Neuroendocrinology

Hormones Endocrine hormones Secreted directly into the blood Controlled by pituitary (master gland) and hypothalamus Exocrine Hormones Secreted into ducts Not controlled by pituitary gland or hypothalamus (e.g., gut hormones)

Hormones Neurotransmitters long latency, long duration of effect (mins/days) short latency, short duration of effect (msec) delivered via blood released directly onto target cells diffuse actions specific actions released from endocrine cells released from neurons This distinction has become blurred; e.g. peptide neurotransmitters/neuromodulators, monoamines, etc.

Pituitary Gland (Hypophysis) Anterior Pituitary (Adenohypophysis) Posterior Pituitary (Neurohypophysis)

Endocrine Hormones` Neurohypophysial hormones Oxytocin Vasopressin Adenohypophysial hormones Direct Actions Prolactin Melanocyte-stimulating hormone (MSH) Somatotrophin (growth hormone; GH) Indirect actions Thyrotrophin (TSH) Corticotrophin (ACTH) Gonadotrophins Luteinizing Hormone (LH) Follicle-stimulating hormone (FSH)

Hypothalamus Adenohypophysis Endocrine Gland Target tissues Control of Adenohypophysial Hormones with Indirect Actions Indirect Loop Short Loop Direct Loop Releasing Factor Trophic hormone Endocrine hormone All loops are negative feedback loops. Increases in the amount of the substances monitored reduces further secretion of those substances. neural inputs Indirect Acting ACTH, TSH, LH, FSH

Hypothalamus Adenohypophysis Target tissues Control of Adenohypophysial Hormones withDirect Actions Indirect Loop Inhibiting factor Direct Loop Releasing Factor All loops are negative feedback loops. Increases in the amount of the substances monitored reduces further secretion of those substances. neural inputs Direct Acting GH, MSH, Prolactin Direct Acting Hormone

Endocrine Hormones Adenohypophysial hormones Direct Actions Somatotrophin (growth hormone; GH) Growth hormone releasing hormone (GHRH)  somatotrophin (GH)  somatic tissues promotes growth by stimulating proteins synthesis of virtually all tissues GH release inhibited by somatostatin

Endocrine Hormones Adenohypophysial hormones Direct Actions Prolactin Somatotrophin (growth hormone; GH) prolactin release inhibited by prolactin inhibiting factor (PIF) PIF secretion inhibited by stimulation of nipples stimulates milk production Prolactin releasing factor  prolactin  mammaries

Endocrine Hormones Adenohypophysial hormones Direct Actions Prolactin Melanocyte-stimulating hormone (MSH) Somatotrophin (growth hormone; GH) MSH releasing factor  melanocyte-stimulating hormone  melanocytes stimulates melanin synthesis in melanocytes

Hypothalamus Adenohypophysis Endocrine Gland Target tissues Control of Adrenocortical Hormones Indirect Loop Short Loop Direct Loop Corticotrophin (ACTH) Cortisol and Aldosterone neural inputs CRF

Endocrine Hormones Adenohypophysial hormones Direct Actions Prolactin Melanocyte-stimulating hormone (MSH) Somatotrophin (growth hormone; GH) Indirect actions Corticotrophin (ACTH) regulates stress hormones and nutrient utilization (glucocorticoids) and water/mineral balance (mineralocorticoids)

Endocrine Hormones Adenohypophysial hormones Direct Actions Prolactin Melanocyte-stimulating hormone (MSH) Somatotrophin (growth hormone; GH) Indirect actions Corticotrophin (ACTH) Corticotrophin releasing factor (CRF) ===> corticotrophin ===> cortisol, aldosterone ===> tissues cortisol inhibits protein synthesis stimulates gluconeogenesis (synthesis of glucose from proteins) inhibits conversion of carbohydrates to fats aldosterone regulates electrolytes, especially sodium principal stress hormone physiological stress—challenges to homeostasis psychological stress—perceived challenges limbic system participation

Corticotrophin Controls secretions from adrenal cortex ad = on, renal = kidney, so adrenal = on the kidney

the adrenal gland is really two glands in one cortex = bark, medulla = core medulla is a modified sympathetic ganglion cortex is an endocrine gland Activity of both medulla and cortex are stress-related

What is stress?

