Maturation Of Circuits Research Articles

Ftz-f1 and Hr39 opposing roles on EcR expression during Drosophila mushroom body neuron remodeling

Developmental axon pruning is a general mechanism that is required for maturation of neural circuits. During Drosophila metamorphosis, the larval-specific dendrites and axons of early γ neurons of the mushroom bodies are pruned and replaced by adult-specific processes. We found that the nuclear receptor ftz-f1 is required for this pruning, activates expression of the steroid hormone receptor EcR-B1, whose activity is essential for γ remodeling, and represses expression of Hr39, an ftz-f1 homologous gene. If inappropriately expressed in the γ neurons, HR39 inhibits normal pruning, probably by competing with endogenous FTZ-F1, which results in decreased EcR-B1 expression. EcR-B1 was previously identified as a target of the TGFβ signaling pathway. We found that the ftz-f1 and Hr39 pathway apparently acts independently of TGFβ signaling, suggesting that EcR-B1 is the target of two parallel molecular pathways that act during γ neuron remodeling.

Multiple roles of the Rho GEF ephexin1 in synapse remodeling

Synapse remodeling, which involves changes in the synaptic structure and their molecular composition, is required for the maturation and refinement of neural circuits. Although synapse remodeling is known to be tightly dependent on the assembly of local actin cytoskeleton, how actin directs the structural changes of synapse and targeting of synaptic proteins are not fully understood. Recently, we identified ephexin1, a Rho guanine nucleotide exchange factor (GEF) that regulates actin dynamics, plays an essential role in the maturation and functioning of the mammalian neuromuscular junction (NMJ). We showed that ephexin1 regulates the synaptic organization of the neurotransmitter receptor acetylcholine receptor (AChR) clusters through RhoA-dependent actin reorganization. Interestingly, ephexin1 has been implicated in the regulation of postsynaptic structure as well as the presynaptic vesicle release at various types of synapses. Our findings thus establish a novel function of ephexin1 in synapse remodeling through regulating the synaptic targeting of neurotransmitter receptors, revealing a versatile role of ephexin1 at synapses.

Laminar-Specific Maturation of GABAergic Transmission and Susceptibility to Visual Deprivation Are Related to Endocannabinoid Sensitivity in Mouse Visual Cortex

The developmental period when neuronal responses are modified by visual experience is reported to start and end earlier in layer 4 than in layer 2/3 of the visual cortex, and the maturation of GABAergic inhibitory circuits is suggested to determine the timing of this period. Here, we examine whether the laminar difference in such timing corresponds to a difference in the time course of the functional maturation of GABAergic synaptic transmission to star pyramidal and pyramidal cells in layers 4 and 2/3, respectively, of the mouse visual cortex and whether the development of the strength of GABAergic transmission is affected by visual deprivation in a laminar-specific manner. Our analysis of developmental changes in inhibitory postsynaptic currents of star pyramidal and pyramidal cells evoked by electrical stimulation of afferents or action potentials of fast-spiking GABAergic neurons revealed that there was a sequential maturation of GABAergic function from layers 4 to 2/3. The maturation of inhibition in layer 4 occurred at postnatal week 3, which preceded by 1 week that of layer 2/3. Visual deprivation by dark rearing arrested the functional development of GABAergic transmission in layer 2/3, whereas dark rearing was not so effective in layer 4. GABAergic synapses in layer 2/3 were sensitive to an agonist for cannabinoid type 1 receptors and not normally matured in receptor knock-out mice, whereas those in layer 4 were not so. These results suggest laminar-specific maturation of inhibition and susceptibility to visual deprivation, which may be related to the laminar difference in sensitivity to endocannabinoids.

CREB-Dependent Regulation of GAD65 Transcription by BDNF/TrkB in Cortical Interneurons

In the cerebral cortex, the functional output of projection neurons is fine-tuned by inhibitory neurons present in the network, which use γ-aminobutyric acid (GABA) as their main neurotransmitter. Previous studies have suggested that the expression levels of the rate-limiting GABA synthetic enzyme, GAD65, depend on brain derived neurotrophic factor (BDNF)/TrkB activation. However, the molecular mechanisms by which this neurotrophic factor and its receptor controls GABA synthesis are still unknown. Here, we show a direct regulation of the GAD65 gene by BDNF-TrkB signaling via CREB in cortical interneurons. Conditional ablation of TrkB in cortical interneurons causes a cell-autonomous decrease in the synaptically enriched GAD65 protein and its transcripts levels, suggesting that transcriptional regulation of the GAD65 gene is altered. Dissection of the intracellular pathway that underlies this process revealed that BDNF/TrkB signaling controls the transcription of GAD65 in a Ras-ERK-CREB-dependent manner. Our study reveals a novel molecular mechanism through which BDNF/TrkB signaling may modulate the maturation and function of cortical inhibitory circuits.

