Biological Neuroscience: Chapter 7

Hormones: The other chemical messenger
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Hormones are partially or wholly responsible for the following behaviors/characteristics/processes:

-Anatomical differences and developmental changes

-Organizing effects:
-Expression of primary and secondary sex differences

-Conception, pregnancy, lactation

-Sexual differentiation of the brain
-Muscle development

-Self-regulated behaviors

-Activating effects:
-Sexual behavior
-Eating, drinking, voiding
Defining feature of hormone v. neurotransmitter is in how they are released and the type of that are receptors activated

- Not brain vs. body: Both Hormones (e.g., cortisol) and Neurotransmitters act in the brain.

- Not CNS vs PNS: Many neurotransmitters (e.g., acetylcholine) are active in the peripheral nervous system

-Not the substance itself: Some substances can act as both neurotransmitters and neurohormones (e.g., epinepherine, cortisol)
- Hypothalamus --> Gonadotropin-Releasing hormone (GnRH)

- Anterior pituitary:
- Follicle Stimulating hormone (FSH)
-Luteinizing Hormone (LH)

Follicle Stimulating hormone and Gonadotropin-Releasing hormone --> Reproductive System

- Ovaries: Estrogens, Progesterone

- Testes: Testosterone

- Adrenal glands:Testosterone, Progesterone
Study of the relationship between hormones and the nervous system

First experiment, Berthold (1849):
-Castrated roosters, found that they no longer engaged in sex-stereotyped behavior (e.g., crow, approach females, act aggressively)

-Re-implanted one testicle in the body cavity: reemergence of sex-stereotyped behavior

-Berthold noted that the testis did not reestablish nerve connections.

-Berthold concluded that a chemical produced by the testes and released into the circulatory system influenced sex-stereotyped behavior
Typical brain-hormone connection
-brain --> hormone --> target:organ/tissues

-Brain --> hormone --> endocrine gland --> hormone --> organ/tissue

sexual development:
- Genes (Y chromosome) releases protein or not --> ovaries/testes

-ovaries/testes --> hormones -->
- target in peripheral tissues --> sexual anatomy

