34Vertebrate Models: The Hippocampus35Vertebrate Models: The Hippocampus36Vertebrate Models: The Hippocampus37Vertebrate Models: The Hippocampus38Animal Models of Learning (Vertebrates)Morris water maze: standard test for spatial memory in rodentsRats with bilateral hippocampal damage cannot learn/rememberthe location of the hidden platform.39Animal Models of Learning (Vertebrates)Rats with bilateral hippocampal damage cannot learn/remember thelocation of the hidden platform.Injection of NMDA blockers into the hippocampus also abolishesbehavioral improvement and learning (Richard Morris).Another experimental method: genetic manipulation (“knockout”) ofgenes that make molecules thought to be involved in learning andmemory. Gene knockout can be restricted to specific regions of thebrain (Susumu Tonegawa).Does boosting the number of NMDA receptors produce an increasein memory performance? Overexpression of NMDA receptors ingenetically altered mice can result in enhanced learning (Joe Tsien,1999).40Neuronal Memory: Unity or Diversity?Studies suggest:Intracellular signalling mechanisms and changesin gene expression are critical. Proteinsynthesis is required for long-term memory.Common set of molecular mechanismssubserving different kinds of memory (e.g.explicit, implicit).Mechanisms are evolutionarily conserved over abroad range of species, from invertebrates(Aplysia, Drosophila) to primates.41Human MemoryThe cognitive neuroscience of memory aimsat how humans record, retain and retrieveexperience in terms of specific memorysystems – networks of neurons that supportdifferent mnemonic processes (after Gabrieli,1998)42AmnesiaAmnesia: difficulty in learning new information, or inremembering the past – resulting from neurologicalinjury or disease.Often occurs in the absence of other cognitivedeficits – normal perceptual and motor skills, normalintelligence, intact language and social skills.Causes of amnesia: focal or degenerative injury.-Focal causes: head injury, electroconvulsivetherapy, stroke, bilateral lesions of the medial lobe.- Other forms of amnesia: dementia-related,Alzheimer’s etc.43AmnesiaImpairment: retrograde memory loss, oftengraded (very recent memories are mostaffected), time-limited, often sparing very oldmemories.Impairment: anterograde memory, formation ofnew memories from the date of the lesiononwards, irreversible.Global amnesia: usually after bilateral lesions ofthe medial temporal lobe, affects verbal andnonverbal material, all sensory modalities.44AmnesiaRetrograde amnesiaAnterograde amnesia45Timing of Anterograde andRetrograde EffectsRetrograde and anterograde amnesia afterelectroconvulsive therapy46AmnesiaIntact (often): remote memory, e.g. childhood.Intact: short-term or working memory,information can be held for several minutes ifrehearsal is allowed – but recall after distractinginterval is impaired. No increased proficiencywith repeated presentations if word lists etc.Intact: motor, perceptual or cognitive capacities.47Amnesia: Diencephalic LesionsAlcoholic Korsakoff’s syndrome (brain damagecaused by vitamin deficiency).Damage to medial thalamus, often mammillarynuclei (fimbria/fornix output of hippocampus).Declarative memory is affected, butnondeclarative memory is preserved.Exact causes for medial thalamic disruptions(interactions with medial temporal lobe system?)are still unclear.48Amnesia: Medial Temporal LesionsCauses: resection (surgery), anoxia, herpessimplex encephalitis, infarction, or sclerosis.First lesions in most cases of Alzheimer’s D. occurin medial temporal lobe.Medial temporal lobe system:- parahippocampal region (parahippocampal andperirhinal cortices)- hippocampal region- amygdala (role?)49Patient H.M.Bilateral resection of the medial temporal lobe(1953) to ameliorate severe epileptic attacks,possibly due to a bicycle accident at age 9 (“afrankly experimental operation”).First report of “a very grave, recent memory loss”in 1954 by Scoville.Scoville and Milner (1957): memory appears tohave a distinct neural substrate, inspired animalmodels of amnesia.50Patient H.M.H.M. has above normal intelligence (IQ 117).Normal digit span (working memory measure) of6-7 items“Every day is alone in itself … everything looksclear to me, but what happened just before? … It’slike waking from a dream. I just don’t remember.”51Patient H.M.H.M.’s lesion: surgeon’s estimate (left); MRI result (right) –although some of the posterior hippocampus was not removed,the tissue appeared atrophied.Corkin et al., 199752Patient H.M.After:Corkin et al., 199753Patient H.M.Corkin et al., 199754Patient R.B. and G.D.Study of R.B. and other patients (G.D. etc.)showed that damage limited to (a specificsubfield of) the hippocampal formation wassufficient to produce clinically significantanterograde memory loss.Lesion: limited to the CA1 field ofhippocampus (bilateral).55Patient G.D.: Memory TestBut: G.D. had near-normal recall of autobiographical(episodic) memories over all decades of his life (noevidence of severe retrograde amnesia)56Patient G.D.Rempel-Clower et al., 1996normal hippocampushippocampus of patient G.D.57Role of HippocampusHippocampus is involved in transfer of short-term into long-term memories. It is not therepository of long-term memory.Lesions of subfield CA1 lead to severeanterograde but only limited retrogradeamnesia. Anterograde amnesia is aggravatedand retrograde effects extend further into thepast if lesions extend into entorhinal orperirhinal cortices.Long-term memories are consolidated withinneocortex.58Spared Learning in AmnesicsAmnesia often does not affect skill learning,sensorimotor learning, some cognitive skills(e.g. learning to read words in a mirror), somesemantic knowledge (verbal information aboutpeople etc.), conditioning, priming.59Animal ModelsDelayed nonmatch-to-sample task (Mishkin, 1978) – test ofrecognition memory. (“…only a few days are needed to instill thisprinciple of choosing the novel object, since it is one to which thenaturally inquisitive monkey is already predisposed.”)novelfamiliarVariable delay periode.g. 20 sec - minutes(error response shown)60Animal Models61Animal ModelsMishkin, 1982Animal modelsattempted to addressthe question whichbrain regions actuallywere causing the severeamnesia in cases likeH.M.62GARNISH63PET Study of MemoryTask: Word stem completion task (priming)GAR64PET Study of MemorySquire et al., 1992Task: Word stem completion taskBefore scans are