by Donald Pfaff
Antisense DNA technology: antisense riboprobes for neuronal NOS, 101–102; causal role of enkephalin gene, 110; against ER-α, 186; masculinization, 147; oligodeoxynucleotide (ODN), 149, 185; against OT receptor mRNA, 97; PR blocker for, 88; against PR mRNA, 141, 144, 145f, 229
Arcuate nucleus: estrogen binding in, 14; estrogen treatment effects on OT mRNA, 97; kisspeptin neurons in, 202; labeled neurons in, 23–24, 26; mRNA encoding for leptin receptor, 197; neuroendocrine functions of, 16; pituitary controls by, 11; sex hormone concentration in, 29
Arginine-vasopressin (AVP): locations and functions, 180–181. See also Oxytocin (OT)
Ascending sensory pathways, 55–58. See also Cutaneous / epithelial sensation
Autism: genetic mutations, 234–235; sex differentiation factors in, 233–234
Autoimmune disorders, 235–236
Bed nucleus, stria terminalis: amygdala / diencephalon communications, 13; ER-α gene in, 133–134
Behavior-ovulation coordination, 72–73
Brain-body relations: behavioral components, 198–201; body-wide coordination, 195–198; GnRH neuron roles in, 200; leptin, 196–197; principles of behavioral regulation, 207–212; time, 202–207
Cutaneous / epithelial sensation: ascending pathways for, 55; convergence of pathways for, 71–72; dorsal horn processing, 69; estrogen effects on promoters, 55; hindbrain reticular neurons to midbrain, 57; initiation of lordosis, 53–55; neural pathways to spinal cord, 199–201; receptors in genital tissues, 198–199
Descending pathways: hypothalamus to MCG, 58–60; lower brainstem, 60–64; lower brainstem module, 69; medullary reticular formation (NGC), 58–60; medullary / spinal pathway damage, 63; motor neurons in spinal cord, 66f; motor output /motor neurons, 64–67; spinal module for, 69–71
Electrophysiology studies: dorsal root ganglion recordings, 54–55; hypothalamic and estrogen-supported action potentials, 34; lateral vestibular nucleus stimulation and lesions, 61–62; MCG lesions and stimulation, 51–53; MCG stimulation with estrogen treatment, 52f; medullary reticular formation stimulation, 62f; motor neuron recordings, 64–65; NGC lesions, 63; NGC neurons to cutaneous stimuli, 56; NGC stimulation, 60–61; OT actions, 97–98; oxytocin receptor (OTR) system, 183–184; stimulation / lesioning of VMH, 45–51; VMH neurons, 43, 45–49; VMH stimulation, 50f
Endocrine-neural link: brain impact of, 34–37; in vertebrates, 16–29
Enkephalin gene expression: fear response and, 150; in female sexual behavior, 149; induction by estrogen, 240; in VMH for lordosis, 101, 110. See also Preproenkephalin (PPE) gene
Epigenetic changes: in developing brain, 117; by histone modification, 112; stress, 143; X and Y chromosome expression in neurons, 230–232
Estradiol-binding neurons: α1 receptor adrenergic signaling, 89–90; binding capacity of, 13; fear response and, 222–223; neuron groups, 11; nuclear activity of, 10; preoptic implants and maternal behavior, 185–186; ventromedial hypothalamic neurons, 15
Estrogen: in CNS arousal, 222, 224; effect on muscarinic receptors, 45–46; effects on adrenergic systems, 42, 92; facilitation of gene expression, 85f; feedback regulation by, 29–30; neuronal growth in VMH, 104–105; nNOS transcription enhancement, 119; protein synthesis induced with, 83–84; rRNA synthesis in VMH neurons, 104–105; transcription from NOS gene, 103
Estrogen-binding neurons: amphibians, 18–19; dorsal horn of spinal cord, 55; fish brain, 18; hamster brain, 16; localization of, 10–13; mink, 26–27; primate brains, 27; quantification of activity, 14–15; reptiles, 21–22
