Lecture 4- Brain disorders involving deficits of learning and memory Flashcards
What are the seven common disorders involving learning and memory deficits?
•Mental retardation/learning disorders •Alzheimer’s disease, dementia •Huntington’s disease •Post-traumatic stress disorder (PTSD) •Depression •Schizophrenia •Addiction
What is Huntington’s disease?
-Progressive neurodegenerative disorder affecting the cerebral cortex and striatum -HD is the most common polyglutamine neurodegenerative disease (the others are mainly spinocerebellar ataxias)
What are the symptoms of Huntington’s?
-Motor (e.g.chorea), cognitive (e.g.learning and memory deficits) and psychiatric (e.g. depression) symptoms -involves neurdegeneration -leads to form of dementia -depression even in mice so it is not just situational
When is the onset of Huntington’s?
-Onset usually in fourth or fifth decade of life (5% of cases have juvenile onset)
How long does it take for a Huntington’s patient to die after symptoms start to show?
-progresses for 10-20 years before death
What are the brain regions affected by Huntington’s?
-striatum and cerebral cortex are the most affected areas in the brain
What is Huntington’s caused by?
- Caused by a CAG repeat expansion encoding an expanded polyglutamine tract in the huntingtin protein
- the repeats are dynamic= can change within cells of the same body and between generation
- caused by a dynamic mutation
What does the age of onset depend on?
-Age of onset inversely proportional to CAG repeat length, and often occurs earlier in subsequent generations (genetic anticipation)
How does Huntington’s disease happen (DNA picture)?
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What are the Huntington’s disease transgenic mice?
• R6/1 mice expressing human HD transgene (~115 CAG repeats) encoding expanded polyglutamine • Progressive neurodegenerative phenotype similar to human HD, including motor, learning and memory deficits • Shrinkage of cortex and striatum,etc.
How is mice behaviour analysed? (5)
- Locomotor habituation (e.g. photobeam arenas) 2. Motor learning (e.g. repeated accelerating rotarod): motor learning, implicit learning, mice can learn ti improve their motor behaviour in tasks, realise over time what is happening 3.Discrimination learning (e.g. somatosensory or visual) 4. Short-term spatial memory (e.g. T-maze, Y-maze) 5. Long-term spatial memory (e.g. Morris water maze, Barnes circular maze)
What happens when you put a mouse in a photobeam arena?
-Data analysis of upper (vertical movements) and lower (horizontal movements) 8 x 8 arrays of photobeams over 30 minutes -explore a lot at first few tries, later it habituates= explores less
How are motor abilities and learning on the accelerating rotarod affected in the Huntington’s mice?
-motor sign= when holding them by tail they put paws together only if Huntington’s -the rotor= of you repeat it, wild type will improve its performance, but huntington’s won’t
How is short term memory tested in mice?
-spatial working memory -Y maze –one arm blocked off, -then put back in, arm not blocked off -if it spends more time in unexplored= remembers -Huntington’s don’t remember
How is somatosensory discrimination tested in mice?
-put in a box with platforms, shape of a y maze–they can’t see anything in this light, practically blind -different tactile surface -behind one is a reward -they remember behind which one, Huntington’s don’t
What are the barrel cortex plasticity deficits in Huntington’s mice?
-you cut the whiskers, leave only on line -they end up in the barrel cortex, plasticity in the cortex -then do PET -LTD and LTP in the barrel cortex -no experience dependent plasticity in this test in the Huntington mice
How do Huntongton’s mice perform in the Morris water maze?
•Spatial navigation task. •Trained over 4 days to locate the platform. •Probe trial; 5th day no platform present. -huntington’s transgenic mouse has trouble remembering where the platform is -takes much longer to locate the platform despite being trained for it -wild can remember
Do Huntington’s mice have hippocampal LTP deficits?
-yes -deficit in synaptic plasticity
What gene /environment causes Huntington’s?
-huntingtin -mental/physical activity levels?
What gene /environment causes Alzheimer’s?
-APP, Presenilin-1,2, ApoE, etc. -mental/physical activity levels?
What gene /environment causes Parkinson’s?
-alpha-synuclein, parkin, PARK3-9+ etc. -Toxic chemicals?, mental/physical activity levels?
What do gene-environment interactions do?
-mediate experience-dependent plasticity in the healthy and diseased brain
What effect does environmental enrichment have on the brain?
• Exposure to novel enrichment objects of various shapes, sizes and textures from 4 weeks postnatal • Enhances sensory stimulation, motor activity and opportunities for learning and memory • Development of progressive symptoms followed with weekly behavioural testing of enriched (E) and non-enriched (NE) HD mice
What effect does environmental enrichment on the onset of Huntington’s?
-Environmental enrichment delays the onset and progression of disease in Huntington’s mice: experience-dependent plasticity? -delayed onset if more active
What is adult neurogenesis and where does it happen?
adult neurogenesis: birth of new neurons in an adult brain -in dentate gyrus of the brain (hippocampus) -it is disrupted in dementia and depression
What effect do HD and fluoxentine on the adult neurogenesis?
–Flx= prozac
-if given prozac it reccued the deficit in the dentate gyrus in huntigton mice -on right= can specify adult born cells, neurogenesis decreases in huntington mice, but when given prozac it made the effects smaller
What effect do HD and fluoxentine have on spatial memory ability?
-HD= worse -with prozac= improved
What is Alzheimer’s disease?
• Neurodegenerative disorder mainly affecting the cerebral cortex • Dementia, learning and memory deficits • Genetic factors: Amyloid precursor protein (APP) Presenilin-1,2 (PS1, PS2) ApoE, etc. • Environmental factors: mental/physical activity levels?
What causes Alzheimer’s?
- dystrophite neurites and plaques the two major differences in an alzheimer brain
- they cause cognitive deficits, even before the neuronal death
How do AD mice do in spatial memory testing?
-worse
What are the plaques in AD mice brains?
-amyloid plaques produced from the APP protein -the more plaques the worse the learning capacity
How does environmental enrichment affect dementia?
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Summary?
- There are many brain disorders involving learning and memory deficits 2. Correlated deficits of synaptic plasticity and learning/memory can be demonstrated in mouse models of Alzheimer’s and Huntington’s disease 3. Accurate transgenic mouse models are allowing detailed analysis of the complex interaction of genetic and environmental factors in brain disease