I t is “a real or interpreted threat to the physiological or psychological integrity of an individual that results in physiological and/or behavioral responses. In biomedicine, stress often refers to situations in which adrenal glucocorticoids and catecholamines are elevated because of an experience.” McEwen, B. (2000) In G. Fink (Ed.) Encyclopedia of Stress, Vol. 3. San Diego: Academic Press.

What is stress? Is it a demanding stimulus or situation? “I’m under a lot of stress.” Is it a subjective experience? “I’m feeling stressed out.” depression Is it a physiological challenge? hunger, thirst, fatigue Is it an endocrine response? circulating stress hormones

Two types of stress 1. Systemic stress physiological threat 2. Processive stress potential or eventual threa t In adults, responses to processive, but not systemic, stress is blocked by lesions of the hippocampus Systemic stress is also referred to as physiological stress, and processive stress is oten referred to as psychological stress

Endocrine Hormones Adenohypophysial hormones Direct Actions Prolactin Melanocyte-stimulating hormone (MSH) Somatotrophin (growth hormone; GH) Indirect actions Thyrotrophin (TSH) Corticotrophin (ACTH) Thyrotrophin releasing factor (TRF or TRH)  thyrotrophin (TSH)  thyroid gland  thyroxine  tissues regulates development regulates metabolic rate in adulthood

Hypothalamus Adenohypophysis Thyroid Gland Target tissues Control of Thyroid Hormones Indirect Loop Short Loop Direct Loop TRF (TRH) TSH Thyroxine (T 4 ) neural inputs

Thyroid Hormones as Regulators of Development Stimulation of Metamorphosis in Amphibians iin brain, thyroid hormones stimulate secondary neurogenesis of cerebellar Purkinje cells, development of optic tectum e.g. loss of gills, septation of lungs remodeling of gastrointestinal tract loss of tail, growth of limbs Thus, thyroxine stimulates both cell loss (apoptosis) and cell proliferation (mitosis) in different populations

Thyroid Hormones as Regulators of Development Thus, thyroxine stimulates both cell loss (apoptosis) and cell proliferation (mitosis) in different populations. This role contrasts with that of growth hormone. In the absence of growth hormone, tadpoles still undergo metamorphosis but have reduced size. In the absence of thyroxine, tadpoles continue to grow but fail to transform.

Analogous Effects are seen in mammals In mammals, growth hormone deficiency results in dwarfism; thyroid hormone deficiency results in cretinism. Dwarves reach developmental milestones at the normal time; they are simply of shorter stature. Hypothyroid individuals are also small, but more profoundly, developmental milestones are greatly delayed.

15-20 years old, Congo-Kinshasa

Endocrine Hormones Adenohypophysial hormones Direct Actions Prolactin Melanocyte-stimulating hormone (MSH) Somatotrophin (growth hormone; GH) Indirect actions Thyrotrophin (TSH) Corticotrophin (ACTH) Gonadotrophins Gonadotrophin releasing hormone (GnRH) or Leuteinizing hormone releasing hormone (LHRH)  luteinizing hormone (LH) and follicle stimulating hormone (FSH)  gonads (ovaries or testes)  estrogen and progesterone or androgens  tissues organizational effects activational effects

Definitions of Sex Genetic (XX vs XY Gonadal (ovaries vs testes) Hormonal (cyclic vs constant release Morphological (clitoris, labia vs penis, scrotum) Behavioral (gender role behavior) Identity (what you consider yourself to be)

Hypothalamus Adenohypophysis Testes (♂) Ovaries (♀) Target tissues (GnRH) Luteinizing Hormone (LH) Follicle Stimulating Hormone (FSH) Testosterone (♂) Estrogen/Progesterone (♀) Control of Sex Hormones neural inputs

Sexual Dimorphisms Phenotypic differences between males and females They can be: anatomical physiological behavioral cognitive They can be: qualitative quantitative

Effects of Sex Hormones Organizational Effects structural sensitive period irreversible masculinization/defeminization Activational Effects act on existing structure no sensitive period reversible

Bipotential tissues—those that can differentiate into tissues typical of either sex

Bipotential tissues: Undifferentiated tissue that can differentiate into either a male or female form. Sexual Dimophisms: Structures, functions or behaviors that differ qualitatively or quantitatively between the sexes.

