Front Cover 1
Molecular Mechanisms of Hormone Actions on Behavior 4
Contents 6
Contributors 20
About the Editors 24
Introduction 26
Historical and Conceptual Introduction to Molecular Forays Intended to Explain Hormone/Behavior Relations 26
References 29
Part I: Cellular and Molecular Mechanisms of Hormone Actions on Behavior 30
1 Rapid Membrane Effects of Estrogen in the CNS 32
Historical Perspective 32
Estrogen Receptors and Estrogen-Binding Sites 33
ERa and ERbeta 33
Estrogen Signaling 34
Nuclear-Initiated Signaling of Estrogen 34
Novel ERs 34
Membrane-Initiated Signaling of Estrogen 37
Functional Consequences of Membrane-Initiated E2 Signaling 37
17beta-Estradiol and Neuroprotection 37
17beta-Estradiol and Nigrostriatal Motor Pathways 38
17beta-Estradiol, Growth Factors, and Reproduction 40
17beta-Estradiol and GnRH Neurosecretion 41
Effects of 17beta-Estradiol on VMH/Arcuate Neurons: Role in Regulation of Feeding 43
Conclusions: Crosstalk between Membrane Actions and Genome Activation 44
References 46
2 Estrogen Regulation of Neurotransmitter and Growth Factor Signaling 54
Introduction and Overview 54
Potential Molecular Targets of Hormone Regulation of Synaptic Transmission 55
Estrogen Regulation of Classical Neurotransmitters 56
Acetylcholine 56
Dopamine 58
Norepinephrine 60
Serotonin 62
Glutamate 65
GABA 67
Estrogen Regulation of NPs 69
Oxytocin 69
Opioids 70
Cholecystokinin 71
Others 72
Estrogen Regulation of Downstream Molecules Mediating Responses to Transmitters 72
Estrogens and Growth Factor Signaling Pathways 74
Cellular and Molecular Mechanisms Involved in the Interaction of Estradiol and Growth Factors 74
Functional Implications of the Interaction of Estradiol with Growth Factor Signaling 77
Neuroendocrine regulation and reproductive behavior 77
Synaptic plasticity and adult neurogenesis 79
Summary and Conclusions 80
References 81
3 Genetic Mechanisms in Neural and Hormonal Controls Over Female Reproductive Behaviors 96
Summary of Major Points in First Edition of Hormones, Brain, and Behavior 96
Brief Statement of Some Major Findings in the Field: Biophysics and Functional Genomics 97
Introduction to Topics Covered in the Second Edition 98
Molecular Biology of Estrogen Action in the Brain 98
Molecular Biology 98
Effects in Hypothalamic Neurons 99
Molecular and Biophysical Studies of Influences on Sexual Arousal in Female Animals 100
Arousal 100
Gene/Environment Interactions 101
Neurochemical Routes by Which Generalized Arousal Transmitters Can Be Influenced by Female Sex Hormones and Thus Influence Sex 101
Biophysical Routes by Which Generalized Arousal Signals Influence Sex Behavior-Controlling Hypothalamic Neurons 102
Histamine 102
Histamine actions and influences by estrogens 102
Norepinephrine 103
Gq/11-coupled primary signaling pathway 104
Other signaling pathways 104
Roles of ion channels 105
Mechanisms of estrogenic actions 106
Estradiol effects on calcium channels 106
mu-Receptor opioid agonists 106
Mechanisms of estrogen and mu-opioid receptor effects 107
Behavioral implications 108
Prostaglandin D 108
Estrogens and vigilance state control and arousal - behavioral correlates 109
Molecular correlates 109
Neuroanatomical and biophysical correlates 110
Questions leading to new experiments 110
Clinical Aspects of CNS Arousal Mechanisms 110
Summary of Accomplishments in the Field to Date 112
References 113
Further Reading 113
4 Molecular Biology of Estrogen Receptor Action 120
Introduction 121
ER: Ligand-Activated Transcription Factor - and Beyond 122
ER Ligands 122
ER Subtypes 123
ER Isoforms 123
Evolution of NHRs and ER 124
Structural Organization of ER 124
N-Terminal Domain 125
DNA-Binding Domain 125
The Ligand-Binding Domain 126
Mechanisms of ER Action 128
Classical Mechanism of ER Action 128
Molecular aspects of ER activation 128
ER DNA interactions - discrimination from similar response elements 128
ER Coregulators 130
The p160/SRC family 131
CBP/p300 cointegrators 131
TRAP/DRIP mediator complex 131
AF-1 selective coactivators 132
Secondary coactivators 132
Other coactivators 133
ER corepressors 133
ER and the Chromatin 134
Nonclassical Mechanism of ER 135
ERE-independent genomic actions of ER 135
Ligand-independent activation of ER 136
Nongenomic actions of ER 137
ER-mediated gene repression 138
Regulation of ER Activity 139
Post-Translational Modification of ER 139
Phosphorylation 140
Acetylation 141
Ubiquitination 141
Sumoylation 142
ER and Coregulator Dynamics 143
Conclusion 144
References 145
5 Molecular Biology of Androgen Action 152
Introduction 153
Androgen Synthesis and Metabolism 154
Steroid Hormone Biosynthesis 154
Testosterone Metabolism 154
Metabolic Fate of DHT 155
Androgenic Regulation of Gene Transcription 156