P.6.c.001 Cortisol levels and MDMA-induced memory impairment

The present study was undertaken to evaluate the immediate and long-term effects of a single-day exposure to 5-Azacytidine (5-AzaC), a DNA methyltransferase inhibitor, on neurobehavioral abnormalities in mice. Our findings suggest that the 5-AzaC treatment significantly inhibited DNA methylation, impaired extracellular signal-regulated kinase (ERK1/2) activation and reduced expression of the activity-regulated cytoskeleton-associated protein (Arc). These events lead to the activation of caspase-3 (a marker for neurodegeneration) in several brain regions, including the hippocampus and cortex, two brain areas that are essential for memory formation and memory storage, respectively. 5-AzaC treatment of P7 mice induced significant deficits in spatial memory, social recognition, and object memory in adult mice and deficits in long-term potentiation (LTP) in adult hippocampal slices. Together, these data demonstrate that the inhibition of DNA methylation by 5-AzaC treatment in P7 mice causes neurodegeneration and impairs ERK1/2 activation and Arc protein expression in neonatal mice and induces behavioral abnormalities in adult mice. DNA methylation-mediated mechanisms appear to be necessary for the proper maturation of synaptic circuits during development, and disruption of this process by 5-AzaC could lead to abnormal cognitive function.

Differential roles for CaM kinases in mediating excitation–morphogenesis coupling during formation and maturation of neuronal circuits

Ca(2+) -regulated reorganization of actin cytoskeleton is one of the key cell biological events that critically regulate neuronal morphogenesis during circuit formation, spinogenesis during synapse development, and activity-dependent structural plasticity at mature synapses. However, it remains unclear as to what extent the underlying Ca(2+) signaling processes are shared or segregated. Here, we present evidence from the literature that collectively begins to suggest that distinct calmodulin-dependent protein kinase (CaMK) isoforms are differentially expressed in time and in subcellular space, and thus may be selectively activated and engaged by distinct upstream stimuli; each CaMK isoform, in turn, couples to related, but separate, cytoskeletal and transcriptional regulatory pathways, dependent on its abundance or physical proximity with either the upstream or downstream signaling complexes. These signal transduction characteristics provide the basis for better understanding the role of excitation-morphogenesis coupling via multiple CaMKs during neuronal circuit and synapse formation.

Repeated third trimester-equivalent ethanol exposure inhibits long-term potentiation in the hippocampal CA1 region of neonatal rats

Developmental ethanol exposure damages the hippocampus, causing long-lasting learning and memory deficits. Synaptic plasticity mechanisms (e.g., long-term potentiation [LTP]) contribute to synapse formation and refinement during development. We recently showed that acute ethanol exposure inhibits glutamatergic synaptic transmission and N-methyl- d-aspartate receptor (NMDAR)-dependent LTP in the CA1 hippocampal region of postnatal day (P)7–9 rats. The objective of this study was to further characterize the effect of ethanol on LTP in the developing CA1 hippocampus during the third trimester equivalent. To more closely model human ethanol exposure during this period, rat pups were exposed to ethanol vapor (2 or 4.5 g/dL in air, serum ethanol concentrations = 96.6–147.2 or 322–395.6 mg/dL) from P2–9 (4 h/d). Brain slices were prepared immediately after the end of the 4-h exposure on P7–9 and extracellular electrophysiological recordings were performed 1–7 h later under ethanol-free conditions to model early withdrawal. LTP was not different than group-matched controls in the 96.6–147.2 mg/dL group; however, it was impaired in the 322–395.6 mg/dL group. Neither α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR)/NMDAR function nor glutamate release were affected in the 322–395.6 mg/dL ethanol exposure group. These data suggest that repeated in vivo exposure to elevated ethanol doses during the third trimester-equivalent period impairs synaptic plasticity, which may alter maturation of hippocampal circuits and ultimately contribute to the long-lasting cognitive deficits associated with fetal alcohol spectrum disorders.

