Module I - Depression

Question 1

What is stress in biological terms?

Answer 1

• The disruption of homeostasis through physical or psychological stimuli - When person-environment transactions lead the individual to perceive a discrepancy, whether real or not, between the demands of a situation and the resources of the person’s biological, psychological or social systems. How we perceive an event is more predictive of our response to the stressor, than the event itself - Loss of control on its environment (uncertainty, not able to predict or influence its relevant environment)

Question 2

Acute stress:

Answer 2

state of the organism after a transient decrease in the predictability of and/or influence of relevant environmental factors

Question 3

Chronic stress:

Answer 3

state of the organism after a tonic
decrease in the predictability of and/or influence
on relevant environmental factors

Question 4

Salye’s 3 phases of the physiological response to stress:

Answer 4

1. Alarm phase - adrenaline, cortisol release
2. Adaptation/resistance phase - e.g. adrenal
   hypertrophy
3. Exhaustion phase - e.g. ulcers, infection

Question 5

Immediate physiological consequences of the stress response:

Answer 5

• increased cardiovascular tone
• immune activation
• energy mobilization
• Loss of pro- and receptive sexual behaviors; loss of erection
• Water retention and vasoconstriction
• Increased cerebral blood flow and
  cerebral glucose utilization
• Enhanced memory consolidation
• loss of appetite

Question 6

The autonomic response to stress:

Answer 6

• A novel stressful stimulus, once perceived, is relayed from the sensory cortex of the brain through the hypothalamus to the locus coeruleus (LC) in the brain stem
• Increased rate of noradrenergic (NA) activity in the LC makes the subject to become alert and attentive to the environment
• LC/NE system
• If a stimulus is perceived as a threat, a more intense and prolonged discharge of the LC activates the sympathetic division of the ANS
• This activation is associated with specific physiological actions in the system, both directly and indirectly through the release of adrenaline and to a lesser extent noradrenaline from the medulla of the adrenal glands
• The release is triggered by acetylcholine (ACh) released from preganglionic sympathetic nerves

Question 7

GRs vs MRs

Answer 7

MRs:

Question 8

Corticosteroid receptor activation can enhance or inhibit the expression of target genes by:

Answer 8

1) a direct interaction with glucocorticoid response
elements (GRE) in their DNA promoter regio
(2) the interaction with other transcription factors, such as cjun, AP1, NF-B, the TFIID complex, STAT5, or CREB

Question 9

Acute stress-related projections from the central amygdala:

Answer 9

• Lateral hypothalamus (Preganglions in brain stem and spinal chord ~ sympathetic activation)
• Locus Coeruleus ~ arousal
• Medial hypothalamus (Gray areas ~ fear behavior (fight-flight))
• Paraventricular Nucleus (PVN) of Hypothalamus ~ endocrine response (HPA-axis)

Question 10

Hippocampus in HPA action:

Answer 10

• Hippocampus stress-related projections: hypothalamic paraventricular nucleus (PVN) ~ HPA-axis
• Experiments have shown that hippocampus inhibits HPA-axis!

Question 11

MRs and GRs in emotional memory:

Answer 11

Morris Water Escape Task:

• MR block 30 to 45 min before retrieval on day 2, changed the swim pattern (~acquisition)
• Inhibition of GR immediately after acquisition on day 1 results in impaired performance 24 h later (~consolidation)

Question 12

Subtypes of major depression:

Question 13

Beck’s negative cognitive triad involves thoughts about:

Answer 13

1. The self (i.e., self is worthless)
2. The world/environment (i.e., world is unfair)
3. The future (i.e., future is hopeless)

Question 14

Four defensive distances and the types of behaviors and structures associated with them:

Answer 14

1. Anterior cingulate - discriminated avoidance
2. Amygdala - active avoidance
3. Medial hypothalamus - directed escape
4. Periaqueductal grey - undirected escape

Question 15

Effects of CO2 - how does inhaling CO2 change acidity in the brain?