The Androgen Receptor 156
Heat Shock Proteins 158
Coregulatory Proteins 159
Androgen Response Elements 159
Selective AR Modulators 159
Post-Translational Modifications of Histones and AR 160
Histone Acetylation 161
Histone Methylation 161
Nongenomic Androgen Effects in the Nervous System 162
Behavioral and Physiological Evidence 162
Nongenomic Actions of Classical ARs 163
Membrane-Associated ARs 164
Androgen-Mediated Signal Transduction Cascades 164
Pathologies Related to Disrupted Androgen Signaling 165
Androgen Insensitivity Syndrome 165
Spinal and Bulbar Muscular Atrophy 166
5a-Reductase Deficiency 166
Neuroprotective and Neurotherapeutic Effects of Androgens 167
Motoneurons 167
Recovery from Injury 167
Protection from Cell Death 168
Cellular and Molecular Mediators 169
Neuritin 171
Conclusions 172
References 172
6 Androgen Actions on Receptors and Channels: Regulation of Electrical Excitability and Synaptic Transmission 178
Introduction 179
Androgen Effects on Electrical Excitability 179
Androgen Effects on Electrical Excitability in Mammals 179
Androgen Effects on Electrical Activity in Peripheral Structures 185
Androgen Effects on Synaptic Transmission 187
Androgen Effects on Acetylcholine Receptor-Mediated Synaptic Transmission 187
Androgen-sensitive neuromuscular synapses in mammals 188
Androgen-sensitive neuromuscular synapses in anurans 188
Androgen-sensitive transmission in autonomic nervous system ganglia 190
Androgen Effects on GABA Receptors and GABAergic Transmission 191
Genomic regulation of GABAA receptor function 192
Allosteric modulation of GABAA receptors 194
Positive neurosteroids 194
Negative neurosteroids 194
Anabolic androgenic steroids 196
Androgen Effects on Glutamate Receptors 197
Future Directions with Respect to Electrophysiological Modualtion by Androgens 199
References 201
7 Model Systems for the Study of Androgen-Regulated Gene Expression in the Central Nervous System 208
Introduction 208
Androgen-Responsive Brain Regions 209
Androgens: Production and Active Metabolites 209
Mechanism of Androgen Action 210
The AR: Structure and Function 210
The AR Transcriptional Complex 213
General Transcription Factors 213
AR Coregulators 213
Specific Transcription Factors 215
The AR Transcriptome 215
Androgens, the AR, and the CNS 217
Mechanism of AR Action in the CNS 217
The AR Transcriptional Complex and the AR Transcriptome 218
References 218
Further Reading 218
8 Thyroid Hormones in Neural Tissue 222
Introduction 223
Mechanisms for Thyroid Hormone Transport into the Brain 224
Thyroid Hormone Transport in the Bloodstream 224
Thyroid Hormone Delivery to the Hypothalamus 225
Blood-brain and blood-cerebrospinal fluid barriers 225
Thyroid hormone transporters 227
Activation and Inactivation of Thyroid Hormone by Iodothyronine Deiodinases 229
Mechanisms of Thyroid Hormone Action 230
Genomic Actions 230
Nongenomic Actions 233
Role of Thyroid Hormone in Feedback Regulation of Hypophysiotropic Neurons in the HPT Axis 233
Anatomy of Hypophysiotropic TRH Neurons 235
Negative Feedback Regulation of Hypophysiotropic TRH Neurons by Thyroid Hormone 235
TRH Gene and Promoter Regulation 238
Neuronal Regulation of the Set Point for Negative Feedback Regulation of Hypophysiotropic TRH Neurons 239
Adrenergic input from the C1-3 brainstem areas 240
Input from feeding-related neurons of the arcuate nucleus 240
Tanycytes and Regulation of Hypophysiotropic TRH Neurons 242
Thyroid Hormone and Appetite Regulation 245
Effects of Thyroid Hormone on the Hypothalamic Arcuate Nucleus 245
Effects of Thyroid Hormone on the Hypothalamic Ventromedial Nucleus 247
Effects of Thyroid Hormone on Other Appetite-Regulating Peptides in the Hypothalamus 247
Cocaine- and amphetamine-regulated transcript 247
Galanin-like peptide 247
Vasoactive intestinal polypeptide 248
Thyroid Hormone and Reproductive Function 248
Photoperiod Regulation of Reproductive Function 248
Sexual Differentiation and Lordosis Behavior 251
References 251
9 Nuclear Mechanisms of Glucocorticoid Action 262
Introduction 264
Functional Domains of the GR 264
The Activation Function 1 Domain 265
The DNA-Binding Domain 265
The Ligand-Binding AF2 Domain 266
Alternate Receptor Isoforms 267
Nuclear Translocation and the Heat-Shock Protein/Receptor Complex 267
Cytoplasmic Heat-Shock Protein/Receptor Complexes and Nuclear Translocation 267
Hsp/Receptor Complexes within the Nucleus 271
Modification of Promoter Activity in the Context of Chromatin 274
Multiple Transcriptional Coregulators Facilitate GR Action 274
p160 Coactivators Act as Adaptors to Recruit Multi-Protein Coregulatory Complexes 275
The p160 Coactivators Recruit Multiple Acetyltransferase Coactivators 275
The p160 Coactivators Recruit Multiple Methyltransferase Coactivators 276
