Exam 4: Hormones and affective disorders Flashcards
How can hormones influence affet?
Can lower the threshold for the appearance of maladaptive behaviors and feelings in humans
What are affective disorders?
mental disorders characterized by “atypical” behaviors or moods, dramatic changes or extremes of mood
Hormones are strongly associated with many affective disorders but, in particular:
- Depression and postpartum depression
- Perimenstrual (premenstrual) syndrome (PMS)
- SAD
- Anabolic steroid-induced psychosis (“roid rage”)
- Anorexia and bulimia
Bipolar depression
vs
Unipolar deprssion
Bipolar: depression in the presence of at least one episode of mania (excessively elevated mood)
Unipolar: depression in the absence of mania
What are the 2 ends of a mood “continuum”
depression and mania
Mood changes that persist for a long time considered clinically significant
Major depressive disorder: severe symptoms for >2 weeks
Persistent depressive disorder (dysthymia): less severe symptoms for >2 years
How are mice depression tests validated?
Face validity: does mouse behavior look like human behavior?
Construct validity: is the mechanism causing the behavior in the mouse the same as that which underlies the human behavior?
(ex: humans don’t move because they are sad. Mouse not moving because blocking its spinal cord)
Predictive validity: can the response of the mouse predict the response of the human (i.e., if the behavior changes in a mouse given antidepressants, will it change in humans given antidepressants?)
What are the tests to measure depression in a mouse?
- Forced swim test: mouse placed into cylinder of room temperature water and time mouse spends immobile is measured
- Tail suspension test: a mouse is suspended upside down by the tail and time spent immobile is measured
- Sucrose preference test
Forced swim test interpretation and validity
Interpretation: a mouse that spends more time immobile than swimming is in a state of “behavioral despair”
Okay face validity: immobile mice look like they’ve given up, though this is anthropomorphic
Poor construct validity: mouse could just be saving energy, not in despair
Good predictive validity: antidepressants reduce immobility time, and do so better than other kinds of drugs
Tail suspension test interpretation and validity
Interpretation: a mouse that spends more time immobile than struggling is in a state of “behavioral despair”
Okay face validity: immobile mice look like they’ve given up, though this is anthropomorphic
Poor construct validity: the mouse could actually just be saving energy, not in despair
Good predictive validity: antidepressants reduce immobility, do so better than other kinds of drugs
Sucrose preference test interpretation and validity
Interpretation: mice should prefer sugar water, mice that don’t are exhibiting anhedonia
Great face validity: similar tests in humans yield similar results (depressed humans don’t show a preference)
Good construct validity: probably more evolutionary overlap in mechanism for preferring sucrose
Good predictive validity: antidepressants rescue sucrose preference
Before: mouse greatly preferred sugar. When depressed, do not care at all which one it gets
HPT axis
TRH stimulates the release of thyroid-stimulating hormone (TSH) from the pituitary, stimulates thyroid hormone (T3 and T4) production from the thyroid gland
Thyroid function in depressed patients
Have reduced thyroid function
Less TSH is released from the pituitary in response to endogenous or exogenous TRH
What happens when TRH injection given to depressed patients?
significantly reduces depression scores on a mood assay (but duration of effect varies from hours to weeks)
Thyroid hormone can reduce inhibitory serotonin receptors and increase excitatory serotonin receptors:
Hypothyroid animals have decreased brain serotonin levels
Thyroid hormone injection increases brain serotonin
T3 accelerates the antidepressant response when used in combination with SSRIs
SSRIs: prolong serotonin presence; thyroid hormone marks those synaptic receptors excitatory)
HPA axis in patients with major depressive disorder
HPA is disinhibited:
* high gcc levels
* failure to respond to DEX suppression test
* high [CRH] in csf
* blunted ACTH release in response to CRH injection
* Disturbed circadian regulation of gcc release
Dysfuncitonal beause reduced gcc negative feedback
Timing of glucocorticoid release in patients with major depressive disorder
Timing disrupted
Non-depressed subjects: strong circadian regulation, released each day in the early morning
Depression: rises soon after sleep onset (when stress is presumably low) and steadily decreases during the day (when stress is presumably high)
Depressed patients have: higher baseline, earlier peak, and lower amplitude (peak-trough) glucocorticoid rhythms compared to non-depressed controls
Glucocorticoid system in depressed patients is dysfunctional: Higher, not so much of a peak (weaker signal), and shifted so it occurs at the wrong time
Dexamethasone suppression test
- administration of the synthetic glucocorticoid dexamethasone (DEX) at midnight normally enhances HPA axis negative feedback and suppresses endogenous glucocorticoid levels for 24 h
- Should produce NO cortisol
What 2 diseases are comorbid with depression?