- Target in brain --> anatomy AND gender identity
XX, XY: What are the differencesGonads: - Ovaries, Testes Ducts: - XX: Uterus, vagina, fallopian tubes - XY: seminal vesicles, vas deferens External Reproductive organs: -Labia, Clitoris -Penis/Scrotum Secondary sex characteristics: -Breast, shoulders, hips, body hair Brain: -Size, differences in anatomical structures (e.g., hypothalamus, amygdala) and lateralization Behavior: -In humans, it is a matter of degreeThe stages of anatomical sexual developmentConception: XX, XY 6 wks: Primordial gonads --> ovaries/testes 12 weeks: Ductwork --> - Wolfian (male): Vas Deferens, Seminal Vesicles - Mullarian (female): Fallopian Tubes, Uterus *8-15 weeks Bipotential Precursor --> Primary sex characteristics (external genitals) -Penis/Scrotum -Labia, Clitoris 10-13 years (Puberty) Secondary Sex Characteristics: - Breasts, shoulders, hips, body hair *Brains also begin to develop sex differences at 8 WKSHow do you make a man? (5 steps)1. Genes: XY - Gene on Y produces Sry protein signals the primordial gonads. 2. (6 wks) Primordial Gonads Medulla matures into testes - Fetus: 11 cm (shrimp) - Sry protein --> Medulla 3. (12 weeks) Testosterone causes Ductwork to mature into seminal vesicle & vas deferens - Testes secrets testosterone - Testosterone causes Wolfian system to develop into seminal vesicle and vas deferens and testes to descend - Testes also secrete Mullerian-inhibiting substance --> causes Mullarian system to deteriorate 4. (8 weeks) External reproductive organs (penis and scrotum) begin to develop - Testes produce a surge of testosterone which causes the bipotential precursor to morph into a penis and scrotum - At 12-15 weeks you can see sex differences on sonogramHow to become a woman?1. Genes: XX - No Y, no SRY 2. (6 wks) Gonads: Cortex develops into ovary 3. (12 wks) Absence of Testosterone causes Ductwork to mature into Fallopian tubes, uterus, and upper portion of vagina - In the Absence of testes (and thus absence of testosterone & Mullerian inhibiting substance), the Mullerian system develops & Wolffian system deteriorates 4. (8 wks) External reproductive organs (clitoris, labia) begin to develop: - Lack of testes/ testosterone means that the bipotential precursor will develop into female external genitals - 12-15 weeks: sonogram can detect sexAnatomical sexual characteristics from birth until pubertyGonads - Ovaries, Testes Ducts: - XX: Uterus, vagina, fallopian tubes - XY: seminal vesicles, vas deferens External Reproductive organs- not well developed - Labia, Clitoris - Penis/Scrotum Secondary Sex Characteristics - Not presentPuberty (step 5)Caused by a cascade of hormones from the HPA axis - Development of Secondary Sex Characteristics: Body hair, breast & penis development - Hypothalamus: Releases Gonadotropin releasing hormones (GnRH) - --> ovaries/testes --> androgens, estrogens - Both males and females have both androgens and estrogens. - Balance determines the direction of development - "male" vs. "female" sex hormones play important roles in the development of both sexes adrenal cortex --> androgens - Pubic and axillary hair Anterior Pituitary --> Growth Hormone - --> bones/muscle --> growth spurtBrainSex differences: - Hypothalamus (prenatal development: tissue observable ~ 8 wks) - Sexually Dimorphic Nuclei (SDN) control release of sex hormones - Size differences: Male Hypothalamus (particularly pre-optic area) is larger than that of Female. At birth, 20% of adult SDN cells are present. - Determines whether gonadotropins cycle for XX (GnRH initiates ovulation and the menstrual cycle) or remain at a steady state for XY - Human XY: Testes release testosterone which masculinizes the XY hypothalamus - Human XX: Lack (or low levels of) testosterone does NOT masculinize the XX hypothalamus - Corpus callosum: Female> Male -Amygdala Other factors: -XX, XY genetic influences - Both estrogens and testosterone have effects on brain development - Different regions of the brain have receptors for sex hormones - trigger cell growth - dendritic branching - synaptogenesis - regulate the activity at synapsesIntersexA general term used for a variety of conditions in which a person is born with a reproductive or sexual anatomy that doesn't seem to fit the typical definitions of male or femaleWhat causes someone to be intersex?Intersex development is caused by a mis-step in the stages of pre-natal sexual development -The earlier in the process, the more profound the anatomical effectsIntersex developmentStages of prenatal sexual development coincide with prenatal surges of Testosterone - First 12 weeks - XY - Gonads - Ductwork - External genitals - Hypothalamus development Second half of pregnancy - - Further sexual differentiation of brain development Puberty (both estrogens and androgens) - Secondary sex characteristics (puberty) Because brain and body develop at different stages of pregnancy, they are subject to disconnectionGenotypegenetic makeup of an organismPhenotypeAn organism's physical appearance, or visible traits.Mechanisms for Intersex: XYEarly/Genetic Phase: At 6 weeks, if the Y chromosome fails to produce SRY protein - Ovaries would develop instead of testes - Genotype XY, but Phenotype XX - "Streak" Ovaries- non functional - Ductwork: Uterus, vagina, fallopian tubes - Primary sex characteristics: Labia, Clitoris Ductwork Phase I: If testicles failed to develop=NO Testosterone (T) or Mullerian Inhibiting Substance (MIS) - Nonfunctional Testes - Genotype XY, but Phenotype XX - Ductwork: Uterus, vagina, fallopian