Learning and Memory

• • Classical conditioning: recall: Pavlov’s dog
  • Simple learning and memory: passive, only receives environmental cues
• • Operant conditioning:
  • Active learning, subject behaviour is either reinforced/punished → changes probability of behaviour occurring again
• • Long term memory: 
  • Retention of information that has been stored and has not occurred recently
  • Large capacity, enduring and can be stimulated without cue/hint
• • Short term memory:
  • Retention of information in its original sensory form for a brief moment
  • Limited capacity and fades quickly without rehearsal
• • Working memory
  • Retention of information for long enough for a cognitive process to occur - your brain decides if the information is to be kept or not to be kept
• • Testing working memory: Delayed response task - responding to something you heard/saw a little bit ago - ex: radial maze
  • Radial maze: in a maze with 8 corridors, 4 are blocked and treats are placed in the non blocked arms for the mouse to retrieve
  • Mouse and doors are removed and treats are placed where it was once blocked off
  • Mice learn that food is not being replaced in a same place and learn that food will move
• Testing working memory:

  • Errors measuring working memory
  • Across phase errors: going to an arm that had a pellet, no longer does
  • Only occurs in test
  • Occurs more often than within phase
  • Within phase errors: eats the food and goes back to the same arm
  • Occurs in both training and test
• • Consolidation: transfer of info from short term to long term memory
  • Requires the use of the hippocampus (HPC)
  • Rats w/lesions to dorsal HPC show impairment of consolidation
• • HPC role in memory: H.M. case study, 27 y/o w/medication resistant epilepsy 
  • H.M.: patient with lateralized brain damage, underwent bilateral removal of HPC, AMY and surrounding structures to help his epilepsy (as they couldn’t pinpoint an area)
  • Result: seizures improved and no damage to intellect, language or personality
  • Short term/working memory was fine, could hold a number (if no distraction) for 15 mins → problem: could not consolidate memories into long term memories
  • Long term memory:  he retained his memories that occurred before removal but couldn't form new ones. 
• Anterograde amnesia: (forward amnesia) impaired ability to form memories after surgery → severe for HM
• Retrograde amnesia: (backward amnesia) impaired ability to recall memories before surgery → moderate, esp in events soon before surgery (possibly memories that hadn’t been able to consolidate)
• Semantic memory: memories of factual information → HM could only form weak semantic memories and needed very obvious cues to recall
• Episodic memory: memories of personal events → HM couldnt recall any personal event past his surgery and couldn’t use the past to predict the future nor could hints help
• Explicit/declarative memory: intentional recall of information that one recognizes as a memory (ex: when you’re in your final for nsci)
• Implicit memory: recall of information but not understanding why you may recall the information (ex: HM was unknowingly comfortable with his psychiatrist)
• • Common amnesia symptoms:
  • Normal working memory unless distracted
  • Severe anterograde amnesia and some retrograde (only just before surgery)
  • Severe loss of episodic memory (as is with anterograde amnesia)
  • Implicit memory > explicit memory
  • Intact procedural memory
• • Other important brain regions for memory:
  • Cerebral cortex
  • Caudate & putamen (dorsal striatum)
  • Prefrontal cortex: for working memory
  • Amygdala: for fear memory and learning (emotional stimuli)
• • Alzheimer's Disease
  • Behavioral symptoms: (in order of occurrence)
  • Gradual memory loss - disruption of daily life
  • Reduced arousal (AD affects HPC very early on)
  • Difficulties planning or problem solving (impairment of executive function)
  • Difficulty solving familiar tasks
  • Confusion of time or place
  • New problems with writing/speaking
  • Misplacing things/losing ability to retrace steps
  • Decreased judgment
  • Withdrawal from social activities
  • Changes in mood (depression) and personality
  • Delusions
• • No current cure with few treatments, is fatal
  • Number of affected expected to double in 15 yrs (as elderly increase in underdeveloped countries - age is a risk factor)
  • Highly affects women (estrogen is a neuroprotective factor and it drops dramatically in menopause)
• • Risk factors
  • Age
  • Genetics
  • ApoE gene (carries lipids) and others: early onset AD - 5% are familial AD
  • 95 are sporadic AD - late onset
  • Gender - women: in menopause, E drops dramatically = less neuroprotective factors
  • Head injuries
  • Metabolic disorders: they often co-occur
  • Obesity
  • Diabetes
  • Cardiovascular disease
• • Myths about AD
  • It’s genetically determined: only 5% are early onset
  • Only affects elderly: again - early onset
  • There is a cure: nope, most treatments don’t treat root cause
  • Memory loss = AD: nope, a whole host of other behavioral problems
• • Morphology of the brain shows overall shrinkage in AD patients - smaller gyri and hugely enlarged ventricles - majorly deteriorated dendritic trees
  • Brain proteins in AD at molecular level
  • Years before behavioral symptoms start, brain demonstrates accumulation and clumping of proteins
  • Amyloid beta (AB): extracellular plaques
  • Tau: hyperphosphorylated, intracellular tangles
  • This makes it so AD can only be 100% confirmed post mortem
• • Animal models of AD
  • There are many animal models of AD (ex: transgenic models, 3xTg-AD (3x transgenic) mice)
• • Exercise and neuroprotection in 3xTg-AD mice
  • Using female transgenic (Tg) and non transgenic (NTg)
  • Mice received sham/OVX (mimic E drop @ menopause) at 4 months (when they were reproducibly capable)
  • Receive running wheel/no running wheel at 6 months
  • Morris running wheel at 9 months
• Exercise and neuroprotection in 3xTg-AD mice

  • Running through opaque water to find a platform - only with pictures to ground rodent - HPC dependent - requires consolidation of memories to remember where the platform is
  • DV: latency in finding platform or distance traveled
  • Probe trial: do the mice remember where the platform was - also HPC dependent
  • How long does is spend in the quadrant where the platform was vs the opposite?
  • HPC and cerebral cortex then collected and western blotted for AB and tau
• Exercise and neuroprotection in 3xTg-AD mice

  Results

  Just the ovariectomy is enough of an insult - exercise still overpowers 3xTg and OVX

  Mice who received exercise regardless of OVX, Tg or OVX + Tg, shows significant improvement
• Western Blot Results:

  Amount of APP(is in all species) /C99 (portion of human AB trans gene) - looking at ratio of APP:C99 in HPC and cerebral cortex

  Molecular results were not as clear as behavioral results - no sig difference results with tau → suggests exercise might be alleviating something else that doesn't go through AB/tau pathways
• • Is AB an antimicrobial peptide?
  • Recall: APP: amyloid precursor protein: if we all have it? What does it do?
  • Key component of innate immune system: antimicrobial peptides/complement proteins → bind to pathogens (as first responders) → is APP one of these?
• • Is AB an antimicrobial peptide?
  • Study: does sequence similarity = functional similarity?
  • Temporal lobe (has higher AB naturally) & Cerebellum from AD and non AD - thought that AD had more AB in temporal lobe → pieces put into growth substance with microbes and measured microbial growth
  • Results: AD showed significantly less growth only in Temp. L. (lots of AB), cerebellum shows no difference (normally doesnt have much AB)
  • Problem: there might be something else different in the temp.L than just AB → inconclusive
• Is AB an antimicrobial peptide?

  • Samples were incubated with immunoglobulin (generic antibody, doesnt bind AB) or anti-AB antibody (neutralizing AB: should have less effect)
  • Results:
  • In Temp.L.
  • AD w/IgG showed less growth
  • AD w/a AB: increased growth, neutralization of AB = dec antimicrobial
  •  In Cerebellum: no significant difference