Multiple Coactivators Associate with the p160 Protein N-Terminus 277
Regulation by Corepressor Complexes 277
Regulation by ATP-Dependent Chromatin-Remodeling Complexes 278
Proteasome Machinery Affecting GR Activity 279
Covalent Modification of the GR 280
Phosphorylation 280
Ubiquitination 281
Sumoylation of GR 282
GR Acetylation 282
Promoter-Specific Control of GR Activity 283
GRE Sequence Variability 284
Tethering of GR to Promoters via Protein-Protein Interactions 284
Promoter Interactions and Allosteric Modulation of GR Activity 285
Time-Dependent Modification of Promoter Activity 285
Slow Promoter Cycling 285
Fast Dynamics 286
Genome-Wide Action of the GR 286
Global Organization of Receptor-Responsive Genes 286
Nuclear Architecture and Looping 287
References 287
10 Acute Corticosteroid Actions in the Brain: Cellular Mechanisms and Behavioral Consequences 298
Introduction 298
The Importance of Rapid Responses to Corticosteroids in the Face of Threat 299
Rapid Effects of Corticosteroids on Behavior 300
Acute Regulation of Reproductive Behaviors 301
Acute Regulation of Agonistic Behaviors 302
Acute Regulation of Behavioral Activity 303
Acute Corticosteroid Effects on Learning and Memory 304
Common Themes in Rapid Behavioral Actions of Corticosteroids 306
Rapid Neurophysiological Actions of Corticosteroids That May Underlie Behavioral Responses 306
Brainstem 307
Hypothalamus 308
Hippocampus 309
Multiple Signal Transduction Pathways for Corticosteroids That May Underlie Rapid Neural and Behavioral Responses 311
Direct Interactions of Corticosteroids with Plasma Membranes 311
Receptors for Initiating Rapid Corticosteroid Actions 312
Intracellular receptors acting through novel mechanisms 313
Novel, membrane-associated receptors for corticosteroids 314
Rapid modulation of monoamine transport by corticosteroids 315
Rapid corticosteroid action mediated by the binding of CBG to membranes 316
Receptor Dynamics That Might Mediate Context Dependency in Corticosteroid Action 316
Downstream of Receptors: Molecules Involved in Rapid Corticosteroid Signaling 318
Protein Kinases 318
Calcium 318
Corticosteroid Modulation of Endocannabinoid Signaling 319
Summary: Toward an Appreciation of Rapid Corticosteroid Action 319
References 320
11 Corticosteroid Actions on Electrical Activity in the Brain 330
Introduction 331
Corticosteroid Receptors 332
Distribution 332
Access and Activation of the Receptors 333
Regulation of Gene Transcription 333
Cellular Actions of Corticosteroid Hormones in Brain 334
CA1 Hippocampal Area 334
Rapid effects 334
Slow effects on ionic conductances 335
Slow effects on amino acid-mediated transmission 336
Slow effects on aminergic transmission 337
Rapid and slow effects on synaptic plasticity 338
Dentate Gyrus 340
Amygdala 342
Relevance in Health and Disease 342
Behavioral Adaptation 342
Ischemia, Epilepsy 344
Chronic Stress 344
Mechanism of Action 346
Concluding Remarks 347
References 348
12 Molecular Genomics of Mineralocorticoid Actions 354
Introduction 354
MR Structure 355
N/C-Interaction 357
Evolutionary Considerations 357
Tissue Distribution 358
Ligands of the MR 359
11bHSD2 and Pre-Receptor Regulation of the MR 359
Genomic versus Nongenomic Mineralocorticoid Actions 361
Transrepression and the MR 362
Transactivation by the MR 362
Coregulators for the MR 363
Aldosterone-Induced Genes 364
Mutations of the MR 365
Animal Models 366
Conclusions 366
References 366
13 Molecular Genomics of Progestin Actions 372
Introduction 372
PR Structure and Genomic Mechanisms of Action 372
Progestin-Regulated Genes 375
PR-Responsive Genes in Human Breast Cancer Cells 375
Progestin-Regulated Genes in Brain 376
Nuclear Receptor Coregulators and PR 376
Coactivators of PR 377
The p160 family 377
Other coactivators of PR 378
CREB-binding protein 378
Steroid receptor RNA activator 379
Jun dimerization protein-2 379
Chromatin remodeling and PR 380
Function of PR coactivators in brain 380
Corepressors and PR 384
PR Phosphorylation 384
Direct PR Phosphorylation in Breast Cancer Models 384
PR Ser294 Phosphorylation in Breast Cancer Models 385
MAPK and PR Function in Brain 386
Extranuclear Actions of PR 387
Integration of Rapid Signaling and Nuclear SR Actions 388
Integrated SR Actions in Gene Expression 388
Summary and Conclusions 389
References 390
14 Mechanism of Progesterone Receptor Action in the Brain 400
Introduction 401
Structure and Function of PRs: An Overview 401
Structural Organization 402
Gene Activation 402
Coactivators and Repressors 403
Coactivators 403
SRC-1/NcoA-1 403
TIF2/GRIP1/NcoA2/ SRC-2 404
p/CIP/ACTR/AIB1/TRAM-1/RAC3/SRC-3 404
Cointegrators: CBP/p300 404
E3 ubiquitin-protein ligases: E6-AP and RPF-1 405