- Cushing’s syndrome (hypercortisolism)
- Addison’s disease (hyporcortisolism)
what is likely the primary factor of depression?
dysregulated glucocorticoid production
When do women experience depression at nearly 2x the rate of men?
Rodent evidence
after puberty and before menopause (during reproductive years)
Rodents show increased depression-like behavior during metestrus/diestrus (low estrogen) and when ovariectomized, behavior can be rescued with estradiol implant
Fluctuations in …….. are associated with depression
ovarian hormones (estrogen, progesterone)
Effect of estrogen on women’s depression
- Extremely high levels of estrogen (15-20x therapeutic dose) gretly improves mood in >90% of women with severe depression
- Physiological levels of estrogen improve mood in non-depressed women but not in clinically depressed women
- Depressed women have significantly lower levels of estrogen than non-depressed women
- Estrogen withdrawal correlated with depression: depressed women treated with estrogen then switched to a placebo significantly increase their depression symptoms
- If depressed, estrogen withdrawal is worse
How do estrogen and antidepressants have similar effects on molecular pathways in the brain?
Upregulate: BDNF, CREB, TrkB; promote synaptic function
Downregulate: GSK3; inhibit synaptic function
Together these effects lead to a potentiation (strengthening) of synapses in the hippocampus and cortex
What have most studies concluded about impariment in women in menstruation
not detected any significant impairments in most women (~3% of women experience PMS symptoms to a degree that it interferes with normal functioning)
Why does prevalence of PMS vary widely?
- 20-90%
- Differences in criteria used to define PMS, all PMS data are based on self-reports (retrospective or prospective)
DSM-V criteria for premenstrual dysphoric disorder (PMDD)
much more strict (>5 symptoms present in most menstrual cycles over the past year, seriously interferes with normal functioning, not the exacerbation of another mood disorder)
and prevalence is much less (5-10%)
When do most mood changes with PMS occur?
during late luteal phase, when progesterone is high and estrogen is low
PMS and progesterone
No consistent relationship: women with PMS have higher progesterone 10 days prior to menstruation, but no difference in progesterone 4 days prior to menstruation
PMS and allopregnanolone (progesterone metabolite)
affect GABA (inhibitory) neurons by binding to benzodiazepine receptors (enhance the inhibitory effects of GABA)
Benzodiazepine withdrawal associated with elevated moodiness and aggressiveness
Women with higher levels of progesterone
may experience greater “withdrawal” from progesterone-mediated benzodiazepine activation
Progesterone treatment
vs
Progesterone treatment + thyroid hormonet treatment
Progesterone treatment: alleviates some but not all PMS symptoms
Combined with thyroid hormone treatment: alleviates most depressive symptoms of PMS
What does completely preventing sex hormone cycling do?
abolishes PMS symptoms
What does GnRH agonist treatment do?
Eliminates menstrual cycles and significantly reduces PMS symptoms
but symptoms persist when given GnRH agonist + estrogen or progesterone
How do sex steroid concentrations differ between women with PMS symptoms and those without symptom?
