SOCIAL EXPERIENCE AND REMODELING OF AMYGDALAR CIRCUITS IN RAT ADOLESCENCE
Holly Marie Moore
New York State Psychiatric Institute, New York, Ny 10032
Grant 5RC1MH088740-02 from National Institute Of Mental Health
Abstract: This application addresses broad Challenge Area 15 (Translational Science), and the Specific Challenge Topic 15-AA-101 Determining If and How Adolescent Behaviors Affect Connections in the Developing Brain. Adolescence is a developmental period associated with non-linear changes in affective and social behavior, and a rapid rise in the risk of onset for a number of psychiatric disorders. Despite the large range in social and cognitive characteristics across mammalian species, many species show similar behavioral changes during the transition from the peri-pubertal period to adulthood. This apparent behavioral homology may reflect well-conserved neurodevelopmental processes that are specific to, or differently regulated in, adolescence. Despite the potential importance of such changes to psychiatric disorders, relatively few studies have directly examined neural circuit structure during adolescence. To address this, we recently completed a quantitative tract-tracing study, showing that in the rat, prefrontal cortical (PFC) inputs to the basal amygdala (BA) undergo pruning during the period analogous to late adolescence. The remodeling of PFC inputs to the BA, and possibly similar changes in temporal cortical inputs, may be important in the adaptive maturation of affective and social behavior. Conversely, disruptions of these neurodevelopmental processes may contribute to the emergence of neuro- and psychopathology in adolescence or young adulthood. These data make clear that the study of behavioral influences on adolescent brain circuitry must first take into account ongoing developmental processes that may be intrinsic to the neural circuit of interest. Herein, we postulate that, similar to the regulation of pruning in sensory cortical circuits earlier in development, pruning of prefrontal and temporal cortical inputs to the amygdala can be modified by experience. Given that adolescence in the rat (P25-P55; see Proposal for justification of age range) is associated with increased responsiveness to peers, we propose to test the hypothesis that during adolescence, social experience modulates the structural remodeling of cortico-amygdalar circuits. Thus, following characterization of remodeling in temporal cortical inputs to the BA, we will test whether during adolescence, pruning of PFC and temporo-limbic cortical inputs to the BA can be modified by social experience. Given that BA circuits are recruited by salient appetitive or aversive events, the social conditions will range from peer/play-enriched to isolation with threat. Beginning in young ("pre") adolescence (P24) rats will be housed in one the following conditions with peers (which features vigorous play in adolescent rats), peer deprivation (housing with aged ovariectomized female), full social deprivation (single housing), or single housing with intermittent social threat (aggressive male). We will also test whether the effects of these social manipulations on cortico-amygdalar circuits are greater when experienced in adolescence relative to in adulthood. The differential effects of these social environments on cortico-amygdalar connectivity will be assessed with quantitative retrograde tracing methods. These studies will yield a more complete understanding of the structural and functional maturation of cortico-limbic circuits during adolescence. During adolescence and young adulthood, the risk for many mental illnesses increases sharply. However, the neurodevelopmental changes that may underlie this increased vulnerability are not understood. The proposed studies will begin to bridge this important gap in our knowledge. Our findings will yield a more complete understanding of adolescence as a unique, sensitive period of development for brain circuits that mediate emotional regulation and social cognition. Moreover, the findings will contribute to the development of novel strategies for preventing the psycho- and neuropathology associated with many psychiatric disorders including schizophrenia, anxiety, and substance abuse disorders