L7/SPA 405
HMG-1/2 405
Steroid receptor RNA activator 405
ASC2/TRBP/RAP250/NRC/PRIP/NCoA6/AIB3/KIAA0181 405
Corepressors 405
NRs and Chromatin 406
Coactivators and acetylation 406
Chromatin-remodeling proteins 406
Corepressors and deacetylation 406
Receptor Activation and Phosphorylation 406
PR Isoforms 407
Ligand-Independent Activation of PRs 408
Cellular Function of Progesterone in the CNS 409
Reproductive Physiology and Behavior 409
Species Variations 410
PRs in the CNS 410
Spatial and Temporal Correlation between PR Induction and Behavior 411
Estrogen-Inducible versus Estrogen-Noninducible PRs 411
PR Isoforms in the Brain 412
Progestin Receptor Activation in the Brain: Relationship to Female Sexual Behavior 412
Genomic Mechanisms 413
Nongenomic Mechanisms 413
Ligand-Independent Mechanism: An Alternate Mechanism of PR Action in the CNS 415
Mechanisms of Action of Progesterone and DA on Female Reproductive Behavior 416
Interactions between Progesterone and Neurotransmitters 416
DA Signaling and PR Pathway Convergence 417
Multi-signal Pathway Reinforcement 418
Coactivators and PRs in the Brain 420
PRs and CNS Drug Actions 421
PRs and Male Sexual Behavior 421
PRs in Development 422
PRs and Other Behavioral Effects 423
Summary and Conclusions 423
References 424
Further Reading 424
15 Progesterone: Synthesis, Metabolism, Mechanisms of Action, and Effects in the Nervous System. An Overview 438
Introduction 439
PROG Synthesis and Metabolism 441
Biosynthetic Pathways of PROG 441
Conversion of cholesterol to pregnenolone 441
Conversion of pregnenolone to PROG 443
Metabolism of PROG 443
Origins of PROG in the Nervous System 444
PROG synthesized by the endocrine glands 444
PROG synthesized within the nervous system 446
Modes of PROG Action 448
The Intracellular PR and Its Isoforms 448
Identification of PRs in the nervous system 449
Structure of the PR 450
PR isoforms 450
Intracellular distribution of the PR 452
Activation of target genes by PROG 453
Coregulators of the PR 453
Regulation of PR expression by hormones 454
Ontogeny of brain PRs 455
Interactions between the PR and Signal-Transduction Pathways 456
Membrane Receptors of PROG 456
PR in Xenopus oocytes 457
PR in spermatozoa 458
A membrane receptor of PROG in the brain: Protein 25-Dx 459
Binding sites for PROG in neuronal membranes 459
Sigma 1 receptors 460
GABA-A receptors 461
Nicotinic acetylcholine receptors 462
Functions of PROG 462
Reproductive Functions 462
Female sexual behavior 462
Male sexual behavior 465
Gonadotropin secretion 465
Sexual differentiation 467
Nonreproductive Functions Involving the Modulation of Neurotransmission 468
Anesthetic actions 468
Sleep 468
Analgesic actions 469
Anxiety 469
Stress 470
Depression 470
Memory 471
Alcohol dependence 471
Seizure susceptibility 472
Brain development 472
Trophic and Protective Effects 473
Neuroprotective effects of PROG 473
Effects of PROG on myelination 474
Perspectives 476
References 477
16 Neuroactive Steroids and the GABA-A Receptor 494
Introduction 495
Steroid Synthesis 495
Historical Overview 495
The GABAA Receptor 496
Steroid-Binding Site 497
Steroid Levels 497
Synaptic Current 498
The GABAR d Subunit and Steroid Sensitivity 498
Cl-Dependent Steroid Effects at a4b2d GABAR 499
The d-Subunit and Tonic Inhibitory Current 499
Localization of Other Receptor Subtypes 500
GABAA Receptor Plasticity 500
Relevance for PMS 501
Kinetics of a4-Containing GABAR 501
Hippocampal Excitability 502
a4-Expression and Seizure Susceptibility: Relevance for Catamenial Epilepsy 502
In vitro Studies 502
Steroid-Induced Changes in GABAR Subunit Expression 503
Pregnancy and THP Withdrawal 503
Steroid Withdrawal and Hypothalamic Neurons 503
d-GABAA Receptor Subunit Expression: Regulation by THP 504
THP Withdrawal and CA1 Hippocampus 504
Relevance for PMS 504
Estrous Cycle 505
Periaqueductal Gray 506
Puberty 506
Conclusions 506
References 507
Part II: Development of Hormone-Dependent Neuronal Systems, Sexual Differentation 512
17 Sex Differences in the Brain in the Age of Genetics 514
Introduction 515
Intrinsic Differences in XX and XY Cells: Direct Genetic Effects Causing Sex Differences 515
Historical Antecedents 515
Mouse Models for Studying Sex Chromosome Effects on Neural and Other Somatic Phenotypes 516
Mice with allelic differences in the Y chromosome 516
FCG: Mice with different complements of X and Y genes 517
Sex chromosome aneuploid mice (XO, XXY, XYY, etc.) 517
Mice with altered sex chromosomes 517
Mice differing in genomic imprint of the X chromosome 517
Mice transgenic for X or Y genes 517
Mice with different strain origin of the X chromosome 518
Mice lacking gonads 518
Recent Evidence for Direct Genetic Origin of Some Sex Differences in the Brain 518
