Mechanisms of Memory (J. David Sweatt)
+ - 1 The basics of psychological learning and memory theory
+ Trace conditioning + Operant conditioning + Hippo.-dependent contextual fear conditioning + Taste learning + Conditioned taste aversion
Short-term memory links the sensory input and long-term memory, or the recall of old memory and further utilization
Auditory sensory store: echoic memory. Visual store: iconic memory
Associative conditioning: cause-effect
But mislearned association can happen: superstitious
Needs contiguity and contingency
Delay and trace conditioning look similar, but they are quite different. Trace conditioning needs hippocampus
+ - 2 Studies of human learning and memory
First observation: distraction and interference immediately after training disrupt long-term memory formation
Memories of less than 2 years old is more susceptible to seizure-associated transient loss
Double dissociation: deficits in A not B only affect function a not b, thus system A and B have separate and distinct functions
Patient H.M.: removal of medial temporal lobe lead to failure of new memory formation, but old memories were intact
Memory consolidation is a central attribute of hippo.: downloads information to the cortex for long-term storage
Cellular mechanism that is likely to allow hippo. serve its function: long-term potentiation (LTP)
+ - 3 Non-associative learning and memory
+ - 3.1 Introduction-the rapid turnover of biomolecules
3.2 Short-term, long-term, and ultralong-term forms of learning
+ - 3.3 Use of invertebrate preparations to study simple forms of learning
+ - 3.4 Short-term facilitation in Aplysia is mediated by changes in the levels of intracellular second messengers
Reaction Category 1-Altered levels of Second Messengers: Serotonin binding leads to increasing of cAMP. Activities of cAMP-dependent kinases PKA and PKC enhanced, phosphorylating potassium channels and vesicle release machinery, which increases the release of glutamate into synapse
+ - 3.5 Long-term facilitation in Aplysia involves altered gene expression and persistent protein kinase activation-a second category of reaction
Reaction Category 2-Generation of long Half-life Molecules: Long-lasting elevation of cAMP => activation of PKA => phosphorylation of CREB + ERK and MAPK repression of neg. regulator of CREB => altered gene expression (?) i.e. ubiquitin system => proteolytic degradation of the PKA regulatory subunit => increase ratio of active catalytic to reg. subunits => persistent activation of PKA until protein turnover + somehow DAG-responsive effector PKC is also activated
+ - Intermediate-Term Facilitation in Aplysia
+ - 3.6 Long-term synaptic facilitation in Aplysia involves changes in gene expression and resulting anatomical changes
TBL-1. Hypothesis: serotonin => TBL-1 secretion into extracellular space => converts TGF-beta to active form => TGF-beta binds to its receptor => signal transduction that promote expression of TBL-1 => positive feedback loop
CPEB. Hypothesis: prion-like translation regulator, also marks synapse
+ - 3.7 Attributes of chemical reactions mediating memory
3.8 Sensitization in mammals
+ - 4 Rodent behavioral learning and memory models
Cue-plus-Contextual Fear Conditioning
+ - Cued Fear Conditioning
+ - Contextual Fear Conditioning
Control: rule out sensory or motor dysfunction from learning and memory deficiency; retrain or overtrain to rule out disability to present fear
Passive avoidance training
+ - Extinction of Fear Conditioning
Searching for engram failed: complex memories are held in (or at least accessed by) broadly distributed loci in the CNS
Hippocampal “place cells”
Non-specificity
Mixed nature of task: learning, memory and recall
There may be compensation, causing false negative
