FALSE

CRH neurons are VERY sensitive to changes in internal and external environment.

CRF (41 aa polypeptide)= central regulator/integrator of stress response.

Acts as a:

1. Hypophysiotropin (HPA axis; HPT axis particularly in non-mammals)

2. Neurotransmitter and neuromodulator - acts at synapses b/w neurons and modifies actions/sensitivity of neurons on pre or post-synaptic neuron. Affects:

- Locomotion (hindbrain)

- Strongly inhibits appetite

- Increases vigilance and fear (lots of CRF neurons in amygdala)

- Activates autonomic sympathetic system

3. Growth factor, cytoprotective

CRF binding protein produced by...

What is its affinity like?

CRFBP produced by neurons in the hypopituitary system.

Has equal or greater affinity than receptor.

***

CRF is the ONLY neuropeptide with a binding protein!

...CRFBP probably for sequestering CRF in tissues b/c of growth factor roles.

CRF

Urotensin/Urocortin 1

Urocortin 2

Urocortin 3

***

All vertebrate tetrapods and a lot of fish have all 4 of these genes

Wylie Vale first isolated CRF in human brain.

Carl Lederis first isolated Urotensin 1 in fish.

Caudal neurosecretory organ in fish that secretes urotensin 1 and urotensin 2

What is its primary function?

Urophysis

Primary function is osmoregulation

***

Urotensin 1 is CRF-like

Urotensin 2 is Somatostatin-like

Cause vasoconstriction and increased blood pressure.

***

Urotensin 2 found in human brain and may play a role in hypertensive d/os.

CRF binds best with CRFR1 and binds less well with CRFR2

UCN1 binds best with CRFR2 and less well with CRFR1

UCN2 and UCN3 only bind to CRFR2

How do the actions of CRFR1 and CRFR2 differ?

Where is CRFR2 expressed?

What are CRFR1 KO mice like?

CRFR1-->arousal, anxiety-like behavior, activation of HPA axis

CRFR2-->slow, adaptive recovery from stress, appetite suppression, regulation of HPT axis in non-mammals

CRFR2 expressed in TSH cells of anterior pituitary and feeding control center

CRFR1 KO mice are much less anxious and take more risks

GC effects on:

PVN

Pituitary

Amygdala

Hippocampus

GC--|PVN

GC--|Pituitary

GC-->Amygdala

GC-->Hippocampus

***

Mediated through classical nuclear receptors (slow) but also can work rapidly thorugh membrane receptors.

GC w/ CRF promoter (turns it off)

Corticosterone increases CRF mRNA expression in amygdala but decreases in PVN

CRFR1 KO mice -->

CRFR2 KO mice -->

CRFR1 KO mice --> "mellow mice"

CRFR2 KO mice --> "neurotic mice"

What are the effects of glucocorticoids on:

LH and FSH

TSH

GH

Plasma glucose

Visceral obesity

Linear growth

Immune activity

Decreases LH, FSH, TSH, GH

Increases plasma glucose, insulin resistance, gluconeogenesis (but decreases uptake by skeletal muscle so it can go to brain)

Increases visceral obesity

Decreases linear growth

Decreases immune activity - anti-inflammatory

Hindbrain (preganglionic neurons) secrete ACTH at spinal cord

Spinal cord secretes ACh at the adrenal medulla (postganglionic neurons of the SNS)

Adrenal medulla secretes EPI

Spinal cord also secretes NE at the heart

L-Tyrosine --(Tyrosine hydroxylase)-->L-DOPA

L-DOPA --(Dopa-decarboxylase (AADC))-->DA

DA--(DA-beta-hydroxylase)-->L-NE

L-NE--(PNMT enzyme)-->EPI

What are NE and EPI broken down by?

Monoamine oxidases (MAO)

Catechol0-O-methyltransferase (COMT)

***

90% removal by reuptake by site of origin...only small fraction getsw out to circulate.

MAO and COMT expressed locally in adrenal medulla

2nd way of removal= by liver which has MAO

3rd= conjugate with sulfates or glucuronides and excretion from kidney

Increased heart rate (more blood to the brain)

Increased vasoconstriction in relation to digestion

Increased vasodilation in skeletal muscle and lungs

Increased glycogenolysis

Affects of CHRONIC stress on:

Muscle cells

Immune function

Reproduction

Blood pressure

Memory and learning

Chronic stress -->

Muscle cell apoptosis

Suppression of immune system

Suppression of reproduction

Hypertension

Impaired memory and learning

also

Depressive d/os

Neurodegeneratoin

Hirsitism and Virilism in women

How does EPI affect:

Liver

Pancreatic Islets

Muscle

Fat

Liver: increase beta2 activity to increase glycogenloysis and gluconeogenesis

Pancreatic Islets: decreases alpha activity (insulin) and increases beta activity (glucagon)

Muscle: increases beta2 activity to increase glycolysis and decrease glucose transport

Fat: increase beta1,2,3 activity to increase lipolysis

All leads to an increase in plasma glucose

How does acute stress response affect:

Cardiovascular tone

Non-essential functions like appetite and reproduction

Immune system

Cerebral blood flow and glucose utilization

Energy mobilization

Memory consolidation

Increased cardiovascular tone

Decreased non-essential functions

Increased immune system

Increased cerebral blood flow and glucose utilization

Increased energy mobilization

Increased memory consolidation

Increased catecholamines, CRF, ACTH, GCs, AVP, and Renin

Decreased gonadoptropins and gonadal steroids

What causes Addison's disease?

What are the symptoms?

Primary adrenocortical insufficiency

Mostly autoimmune and generally occurs later in life

rare

Weaknesss and fatigue

Nasuea and vomiting

Hypotension

Hypoglycemia

What is Cushing's disease?

Most common cause?

Chronic glucocorticoid excess

Can occur from abnormalities from adrenals or pituitary. Most commonly ACTH dependent, but can be ACTH independent.

--> Obesity

skin changes (atrophy of epidermis)

Hirsutism

Gonadal dysnfunction

Psychological d/os

Muscle weakness

Most common cause= tumor in pituitary that secretes too much ACTH

..sometimes tumor in adrenal cortex

Caused by excessive adrenal or ovarian androgen secretion or excessive conversion of androgenic precursors in peripheral tissues

Hirsutism due to MILD elevation in androgens (adrenal overproduction or peripheral conversion).

Virilism due to SEVERE overproduction of androgens --> baldness, muscle enlargement, deepening of voice, clitoral enlargement...

The GOOD - stress hormones can accelerate development if present AFTER a critical developmental stage.

The BAD - stress hormones retard growth and development if present BEFORE a critical developmental stage.

Maternal malnutrition --> increased glucocorticoids --> growth retardation --> increased food intake as juvenile/adult to catch up with growth - hyperreactive stress axis and insulin resistance syndrome

***

Increased GCs-->decreased GCR in hippocampus-->increased appetite, catch up growth, and hyperreactive stress axis