Castrate male hamster at birth Prototypical Experiment (Males) (before period of brain differentiation) Test in adulthood place with receptive female inject with testosterone male typical behavior low mounting, intromission (ejaculation not possible) female-typical behavior high darting, ear-wiggling, lordosis place with male inject with estrogen and progesterone

Neuter female hamster at birth and inject with testosterone Prototypical Experiment (Females) (before period of brain differentiation) Test in adulthood place with receptive female inject with testosterone male typical behavior high (mounting) female-typical behavior low (ear-wiggling, darting, lordosis) place with male inject with estrogen and progesterone

Differentiation of the Brain Masculinization Induction of male characteristics paradoxically, dependent on estradiol Defeminization Suppression of female characteristics Two processes both are dependent of fetal androgens

estrodiol aromatase5-alpha reductase cholesterol DHT

Why aren’t all females masculinized? α-fetoprotein binds to estradiol extracellulary and prevents entry into cell

♁ ♂ medial preoptic area (MPOA) = “the” sexually dimorphic nucleus (SDN)

Sexual Differentiation Female is the “default sex;” no sex hormones are required for normal organization of the brain or peripheral tissues. Male development requires that testosterone be secreted from the fetal testes during a sensitive period of development. Masculinization and defeminization of the brain requires the conversion of testosterone to estradiol by neurons of the brain. Masculinization of peripheral tissues requires conversion of testosterone to dihydrotestosterone (DHT).

Sexual Dimorphisms Phenotypic differences between males and females They can be: anatomical physiological behavioral cognitive They can be: qualitative quantitiave

estrodiol aromatase5-alpha reductase cholesterol DHT

XX Congenital Adrenal Hyperplasia (CAH)

estrodiol aromatase5-alpha reductase cholesterol DHT

Female Spotted Hyena

estrodiol aromatase5-alpha reductase cholesterol DHT

estrodiol aromatase5-alpha reductase cholesterol DHT

Endocrine Hormones Adenohypophysial hormones Direct Actions Prolactin Melanocyte-stimulating hormone (MSH) Somatotrophin (growth hormone; GH) Indirect actions Thyrotrophin (TSH) Corticotrophin (ACTH) Gonadotrophins LH and FSH stimulate ovulation in females and spermatogenesis in males Gonadotrophin releasing hormone (GnRH) or Leuteinizing hormone releasing hormone (LHRH)  luteinizing hormone (LH) and follicle stimulating hormone (FSH)  gonads (ovaries or testes)  estrogen and progesterone or androgens  tissues Testosterone masculinizes and defeminizes fetus Produce secondary sex characteristics and activate gender-typical behavior

1. LH and FSH stimulate follicular development 2. Developing follicles secrete estrodiol 3. Increasing estrodiol stimulates GnRH release 4. LH surge stimulates ovulatoin 5. Luteinized cells secrete estradiol, progesterone 6. Luteinized cells degenerate.

Gladue, Green & Hellman,(1983), Science, 225,

♁ ♂ medial preoptic area (MPOA) = “the” sexually dimorphic nucleus (SDN)

Correspond to MPOA of rodents

Endocrine Hormones Neurohypophysial hormones Oxytocin Adenohypophysial hormones Direct Actions Prolactin Melanocyte-stimulating hormone (MSH) Somatotrophin (growth hormone; GH) Indirect actions Thyrotrophin (TSH) Corticotrophin (ACTH) Gonadotrophins Luteinizing Hormone (LH) Follicle-stimulating hormone (FSH) stimulation of cervix, nipples ===> oxytocin primes maternal behavior stimulates milk ejection

Endocrine Hormones Neurohypophysial hormones Oxytocin Vasopressin Adenohypophysial hormones Direct Actions Prolactin Melanocyte-stimulating hormone (MSH) Somatotrophin (growth hormone; GH) Indirect actions Thyrotrophin (TSH) Corticotrophin (ACTH) Gonadotrophins Luteinizing Hormone (LH) Follicle-stimulating hormone (FSH) low blood pressure  vasopressin (ADH) kidneys retain more water

Endocrine Hormones Neurohypophysial hormones Oxytocin Vasopressin Adenohypophysial hormones Direct Actions Prolactin Melanocyte-stimulating hormone (MSH) Somatotrophin (growth hormone; GH) Indirect actions Thyrotrophin (TSH) Corticotrophin (ACTH) Gonadotrophins Luteinizing Hormone (LH) Follicle-stimulating hormone (FSH)