Direct Effects of Sry 518
Studies of FCG Mice 518
General considerations 518
Septal vasopressin 520
Sex chromosome effects on TH neurons in vitro 520
Aggression and parental behavior 521
Nociception 521
Habit formation 522
Brain diseases: Neural tube closure defects 522
Brain diseases: MS 522
Study of Sex Chromosome Aneuploids 522
Compensation 523
Sex Chromosome Effects in Species Other than Mice 523
Sex Differences Go Global: Sex Differences in Gene Networks and Their Evolution 524
Summary and Prognosis 526
References 527
18 Sexual Differentiation of the Brain: Mode, Mechanisms, and Meaning 530
Introduction 531
Ten Things We Know 531
Hormones Cause Sex Differences by Acting during Development as well as in Adulthood 531
There Are Sex Differences in Behavior 532
There Are Sex Differences in Physiology 534
There Are Sex Differences in Disease Susceptibility 535
There Are Sex Differences in Neural Structure, Glial Structure, and Connectivity 535
Neural structure 536
Glial cells 536
Synaptic connectivity 536
There Are Sex Differences in Neurochemistry 537
Sex differences in gamma-aminobutyric acid signaling during development 537
Sex differences in neurotransmitters in adulthood 537
Sex differences in steroid receptor expression 538
Androgens as well as Estrogens Play a Role in Sexual Differentiation of the Brain 538
There Is a Direct Genetic Contribution to Sexual Differentiation 539
Sex Differences Are Context Dependent 540
Sexual Differentiation Depends on Four Key Processes 541
Recent Progress in Understanding the Four Key Processes 541
Neurogenesis 541
Cell Migration 542
Cell Death 543
Differentiation of Circuits 545
Axonal growth 545
Dendritic growth and branching 546
Synaptogenesis 546
Arcuate nucleus 547
The POA of the hypothalamus 547
VMN of the hypothalamus 548
Differentiation of neurochemical phenotype 550
Seven Unanswered Questions 551
Are Sex Differences Necessary? 551
Do Sex Differences in Brain Structure Beget Sex Differences in Brain Function? 553
How Pervasive Are Gene Effects? 554
Is Partner Preference Sexually Dimorphic? 555
How Can Effects of Sexual Differentiation Last a Lifetime? 556
What Are the Actual Steroid Levels in the Brain during the Sensitive Period of Sexual Differentiation? 557
Have We Neglected the Neuro in Neuroendocrinology? 558
References 559
Further Reading 559
19 Early Life Experiences: Enduring Behavioral, Neurological and Endocrinological Consequences 568
Introduction 569
Hypothalamic-Pituitary-Adrenal Axis 569
Development of the HPA Axis 570
Neonatal development of the HPA axis 570
Pubertal development of the HPA axis 571
Neonatal Experiences and Enduring Behavioral, Neurological, and Endocrinological Consequences 573
Individual Differences in the Development of the HPA Axis and Neonatal Experience 573
Neonatal Handling 574
Neonatal handling and behavior 574
Neonatal handling and brain 576
Neonatal handling and endocrine function 577
Neonatal Novelty Exposure 577
Neonatal novelty exposure and behavior 578
Neonatal novelty exposure and brain 580
Neonatal novelty exposure and endocrine function 580
Neonatal novelty exposure and maternal influence 582
Maternal Deprivation 582
Maternal deprivation and behavior 583
Maternal deprivation and brain 583
Maternal deprivation and endocrine function 584
Pain, Fear Conditioning, and Context of Early-Life Adversity 585
Odor-shock conditioning and behavior 585
Odor-shock conditioning and brain 586
Odor-shock conditioning and endocrine function 586
Functional Consequences of Early-Life Experiences 586
Pubertal Experiences and Enduring Behavioral and Endocrine Consequences 587
Pubertal Experience and Behavior 587
Pubertal Experience and Brain 588
Pubertal Experience and Endocrine Function 588
Adolescence as a Period of Intervention to Mitigate Early Developmental Insults 589
Reversals of Perinatal Insults through Pubertal Environmental Enrichment 589
Mitigation of Perinatal Brain Damage through Pubertal Environmental Enrichment 589
Conclusions 590
References 590
20 Thyroid Hormones and Brain Development 598
Introduction 598
An Overview of Brain Development and the Effects of Thyroid Hormone 599
Action of Thyroid Hormones on Neurogenesis 599
Action of Thyroid Hormones on Cell Migration 599
Action of Thyroid Hormones on Myelination 600
Other Structural Defects Caused by Hypothyroidism 600
Thyroid Hormones in Brain 601
Sources of Thyroid Hormone for the Fetus 601
Expression and Regional Distribution of Deiodinases 602
Type 2 deiodinase 602
Type 3 deiodinase 603
Transport of Thyroid Hormones to the Brain 604
The brain barriers 604
Thyroid hormone transporters 604
Thyroid Hormone Action 604
The Nuclear Pathway of Thyroid Hormone Action 604
Modulation of Transcription by Nuclear Receptors for Thyroid Hormone 605
