Cellular NeurobiologyBIPN140

Second midterm is next Tuesday!! Covers lectures 7-12 (Synaptic transmission, NT & receptors, intracellular signaling & synaptic plasticity).

Review session is on Monday (Nov 14th) before midterm 6:00-8:00 PM at 3500 Pacific Hall (Code: 127894). Please come with questions.

PS 6 Q&A is now posted on the website2015 Problem sets #4~ #6 and 2nd midterm are also posted!

Chih-Ying’s Office Hour: Monday, 1:00-2:00 PM, Bonner Hall 4146

BIPN140 Lecture 14: Learning & Memory

Su (FA16)

1. Categories of Memory

2. Anterograde v.s. Retrograde Amnesia

3. Brain regions critical for memory

The Major Qualitative Categories of Human Memory (Fig. 31.1)

Declarative memory:1. The storage and retrieval of material that is available to consciousness.2. Can be expressed by language (human-specific, e.g. remember someone’s name, past

events, or images)3. Requires functional medial temporal lobe, especially hippocampus.

Non-declarative memory:1. Also known as procedure memory (riding a bike, playing games, climbing etc.)2. Not readily available in consciousness; information that is acquired and retrieved

unconsciously; might not even be aware of it until asked to do so.3. Does not require medial temporal lobe

classical conditioning

Memory: the encoding, storage and retrieval of learned information.

semanticepisodic

Priming: a change in the processing of a stimulus due to a previous encounter with the same or similar stimulus

Immediate memory:1. Effective duration: fractions of a second2. Capacity: very large (each sensory modality has its own register)3. Routine ability to hold ongoing experiences in mind; current attention.4. Can enter long-term memory

Temporal Categories of Memory: Phases of Memory (Fig. 31.2)

Working memory (short-term memory):1. Effective duration: seconds to minutes2. Capacity: narrower but more goal-oriented (related to attention; e.g. looking for your keys

while remembering where you have looked; remembering a phone number to call someone immediately, “normal digital memory span” is 7-9 numbers; holding a casual conversation)

3. Extension of immediate memory; active rehearsal4. Important for both declarative and non-declarative memories.5. Can enter long-term memory; active rehearsal (reactivation).

Temporal Categories of Memory (Fig. 31.2)

Long-term memory:1. Duration: much longer, days, weeks, or even a lifetime.2. Consolidation: a process to transfer of immediate or working memories (one brain domain) to

long-term (another domain); successful transfer requires series of consolidation steps.3. Reconstruction: in order to maintain long-term memories, we need to revisit and re-encode

them; such processes are known as “reconstruction” (trade-off: reducing accuracy)

Forgetting:1. Removal of information (most information that enter immediate and working memories are

promptly forgotten; unburden our brain with information that is no longer relevant or meaningful; important for retaining or focusing on significant information)

2. Amnesia: pathological forgetting of previously stored information and/or the inability to store new information (instructive to the neurological underpinnings of memory)

Patient H.M. & Brenda Milner (Box 31c)

After surgical bilateral lobotomy of the medial temporal lobes (including hippocampus, adjacent amygdaloid complex and entorhinal cortex) at the age of 27, H.M. could no longer form new declarative memory (anterograde amnesia).

Reported by Brenda Milner, a pioneer in neuropsychology, H.M. also suffered moderate retrograde amnesia that is temporally graded; he could not remember events closer to his surgery but his childhood memories appeared unaffected, suggesting medial temporal lobes are not a permanent repository for such information.

“Every day is alone; whatever enjoyment I’ve had and whatever sorrow I’ve had”.

http://www.pbs.org/wgbh/nova/body/corkin-hm-memory.html

(H.M. 1926-2008)(Brenda Milner, 1918-)

H.M.: Learning without Realizing it

(Kandel et al., Principles of Neural Science, 5th Edition)

However, his working memory and long-term procedural memory were intact. He can learn to perform new tasks (intact working memory) without “remembering” that he has learned the task before.