Answer 15

CO2 + H2O –> H+ + HCO3-

• a change in pH of >= 0.1uM is fatal

Question 16

From anxiety to panic the regions involved change thus:

Answer 16

Prefrontal cortex & lateral amygdala for anxiety

Central amygdala and periaqueductal gray for panic

Question 17

BDNF level changes in depression and stress by brain region

Answer 17

BDNF levels decrease in the hippocampus and PFC

BDNF increase in nAcc and amygdala (BLA)

Question 18

Neurotoxic effects of stress

Answer 18

Chronic exposure to glucocorticoids is neurotoxic, and preclinical studies have shown that hippocampal granule cells are particularly sensitive to these effects. Prolonged glucocorticoid exposure leads initially to a loss of glucocorticoid receptors (GR) in hippocampal granule cells, with a consequent disinhibition of the HPA axis and a further increase in corticosteroid stimulation. If further prolonged, the consequences of the loss of GR-mediated effects for granule cell function, as well as hyperstimulation through the activation of other, primarily glutamatergic mechanisms become severe: they include a hyperactivation of calcium-dependent enzymes leading to the production of neurotoxic free radicals, a decrease in glucose transport into the cell with a consequent loss of energy capacity, and a decreased production of brain-derived neurotrophic factor (BDNF).

Prolonged exposure to stress or high levels of glucocorticoids causes atrophy of apical dendrites, and ultimately, granular cell death.

Question 19

Inhibition of the HPA axis:

Answer 19

The hippocampal inhibitory control of the HPA axis is exerted via several multisynaptic pathways projecting from the subiculum to the paraventricular nucleus of the hypothalamus. The subiculum sends glutamatergic projections to the bed nucleus of the stria terminalis, the lateral septum, and different hypothalamic nuclei, all of which send GABAeric projections to the paraventricular nucleus

Question 20

Stress effects on the nAcc:

Answer 20

The stress-responsive neuropeptide CRF causes DA release within the nucleus accumbens, and a rewarding effect, but following acute exposure to severe stress, CRF no longer releases DA, and its effect is now aversive (Lemos et al., 2012). These results parallel the clinical finding of decreased responsiveness to reward but no change in responsiveness to punishment in the ventral striatum of depressed patients.

Question 21

Link between stress and anhedonia:

Answer 21

There is an indirect excitatory connection from the ventral subiculum of the hippocampus to the VTA, via the nucleus accumbens and ventral pallidum, suggesting that a decrease in DA cell firing could follow from a decrease in hippocampal activity, which itself is the result of chronic stress.

Question 22

Pathways of post-transductional antidepressant action:

Answer 22

• actions of 5HT and NA are mediated by their binding to G-protein coupled receptors that stimulate or inhibit synthesis of the intracellular sec- ond messenger cyclic AMP
• This leads in turn to changes in the activity of protein kinase A (PKA), which interacts in a complex fashion with other protein kinases (MAPK and CaMK)
• resulting in changes in the activity of the nuclear transcription factor cAMP response element-binding (CREB)
• CREB induces transcription of the BDNF gene into pro-BDNF. In the cytoplasm, pro-BDNF will mature into mBDNF which is then trafficked to dendrites and axons
• Once released, mBDNF binds to TrkB receptors located on neural progenitor cells, which will contribute to the maturation of these cells and their differentiation into new hippocampal neurons.

Question 23

Region-specificity of CREB:

Answer 23

• decreased CREB levels in post-mortem studies of suicide victims
• increase in CREB in the hippocampus after chronic antipsychotics
• decrease in CREB in the nucleus accumbens produces antipsychotic-like effects

Question 24

What are the links between the HPA axis and BDNF?

Answer 24

• Stress-induced hyperactivity of the HPA axis and the resultant increase in glucocorticoid level reduce BDNF expression.
• Glucocorticoid receptors directly influence the function of TrkB, the BDNF receptor.