Keywords: 12-20 years old; 21+ years old; 55 kDa Erythrocyte Membrane Protein; ARHGEF5; ARHGEF5 gene; Accounting; Address; Adolescence; Adolescent; Adolescent Behavior; Adolescent Youth; Adult; Affect; Affective; Age; Amygdala; Amygdaloid Body; Amygdaloid Nucleus; Amygdaloid structure; Anxiety; Area; Behavior; Behavioral; Brain; CD71 Antigen; Caspase 1, Apoptosis-Related Cysteine Protease; Caspase 1, Apoptosis-Related Cysteine Protease (Interleukin 1, Beta, Convertase); Caspase-1; Cell Nucleus; Characteristics; Cognition; Cognitive; Common Rat Strains; Data; Deposit; Deposition; Development; Developmental Process; Disease; Disorder; Dorsal; EC 3.4.22.36; EMP55; Emotional; Encephalon; Encephalons; Entorhinal Area; Entorhinal Cortex; Environment; Erythrocyte Membrane Protein p55; Event; Expression Profiling; Expression Signature; Female; GEF5; Gene Expression; Housing; Human; Human, Adult; Human, General; ICE Protease; IL-1 beta Convertase; IL-1 beta-Converting Enzyme; IL-1b Converting Enzyme; IL1B-Convertase; IL1BC; Injection of therapeutic agent; Injections; Interleukin 1-B Converting Enzyme; Interleukin 1-Beta Convertase; Interleukin-1 Beta Converting Enzyme; Interleukin-1 Converting Enzyme; Interleukin-1beta Converting Enzyme; Knowledge; Label; Learning; MPP1 protein, human; Mammals, Rats; Man (Taxonomy); Man, Modern; Maps; Mediating; Memory; Mental disorders; Mental health disorders; Methods; Modeling; Molecular Fingerprinting; Molecular Profiling; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; Neurons; Nucleus; Optical Methods; P45; P60; PEMP; Palmitoylated Membrane Protein 1; Palmitoylated Membrane Protein 1 55kD; Pattern; Plastics; Play; Prefrontal Cortex; Prepuberal state; Process; Psychiatric Disease; Psychiatric Disorder; Psychopathology; Puberty; Rat; Rattus; Recruitment Activity; Regulation; Relative; Relative (related person); Risk; Schizophrenia; Schizophrenic Disorders; Sensory; Social Behavior; Social Conditions; Social Environment; Social Interaction; Social Perception; Social isolation; Societal Conditions; Stimulus; Structure; Structure of entorhinal cortex; Substance abuse problem; TFR1; TFRC protein, human; TIM; TIM1; Tag; Testing; Thalamic structure; Thalamus; Time; Tracer; Transferrin Receptor 1; Transferrin Receptor Protein 1; Translational Research; Translational Research Enterprise; Translational Science; Unspecified Mental Disorder; abnormal psychology; ing; abuse of substances; adolescence (12-20); adult human (21+); adult youth; aged; amygdaloid nuclear complex; behavior change; behavior influence; behavioral influence; cortico-limbic circuits; dementia praecox; deprivation; disease/disorder; emerging adult; entorhinal cortex; experience; experiment; experimental research; experimental study; human MPP1 protein; human TFRC protein; human puberty; innervation; interest; juvenile; juvenile human; male; membrane protein, palmitoylated 1, 55kDa, human; mental illness; molecuar profile; molecular signature; nerve supply; neural circuit; neural circuitry; neuronal; neuropathology; new approaches; novel approaches; novel strategies; novel strategy; p55; p90; palmitoylated erythrocyte membrane protein p55, human; peer; postnatal; prepuberty; prevent; preventing; psychological disorder; recruit; research study; schizophrenic; social; social climate; social cognition; social context; social deprivation; social group; sociobehavior; sociobehavioral; socioenvironment; substance abuse; teenage; thalamic; translation research enterprise; young adult
Relevance: Relevance: During adolescence and young adulthood, the risk for many mental illnesses increases sharply. However, the neurodevelopmental changes that may underlie this increased vulnerability are not understood. The proposed studies will begin to bridge this important gap in our knowledge. Our findings will yield a more complete understanding of adolescence as a unique, sensitive period of development for brain circuits that mediate emotional regulation and social cognition. Moreover, the findings will contribute to the development of novel strategies for preventing the psycho- and neuropathology associated with many psychiatric disorders including schizophrenia, anxiety, and substance abuse disorders