Ontogenesis and migration of metallothionein I/II-containing glial cells in the human telencephalon during the second trimester

Metallothioneins (MT) belong to a widespread family of proteins characterized by a high metal content (mainly Cu 2+ and Zn 2+) and by the presence of cysteine residues. The expression of metallothionein I–II (MT I/II), glial fibrillary acid protein (GFAP), and vimentin was examined in a series of 16 developing human brains of the second trimester. The brains of a stillborn/newborn individual and two postnatal individuals were studied for comparison. MT I/II-containing cells became consistently and clearly visible only from gestational week 21 onwards. On the other hand, several densely packed GFAP- and vimentin-containing elements were evident in the neuroepithelium at several periventricular locations and in the subventricular zone of all fetuses of the series. GFAP- and vimentin-containing elements also entered the intermediate plate, but only a few elements were evident in the outer layers of the maturing cortex. The relatively late onset of MT I/II expression and their distribution are discussed in relation to the uptake of trace elements during the last trimester of pregnancy, and the role of astrocytes in neuronal guidance and maturation of cortical circuits.

Synaptic maturation of the Xenopus retinotectal system: Effects of brain‐derived neurotrophic factor on synapse ultrastructure

Synaptogenesis is a dynamic process that involves structural changes in developing axons and dendrites as synapses form and mature. The visual system of Xenopus laevis has been used as a model to study dynamic changes in axons and dendrites as synapses form in the living brain and the molecular mechanisms that control these processes. Brain-derived neurotrophic factor (BDNF) contributes to the establishment and refinement of visual connectivity by modulating retinal ganglion cell (RGC) axon arborization and presynaptic differentiation. Here, we have analyzed the ultrastructural organization of the Xenopus retinotectal system to understand better the maturation of this synaptic circuit and the relation between synapse ultrastructure and the structural changes in connectivity that take place in response to BDNF. Expression of yellow fluorescent protein (YFP) followed by preembedding immunoelectron microscopy was used to identify RGC axons specifically in living tadpoles. Injection of recombinant BDNF was used to alter endogenous BDNF levels acutely in the optic tectum. Our studies reveal a rapid transition from a relatively immature synaptic circuit in which retinotectal synapses are formed on developing filopodial-like processes to a circuit in which RGC axon terminals establish synapses with dendritic shafts and spines. Moreover, our studies reveal that BDNF treatment increases the number of spine synapses and docked vesicle number at YFP-identified synaptic sites within 24 hours of treatment. These fine structural changes at retinotectal synapses are consistent with the role that BDNF plays in the functional maturation of synaptic circuits and with dynamic, rapid changes in synaptic connectivity during development.

Possible role of cooperative action of NMDA receptor and GABA function in developmental plasticity

The maturation of cortical circuits is strongly influenced by sensory experience during a restricted critical period. The developmental alteration in the subunit composition of NMDA receptors (NMDARs) has been suggested to be involved in regulating the timing of such plasticity. However, this hypothesis does not explain the evidence that enhancing GABA inhibition triggers a critical period in the visual cortex. Here, to investigate how the NMDAR and GABA functions influence synaptic organization, we examine an spike-timing-dependent plasticity (STDP) model that incorporates the dynamic modulation of LTP, associated with the activity- and subunit-dependent desensitization of NMDARs, as well as the background inhibition by GABA. We show that the competitive interaction between correlated input groups, required for experience-dependent synaptic modifications, may emerge when both the NMDAR subunit expression and GABA inhibition reach a sufficiently mature state. This may suggest that the cooperative action of these two developmental mechanisms can contribute to embedding the spatiotemporal structure of input spikes in synaptic patterns and providing the trigger for experience-dependent cortical plasticity.

