The Medial Temporal Lobe “Memory System”

Squire & Zola 1996

Delayed Non-Matching to Sample (DNMS) as
a Model of Declarative Memory
Combined Removal of the Amygdala and
Hippocampus Impairs DNMS Performance
4 lesion groups:
1. Control 300
C

Number of Errors
2. Amygdala
A
3. Hippocampus
200 H
4. Combined Amygdala & A&H
Hippocampus
100

0
Pre-op Post-op

Mishkin 1978
 Conflicting Evidence Regarding the Role of
MTL Structures for DNMS
• Zola-Morgan & Squire (1986)
• Aspiration lesions of the hippocampus impaired DNMS performance in the
absence of amygdala damage
• Murray and Mishkin (1986)
• Combined transection of rhinal cortex and amygdala impaired DNMS
performance in the absence of hippocampus damage

One commonality between all of these studies was the damage that occurred
to adjacent cortex, including the perirhinal, parahippocampal, and entorhinal
corticies
Aspiration lesions can damage surrounding
cortical tissue
Murray & Mishkin (1998)
• Combined neurotoxic lesions of the hippocampus and amygdala,
sparing adjacent cortex, failed to impair DNMS
 Winters et al. (2004)
• Functional double dissociation between perirhinal cortex and
hippocampus
• Perirhinal cortex, but not hippocampus, is required for object
recognition
Winters et al. (2004)
• Functional double dissociation between perirhinal cortex and
hippocampus
• Hippocampus, but not perirhinal cortex, is required for spatial
memory
Murray & Mishkin (1998)
• Combined neurotoxic lesions of the hippocampus and amygdala,
sparing adjacent cortex, failed to impair DNMS
 Summary of MTL Function in Declarative
Memory

• Removal of the MTL results in deficits in declarative memory function

(LTM in particular)

• Homogeneity of Function?
• The idea that all the regions within the MTL are equally important
for declarative memory function
• Not likely! HPC vs. PRH functional dissociation
Memory Formation & Storage
Cellular and Molecular
Stabilizing Memories for Long-Term Storage

Consolidation

Behavioural Event Short-term memory Long-term memory

Acquisition

(Alberini, 2008; Dudai, 2004; McGaugh, 2000)

Stabilizing Memories for Long-Term Storage
Consolidation

Short-term memory Long-term memory

Active Inactive

Vulnerable to Less Vulnerable to

Disruption Disruption
Hebb’s (1949) Cell Assembly
Concept
”When an axon of cell A is near enough to
excite cell B and repeatedly or persistently
takes part in firing it, some growth process or
metabolic change takes place in one or both
cells such that A’s efficiency, as one of the cells
firing B, is increased.”
…or cells that fire together wire together
Long-term Potentiation in the Hippocampus

Neurobiology of Learning and Memory, 2014; Fig 2.6

Long-term Potentiation in the Hippocampus
LTP Induction: Glutamate Receptors

Neurobiology of Learning and Memory, 2014; figure 3.5

LTP Induction: NMDA Receptors
“The coincidence detectors”

Neurobiology of Learning and Memory, 2014; figure 3.8

Glutamate Receptors in Perirhinal Cortex Mediate Object
Memory Acquisition and Consolidation
Sample Choice

24 hrs

Acquisition/Encoding Consolidation Retrieval

Prediction: Inhibiting NMDA or AMPA receptors prior to the sample phase

will impair object memory
Winters et al., 2005
 Glutamate Receptors in Perirhinal Cortex Mediate Object
Memory Acquisition and Consolidation
• Antagonists:
• NMDA receptor antagonist: AP5
• AMPA receptor antagonist: CNQX

• Want to administer the antagonists directly

into the brain
• Brain region important for object memory?
à Perirhinal cortex

PRh
Neurobiology of Learning and Memory figure 9.10
 Glutamate Receptors in Perirhinal Cortex Mediate
Object Memory Acquisition and Consolidation

Sample Choice

24 hrs

AP5 or Saline

Inhibition of NMDA receptors in perirhinal cortex blocks

object memory acquisition/encoding
Winters et al., 2005
 Glutamate Receptors in Perirhinal Cortex Mediate
Object Memory Acquisition and Consolidation

Sample Choice

24 hrs

CNQX or Saline

Inhibition of AMPA receptors in perirhinal cortex blocks

object memory acquisition/encoding
Winters et al., 2005
 LTP Induction LTP Expression

“Memory Acquisition” “Memory Retrieval”

 Glutamate Receptors in Perirhinal Cortex Mediate
Object Memory Acquisition and Consolidation

Sample Choice

24 hrs

Inhibition of AMPA or NMDA receptors in perirhinal

cortex blocks object memory consolidation. Winters et al., 2005
Glutamate Receptors in Perirhinal Cortex Mediate Object
Memory Acquisition and Consolidation…and Retrieval!

Sample Choice
24 hrs

Inhibition of AMPA, but not NMDA, receptors in perirhinal

cortex blocks object memory retrieval.
Winters et al., 2005
Glutamate Receptors in Perirhinal Cortex Mediate Object
Memory Acquisition and Consolidation…and Retrieval!

• Conclusions:

• NMDA receptors in perirhinal cortex are required for object memory

acquisition/encoding and consolidation
à NMDA receptors for consolidation & LTP induction

• AMPA receptors in perirhinal cortex are required for object memory

acquisition/encoding, consolidation, and retrieval
à AMPA receptors for consolidation & LTP induction and
expression