Estrogen receptor (ER): α-βERKO behavioral effects, 141; binding, 9; ER-α and ER-β behavior comparison, 150; ER-β cloning, 14; in female rat brain, 12f; function, 29; neurons in amphibians, 19f; protein products of, 30–32; as transcription factors, 79; in VMH hypothalamus of monkey, 28f
Estrogen receptor α (ER-α): behavioral effects of blocking, 131f; BNST, 133–134; courtship behavior, 223–224; expression for female-specific sex behavior, 229–230; in generalized arousal, 220–221, 222, 224; knockout (αERKO) and lordosis, 130; masculinization of brain, 116–117; maternal behavior after silencing of, 137; maternal behavior negated by reduction in, 206; medial amygdala (MePD), 133–134; nutritional requirements, 136; oxytocin-producing neurons and, 15; protein product distribution, 30; sexual incentive behavior, 204; social recognition gene requirements, 136; VMH, 133–134
Estrogen receptor β (ER-β): βERKO and sexual behavior, 142; βERKO on courtship locomotion, 135–136; cloning of, 30; lordosis behavior, 130; mPOA neurons, 135; reproductive behavior regulation, 139–140; social recognition gene requirements, 136; VMH metabolic regulation, 136
Estrogen response element (ERE): competitive DNA binding, 109–110; competitive TR / ER binding, 115–116; TR / ER interactions, 111–112
Estrogen-responsive genes, 9, 85
Estrogen-sensitive electrical activity, 34
Estrogen-stimulated synthetic events: α-adrenergic receptors, 89; enkephalin and δ-opioid receptor, 98–101; gonadotropin-releasing hormone (GnRH), 94–96; growth process in hypothalamic neurons, 103–109; histamine, 92; hypothalamic neurons, 80–81; muscarinic cholinergic receptor, 92–94; neuronal nitric oxide synthase (nNOS), 101–103; oxytocin (OT) and oxytocin receptor, 96–98; progesterone receptor, 84–88; transcription factor competition, 109–112
Estrogen treatment: in behavioral effects of GnRH, 173; histone modification, 112; ultrastructural changes with, 105–109, 106f
Female behavior: ER-α expression requirement, 141–142. See also Sex differences
Forebrain module, 72
γ-aminobutyric acid (GABA) neurons: in estrogenic control of GnRH transcription, 202; estrogenic effects on GnRH mRNA, 176
Gene / behavior relationships: GnRH knockout effects, 147; for neuropeptides, 146–150; pathology, 128–130; reproductive behavior, 138–139. See also Kallmann’s syndrome
Generalized arousal (GA): arousal-related transmitters, 216; characteristics of, 218–219; genes for regulation of, 220; ion channels in, 216–217; links to sexual arousal, 222–224; mechanisms of, 219–222; for reproductive behavior, 215–218
Genes regulating behavior: causal relationships, 151–152; enkephalin, 149–150; epigenetics, 143–144; ER-α, 130–139; ER-α and ER-β comparison, 150; ER-β, 139–143; gonadotropin-releasing hormone (GnRH), 147; human behavior, 151–152; modification of expression in brain, 132; oxytocin, 147–148; progesterone receptor mRNA, 144–146; SRY gene, 150–151; TR isoform effects, 146
Genomic stress response, 143
Genotype / age interactions: in aggressive behavior, 140–141; ER-β gene expression, 142
Glutamatergic neurons: ER-α expression colocalization with, 15; excitation of GnRH neurons, 175; hormonal synergy with, 15; NO action with, 101; NO effects, 119
GnRH neurons: characteristics of, 175; developmental migration of, 159–160; estrogenic effects on mRNA in, 176; migration in human brain, 164–169; migration in mouse, 162f, 163f; migration in salmon, 164f; migration in vertebrates, 160–164