Experience-Dependent Changes in Excitatory and Inhibitory Receptor Subunit Expression in Visual Cortex

Experience-dependent development of visual cortex depends on the balance between excitatory and inhibitory activity. This activity is regulated by key excitatory (NMDA, AMPA) and inhibitory (GABAA) receptors. The composition of these receptors changes developmentally, affecting the excitatory–inhibitory (E/I) balance and synaptic plasticity. Until now, it has been unclear how abnormal visual experience affects this balance. To examine this question, we measured developmental changes in excitatory and inhibitory receptor subunits in visual cortex following normal visual experience and monocular deprivation. We used Western blot analysis to quantify expression of excitatory (NR1, NR2A, NR2B, GluR2) and inhibitory (GABAAα1, GABAAα3) receptor subunits. Monocular deprivation promoted a complex pattern of changes in receptor subunit expression that varied with age and was most severe in the region of visual cortex representing the central visual field. To characterize the multidimensional pattern of experience-dependent change in these synaptic mechanisms, we applied a neuroinformatics approach using principal component analysis. We found that monocular deprivation (i) causes a large portion of the normal developmental trajectory to be bypassed, (ii) shifts the E/I balance in favor of more inhibition, and (iii) accelerates the maturation of receptor subunits. Taken together, these results show that monocularly deprived animals have an abnormal balance of the synaptic machinery needed for functional maturation of cortical circuits and for developmental plasticity. This raises the possibility that interventions intended to treat amblyopia may need to address multiple synaptic mechanisms to produce optimal recovery.

The Development of Phasic and Tonic Inhibition in the Rat Visual Cortex

Gamma-aminobutyric acid (GABA)-ergic inhibition is important in the function of the visual cortex. In a previous study, we reported a developmental increase in GABA(A) receptor-mediated inhibition in the rat visual cortex from 3 to 5 weeks of age. Because this developmental increase is crucial to the regulation of the induction of long-term synaptic plasticity, in the present study we investigated in detail the postnatal development of phasic and tonic inhibition. The amplitude of phasic inhibition evoked by electrical stimulation increased during development from 3 to 8 weeks of age, and the peak time and decay kinetics of inhibitory postsynaptic potential (IPSP) and current (IPSC) slowed progressively. Since the membrane time constant decreased during this period, passive membrane properties might not be involved in the kinetic changes of IPSP and IPSC. Tonic inhibition, another mode of GABA(A) receptor-mediated inhibition, also increased developmentally and reached a plateau at 5 weeks of age. These results indicate that the time course of the postnatal development of GABAergic inhibition matched well that of the functional maturation of the visual cortex. Thus, the present study provides significant insight into the roles of inhibitory development in the functional maturation of the visual cortical circuits.

Developmental trajectories of prefrontal cortical circuits

Event Abstract Back to Event Developmental trajectories of prefrontal cortical circuits David Lewis1* 1 University of Pittsburgh, United States The maturation of behaviors dependent on prefrontal cortical circuitry in primates is protracted and complex, and is associated with substantial refinements in both structural and functional markers of excitatory and inhibitory neurotransmission. For example, the levels of pre-synaptic (e.g., GABA membrane transporter) and post-(e.g., GABA-A receptor subunits) synaptic proteins that regulate GABA neurotransmission from chandelier GABA neurons to the axon initial segment (AIS) of pyramidal neurons undergo marked changes perinatally and during adolescence. Furthermore, proteins that are involved in regulating synapse structure and receptor localization at the AIS (e.g., ankyrin-G, ßIV spectrin, and gephyrin) exhibit distinct developmental trajectories, with different types of changes occurring perinatally and during adolescence. In concert with other data, these findings reveal a two-phase developmental process of GABA synaptic stability and neurotransmission at chandelier cell inputs to pyramidal neurons that might contribute to the protracted maturation of cognitive processes dependent on prefrontal circuitry. Consistent with these observations, the expression of GABA-A receptor α1 and α2 subunits, which confer different functional properties to GABA-A receptors progressively increase and decrease, respectively, throughout postnatal development including adolescence. Furthermore, as predicted by the different functional properties of α1-containing versus α2-containing GABA-A receptors, the duration of inhibitory currents was significantly shorter in post-pubertal than in pre-pubertal animals. Thus, the developmental shift in GABA-A receptor α subunit expression continues through adolescence, inducing a marked change in the kinetics of GABA neurotransmission. In contrast, the functional maturation of excitatory synapses to pyramidal neurons appears to be complete prior to adolescence, although the number of these synapses is substantially reduced during adolescence. Together these findings support a complex process of circuit maturation in the primate prefrontal cortex, suggesting that different components of these circuits have specific sensitive periods when they may be more liable to disruption from environmental exposures or to enrichment from experience. Conference: The 20th Annual Rotman Research Institute Conference, The frontal lobes, Toronto, Canada, 22 Mar - 26 Mar, 2010. Presentation Type: Oral Presentation Citation: Lewis D (2010). Developmental trajectories of prefrontal cortical circuits. Conference Abstract: The 20th Annual Rotman Research Institute Conference, The frontal lobes. doi: 10.3389/conf.fnins.2010.14.00002 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 24 Jun 2010; Published Online: 24 Jun 2010. * Correspondence: David Lewis, University of Pittsburgh, Pittsburgh, United States, lewisda@upmc.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers David Lewis Google David Lewis Google Scholar David Lewis PubMed David Lewis Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Visual Experience–Independent Functional Expression of NMDA Receptors in the Developing Rabbit Retina