Control: selective deficit in contextual versus cued fear conditioning; selective effects on short-term versus long-term memory; selective deficit in trace versus delay conditioning
+ - 5 Associative learning and unlearning
Purkinje neurons are the only output neurons from the cerebellar cortex, use gamma-amino butyric acid (GABA) as their neurotransmitter, thus they are inhibitory
LTD at their parallel fiber inputs leads to a net loss of inhibitory output onto motor pattern generators downstream
Frontal cortex, the amygdala, and the nucleus accumbens. These three brain subregions are components of the limbic-corticostriatal loop
+ - 6 Hippocampal function in cognition
+ - A. Space
+ - B. Timing
Re-entering the place field makes CA1 pyramidal cells' firing rate higher, latency of respond shorter, dendritic action potential back-propagation increasing
Memory for Real Time—Episodic Memory, Ordering, and the CS-US Interval
Trace fear conditioning is dependent on NMDA receptor function in CA1 pyramidal neurons
Hypothesis: the maintenance of a representation of a sensory stimulus, in the absence of any continued presentation of the stimulus itself
+ - C. Multimodal Associations—The Hippocampus as a Generalized Association Machine and Multimodal Sensory Integrator
Arc as an activity-dependent molecular marker to track the activity of specific ensembles of pyramidal neurons
CA1 pyramidal cells respond selectively to a certain combination of features
D. The Hippocampus is also Required for Memory Consolidation
+ - 7 Long-term potentiation-a candidate cellular mechanism for information storage in the central nervous system
+ - 7.1 Hebb's postulate
Broadly accepted hypothesis: Memories are stored as alterations in the strength of synaptic connections between neurons in the CNS
Hebb said: "When an axon of cell A ... excites cell B and repeatedly or persistently takes part in ring it, some growth process or metabolic change takes place in one or both cells so that A’s ef ciency as one of the cells ring B is increased." (1949)
+ - 7.2 A breakthrough discovery--long-term potentiation in hippocampus
Open ligand (neurotransmitter)-gated ion channels
A more subtle role—modulating neuronal function through eliciting intracellular second-messenger generation. Almost all neurotransmitters have specific subtypes of receptors that act in this fashion
+ - Second messenger
cAMP/PKA
PLC/DAG/PKC
PLC/IP3/CaMKII
PLA2
Important targets are: pre-synaptic proteins associated with neurotransmitter release, membrane K+ channels, Ca2+ channels and Na+ channels, nuclear transcription factors regulating gene expression, the protein synthesis machinery, and the cytoskeleton
PPF: when two single stimulus pulses are applied with interpulse intervals ranging from 20–300 milliseconds, the second EPSP produced is larger than the first
PTP: for example, in experiments where LTP is induced with one or two one-second, 100Hz tetani, a large and transient increase in synaptic efficacy is produced immediately after high-frequency tetanus
NMDA-independent
+ - 7.3 NMDA Receptor-Dependence of Long-Term Potentiation
Calcium influx via NMDA or maybe intracellular calcium
NMDA: glutamate dependence (pre-synaptic activation) *and* voltage dependence (post-synaptic activation), able to detect coincidence, rule out non-correlations
Glutamate slightly precede back-propagation action potential (pairing): opening of NMDA receptor
Back-propagation action potential arrives before the excitatory post-synaptic potential (backward pairing): synaptic depression
+ - 7.4 NMDA Receptor-Independent Long-Term Potentiation
+ - 7.5 A Role for Calcium Influx in NMDA Receptor-Dependent Long-Term Potentiation
+ - 7.6 Pre-Synaptic Versus Post-Synaptic Mechanisms
Increasing glutamate concentrations in the synapse (pre-synaptic) or by increasing the responsiveness to glutamate by the post-synaptic cell?