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: RFA-OD-09-003
5RC1MH088740-02 (2010): $379059
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Holly Marie Moore
SOCIAL EXPERIENCE AND REMODELING OF AMYGDALAR CIRCUITS IN RAT ADOLESCENCE
Holly Marie Moore
New York State Psychiatric Institute, Room 1914 - Unit #33, New York, Ny 10032
Grant 1RC1MH088740-01 from National Institute Of Mental Health
Abstract: This application addresses broad Challenge Area 15 (Translational Science), and the Specific Challenge Topic 15-AA-101 Determining If and How Adolescent Behaviors Affect Connections in the Developing Brain. Adolescence is a developmental period associated with non-linear changes in affective and social behavior, and a rapid rise in the risk of onset for a number of psychiatric disorders. Despite the large range in social and cognitive characteristics across mammalian species, many species show similar behavioral changes during the transition from the peri-pubertal period to adulthood. This apparent behavioral homology may reflect well-conserved neurodevelopmental processes that are specific to, or differently regulated in, adolescence. Despite the potential importance of such changes to psychiatric disorders, relatively few studies have directly examined neural circuit structure during adolescence. To address this, we recently completed a quantitative tract-tracing study, showing that in the rat, prefrontal cortical (PFC) inputs to the basal amygdala (BA) undergo pruning during the period analogous to late adolescence. The remodeling of PFC inputs to the BA, and possibly similar changes in temporal cortical inputs, may be important in the adaptive maturation of affective and social behavior. Conversely, disruptions of these neurodevelopmental processes may contribute to the emergence of neuro- and psychopathology in adolescence or young adulthood. These data make clear that the study of behavioral influences on adolescent brain circuitry must first take into account ongoing developmental processes that may be intrinsic to the neural circuit of interest. Herein, we postulate that, similar to the regulation of pruning in sensory cortical circuits earlier in development, pruning of prefrontal and temporal cortical inputs to the amygdala can be modified by experience. Given that adolescence in the rat (P25-P55; see Proposal for justification of age range) is associated with increased responsiveness to peers, we propose to test the hypothesis that during adolescence, social experience modulates the structural remodeling of cortico-amygdalar circuits. Thus, following characterization of remodeling in temporal cortical inputs to the BA, we will test whether during adolescence, pruning of PFC and temporo-limbic cortical inputs to the BA can be modified by social experience. Given that BA circuits are recruited by salient appetitive or aversive events, the social conditions will range from peer/play-enriched to isolation with threat. Beginning in young ("pre") adolescence (P24) rats will be housed in one the following conditions with peers (which features vigorous play in adolescent rats), peer deprivation (housing with aged ovariectomized female), full social deprivation (single housing), or single housing with intermittent social threat (aggressive male). We will also test whether the effects of these social manipulations on cortico-amygdalar circuits are greater when experienced in adolescence relative to in adulthood. The differential effects of these social environments on cortico-amygdalar connectivity will be assessed with quantitative retrograde tracing methods. These studies will yield a more complete understanding of the structural and functional maturation of cortico-limbic circuits during adolescence. During adolescence and young