DO NOT DIFFER
differences in target tissue sensitivity and/or abnormal responses to normal concentrations of sex steroids
When do mood changes occur in women with PMS?
when sex steroid concentrations change
(do not affect women without PMS)
Menopause and depression relationship
- Menopause is associated with an increased risk of depression
- depressed women undergo earlier menopause
Perimenopause
neuroendocrine state from menopause and postmenopause
Estrogen replacement therapy or combined estrogen/progesterone replacement therapy on depressed women during perimenopause and postmenopause
perimenopause: greatly improves mood
postmenomause: has little effect
Estrogen’s ability to treat depression work best when hormone levels are steady
β-endorphin (endogenous opioid) levels during pregnancy
- constant during the first two trimesters
- rise rapidly during the third trimester
- peak during parturition
- drop immediately afterwards
Who had highest incidence of post partum depression and anxiety symptoms?
Women who had the greatest decrease in B-endorphin levels
Why are higher levels of CRH correlated with a higher risk of postpartum depression?
Rat study
Placenta makes more CRH
High levels of placenta-derived CRH in pregnant rats lead to changes in neuron connectivity in cortex, increased depression-like symptoms, and decreased maternal care
candidate genes and pathways involved in postpartum depression
Estrogen receptor α (ERα)
Estrogen treatment reduces the risk of developing, and decreases symptoms of, postpartum depression in women
Withdrawal of reproductive hormones (estrogen, progesterone) by ovariectomy or by ending pseudopregnancy in rodents? How can it be reduced?
Enough to induce depression-like behaviors
Behaviors can be reduced with estrogen or allopregnanolone (progesterone metabolite) treatment
Allopregnanolone withdrawal
- Allopregnanolone is a GABAA receptor agonist like benzodiazepines: sudden decrease in (prolonged) GABA agonist leads to withdrawal symptoms (like with perimenstrual syndrome)
Decreasing the activity of estrogen receptor alpha (ERα)-expressing GABAergic neurons in POA
increases depression-like behaviors in mice undergoing estrogen and progesterone withdrawal
Increasing the activity of POA ERα+ GABAergic neurons
decreases depression like behaviors in mice undergoing estrogen and progesterone withdrawal
What do POA ERα+ GABAergic neurons project to?
Dopaminergic neurons in the VTA: increase dopamine release through disinhibition
Serotonergic neurons in the dorsal raphe nucleus : increase serotonin release through disinhibition
Depressive symptoms are common in men with
hypogonadism (clinically low testosterone)
Middle-aged, non-depressed men with low testosterone levels have ………. likelyhood of developing depression
higher likelihood
Testosterone therapy in men with “normal” levels of testosterone
can lead to mood disorders including depression!
Why do people use anabolic steroids?
greatly enhance body tissue growth and inhibit or reverse catabolism
Side effects of anabolic steroids
- cardiac hyperthorphy (sudden heart attack)
- Roid rage (extremely aggressive behavior)
Most comon self-reported mood disorder among male bodybuilders that abuse anabolic steroids
Mania
…….to………… association between anabolic steroid abuse and involvement in violent behaviors in young males
moderate to strong
Testosterone on different species
increases aggression (but not motivation to fight) in male rats
increases aggression (but not increased body mass) in male hamsters
increases aggression in female (but not male) mice
Potential mechanism for testosterone and aggression
Anabolic steroids reduce serotonin signaling in brain circuits (VMH) that regulate aggression
How does synapse potentiation work in males vs females
Males: through Erα
Females: through ERβ
What does a single dose of intravenous allopregnanolone do?
Significantly reduces postpartum depression symptoms; persists for >1 month after treatment.
Alterations in brain connectivity/genes seen in
- patients with depression
- also differ between men and women
Between depressed men and women, who was more social avoidance?
Women
Why are sex differences difficult to model in rodents?
because rats and laboratory mice are social animals where females experience little social stress
Male vs female california mice territorial aggression
Both engage in territorial aggression –> experience social stress
Social defeat
intruder mouse placed in the cage of an aggressive resident to induce stress in the intruder
Social defeat in california mice
Leads to reduced social interaction for a few days in male but weeks in females
What does social defeat stress do in the brain?
- activates oxytocin neurons in the BNST in males and females
- active for >10 weeks in females, but not males – sex difference in enduring effect of social stress on neuronal sensitivity
Oxytocin in mice
- Genetically knocking down oxytocin or blocking oxytocin receptors prevents the persistent effect of social defeat on behavior
- Pharmacologically activating oxytocin receptors mimics social defeat in unstressed females, but increases social interaction in unstressed males
Intranasal oxytocin after a social stress test
Women with major depression
- oxytocin after a social stress test: increases feelings of distress in women but reduces distress in men
- Women with major depression: typically have elevated oxytocin levels in their blood
What is learned helplessness and what can induce it?