Insights: different categories of memory (declarative/non-declarative) are likely mediated by different areas of the brain (different anatomical substrates for anterograde and retrograde amnesia). Encoding and retrieval of long-term memory information may also be mediated by distinct systems.

Brain Areas Associated with Declarative Memory Disorders (Fig. 31.9a)

Hippocampus:1. tri-synaptic circuit: perforant path => granule

cells/mossy fibers => CA3 pyramidal neurons/Schaffer collaterals => CA1 pyramidal neurons

2. Not required for immediate or working memory (H.M. could still hold a short conversation).

3. Required for declarative memory.4. Its subcortical connections are also important:

mammillary bodies and dorsal thalamus

Amygdala: required for fear-based memory

Spatial Learning & Memory in Rodents Depends on the Hippocampus (Fig. 31.10)

Water Maze: Rats are placed in a circular tank about the size of a kiddie pool that is filled with opaque water

(so that the animal can not “see” where the platform is). A small platform is located just bellows the surface.

The surrounding environment contains visual cues such as windows, doors, clock etc. that serve as landmarks.

As the rat searches for the resting platform, the pattern of their swimming (indicated by the traces) is monitored by a video camera.

After a few trials, normal rats rapidly reduce the time required to find the platform, whereas rats with hippocampal lesion do not.

Hippocampus: a conversed brain region for initial encoding and consolidation of memory.

The Case of London Taxi Drivers (Fig. 31.12A)

Spatial hypothesis of hippocampal function: the spatial maps stored in the hippocampus enable flexible navigation by encoding several routes to the same direction.

(Maguire et al., PNAS 97:4398-4403, 2000)

Structural brain scans show that the posterior hippocampus, a region specialized for remembering spatial information, is larger in taxi drivers (n=16) than in age-matched controls (a form of structural plasticity?).

The anterior hippocampal region may be involved in encoding of new environmental layouts?

“Mental maps” are stored in the posterior hippocampus?

Hippocampus size scales positively with experience as a taxi driver.

“Correlative” support of the importance of hippocampus in human spatial memory.

(n=16)

The Case of E.P.

Spatial hypothesis of hippocampal function: the spatial maps stored in the hippocampus enable flexible navigation by encoding several routes to the same direction. Is it so for humans??

(Teng & Squire, Nature 400: 675-677, 1999)

Due to viral encephalitis that destroy his hippocampus, E.P. became severely amnesic at 69. Larry Squire’s team visited him over 200 times, but he never remembered seeing them. The main study was conducted when E.P. was 76.

E.P. grew up and lived in Hayward C.A. till the age of 28. He moved to Encinitas after he became amnesic.

When asked to described how to navigate from his home to different locations in the Hayward area (familiar navigation), between different locations in the area (novel navigation), and how to make a detour (alternative routes), E.P. performed as well as age-matched controls (intact remote spatial information, >48 year-old memories).

However, when tested for routes at current address, E.P. performed very poorly.

Take home: the hippocampus is essential for the formation of long-term declarative memories (both spatial and non-spatial), but it is not the permanent repository for those memories nor is it required for the retrieval of those memories.

The Case of E.P.

Larry Squire’s Patient EP (https://www.youtube.com/watch?v=3XHfJiSmEy8)

Classical Conditioning (Associative Learning)

(Kandel et al., Principles of Neural Science, 5th Edition)

Memory Engram (Fig. 31.3) Retrograde amnesia: the loss of memory for events preceding an injury or illness is more typical of the generalized lesions associated with head trauma and neurodegenerative disorders, suggesting that the long-term storage of memories is distributed throughout the brain.

Studying patients with retrograde amnesia to identify regions for long-term storage => difficult and inconclusive.

Engram: the biophysical or biochemical changes in the brain by which memory traces are stored

Defined population of neurons correspond to a specific memory trace? What are the cellular correlates of a memory engram? Are they distributed over the cortex?

Karl Lashley’s lesion experiments: the location of the lesions did not matter much; only the extent of the destruction and the difficulty of the task seemed important (mass action principle).