Extragenomic Pathways of Thyroid Hormone Action 605
Nuclear Thyroid Hormone Receptors in the Brain 606
Mechanisms of Thyroid Hormone Action in the Brain 607
Regulation of Brain Gene Expression by Thyroid Hormone 607
Mechanisms of Action of Thyroid Hormones on Myelination 608
Mitochondrial Actions of Thyroid Hormones 609
Control of Cell Migration 609
Control of Neural Cell Differentiation 610
Regulation of the Expression of Genes Involved in Signaling 610
Transcription Factors and Splicing Regulators 611
Mechanisms of Gene Regulation by Thyroid Hormone 611
Epidemiological and Clinical Aspects 612
Iodine Deficiency Disorders - Endemic Cretinism 612
Congenital Hypothyroidism 612
Maternal Hypothyroidism and Maternal Hypothyroxinemia 614
The Hypothyroxinemia of Prematurity 614
Thyroid Hormone Transporter Mutations 615
Triiodothyronine Receptor Mutations 615
Conclusions and Perspectives 616
References 617
21 Neuroendocrine Regulation of Puberty 628
Introduction 629
The Central Role of Luteinizing Hormone-Releasing Hormone in Sexual Development 629
Historical Perspectives 629
Species Differences 630
Developmental Patterns of Hormone Synthesis and/or Secretion 631
Luteinizing Hormone-Releasing Hormone 631
Pituitary Gonadotropins 635
Gonadal Steroids 639
The testes 639
The ovary 641
Metabolic Hormones 642
Growth hormone 642
Insulin-like growth factor-1 642
Leptin 643
The Neuroendocrine Control of the Onset of Puberty 644
Regulation of LHRH Secretion 644
The transsynaptic control of LHRH neurons 644
Excitatory neurotransmission 644
Glutamate 644
Norepinephrine 647
Dopamine 648
Neuropeptide Y 649
Galanin 651
Inhibitory neurotransmission 651
Gamma-aminobutyric acid 652
Endogenous opioids 657
Neuropeptide Y 657
Melatonin 658
Kisspeptin and its receptor GPR54: The new players 659
Glial regulatory inputs affecting LHRH neurons 661
Glia-LHRH neuron connectivity 661
Molecules mediating glia-LHRH neuron adhesiveness 662
Soluble molecules involved in glia-to-LHRH neuron communication 664
Growth factors 664
Other glial-derived factors 668
Neuron-to-glia communication in the hypothalamus 669
Hypothalamic astrocytes and glutamate metabolism 669
Gonadal steroids and astrocyte function 670
Estradiol and glial morphology 670
Interactions of gonadal steroids with the hypothalamic erbB signaling system 671
Environmental cues 672
The Neuroendocrine Cascade 673
Central initiating events 673
Potential upstream controlling genes 676
Integration of a clock mechanism 678
The endocrine response 679
Genetics of Puberty 680
Adolescent Brain: Behavioral Puberty 680
References 682
22 Sex Steroids and Neural Growth in Adulthood 706
Introduction 706
The Concept of Activational Effects of Gonadal Hormones 707
Neuronal Growth and Plasticity during Four Life Stages 708
Puberty 708
The initiation of puberty 708
The adolescent brain is primed for pubertal metamorphosis 709
Hormone-dependent pubertal growth in the SNB 709
Pubertal growth in the brain 711
The Estrous Cycle 713
The medial amygdala 713
The arcuate nucleus 714
The ventromedial nucleus 715
The hippocampus 715
Pregnancy, Lactation, and Maternal Behavior 717
Maternal behavior is regulated by estradiol, prolactin, and oxytocin 717
Morphological changes due to pregnancy 717
Morphological plasticity due to lactation and motherhood 717
Across the Seasons 719
Effects of photoperiod on the SNB 720
Effects of photoperiod on the medial amygdala 720
Effects of photoperiod on spatial ability and the hippocampus 721
Novel Mechanisms of Gonadal Steroid Action in the Adult Mammalian Brain 723
Rapid Actions of Androgens and Extranuclear ARs in the Brain 723
Extranuclear Estrogen Receptors 725
Summary and Conclusions 727
References 728
23 Adult Neurogenesis in the Mammalian Brain 736
Introduction to Adult Hippocampal Neurogenesis in the Mammalian Brain 737
Historical Perspective 737
Quantification of Neurogenesis: Cell Proliferation, Death, and Survival 737
Endogenous Markers of Cell Proliferation and New Neuron Survival 739
Gonadal Hormone Regulation of Adult Hippocampal Neurogenesis 741
Natural Fluctuations in Estrogen Levels and Adult Hippocampal Neurogenesis 741
Estrogens and Cell Proliferation 742
Estrogens and Cell Survival 744
Estrogen Receptors and Adult Neurogenesis 745
Progesterone and Adult Hippocampal Neurogenesis 747
Androgens and Adult Hippocampal Neurogenesis 747
Neurosteroids and Adult Hippocampal Neurogenesis 748
Adrenal Hormone Regulation of Adult Hippocampal Neurogenesis 749
Glucocorticoids Suppress Cell Proliferation and Cell Survival 749
Mineraloglucocorticoid Receptors and Glucocorticoid Receptors and Neurogenesis 750
Sex Differences in the Effects of Adrenal Steroids on Neurogenesis 751