Glucocorticoids appear regulate the expression of BDNF. A possible “direct” mechanism could be the activated GR/MR receptors that can act directly as transcription factors binding to their common glucocorticoid response element (GRE). A putative GRE has indeed been found in the BDNF gene in promoter region IV

GR directly interacts with TrkB, and promotes the BDNF-triggered phospholipase C gamma (PLC-y) signaling pathway for glutamate. release via the glutamate transporter. Under normal conditions, the PLC-y is an important second messenger for synaptic plasticity and long-term potentiation In chronic stress, similar to that as seen in depression, this pathway is altered.

Question 25

Dexamethasone supression test

Answer 25

In normal healthy individuals, pretreatment with dexamethasone (DEX) prevents a substantial release of ACTH and cortisol after administration of human CRH. DEX can thus activate GRs, which leads to inhibition of the structure they are present on. If, however, the same protocol is applied to depressed patients, an increased secretion of ACTH and cortisol can be observed, exceeding by far the levels of healthy controls. Since depressed patients have a GR dysfunction, DEX is unable to inhibit underlying structures causing the response of ACTH and cortisol release to be substantially larger than in healthy controls.

Question 26

Nerve growth factors associated with plasticity regulation in depression:

Answer 26

The most common factors associated are: nerve-growth factor (NGF), brain-derived neurotropic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4)

Question 27

All about NGF

Answer 27

This protein is associated with the survival maintenance of sympathetic and sensory neurons and causing axonal growth.

Question 28

BDNF levels by brain region in depression:

Answer 28

Decreased: hippocampus & PFC

Increased: nAcc & amygdala

Question 29

BDNF TrkB - 3 main signaling cascades:

Answer 29

s. BDNF binds
TrkB with high affi nity to induce its dimerization and autophosphorylation of tyrosine residues in the cytoplasmic kinase domain that serve as docking sites for effector molecules and trigger the activation of three main signalling pathways: PLCγ, PI3K and ERK cascades, which ultimately lead to the phosphorylation and activation of the transcription factor CREB that mediates transcription of genes essential for the survival and differentiation of neurons.

• The recruitment of PLCγ increases intracellular Ca2+ levels and leads to the activation of CaMKII to
  phosphorylate CREB
• PI3K can be activated via the Shc/Grb2/SOS complex
  through Gab1 and by IRS1/2. Lipid products generated by the activated PI3K, the phosphatidylinositides, bind and activate protein kinase Akt, upstream of CREB
• The ERK cascade can be activated both by the Shc/Grb2/SOS complex and by PI3K. ERK phosphorylation leads directly to CREB phosphorylation.

Question 30

Symptoms of generalized anxiety disorder:

Answer 30

¾ Long–lasting anxiety that is no lasting anxiety that is not focused on any particular t focused on any particular
object or situation
¾ Unspecific
¾ Unable to articulate the specific fear
¾ Unable to control worries
¾ Persistent muscle tension and autonomic fear reactions
¾ The development of headaches, heart palpitations,
dizziness, and insomnia

Question 31

Comorbidity of depression and anxiety:

Answer 31

58 percent of those with major depression also suffer from lifetime anxiety

Question 32

Animal models of depression:

Answer 32

Animals showing depressive symptoms:

• Chronic mild stress Chronic Chronic mild stress
• Social stress/defeat
• Prenatal stress
• Maternal deprivation/separation
• Inescapable shock
• Olfactory bulbectomy
• Genetic models (transgenic & k.o.)

Question 33

Describe the chronic mild stress model of depression:

Answer 33

2 randomly assigned stressors per 24h for at least 3 weeks
Stressors:
- food and water deprivation
- 2h light cycle during dark phase
- confined housing
- cage tilt cage tilt
- moistened saw dust
- stroboscopic light flashes
- paired housing

Question 34

Animal tests of anxiety & depression:

Answer 34

Tests for assessing behavioral symptoms:
- Open field test ~ fear/anxiety
- Elevated plus/zero maze test ~ fear/anxiety
- Home cage emergence test Home cage emergence test ~ fear/anxiety/impulsivity ~ fear/anxiety/impulsivity
- (Modified) Forced swimming test (FST) ~ unconditioned
helplessness/behavioral despair helplessness/behavioral despair
- Sucrose Sucrose preference or intake test ~ preference or intake test ~ anhedonia