Week 6

Question 1

resilience
* Resilience is **
* Multiple techniques are used to promote resilience to stress including **s( i.e. **), versus **, have proven to promote ** and achieve
**
* Some connection to ** according to Eric Nestler

Answer 1

resilience
* Resilience is the brain’s capacity to cope with environmental stress and to achieve stable psychological functioning in response
to this prolonged stress
* Multiple techniques are used to promote resilience to stress including active coping strategies( i.e. in which qualities or
perceptions of stressors are reassessed), versus avoidant coping, have proven to promote behavioral adaptability and achieve
psychological resilience
* Some connection to deltaFosB according to Eric Nestler

Question 2

What does deltaFosB do?
* Also found in the ** (**)
* ** ** (see next slide)
* ** in individuals with stress induced depression at autopsy and in animal models of **
* ** was shown to increase the expression of this transcription factor
* Resilient animals had **
- ΔFosB in brain reward circuits
**

Answer 2

What does deltaFosB do?
* Also found in the nucleus accumbens (reward pathway)
* Transcriptional activator (see next slide)
* Low levels in individuals with stress induced depression at autopsy and in animal models of social defeat
* Antidepressant medication was shown to increase the expression of this transcription factor
* Resilient animals had high levels of this protein
- ΔFosB in brain reward circuits
mediates resilience to stress and
antidepressant responses

Question 3

What is MKP-1 (Phosphatase)
* Other parts of the pathway including **
and ** were down-regulated in the
** compared to **
* Used CUS rat model of stress and observed similar results
* Overexpression of this gene via viral delivery lead to ** (**)
* Knockouts **

Answer 3

What is MKP-1 (Phosphatase)
* Other parts of the pathway including MEK
and ERK1/2 were down-regulated in the
MDD brains compared to control
* Used CUS rat model of stress and observed similar results
* Overexpression of this gene via viral delivery lead to changes in sucrose preference (anhedonia)
* Knockouts resistant to CUS

Question 4

PUFAs

• Epidemiological, biological and clinical studies implicate that ** are important in the development and treatment of various mental illness, including ** and ** disorders
• ** (PUFAs) (also known as ** or **) are essential macro-nutrients and must be obtained from ** because **
• Omega-3 PUFAs consist of () and
  , and their precursor, ** (**) ; EPA and DHA are found primarily in ** such as **, and in fish-oil supplements; ALA include flax seed, canola, soybean, walnuts, and leafy green vegetables
• One mechanism by which n-3 PUFAs could treat depression is by inhibiting ** from ** by acting on
• However, oral delivery of PUFAs **
• Authors utilized the ** mice, which convert **to ** ** (avoiding unicorns/confounds

Answer 4

• Epidemiological, biological and clinical studies implicate that omega-3 fatty acids are important in the development and treatment of various mental illness, including mood and anxiety disorders
• Omega-3 polyunsaturated fatty acids (PUFAs) (also known as n-3 fatty acids or “fish oil”) are essential macro-nutrients and must be obtained from dietary sources because the body cannot synthesize
  them effectively
• Omega-3 PUFAs consist of eicosapentaenoic acid (EPA) and
  docosahexaenoic acid (DHA), and their precursor, alpha-linolenic acid (ALA) ; EPA and DHA are found primarily in fatty fish, such as salmon, and in fish-oil supplements; ALA include flax seed, canola, soybean, walnuts, and leafy green vegetables
• One mechanism by which n-3 PUFAs could treat depression is by inhibiting n-6 fatty acid arachidonic acid (AA) from converting
  into eicosanoid (a precursor of pro-inflammatory mediators) by acting on cyclooxygenase and lipoxygenase pathways
• However, oral delivery of PUFAs have been “unicorns” of their own
• Authors utilized the transgenic Fat-1 mice, which convert n-6 PUFA to n-3 PUFA directly in the brain (avoiding unicorns/confounds

Question 5

Neuroinflammation model

• Model induced by ** (ICV) delivery of ** (LPS)
• This delivery activates the ** and the ** (M1 vs M2 microglia from last slide…)
• It significantly induces**r and impairs **
• It causes the dysfunction of ** and induce ** loss in the ** and **

Answer 5

• Model induced by intra-cerebroventricular (ICV) delivery of lipopolysaccharides (LPS)
• This delivery activates the HPA axis and the microglial innate immune response (M1 vs M2 microglia from last slide…)
• It significantly induces anxiety and depression-like behavior and impairs memory
• It causes the dysfunction of monoamine neurotransmitters and induce serotonergic neuron loss in the hippocampus and Raphe
  nucleus

Question 6

Fat-1 mice
* Fat-1 mice carry ** from the** (**)
* They endogenously convert **to **. The animals attain ** of ** even when fed an **

Answer 6

Fat-1 mice
* Fat-1 mice carry the Fat-1 transgene from the roundworm Caenorhabditis elegans (Omega-3 fatty acid desaturase)
* They endogenously convert n-6 to n-3 PUFAs. The animals attain high tissue levels of n-3 PUFAs even when fed an n-6
PUFA-rich diet

Question 7

1. Neurogenesis theory
   * Neurogenesis declines with **, and is disrupted in ** (e.g. **) and other conditions (e.g. **)
   * Enhancing neurogenesis may have the potential to **
2. Neurogenesis
   * Young adult-born neurons demonstrate greatly enhanced ** and ** relative to **
   * Adult-born neurons are readily activated by **
   * Adult-born neurons contribute significantly to
3. Neurogenesis – in the beginning
   - In adult animals, there are at least ** areas where neurons are formed continuously from ** located in the ** (**) as well as in the
   **. Those neurons ** and become incorporated into ** in the **

Answer 7

1. Neurogenesis theory
   * Neurogenesis declines with age, and is disrupted in neurodegenerative diseases (e.g. Alzheimer’s Disease, Schizophrenia) and other conditions (e.g. Depression, Stress)
   * Enhancing neurogenesis may have the potential to rescue memory dysfunction in some disease states
2. Neurogenesis
   * Young adult-born neurons demonstrate greatly enhanced excitability and synaptic plasticity relative to developmentally-generated neurons
   * Adult-born neurons are readily activated by learning experiences
   * Adult-born neurons contribute significantly to certain forms of memory performance
3. Neurogenesis – in the beginning
   - In adult animals, there are at least 2 areas where neurons are formed continuously from progenitor cells located in the subgranular zone (SGZ) as well as in the
   subventricular zone. Those neurons differentiate and become incorporated into neuronal circuits in the dentate gyrus

Question 8

Neurogenesis and ADMs
* Known since 1997 that there was an decrease in neurogenesis in the ** of animal models with ** (Gould et al., 1997; Malberg et al., 2000)
* Particularly with they could reverse these observed effects
- Studies have linked low ** in blood to
**

Answer 8

Neurogenesis and ADMs
* Known since 1997 that there was an decrease in neurogenesis in the hippocampus of animal models with induced depression (Gould et al., 1997; Malberg et al., 2000)
* Particularly with fluoxetine (Prozac) they could reverse these observed effects
- Studies have linked low BDNF in blood to
depression

Question 9

BDNF might play a role
Some evidence suggests that enhancing the
** acts to increase **. This, in turn ameliorates **

Answer 9

BDNF might play a role
Some evidence suggests that enhancing the
monoaminergic system acts to increase nuclear expression of BDNF. This, in turn ameliorates some of the structural
effects of major depression.