Developmental Exposure to Elevated Glucocorticoids Alters Neurogenesis into Adulthood 752
Peptide Hormones and Adult Neurogenesis 753
Adult Hippocampal Neurogenesis Across the Life Span 753
Adult Hippocampal Neurogenesis and Aging 753
Adult Neurogenesis during Pregnancy and the Postpartum 754
Functional Relevance of Adult Hippocampal Neurogenesis 755
Adult-Generated Neurons in the Hippocampus Are Possibly Functional 755
Role of Adult-Generated Neurons in the Hippocampus 756
Conclusion 759
References 759
Further Reading 759
24 Estrogen and Progesterone in Aging and Damaged Nervous Systems 770
Introduction to the Problem of Damaged Neural Systems 771
Biologic Sex Differences in Response to Central Nervous System Injury 772
Progesterone Is More than Just a Female Sex Hormone 773
How Did Progesterone Come into Play as a Treatment for Brain Injury?: Early Background 774
Progesterone in Other CNS Injury Models 779
Progesterone and Neurodegenerative Disorders 780
Niemann-Pick Type C Disease 780
Multiple Sclerosis 781
Diabetic Neuropathy 781
Progesterone and Stroke 781
Progesterone Is Neuroprotective in Several Species 782
Mice 782
Cats 783
Rabbits 783
Clinical Results in the Treatment of TBI 784
Progesterone's Neuroprotective Mechanisms 784
Edema 784
Lipid Peroxidation and Oxidative Stress 785
Inflammation 786
Cytokines 786
Inflammatory immune cell activation 787
Inflammation and apoptosis in the gut 787
Apoptosis and DNA Repair 787
Proapoptotic proteins 787
Antiapoptotic proteins 788
Gamma-aminobutyric acid-A 788
Myelin repair 788
Neurotrophic factors 788
Demyelination 788
Estrogens: Early Observations and Hypotheses 788
Estrogens as Neuroprotectants in Ischemic Brain Injury 789
Summary of the Evidence 789
Difficulties in Estrogens' Translation to Clinical Therapy 789
Estrogens and TBI 793
E2 and Protection: Molecular Mechanisms 793
Role of ER-Mediated Mechanisms 793
Genomic versus Nongenomic Mechanisms 794
E2 Synthesis in Injured Brain 795
Effects on Peri-Injury Perfusion 795
Interactions with Postinjury Inflammation 795
E2 Protects against Oxidant Stress and Mitochondrial Mechanisms 795
Androgens: The Understudied Steroid Family 796
Conclusions and Emerging Hypotheses 796
References 797
Part III: Neuropeptides & Neuromodulators
25 Oxytocin 808
Introduction 809
OT Synthesis and Release 809
OT Biosynthesis 809
OT Release 810
Distribution and Regulation of OT Receptors 811
OTR Gene Structure 811
OTR Distribution 812
OTR Regulation 812
Hormonal regulation 812
Developmental regulation 814
OT Actions 815
Cellular Actions 815
Behavioral Effects 815
Food intake and salt appetite 816
Mood and anxiety 816
Antinociception 816
Social recognition and affiliation 817
Female sexual receptivity 817
Male sexual behavior 818
Maternal behavior 818
Pair bonding in monogamous species 819
Human behavior 820
Conclusions 821
References 822
26 Vasopressin Receptors 828
Introduction 828
Brief History and Overview of the Neurohypohyseal Hormones 828
Physiological Importance of AVP for Body Water Homeostasis 829
Vasopressin Receptors 829
Vasopressin V1aR 830
Vasopressin V1bR 830
Vasopressin V2R 831
Antagonists of AVPR 831
Mutations of AVPR 832
AVPR1a Mutations 832
AVPR1b Mutations 832
AVPR2 Mutations 832
Brain AVPR 833
Localization of Brain AVP 833
Functions of Brain V1aR 833
Functions of Brain V1bR 835
References 835
27 The Cell Biology of Oxytocin and Vasopressin Cells 840
Introduction 841
Anatomy of the Oxytocin and Vasopressin Neurosecretory Systems 842
Synthesis and Trafficking of Oxytocin and Vasopressin 843
Co-Localization of Neuroactive Substances 845
Coupling of Neurohormone Release and Electrical Activity 847
Major Afferent Inputs to the Magnocellular Nuclei 847
Glutamatergic Afferents 848
Gamma-Aminobutyric Acidergic Afferents 848
Noradrenergic Afferents 849
Electrophysiological Activity of Oxytocin and Vasopressin Neurons 850
Control of the Electrophysiological Behavior of Oxytocin and Vasopressin Neurons 850
Intrinsic Membrane Properties 851
Synaptic Mechanisms 853
Autoregulation 855
Morphological Plasticity of the Adult Hypothalamo-Neurohypophysial System 856
Neuronal-Glial Remodeling 856
Synaptic Remodeling 857
Permissive Factors for Morphological Plasticity 858
Expression of F3/contactin in oxytocin and vasopressin neurons 858
HNS neurons and glia express PSA-NCAM 858
Other cell adhesion molecules in the HNS 859
Cytoskeletal proteins in HNS cells 859
Factors That Can Induce Morphological Plasticity 860
Functional Implications of Morphological Remodeling 861
Immediate consequences on neuronal and glial function 861
Overall consequences of morphological plasticity 862
References 863
28 Energy Partitioning, Ingestive Behavior and Reproductive Success 874
Introduction 874