Activation of the NMDA glutamate receptors is critical for the initiation of synaptic plasticity. In the developing rat retina, NMDA receptor function has been associated with visual experience, though the light-dependent regulation of the subunit composition of the NMDA receptors is controversial. In the present study, the functional expression of NMDA receptors in the developing rabbit retina was characterized and the impact of light deprivation on how the subunit composition of NMDA receptors is regulated was examined. Antibodies against NR1 and NR2A/B were used to examine neonatal expression patterns of the NMDA receptor subunits. Furthermore, the functional NMDA receptors were mapped using the agmatine (AGB) activation assay. Although NR1 and NR2A/B subunit immunoreactivity was prominently detectable only immediately after birth, AGB activation assay showed that functional NMDA receptors could be identified as early as embryonic day 21. No significant difference was observed between normal- and dark-reared animals in terms of their NR1 and NR2A/B expression. In addition, a comparison of AGB permeation between normal- and dark-reared animals showed no difference in functional expression of NMDA receptors. These results indicate that NMDA receptors participate in the synaptic maturation of retinal circuits during the early stages of development but that the functional NMDA receptors, including their subunit composition, in the developing rabbit retina are independent of the rabbit's visual experience.

Adult consequences of post-weaning high fat feeding on the limbic-HPA axis of female rats.

The peripubertal period is critical for the final maturation of circuits controlling energy homeostasis and stress response. However, the consequence of juvenile fat consumption on adult physiology is not clear. This study analyzed the adult consequences of post-weaning fat feeding on limbic-hypothalamic-pituitary-adrenal (HPA) axis components and on metabolic regulators of female rats. Wistar rats were fed either a high fat (HF) diet or the normal chow from weaning to puberty or to 3 months of age. Additional groups crossed their diets at puberty onset. Plasma leptin, insulin, and corticosterone levels were determined by radioimmunoassay and their brain receptors by western blot analysis. Adult HF-fed animals though not overweight, had higher corticosterone and reduced glucocorticoid receptor levels in the hypothalamus and hippocampus, compared to the controls. The alterations in HPA axis emerged already at puberty onset. Leptin receptor levels in the hypothalamus were reduced only by continuous fat feeding from weaning to adulthood. The pre-pubertal period appeared more vulnerable to diet-induced alterations in adulthood than the post-pubertal one. Switching from fat diet to normal chow at puberty onset restored most of the diet-induced alterations in the HPA axis. The corticosteroid circuit rather than the leptin or insulin system appears as the principal target for the peripubertal fat diet-induced effects in adult female rats.

Changes in mid‐to‐late latency auditory evoked reponses in the chicken during neural maturation

Utilizing the special advantages offered by the protracted maturation of neural circuits in chicken forebrain this study investigates the functional consequence of maturation using auditory evoked response potentials (AERPs) in behaving animals. Repeated measures AERP recordings were undertaken between weeks 1 and 8 posthatch. Quantitative analysis revealed a significant decrease in amplitude of the positive AERP component and a decrease in latency of the negative AERP component with maturation. AERPs were also utilized to investigate perturbed maturation via the induction of chemically induced hypothyroidism. Results from this study showed that the induction of late onset hypothyroidism produces measurable effects on the chicken AERP consistent with perturbation in maturation of neuronal circuits and synapses. This suggests that AERPs may be useful noninvasive functional measures of brain maturation that can be used to study the effects of endogenous or exogenous factors on brain maturation in the chicken. Since human brain also exhibits a protracted maturation period the availability of a well-characterized animal model for protracted brain maturation provides an opportunity to identify molecules, genes and environmental factors that are important in the regulation of maturation. The protracted maturation of neuronal circuits observed in chicken forebrain offers such a model.