Take home message: Acquiring declarative memories depends on the integrity of the medial temporal lobes, storing them over the long term depends on a distributed cortical network that is seriously impaired only when large portions of it are destroyed.

The Acquisition and Storage of Declarative vs Non-declarative Information (Fig. 31.17)

Short-term and long-term memories are stored at different brain regions.

Human patients with brain lesions: declarative and non-declarative memories have different storage sites and acquisition pathways (the dissociation of memory systems).

However, individual memory traces are not randomly distributed over the cortex. Memories are most likely stored primarily within the brain regions originally involved in processing each kind of information.

For example, visual cortices store memory traces for visual information, auditory cortices store memory traces for auditory information, etc.

Priming: sensory association cortex

Eye-blink conditioning: cerebellum

Huntington’s/Parkinson’s diseases (basal ganglia): impair motor skill learning

(Kandel et al., Principles of Neural Science, 5th Edition)

Memory and Aging (Fig. 31.18 & 31.19)

The human brain reaches its maximum size (or weight) at early adult life (around 20) and decreases progressively thereafter (age-related, slight but significant shrinkage of the brain).

This decrease evidently represents the gradual loss of neural circuitry in the aging brain (synapse count goes down, too), which presumably underlies the progressively diminished memory function in older individuals. That is, memory engrams likely deteriorate with age.

During remembering, activity in prefrontal cortex was restricted to the right prefrontal cortex (the brain images are left-right reversed) in both young participants and elderly subjects with poor recall.

In contrast, elderly subjects with relatively good memory showed activation in both right and left prefrontal cortex likely through compensatory activation of cortical tissue that is less fully engaged in average older individuals.

Mentally active, high-performing older adults may offset declines in processing efficacy.

Eric Kandel is 87; Brenda Milner is 98

Background: Ablation or disruption of hippocampal neurons impairs memory, suggesting that hippocampus is necessary for memory formation. However, it is unclear whether activation of a specific population of hippocampal neurons that were activated during learning is sufficient to elicit the behavioral output of a specific memory. Is there specific memory engram in the hippocampus?

Experiments: Use a genetic approach + viral injection to selectively express ChR2 in hippocampal neurons that are activated during learning. Later on, use blue light to activate ChR2 expressed in those neurons and see whether animals behave as if they recall a fear memory (freezing).

Results: Optogenetic activation of those hippocampal neurons is sufficient to induce fear memory. In addition, light-induced fear memory recall is context-specific, that is, activation of cells labeled in a different context does not induce fear memory. Therefore, activation of a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory.

Fig. 1. Selective labeling of dentate gyrus cells by ChR2-EYFP

Dentate gyrus (DG): critical in discriminating between similar contexts of fear memory.

About 2-4% of the neurons are activated (immediate early gene expression) in a given context.

DG is an ideal target for the formation of contextual memory engrams that represent discrete environments.

c-fos promoter + tTA (tetracycline trans-activator) => suppressed by doxycycline

Tetracycline responsive element (TRE) site + ChR2-EYFP

DG CA1 CA3ChR2-EYFP c-fos-shEGFP c-fos-shEGFP

Fig. 2. Activity-dependent expression and stimulation of ChR2-EYFP

Dox (-) Dox (-) DoxFC

(-) DoxNS

5 days 30 days

seizure c-fos positive stainingafter blue light stimulationExp: TRE-ChR2-EYFPCtrl: TRE-EYFP

Fig. 3. Optical stimulation of engram-bearing cells induces post-training freezing

Light-induced memory recall

No shock, just CS No ChR2, negative control

CS induced freezing: ~60%

Bilateral injection

Direct activation of a subset of neurons involved in the formation of a memory is sufficient to induce the behavioral expression of that memory!!

Fig. 4. Labeling and stimulation of independent DG cell populations (context specific)

Open field

ChR2-EYFP(context C)

c-fos(context B)

Two separate populations of DG neurons are recruited to represent two different contexts