A Biological Perspective on Ingestive and Reproductive Behavior 876
A Physiological Framework: Sensory Detectors, Central Effectors, and Hormonal Mediators and Modulators 880
Peripheral Hormones 882
Reproductive Hormones are Affected by Energy Availability 882
Reproductive Hormones Control Energy Intake and Partitioning 888
Activational (adult) effects of reproductive hormones on energy partitioning 888
Developmental (organizational) effects of steroids on energy intake and partitioning 891
Insulin 893
Leptin 895
CCK and Other Peripheral Satiety Peptides 900
Ghrelin 900
Adrenal Hormones and Thyroid Hormones 900
A Neuroanatomical Perspective on Ingestion and Reproduction 901
Sensory Stimuli for Reproduction and Ingestion 901
Exterosensory stimuli influencing reproduction 901
Exterosensory stimuli controlling ingestion 902
Interosensory stimuli controlling reproduction and ingestion 904
The nature of the primary metabolic sensory signal 905
The location of the detectors of metabolic stimuli 906
Behavioral State and Circadian Timing 907
Neural Representation of Sensory Objects 907
Motor Control 908
Components of the motivated behavior controller network 908
Paraventricular nucleus 908
Lateral hypothalamic area 909
Regions that provide inputs to behavior controllers 910
Arcuate Nucleus 910
Ventromedial nucleus 911
Caudal brainstem 912
Integration of Ingestion and Reproduction 913
References 914
Further Reading 914
29 Stress, Opioid Peptides and their Receptors 928
Introduction: The Concept of Stress 929
Opioid System 930
Multiple Opioid Peptides 930
Opioid Receptor Subtypes and Their Ligands 931
Distribution of Opioid Peptides and Receptors in the Stress Network 931
POMC System 931
PENK System 932
PDYN System 932
Endomorphins 932
Opioid Receptors 932
Involvement of Opioids in the Behavioral and Physiological Response to Stress 933
Locomotor Activity 933
Reward 934
Nociception. Stress-Induced Analgesia 935
Thermoregulation - Stress-Induced Hyperthermia 939
Feeding Behavior 940
Cardiovascular Effects 940
Respiration 942
Reproduction 942
Involvement of Opioids in Modulation of the HPA Axis 942
CRF System 942
Vasopressin and Oxytocin System 943
Stress-Induced Alterations in Endogenous Opioidergic Systems 944
HPA Axis 944
POMC system 944
PENK system 946
PDYN system 947
Opioid Receptors 947
Multiple Neurochemical Interactions with Opioid System in Consequence of Stress 948
Dopaminergic System 948
Adrenergic System 950
Autonomic Nervous System 951
Immune System 952
Opioidergic Control of Stress Responses - Conclusions 952
References 955
30 Gonadotropin Releasing Hormone 972
Introduction 973
GnRH Neuronal Systems 973
Embryonic Development of the GnRH System 973
Postnatal and Adult GnRH Systems 974
GnRH-containing cell bodies 974
GnRH-containing projections 974
Associations with the cerebrospinal fluid 975
Cytology of GnRH hormone neurons 975
Regulation of GnRH Neurons 975
Catecholamines 976
Glutamate 977
Gamma-aminobutyric acid 978
Neuropeptides 979
Neuropeptide Y 979
Vasoactive intestinal polypeptide 980
Endogenous opiates 980
Kisspeptins 981
GnRH Receptors in the Central Nervous System 981
Localization of GnRH Receptors in the Brain 981
Characterization of GnRH Receptors in the Brain 981
Regulation of GnRH Receptor Expression in the Brain 982
Functional Aspects of GnRH Receptors in the Brain 983
Molecular and Cellular Mechanism of GnRH Action in the Anterior Pituitary 983
GnRH Receptor 983
Effector Coupling 984
Receptor-Receptor Interactions 984
Receptor Trafficking 984
Endoplasmic reticulum quality control system and the role of endogenous chaperone proteins 984
Mutant GnRHRs isolated from patients with hypogonadotropic hypogonadism are actually misfolded and misrouted proteins that can 985
The ability to rescue mutant proteins using pharmacoperones has therapeutic potential 986
The rescue approach appears generally applicable to other mutant GPCRs, non-GPCR receptors, ion channels, and enzymes associ 986
References 987
Further Reading 987
31 Corticotropin-Releasing Factor: Putative Neurotransmitter Actions of a Neurohormone 996
Introduction 996
The LC-Norepinephrine System 997
Anatomical Attributes 997
Physiological Attributes 997
CRF, Stress, and the LC-Norepinephrine System 998
Activation of LC Neurons by Stress 998
Activation of LC Neurons by CRF 999
CRF Afferents to the LC 1000
Co-Transmitters in CRF Afferents to the LC 1002
Glutamate 1002
Opioids 1003
Dynorphin 1005
Gamma-amino butyric acid 1005
Plasticity of CRF-Norepinephrine Interactions 1005
CRF Receptors in LC 1005
Agonist and Stress-Induced Internalization of LC Neurons 1006
Structural Plasticity Following Stress 1008
Determinants of LC Activity 1008
Conclusions 1009
References 1010
Subject Index 1016