- a failure to control aversive events – in rodents and humans
- repeated shocks
What does inescapable stress do?
- activates serotonin neurons in DRN
- provides “behavioral immunization” against future inescapable stress exposures due to strengthened prelimbic cortex inputs to the DRN (only in males because escapable stress does not activate the prelimbic cortex in females)
Stressor controllability does not seem to promote resilience to stress in females- could explain the lower rates of major depression in men compared to women
Exposure to repeated stressors
- more rapidly induces anhedonia in female rodents (6 days) than male rodents (21 days)
- cause more epigenetic changes to dopaminergic reward circuits (nucleus accumbens,) in
females: increases expression of DNA methyltransferase, promoting DNA methylation and reducing gene expression
How do repeated stressors influence dopaminergic reward circuit?
- Reduce the activity of VTA dopamine neurons more in females
- fMRI measurements of NAc activity in humans do not show significant differences between men and women
SAD
- patients exhibit symptoms 6 months out of phase in the Northern and Southern hemispheres
- Unique from unipolar depression: hyperphagia (excessive eating), carbohydrate cravings, hypersomnia (excessive sleeping)
- Sometimes considered “atypical bipolar disorder”: patients often regain energy, become manic during summer
- Prevalence ~5-10%, more in higher latitudes, women > men
SAD phase shift hypothesis
SAD may involve improperly entrained (synchronized) circadian rhythms
Standard treatment for SAD
- phototherapy (bright light therapy), when given during the early morning can realign mistimed circadian rhythms and improve mood
- Light treatment in the evening has little or no effect: light in the morning causes a phase advance (shifts circadian rhythms earlier in the day)
- Experimental phase advances (but not phase delays) can temporarily alleviate depression in depressed patients
- Phototherapy shifts circadian rhythms (and improves mood) by altering the timing of melatonin release
- Melatonin is normally released from the pineal gland at night in both nocturnal and diurnal animals
Onset of melatonin rhythms in SAD patients
two hours later than in controls
- Morning phototherapy phase advances SAD patient melatonin rhythms to that of controls
- Exposure to light at night to inhibit melatonin secretion- Light can both entrain (synchronize) the daily melatonin rhythm and acutely suppress melatonin secretion
Unlike many other mammalian species, humans require ………… to suppress nighttime levels of melatonin
bright light levels (>~2,500 lux)
Anorexia nervosa genetic component
- Reduction in levels of serotonin transporter and serotonin receptor genes leading to a resistance to SSRIs
- More SNPs, mutations, in AgRP gene that lead to an impaired suppression of melanocortin receptor (normal suppression leads to a desire to seek out food during fasting/starvation)
- Twin studies have found a heritability of >50%
How is anorexia nervosa influenced by hormones?
- ovarian hormones: levels of the “drive for thinness,” body dissatisfaction, and dietary restraint vary across menstrual cycle and are typically greatest when progesterone levels are highest
- When starving, endocrine system changes
- Patients have extremely low levels of GnRH and sex steroids, can be restored by normalization of body mass
- Decreased levels of thyroid hormone, elevated levels of glucocorticoid release (hypercortisolism), decreased levels of leptin and insulin
Treating patients with anorexia with leptin
(“starvation hormone”) does not fully reverse low body mass
What is binging phase associated with in menstrual cycle?
low estrogen and elevated progesterone during the menstrual cycle
Reproductive dysfunction less severe in patients with …………
bulimia than patients with anorexia
likely because patients are typically in a normal weight range
Bulimia nervosa hormones
- Slightly elevated levels of glucocorticoids (dysregulation of CRH and ACTH secretion) and GH
- In binging phase (but not purging phase), have significantly less thyroid hormone
- Insulin and leptin levels typically normal
Both luteal: low estrogen and high progesterone