adulthood, the risk for many mental illnesses increases sharply. However, the neurodevelopmental changes that may underlie this increased vulnerability are not understood. The proposed studies will begin to bridge this important gap in our knowledge. Our findings will yield a more complete understanding of adolescence as a unique, sensitive period of development for brain circuits that mediate emotional regulation and social cognition. Moreover, the findings will contribute to the development of novel strategies for preventing the psycho- and neuropathology associated with many psychiatric disorders including schizophrenia, anxiety, and substance abuse disorders
Keywords: 12-20 years old; 21+ years old; 55 kDa Erythrocyte Membrane Protein; ARHGEF5; ARHGEF5 gene; Accounting; Address; Adolescence; Adolescent; Adolescent Behavior; Adolescent Youth; Adult; Affect; Affective; Age; Amygdala; Amygdaloid Body; Amygdaloid Nucleus; Amygdaloid structure; Anxiety; Area; Behavior; Behavioral; Brain; CD71 Antigen; Caspase 1, Apoptosis-Related Cysteine Protease; Caspase 1, Apoptosis-Related Cysteine Protease (Interleukin 1, Beta, Convertase); Caspase-1; Cell Nucleus; Characteristics; Cognition; Cognitive; Common Rat Strains; Data; Deposit; Deposition; Development; Developmental Process; Disease; Disorder; Dorsal; EC 3.4.22.36; EMP55; Emotional; Encephalon; Encephalons; Entorhinal Area; Entorhinal Cortex; Environment; Erythrocyte Membrane Protein p55; Event; Expression Profiling; Expression Signature; Female; GEF5; Gene Expression; Housing; Human; Human, Adult; Human, General; ICE Protease; IL-1 beta Convertase; IL-1 beta-Converting Enzyme; IL-1b Converting Enzyme; IL1B-Convertase; IL1BC; Injection of therapeutic agent; Injections; Interleukin 1-B Converting Enzyme; Interleukin 1-Beta Convertase; Interleukin-1 Beta Converting Enzyme; Interleukin-1 Converting Enzyme; Interleukin-1beta Converting Enzyme; Knowledge; Label; Learning; MPP1 protein, human; Mammals, Rats; Man (Taxonomy); Man, Modern; Maps; Mediating; Memory; Mental disorders; Mental health disorders; Methods; Modeling; Molecular Fingerprinting; Molecular Profiling; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; Neurons; Nucleus; Optical Methods; P45; P60; PEMP; Palmitoylated Membrane Protein 1; Palmitoylated Membrane Protein 1 55kD; Pattern; Plastics; Play; Prefrontal Cortex; Prepuberal state; Process; Psychiatric Disease; Psychiatric Disorder; Psychopathology; Puberty; Rat; Rattus; Recruitment Activity; Regulation; Relative; Relative (related person); Risk; Schizophrenia; Schizophrenic Disorders; Sensory; Social Behavior; Social Conditions; Social Environment; Social Interaction; Social Perception; Social isolation; Societal Conditions; Stimulus; Structure; Structure of entorhinal cortex; Substance abuse problem; TFR1; TFRC protein, human; TIM; TIM1; Tag; Testing; Thalamic structure; Thalamus; Time; Tracer; Transferrin Receptor 1; Transferrin Receptor Protein 1; Translational Research; Translational Research Enterprise; Translational Science; Unspecified Mental Disorder; abnormal psychology; abuse of substances; adolescence (12-20); adult human (21+); aged; amygdaloid nuclear complex; behavior change; behavior influence; behavioral influence; cortico-limbic circuits; dementia praecox; deprivation; disease/disorder; emerging adult; entorhinal cortex; experience; experiment; experimental research; experimental study; human MPP1 protein; human TFRC protein; human puberty; innervation; interest; juvenile; juvenile human; male; membrane protein, palmitoylated 1, 55kDa, human; mental illness; molecuar profile; molecular signature; nerve supply; neural circuit; neural circuitry; neuronal; neuropathology; new approaches; novel approaches; novel strategies; novel strategy; p55; p90; palmitoylated erythrocyte membrane protein p55, human; peer; postnatal; prepuberty; prevent; preventing; psychological disorder; public health relevance; recruit; research study; schizophrenic; social; social climate; social cognition; social context; social deprivation; social group; sociobehavior; sociobehavioral; socioenvironment; substance abuse; teenage; thalamic; translation research enterprise
