# Presentation: 245692

## Department of Health and Human ServicesNational Institutes of HealthNational Center for Research Resources138th Meeting of theNational Advisory Research Resources CouncilJanuary 30, 2008

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- Department of Health and Human ServicesNational Institutes of HealthNational Center for Research Resources138th Meeting of theNational Advisory Research Resources CouncilJanuary 30, 2008

- Research at the National Primate Research Centers
- Neurosciences, Neuroimaging, and
- Neurodegenerative Diseases
- Stuart Zola, Ph.D.
- Director, Yerkes National Primate Research Center

## Brain Disorders Cause the Greatest Burden of Disease Worldwide

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- World Health Organization and Harvard Study, 2003

- Population

## Autism

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- Addiction

- Obesity

- Emotion and Cognition

- Comparative evolution

- Memory impairment

- Post traumatic stress disorder

- Neurodegeneration

- NPRCs:   Neuroscience, Neuroimaging, Neurodegenerative Diseases

## Autism

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- Addiction

- Obesity

- Emotion and Cognition

- Comparative evolution

- Memory impairment

- Post traumatic stress disorder

- Neurodegeneration

- NPRCs:   Neuroscience, Neuroimaging, Neurodegenerative Diseases

## Recognition Memory in monkeys and humans

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**Hippocampus**

**The Medial Temporal Lobe**
**Memory System**

- MTL Memory System

- Neurodegenerative diseases

## The Perplexing Trajectories

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- MCI

- Neurodegenerative
- diseases, dementia,
- AD

- Normal

**Neuropathology**

**Cognitive Ability**

**Primarily**
**Memory**

**Primarily**
**Hippocampus**

**Other Cognitive**
**Abilities**

**Additional Brain**
** ****Regions**

- MCI - Mild Cognitive Impairment

## The Perplexing Trajectories

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- MCI

- Neurodegenerative
- diseases, dementia,
- AD

- Normal

**Neuropathology**

**Cognitive Ability**

**Primarily**
**Memory**

**Primarily**
**Hippocampus**

**Other Cognitive**
**Abilities**

**Additional Brain**
** ****Regions**

- Target area for early detection, translational research

## Recognition memory task combined with

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- Eye Camera

- Eye Camera
- Optics Module

- Monocular
- Visor

- Infrared eye-tracking technology

## 2-min delay   NC 

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- 2-min delay   NC

**Notes:**
NC test (70% on novel)

## 2-min Delay   MCI

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**Notes:**
MCI test (roughly equal looking [46% on novel])

## Increased risk

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##      Translational Research

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-      Translational Research

**1960s-1990s**
- Clarification of the role of the hippocampus in memory;
- Development of recognition memory tasks for monkeys,
- including eye-tracking

**2000**
- Discovery in monkeys of recognition memory tasks specially sensitive to hippocampal damage

**1950s**
- Standardized memory tests for assessing amnesia;  Amnesic case HM implicates the temporal lobe

**2000**
- MCI identified as a precursor to AD; Determination that
- hippocampal pathology is linked to MCI

**2006**
- Memory tasks developed in monkeys adapted for early assessment of MCI; Eye-tracking adapted from work in monkeys

**Research With **
**Nonhuman Primates**

**Clinical Research**
**Applied to Patients**

**2008**
- Rehabilitation of memory impairment using recognition memory tests and eye-tracking to guide training and monitor success: MCI, TBI, HIV

**Notes:**
More that will come out of this that is translational than we have made clear, as illustrated in this slide.
The primate centers initially were places where there were nhps that could be used, but in the last two decades the centers have themselves become centers of research excellence and discovery.

## Longitudinal Studies:

- Cognitive behavioral testing
- Non-invasive imaging
- Genomic profiling
- Metabolite profiling

- 5’LTR

- Flap

- Ubi

- WPRE

- 3’LTR

- htt

- (CAG)n

- 5’LTR

- Flap

- Ubi

- WPRE

- 3’LTR

- APP

*swe*

*Ind*

- Huntington’s disease

- Alzheimer’s disease

**Notes:**
~The top left corner show the injection of lentiviruses carrying the gene constructs that shown on the right for both HD and AD. The green fluorescent insert is a picture of oocyte injected with a GFP lentiviruses that shown where the injected viruses are located. 
~The center cartoon shows that embryos are in vitro culture until 4-8 cells stage when we did embryo transfer. 
~For the resulted monkeys, we will perform longitudinal studies as shown below. 

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## Additional notes

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- Identification of a **glycoaminoglycan (Hyaluronan, HA****)** that **inhibits remyelination** following CNS injury and accumulates in the aging primate brain :: Developing agents to block, degrade, or inhibit HA; determine of HA **influences white matter damage and cognitive decline in nonhuman primates****...**.
- Work in rodents and humans has revealed that **vasopressin** plays important role in regulating social cognition and behavior. Investigations of the evolution of the primate vasopressin receptor gene revealed the primate **AVPR1 gene has a repetitive element in the promoter that in humans has been implicated in autism** and social cognition. There is considerable diversity in chimpanzees: **many chimpanzees are missing this behaviorally relevant region****.** Therefore, **chimpanzees may prove to be a critical model** for understanding how this element contributes to social cognitive processes in humans and this has important implications **for understanding autism****...**
- Using **conditioned fear paradigms with nonhuman primates**, researchers have developed a way to **measure the core symptoms of PTSD****,** namely the inability to feel safe in an environment that should make monkeys (or patients) feel safe. Focus now is on **what areas of the brain are activated**** in the presence of safety cues and ****how is this dysregulated** in maternally separated monkeys that cannot feel safe; **reversible brain inactivation strategies****... **
**First *****in vivo***** evidence that stress** (including early life stressful experiences (maternal separation, infant maltreatment by mothers) can lead to **increased activation of pro-inflammatory signaling pathways**, lead in turn to increased release of pro-inflammatory cytokines that can then cause **alterations in brain serotonin, subsequently linked to psychopathology****...**