Normal development of brain circuits.

Spanning functions from the simplest reflex arc to complex cognitive processes, neural circuits have diverse functional roles. In the cerebral cortex, functional domains such as visual processing, attention, memory, and cognitive control rely on the development of distinct yet interconnected sets of anatomically distributed cortical and subcortical regions. The developmental organization of these circuits is a remarkably complex process that is influenced by genetic predispositions, environmental events, and neuroplastic responses to experiential demand that modulates connectivity and communication among neurons, within individual brain regions and circuits, and across neural pathways. Recent advances in neuroimaging and computational neurobiology, together with traditional investigational approaches such as histological studies and cellular and molecular biology, have been invaluable in improving our understanding of these developmental processes in humans in both health and illness. To contextualize the developmental origins of a wide array of neuropsychiatric illnesses, this review describes the development and maturation of neural circuits from the first synapse through critical periods of vulnerability and opportunity to the emergent capacity for cognitive and behavioral regulation, and finally the dynamic interplay across levels of circuit organization and developmental epochs.

S4.3 Neurturin and GDNF effects on maturation and plasticity of urogenital innervation

Many of the secretory and motor functions of the urogenital tract are controlled by pelvic autonomic ganglia, which contain both sympathetic and parasympathetic neurons. This co-location of chemically and functionally distinct pathways that receive inputs from different spinal levels leads to interesting questions regarding the cues that control their development, maintenance and responses to injury. In addition, these reflex circuits change dramatically after birth, when voluntary control of voiding develops and later when rising levels of gonadal hormones drive the maturation of neuronal circuits involved in reproductive behaviours.

Neonatal overfeeding leads to developmental programming of adult obesity: you are what you ate

How might perinatal nutrition affect our health and disease susceptibility throughout life? Since Hales & Barker (1992) enunciated the thrifty phenotype hypothesis some 18 years ago, a range of studies in humans and animal models have outlined the effects of nutrient restriction or excess during fetal and neonatal life and the consequences of such manipulation on the ‘developmental programming’ of the metabolic syndrome (see Armitage et al. 2004). Key to the developmental programming concept is that adaptations to environmental perturbations during periods of developmental plasticity can have longstanding impact on adult health. Given the current epidemic of childhood and adult obesity, the role of the postnatal nutritional environment in programming obesity and related disease is a growing focus for many studies. The actions of appetite controlling hormones at sites within the central nervous system are of particular interest as these may underlie programmed obesity. To date, a wealth of information is provided by studies in rodents showing that postnatal overfeeding, or administration of hormones consistent with a state of overfeeding, permanently alters the maturation of hypothalamic appetite circuits (reviewed by Plagemann, 2005).

Functional disturbances within frontostriatal circuits across multiple childhood psychopathologies.

Neuroimaging studies of healthy individuals inform us about the normative maturation of the frontostriatal circuits that subserve self-regulatory control processes. Findings from these studies can be used as a reference frame against which to compare the aberrant development of these processes in individuals across a wide range of childhood psychopathologies. The authors reviewed extensive neuroimaging evidence for the presence of abnormalities in frontostriatal circuits in children and adults with Tourette's syndrome and obsessive-compulsive disorder (OCD) as well as a more limited number of imaging studies of adolescents and adults with anorexia nervosa or bulimia nervosa that, together, implicate dysregulation of frontostriatal control systems in the pathogenesis of these eating disorders. The presence of an impaired capacity for self-regulatory control that derives from abnormal development of frontostriatal circuits likely interacts in similar ways with normally occurring somatic sensations and motor urges, intrusive thoughts, sensations of hunger, and preoccupation with body shape and weight to contribute, respectively, to the development of the tics of Tourette's syndrome, the obsessions of OCD, the binge eating behaviors of bulimia, and the self-starvation of anorexia. Analogous brain mechanisms in parallel frontostriatal circuits, or even in differing portions of the same frontostriatal circuit, may underlie the differing behavioral disturbances in these multiple disorders, although further research is needed to confirm this hypothesis.