Relevance: Relevance: During adolescence and young adulthood, the risk for many mental illnesses increases sharply. However, the neurodevelopmental changes that may underlie this increased vulnerability are not understood. The proposed studies will begin to bridge this important gap in our knowledge. Our findings will yield a more complete understanding of adolescence as a unique, sensitive period of development for brain circuits that mediate emotional regulation and social cognition. Moreover, the findings will contribute to the development of novel strategies for preventing the psycho- and neuropathology associated with many psychiatric disorders including schizophrenia, anxiety, and substance abuse disorders
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 30-SEP-2009
Budget end date: 31-AUG-2010
PFA/PA: RFA-OD-09-003
1RC1MH088740-01 (2009): $309142
GABA NEURON SUBPOPULATION AND THE REGULATION OF CORTICAL NEURONAL AND BEHAVIOR
Holly Marie Moore
Weill Medical College Of Cornell Univ, 1300 York Avenue, Box 89, New York, Ny 10065
Abstract: The overarching goal of Project 4 is to characterize disease-relevant neurophysiological and behavioral phenotypes in two genetic models of developmental interneuronopathies Cyclin D2 nulls and the Six3- CreSmo(FI/FI) conditional nulls of the sonic hedgehog (Shh) pathway developed in Projs. 1 and 2, respectively. Anatomical data provided by Projs 1,2 and 4 and Core B indicate that these two genetic models differ in terms of their impact on MGE-derived interneurons in at least 2 important aspects 1) relative decreases in parvalbumin-expressing (Pv+) vs. somatostatin-expressing (SSN+) subpopulations and 2) differential effects on neocortical and hippocampal subregions. Specifically, the cyclin D2 model exhibits a loss of Pv+ but not SSN+ interneurons in the cortex; moreover the hippocampus shows a more marked reduction in Pv+ interneurons, relative to neocortical regions. On the other hand, the Six3-CreSmo(FI/FI) model shows a loss of both Pv+ and SSN+ interneurons in both neocortex and hippocampus. In Project 4, the impact of these different patterns of interneuron deficits will be determined using a combination of electophysiological, functional-anatomical, and behavioral experiments. Electrophysiological experiments will test the hypothesis that local GABA transmission is reduced in the neocortex and hippocampus of these mutant mice. The behavioral experiments will characterize changes in seizure threshold and fear-related behaviors in response to decreases in efficacy of the GABAA-benzodiazepine receptor. Correlations between behavior and cortical neuron activity will be assessed by telemetry-based EEGs in behaving animals and by quantifying induction patterns of the immediate early gene c-fos following administration of ligands that negatively modulate the GABAA-BZ receptor. Together these studies will characterize the impact of the "maldevelopment" of specific interneuron subpopulations on the functional postnatal development of prefrontal and limbic cortical circuitry mediating mood regulation (specifically, fear) and seizure susceptibility. Pathological development of interneuron populations of the neocortex and hippocampus are thought to contribute to several developmental brain disorders including seizures, cognitive disabilities, autism and schizophrenia. Preclinical research supports the idea that the affective symptoms and cognitive deficits that often accompany these disorders may also be, in part, mediated by a disruption of cortical GABA transmission or its developmental consequences. Thus Project 4 has broad relevance for epilepsy and disorders of mood and cognition