Gonadotropin-releasing hormone (GnRH): behavioral effects of, 173–174; behavioral effects of knockout, 147; chemistry-physiology-behavior link, 169–176; development migration of GnRH neurons, 159; genes expressing, 5; neuromodulatory action of, 172–173; neuronal migration in development, 152; promotion of mating behavior / LH surge, 119
Hippocampus: corticosterone binding in, 14, 28; estrogen effects on OTR mRNA, 97; estrogen receptive cells in, 13; gene expression related to autism, 235; labeled pyramidal neurons in, 17, 27; sex hormone concentrating neuron projection to, 35
Histamine (HA): ion channels for depolarization, 47–48; VMH neurons, 92
Histone modification: in developing brain, 117; estrogen-regulated modification in VMH, 143–144; transcription modified by, 113
Hormone-binding neurons: amphibians, 18–21; birds, 23–27; direct hormonal action on neurons, 9; fish, 17–18; hamster brain, 16; human brain, 28–29; mouse brain, 17; neuroanatomical connections of, 34�
�36; primate brains, 27–28; rat brain tissue, 11; reptiles, 21–23
Hormone-dependent behavioral funnel, 212
Hormone receptors: in brain, 10; corticotropin-releasing hormone receptors, 100; discovery of, 4, 9–10; entry point for neural circuit, 41; importance for behavior, 32–34; ligand-activated transcription factors as, 80; neuronal networks with, 34–37; replication at mRNA level, 29–30; replication at protein level, 30–31; thyroid hormone receptors (TR), 80
Hormones: gene expression in brain, 79–127; genomics, 128–157; impact on brain, 8–39
Hypothalamic neurons: anterior pituitary regulation by, 8; estrogen-triggered growth processes in, 103–109; outflow, 41–53; synthetics events in, 80; transcriptional system in, 112–120; transcription factor competition, 109–113
Hypothalamus: anteroventral periventricular nucleus, 228; estrogen-dependent output of, 4–5; labeled neurons in anterior area of, 11. See also specific nuclei of
In situ hybridization: adrenergic-α1 mRNA expression in VMH, 89; enkephalin gene expression, 101; ER gene expression in hypothalamic neurons, 29–31; gene expression related to lordosis, 73; GnRH gene expression, 94–95; GnRH neuronal migration, 160–164; mRNA for ER-α in VMH neurons, 84; NOS, 101–102; OT gene expression, 96–97, 110, 185; PPE mRNA expression, 98, 149, 217–218; PR mRNA levels in VMH, 86–87; rRNA synthesis in VMH neurons, 104
Ion channels: α1 receptor adrenergic agonists, 89; calcium channels, 90; generalized arousal (GA), 216–217; glutamate agonist, 48–49; histamine (HA), 92; link to neural circuitry, 80; muscarinic cholinergic receptors, 90; norepinephrine, 216–217; potassium channel, 47–48
Kallmann’s syndrome: associated mutations in, 168; migration of GnRH neurons in, 151
Kisspeptin, 202, 203
Limbic-hypothalamic system: anatomical connections of, 34–35; central grey extensions of, 11; ER-α protein in, 30–31; OT system in, 96–97, 137; sex hormone receptors in, 10; social recognition behavior, 136–137; in vertebrates, 26–27, 29, 31, 239, 243
Lordosis behavior: absence in male, 117; αERKO, 130, 132; antisense DNA against OTR, 148f; antisense vector against PR mRNA, 145f; anxiolysis for, 119; causal estrogen-influenced gene expression, 83–84; descending systems for regulation, 59; ER-α expression requirement in females, 141; estrogenic binding for, 32–33; estrogen-sensitive link for, 15; GnRH direct effects on, 170–171; GnRH injection elevation of, 170f; GnRH injection in MCG, 172f; GnRH knockout effects, 147; hierarchical motor control in, 71; histone modification in VMH, 144f; hypothalamic outflow regulation, 49–51; motor neuron effects for, 63; motor response component, 64–66; necessary / sufficient condition for, 41; NOS / NO system in, 102–103; OT effects