tubes - Primary Sex Char: Labia, Clitoris Ductwork Phase II: Testicles release T, but ductwork/precursor are Non-responsive to T - Internal Testes: T and MIS secreted - Genotype XY, XX phenotype - Ductwork non responsive to T: No Vas Deferens or seminal vesicles and testes don't descend - Mullarian Inhibiting substance -->No Uterus or fallopian tubes - BP non responsive to T --> Development of Labia, ClitorisMechanisms for Intersex XXEarly Development: If a XX fetus is exposed to testosterone after 6 weeks - Ovaries - Genotype XX, but Phenotype XY - Combination of ductwork - T --> Seminal Vesicles, Vas Deferens Absence of MIS --> fallopian tubes, uterus, vagina - Scrotum, Penis Ductwork Phase: If an XX fetus is exposed to testosterone between 8-15 weeks - Ovaries - Genotype XX, Phenotype ambiguous to XY - Ductwork: Uterus, and Fallopian tubes - BP will develop along male lines—Enlarged clitoris to penisHormonal effects on sexual developmentAlterations in the hormonal environment affect both internal duct work and external sex characteristics Testosterone- develop male duct work and external sex characteristics Mullarian Inhibiting Substance -suppresses development of female ductworkAndrogenic Insensitivity Syndrome (XY)Androgen Insensitivity (AIS) Cause: Mutation of an androgen receptor gene. Androgen receptors unresponsive to normal levels of testosterone Genes: Y produce SRY -->Testes Gonads: Testes (internal) - Testes --> Testes Normal PRODUCTION of both T and MIS - Some/all tissues not RESPONSIVE to T Testes: do not descend Ducts: Ambiguous, absent - MIS --> No uterus and vagina - Insensitivity to T --> NO Vas Deferens and seminal vesicles External genitals: Typical female* - Insensitive to T (just like the absence) typical female external genitals Secondary sex characteristics: Typical female* - Testes --> estrogens (E) --> pubertal development typically proceeds "normally" Gender identity - typically (almost always?) female Hormones: high testosterone levels.Turner Syndrome (XO))Genetics: XO or X (dysfunctional X) Gonads: Ovaries (but may be comprised of fibrous, non functional tissue) Ductwork: Fallopian Tubes, Uterus External Sex Characteristics: Labia, Vagina Secondary sex characteristics. At puberty, the lack of functioning ovaries disrupt pubertal development - primary amenorrhoea (the absence of a menstrual period) - infertility. However, oocyte donation can make pregnancy possible. Gender identity: typically femaleCongenital Adrenal Hyperplasia (CAH) XX or XYCause: Abnormal synthesis of corticosteroids leading to increased exposure to androgens late prenatally and postnatally Genetics: XX or XY Gonads: Genetically concordant Ductwork: Genetically concordant External Sex Characteristics - Male: Typical - Female: Masculinized external genitals (enlarged clitoris, partially fused labia) Secondary sex characteristics develop typically with hormone therapy Gender identity: Somewhat higher incidence of transgender in femalesNon-hormonally caused conditions that affect primary sex characteristics (XY)Cloacal exstrophy: XY born with malformations of bladder, intestines, and penis (penis may be absent). - (Historically) surgically altered to create female phenotype - 35-53% gender dysphoric to transgender Ablatio penis: Penis accidentally damaged during circumcision - Surgically altered to create female phenotype - Stats hard to come byHistorical approaches determining sex"True sex policy": Sex should be determined by the "key biological criterion of sex" - Pre 19th century: External genitalia - Late 19th century: Gonadal histology (do you have testicles or ovaries?) - mid 20th century: Genotype Olympic sports: - Physical examination - Pee-test 1950s - 1996: - chromosome testing late 1990s --> now - hormone testsCisgenderObservable-Anatomical Sex is consistent with self-imageTransgenderIdentification with a gender that does not match one's biological gender.sexual orientationWho you are sexually attracted toWhat causes people to be transgenderDisclaimer: We don't have a definitive explanation about what causes people to have a gender identity that is different from their anatomical sex. Theories - Social environments - Personal Choice - Biologically determined - Prevailing theory is that prenatal hormonal environment can produce changes in the brain independently of changes that affect development of anatomical differences.Intersex, Transgender and Gender DysphoriaIntersex - Someone who has reproductive anatomical features that are inconsistent with genetic sex, or don't fit the typical definitions of male or female - May or may not have GD Transgender - Reproductive anatomical features are consistent with typical male/female lines - Gender identity is discordant with anatomy - DSM V: Gender Dysphoria (GD): "A marked incongruence between one's experienced/expressed gender and assigned gender" - A CNS-limited form of Intersexuality?GD: Prevalence and clinical outcomes- Prevalence: 1 to 5 x 1,000 people Early onset of GD ~ 1 in 5 persist (?) - Late onset-adolescence or adulthoodWhat does it mean to be transgender?NOT - Transvestite : A transvestite is a person who chooses to dress as the opposite gender, for fun or sexual gratification - Drag: Drag Queens/Kings are individuals who dress as the opposite gender for theatrical purposes - Intersex: Physical characteristics that are either ambiguous or discordant with genetic sex IS - A person whose gender identity is different from his/her phenotypic sex.Transgender and sexual reassignmentPrevalence of transgender (estimates vary based on time (1960's -1990's) and country - MTF: 1 in 1500*-100,000 - FTM: 1 in 2800*-400,000 * *Horton's estimates based on US data, circa 2001 Lifetime prevalence of Gender Confirming surgeries (GCSS) for US (based on surgical data from 2001) - MTF: 1 in 2500 - FTM: 1 in 4,200Treatment ProcessesMtoF - Feminizing hormone treatments: antiandrogen and oestrogen - Hair removal - Surgery: orchidectomy, penectomy, labioplasty, clitoroplasty, vaginoplasty, breast augmentation, facial plastic surgery, thyroid chondroplasty FtoM - Masculinizing hormone treatment: testosterone - Surgery: mastectomy, oophorectomy, hysterectomy, vaginextomy, medoidioplasty or phalloplasty, scrotoplasty, urethroplasty, testicular prostheses Most trans people satisfied with surgical/medical procedures - MtoF: 87%, FtoM 97% (in 1990)A Behavioral Neuroscience Hypothesis TransgenderismWorking Hypothesis: - If intersex conditions are caused by sex hormone abnormalities that occur early in development that affect the development of anatomy (gonads/sex organs) - THEN it seems likely that transgender development is caused by sex hormone abnormalities that occur later in development and/or only affect the development of sex differences in the brain - Strongest evidence for the role of the hypothalamusHormones: What and When do sex hormones affect developmentFour known surges of sex hormones: 6-15 weeks: - Physiological development of anatomical sex characteristics - Gonads, ductwork, external sex characteristics Mid pregnancy (late 2nd trimester - 3rd trimester): - Brain differentiation? Post natal period: - In first few weeks post-partum, a surge of T for boys Puberty: - Development of secondary sex characteristics and activation of interest in sexual activityWhat about the effects of hormones post-nataly?Post natal: - Rhesus monkeys-neonatal castration produced no changes in sex-stereotyped behavior Older age: - Testosterone suppression or gonadectomy in men with prostate cancer produces no change in gender identity Conclusion: Postnatal changes in hormonal environment does not appear to have a marked effect on gender identity or at least gender stereotyped activityWhat sorts of things affect gender identity during fetal development?Genetic: - Polymorphisms in Estrogen receptor (ER A and B), androgen receptors, aromatase genes - Aromatase is the enzyme that converts androgens to estrogens - Some of these are on the X chromosome Epigenetics: - The key factor may be when/whether/where genes for receptors are turned on Maternal use of drugs - anticonvulsant drugs: Phenobarbital/diphantoin - Synthetic estrogens: Diethylstilbestrol (DES) Other - Fraternal birth order effectsWhat do we know about sex differences in the brain?48 healthy, caucasian, educated m/f (presumably Cisgendered) Structural MRI Findings: Sexual dimorphisms in adult brains were found in brain regions that have high sex hormone receptor density during early development Differences in brain volume: - F>M: Frontal, paralimbic areas - M>F: Frontomedial cortex, hypothalamus, amygdala, angular gyrusWhy "mid pregnancy" and why Thalamus/hypothalamus?-Development of sex organs is done by ~ 15 weeks -Significant thalamic/hypothalamic development begins late in the first trimester and continues through the second trimester -There are notable sex differences between men and women in the hypothalamus -There are observed differences between transgender/cisgender - Sexual dimorphic nucleus (SDN)/Preoptic Area (POA) - Central subdivision of the Bed nucleus of the strai terminalis (cBST) - Interstitial Nuclei of the Anterior Hypothalamus (INAH)Thalamus and Transsexual menAutopsy study (Zhou et al 1995): - Central subdivision of the Bed nucleus of the strai terminalis of the thalamus (cBST) - Results: (N=6) Density of cBST in M toF transmen less dense than cisgendered men (hetero and homosexual), similar to Female Why this structure? - Known sex differences in humans - Receptors for sex hormones and connections to the hypothalamus - Known to be related to sexual behavior in miceThalamus/hypothalamus and Transsexual menAutopsy study (Garcia-Falgueras, 2008) Interstitial Nuclei of the Anterior Hypothalamus (INAH): - Results (N=42): larger INAH 3 volume in cisM than MtFtranswomen, 2.3 x more cells. Why this structure? - Known sex differences in humans - Receptors for sex hormones and connections to the cBST - Known to be related to sexual behavior in miceWhat are some other neuroscience theories about Transgender?Miscoded Somatosensory map: - Gender could be/probably is included in the somatosensory homunculus - Theory: Transgender map not aligned with phenotype - Evidence (Ramachandron and McGeouch, 2007): -Cisgender men/women who have penilectomy/mastectomy often report phantom penises/breasts - Transwomen (penilectomy) usually do not report phantom penises and Transmen (mastectomy) don't report phantom breasts.Miscoded maps cont.Compared: 8 Transmen to 8 Cisgender women Functional imaging (MEG, DTI): - Compared physical stimulation (tapping) of hand and breast - No difference between groups in brain response to hand tapping - Breast tapping - Transmen (compared to cisgender W): Reduced activation in one region of the somatosensory cortex (supramarginal gyrus) and secondary somatosensory cortex . Heightened activation in medial temporal lobe. - Supramaginal gyrus is part of the somatosensory cortex and plays a role in perception of body in space - Diminished activation in these regions may explain why breasts don't feel like "self" for transmen