a developmental perspective, beginning with a description of the sources of 5-HT during development. We then summarize the neurological and behavioral alterations that have been observed in the genetic hyposerotonergic models. Although these models appear to have normal brain development and do not exhibit any gross morphological defects, problems in somatic growth and physiological functions have been observed. Abnormal adult behavior is also seen, although whether it results from depletion of 5-HT during development or functional 5-HT deficiencies in adult life remains unclear. Evidence from these hyposerotonergic models suggests that the developing brain may not need 5-HT for the establishment of general organization and structure. However, central 5-HT appears to be necessary for postnatal body growth, maturation of respiratory and vegetative control, and possibly for the development of normal adult behavior. Anat Rec, 2011. © 2011 Wiley-Liss, Inc.

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16. Zhang J, Darling RD, Paul IA, Simpson KL, Chen K, Shih JC, Lin RCS. Altered Expression of Tyrosine Hydroxylase in the Locus Coeruleus Noradrenergic System in Citalopram Neonatally Exposed Rats and Monoamine Oxidase A Knock Out Mice. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1685-1697.

In rodents, noradrenergic (NE) locus coeruleus (LC) neurons are well known to express tyrosine hydroxylase (TH) immunoreactivity. However, due to its very low enzyme activity, NE cortical fibers do not typically express TH immunoreactivity, thus dopamine-β-hydroxylase (DBH) immunoreactivity is commonly utilized as a marker for NE cortical fibers. In this study, we performed double and/or triple immunofluorescent staining using antibodies against TH, DBH, and/or norepinephrine transporter (NET) to investigate the altered NE TH expression of cortical fibers in citalopram (CTM)-exposed rats and monoamine oxidase (MAO) A knock out (KO) mice. We have noted the following novel findings : (1) neonatal exposure to the selective serotonin reuptake inhibitor (SSRI) CTM enhanced NE TH immunoreactive fibers throughout the entire neocortex, and a few of them appeared to be hypertrophic ; (2) slightly enhanced NE cortical TH immunoreactive fibers were also noted in MAO A KO mice, and many of them revealed varicosities compared with the rather smooth NE cortical TH immunoreactive fibers in wild-type (WT) mice ; (3) LC dendrites of MAO A KO mice exhibited beaded morphology compared with the smooth LC dendrites in WT mice. Our findings suggest that both genetic and environmental factors during early development may play a critical role in the regulation and proper function of NE TH expression in the neocortex. Anat Rec, 2011. © 2011 Wiley-Liss, Inc.

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17. Corrigendum. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1611-1611.

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18. Corrigendum. The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology ;2011 ;294(10):1612-1612.

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