of stress on, 189–190; OT receptor activity for, 97; oxytocin effects, 184; PR expression for, 88; protein synthesis in VMH, 83; PR transcription in production of, 231f; quantification of response, 67–68; requirements for regulation, 34; sex differences in, 228; somatosensory and VMH convergence, 57; somatosensory initiation of, 53–55; specific genes involved in, 5; supraspinal control required for, 56; thyroxine effects on, 114; transcriptional activity for, 114; ultrastructural correlation with, 105–109; ventromedial nucleus of hypothalamus, 29. See also Neural circuit for reproductive behavior; Reproductive behavior
Lower brainstem module, 69–70
Luteinizing hormone-releasing hormone (LHRH). See Gonadotropin-releasing hormone (GnRH)
Male behavior. See Sex differences
Maternal behavior: failure with block of expression of ER-α, 138f; mPOA gene expression silencing, 137; OTR agonist reduction of, 186; oxytocin (OT) in, 205–206; pathways for, 204–205; preoptic estradiol implants and, 185; reduced ER-α expression in preoptic area, 206
Metabolic syndrome, 136
Midbrain central grey (MCG): estrogen effects on, 58; hypothalamic projections to, 43; hypothalamic-brainstem reticular formation interaction, 72; hypothalamic-reticular formation relay, 59–60; VMH projections to, 172
Midbrain module, 71–72
Motor mechanisms. See Descending pathways
Muscarinic cholinergic receptors, 62–63, 92–94
Neural cell adhesion molecules (NCAM): GnRH neuronal migration, 166–168, 202; initiation of puberty, 202
Neural circuit for reproductive behavior: ascending pathways, 55–58; descending pathways, 58–64; entry point for, 15, 238; hypothalamic outflow, 41–53; launching points for analysis, 70f; modular, hierarchical nature of, 69–72; motor mechanisms, 64–68; reticulospinal link, 60; sensory inputs for initiation, 53–55; ventral horn of spinal cord, 66f
Neural circuit modules: forebrain, 72; hypothalamic, 43, 72–73; lower brainstem module, 69–70; midbrain, 71–72; pathways of, 70f; spinal, 69–71
Neurotransmitter receptors, 89
Nitric oxide (NO): as gaseous transmitter, 101; retrograde messenger, 102
Nitric oxide synthase (NOS), 101
Norepinephrine: GnRH neuronal suppression by, 175; ion channels, 216–217
Nucleus gigantocellularis (NGC): amplification of motor neuron response, 60–61; axial musculature activation, 60–64; axonal distributions from, 221f; in generalized arousal, 220–221; neurons regulating cortical arousal, 220f; projections to MCG, 57, 58; somatosensory stimuli response, 56; spinal projections to, 57; VMH input to, 60
Overdetermination of reproductive behavior, 118–120
Oxytocin (OT): brain-behavior (gene coexpression), 182–185; chemistry / molecular biology, 179–182; distribution and actions of, 179–180, 181; estrogen effects on promoters, 183f; estrogen sensitivity of, 182; genes expressing, 5; knockout effects on aggression, 187; OTR facilitation of sexual behavior, 147; overcoming stress effects, 186; projections from paraventricular nucleus, 180; reduction of stress effects, 187–191; social recognition gene requirements, 136
Oxytocin receptor (OTR): antisense infusion effects, 147; coexpression of ER mRNA, 182; electrophysiology studies, 183–184; estrogen regulation of transcription, 182; protein kinase C (PKC) signaling by isoforms, 183–184
Paraventricular nucleus (magnocellular portion), 11
Polycomb group, 203
Preoptic area (POA): ER-α expression in medial, 138f; ER-α gene in medial, 133–135; estrogen-binding neurons in medial, 11; suprachiasmatic portion, 11, 13