Keywords: 4-Aminobutanoic Acid; 4-Aminobutyric Acid; ARHGEF5; ARHGEF5 gene; Active Follow-up; Address; Affect; Affective Disorders; Affective Symptoms; Affinity; Age; Agonist; Aminalon; Aminalone; Ammon Horn; Animals; Archives; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; Axon; Behavior; Behavioral; Benzodiazepine Compounds; Benzodiazepine Receptor; Benzodiazepines; Bicuculline; Binding; Binding (Molecular Function); Biostatistics Core; Brain; Brain Diseases; Brain Disorders; Butanoic acid, 4-amino-; CCND2 protein, human; Cell Body; Cell division; Cell membrane; Cells; Cerebral cortex; Chloride; Chloride Ion; Chlorides; Cl- element; Cognition; Cognitive; Cognitive deficits; Connector Neuron; Convulsants; Cornu Ammonis; Coupled; Cues; Cyclic Somatostatin; Cytoplasmic Membrane; Data; Development; Disease; Disorder; Dose; Dysfunction; Encephalon; Encephalon Diseases; Encephalons; Epilepsy; Epileptic Seizures; Epileptics; Erinaceidae; Event; Exhibits; Fear; Frequencies (time pattern); Frequency; Fright; Functional disorder; GABA; GABA Receptor; GEF5; Gene Expression; Generalized Growth; Genetic Models; Genotype; Goals; Growth; Growth Hormone Inhibiting Factors; Growth Hormone-Inhibiting Hormone; Gx Protein; Hand; Hedgehogs; Hippocampus; Hippocampus (Brain); Holly; Hydrogen Oxide; Immediate-Early Genes; In Vitro; Intercalary Neuron; Intercalated Neurons; Interneurons; Internuncial Cell; Internuncial Neuron; Intracranial CNS Disorders; Intracranial Central Nervous System Disorders; Kanner`s Syndrome; Knockout Mice; Lead; Learning; Ligands; Mammals, Mice; Mammals, Rodents; Measures; Mediating; Memory; Methods; Mice; Mice, Knock-out; Mice, Knockout; Mice, Mutant Strains; Modeling; Molecular; Molecular Interaction; Mood Disorders; Murine; Mus; Mutant Strains Mice; Neocortex; Nerve Cells; Nerve Unit; Nervous; Nervous System, Brain; Neural Cell; Neural Transmission; Neurobiology; Neurocyte; Neurons; Null Mouse; P60; Parvalbumins; Pattern; Pb element; Phenotype; Physiologic; Physiologic pulse; Physiological; Physiology; Physiopathology; Plasma Membrane; Population; Position; Positioning Attribute; Predisposition; Probability; Process; Programs (PT); Programs [Publication Type]; Pulse; Pyramidal neuron; Receptor Protein; Receptors, Diazepam; Receptors, gamma-Aminobutyric Acid; Regulation; Relative; Relative (related person); Research Support; Rodent; Rodentia; Rodentias; Role; SMO; SMO protein, human; SMOH; SMOH protein, human; SRIH; SRIH-14; Salaries; Schizophrenia; Schizophrenic Disorders; Science of neurophysiology; Seizure Disorder; Seizures; Services; Severities; Slice; Smoothened; Smoothened Homolog; Somatostatin; Somatostatin-14; Somatotropin Release Inhibiting Factors; Somatotropin Release-Inhibiting Hormone; Sonic Hedgehog (Shh) Pathway; Sonic Hedgehog Pathway; Stimulus; Susceptibility; Synapses; Synaptic; Synaptic Transmission; System; System, LOINC Axis 4; TIM; TIM1; Telemetries; Telemetry; Testing; Tissue Growth; Transmission; Universities; Visuospatial; Voltage-Clamp Technics; Voltage-Clamp Technique; Wages; Water; Work; age dependent; age related; awake; base; behavior test; behavioral test; cell body (neuron); conditioned fear; conditioning; cyclin D2; cyclin D2 protein, human; dementia praecox; disability; disease/disorder; epilepsia; epileptiform; epileptogenic; experiment; experimental research; experimental study; extracellular; fear conditioning; follow-up; frontal cortex; frontal lobe; gamma-Aminobutyric Acid; growth hormone release inhibiting factor; heavy metal Pb; heavy metal lead; hippocampal; hippocampal pyramidal neuron; hippocampal subregions; homotypical cortex; human SMO protein; in vivo; innervation; isocortex; mood regulation; mouse mutant; mutant; neocortical; neopallium; nerve supply; neural; neural cell body; neural mechanism; neurobiological; neuromechanism; neuron cell death; neuron loss; neuronal; neuronal cell body; neuronal cell death; neuronal loss; neurophysiology; ontogeny; pathophysiology; plasmalemma; postnatal; postsynaptic; pre-clinical research; preclinical research; presynaptic; programs; receptor; relating to nervous system; research study; response; schizophrenic; secondary outcome; smoothened homolog (Drosophila), human; social role; soma; synapse inhibition; synaptic inhibition; tool; transmission process; visual spatial
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
5P01NS048120-05_0004 (2010): $216831
5P01NS048120-04_0004 (2009): $217478