Preproenkephalin (PPE) gene: effects of estrogen treatment on, 217; expression and lordosis behavior, 149; hypothalamic expression and lordosis, 149; knockout of PPEKO, 149–150; sex differences in expression, 230. See also Enkephalin gene expression
Progesterone receptor (PR): amplification of estrogen effect, 119; estradiol transcription induction via promoter, 117–118; estrogenic induction, 86–87; with estrogen receptor binding, 30; induction of, 84–89; mRNA manipulation for, 143–144; prevention of stress effects on lordosis, 190
Protein synthesis: estrogen induced, 83–84; for gene expression, 81–82
Puberty: DNA and histone modification in, 203; excitatory and inhibitory inputs with, 201–202; genotype / age interactions, 142; GnRH release with, 173; kisspeptin and, 202; leptin and, 196–197
Reproductive behavior: behavioral chain of, 206; body-wide coordination of nonbehavioral components, 195–198; ER-α expression requirement, 142; ER-α gene, 134; ER-α gene knockout effects, 132; female locomotion in courtship, 134–135; harmonization by GnRH, 176; normal chain of events for, 206; OT prevention of stress effects, 190; OTR mRNA interference effects on, 147, 148f; oxytocin binding in, 182; patterns of gene expression for, 133; PR mRNA reduction and, 144, 145f; social recognition gene requirements, 136. See also Lordosis behavior
Reticulospinal system: motor neuron excitability, 59; synergy with vestibulospinal system, 62–63
Sex differences: autism, 233–234; autoimmune disorders, 235–236; biological import of, 232–233; in brain, 116–117; early testosterone concentrations and, 228–229; ER-α gene disruption in male, 142; ER mRNA regulation by feedback, 29–30; hypothalamic and POA gene expression, 150–151; mechanisms of differentiation, 228–2
30; protein kinase C (PKC) signaling by isoforms, 183–184; PR promoter, 117–118; stress inhibition of sexual behavior, 118; X and Y chromosome expression in, 230–232
Sex hormones: lordosis behavior with, 9–10; receptors in limbic-hypothalamic system, 4; sleep-wake cycle regulation, 222
Sexual behavior. See Reproductive behavior
Signaling systems, 6, 8–9, 36
Social behavior: estrogen / oxytocin linkage in, 186–187; genetic influence on human, 152; measurement techniques, 148; oxytocin binding in, 182; with TR knockout, 146. See also Reproductive behavior
Somatosensory stimuli. See Cutaneous / epithelial sensation
Spinal module, 69
SRY gene, 150–151
Testosterone: genotype / age interactions in aggression, 140–142; Kallmann’s syndrome, 152, 165; labeled cells in vertebrate brain, 18–26; progesterone supplementation of, 9; uptake of tritiated, 13
Thyroid hormone receptors (TR), 14, 80; effects on ER-α transcription, 146; opposing effects of isoforms, 146
Transcriptional systems: convergence of pathways for, 119; estrogen-regulated in VMH, 113–114; repression, 202–203; VMH, 119–120
Transcription factor competition, 109–113
Ultrastructural studies, 105–109
Ventral premammillary nucleus, 11
Ventrolateral portion of VMH (vlVMH): ER mRNA expression in, 30–31; oxytocin effects on electrical activity, 184
Ventromedial hypothalamus (VMH): antisense treatment of, 101; ascending projections from, 42; AVP neurons in, 181; descending projections from, 42–43; effects of arousal-related neurotransmitters, 216; ER, PR, and TR presence in, 116; ER-α gene, 133–134; estrogen sensitivity of transcriptional systems, 118–120; histamine-induced change in membrane potential, 217f; histone modifications in, 114; NO and NADPH diaphorase in, 102; patterns of gene expression, 133; PPE mRNA expression in vlVMH, 98; projections to MCG, 42–44; ventrolateral subdivision of, 42