+ - 7.7 Long-Term Potentiation can Include an Increased Action Potential Firing Component
Most CA1 interneurons are inhibitory using GABA
Interneurons and pyramidal neurons receive same input (glutamatergic Schaffer collateral projections)
Effect of interneurons arrives slightly delayed
Schaffer collateral projections: LTP at pyramidal simultaneously produces LTD at interneurons (and other Schaffer collateral inputs to the same interneurons)
Thus, the interneuron LTD appears to be serving to modulate the behavior of an entire small local circuit of neuronal connections
+ - 7.8 Long-Term Potentiation can be Divided into Phases
Immediate (STP, independent of protein kinase activity), early (by persistently activated protein kinases), and late (change of gene expression?) LTP
A. Early-Long-Term Potentiation and Late-Long-Term Potentiation—Types Versus Phases
+ - 7.9 Modulation of Long-Term Potentiation Induction
Norepinephrine, DA, and ACh-mimicking compounds can all modulate the induction of LTP at Schaffer collateral synapses
BDNF can also modulate the induction of LTP
+ - 7.10 Depotentiation and Long-Term Depression
+ - 7.11 A Role for Long-Term Potentiation in Hippocampal Information Processing, Hippocampus-Dependent Timing, and Consolidation of Long-Term Memory
Blocking NMDA receptors is not the closest thing possible as selectively blocking LTP
LTP is not necessary for hippocampal place field formation. However, loss of LTP is associated with a decreased stability of place fields
NMDA receptor-dependent LTP in area CA1 of the hippocampus also appears to be necessary for multimodal associative learning
NMDA receptor-dependent processes are necessary for reconstituting spatial locations using partial visual cues
ERK activation, CREB activation, Arc induction, C/EBP induction and NMDA receptor are necessary for hippocampus-dependent memory consolidation, which are also known to be necessary for LTP induction, strongly implicate LTP as a component of memory consolidation
LTP does not equal memory. Rather, it is a critical component of the complicated process of memory formation
+ - 8 The NMDA receptor
+ - 8.1 Introduction
Voltage-dependent Mg2+ block of the channel pore. Depolarization of the membrane in which the NMDA receptor resides is necessary to drive the divalent Mg2+ cation out of the pore, which then allows calcium ions to flow through
+ - A. Structure of the NMDA Receptor
NMDA receptor subunits: NR1, NR2A, NR2B, NR2C, and NR2D
NMDA receptor is in fact a large multiprotein complex: many different types of scaffolding proteins and signal transduction molecules
+ - 8.2 NMDA Receptor Regulatory Component 1—Mechanisms Upstream of the NMDA Receptor that Directly Regulate NMDA Receptor Function
+ - 8.3 NMDA Receptor Regulatory Component 2—Mechanisms Upstream of the NMDA Receptor that Control Membrane Depolarization
+ - 8.4 NMDA Receptor Regulation Component 3—The Components of the Synaptic Infrastructure that are Necessary for the NMDA Receptor and the Synaptic Signal Transduction Machinery to Function Normally
A. Cell Adhesion Molecules and the Actin Matrix
B. Pre-Synaptic Processes
C. Anchoring and Interacting Proteins of the Post-Synaptic Compartment—Post-Synaptic Density Proteins
D. AMPA Receptors
+ - E. CaMKII—the Calcium/Calmodulin-Dependent Protein Kinase II
One purpose of the NMDA receptor/PSD-95/cytoskeleton complex is to help localize CaMKII to the PSD domain
+ - 9 Biochemical mechanisms for information storage at the cellular level
Temporal integration mechanisms of this sort involving synaptic tagging and the generation of other persisting but transient signals allow for the cell to build an optimal time window for the efficacy of repeated stimuli
+ - 10 Molecular genetic mechanisms for long-term information storage at the cellular level
Prediction One: blocking changes in gene transcription should block L-LTP induction
Prediction Two: changes in gene and protein expression should occur with L-LTP-inducing stimulation and memory formation
Prediction Three: artificially increasing the capacity of the CNS for transcription of the appropriate genes should lead to an enhancement of L-LTP and long-term memory
The activity of CREB is regulated by phosphorylation at Ser133, which can be phosphorylated by PKA, CaMKII and CaMKIV, MSK1, and RSK2 (among many others). The binding of CREB binding protein (CBP) is also necessary. CBP binding and activation is itself regulated by phosphorylation, in particular phosphorylation and activation by CaMKIV is relevant in the present context
One of the most important co-regulators of this cascade is CaMKIV
BDNF is released with L-LTP inducing stimulation and likely contributes to L-LTP induction and long-term memory by two means. First, it may act via ras to help directly activate the MEK/ERK pathway, a mechanism for augmenting ERK-dependent gene expression. In addition, BDNF, by mechanisms still being worked out, controls phospho-ERK translocation into the nucleus, providing a gate-keeping role for triggering lasting changes
Dopamine co-application during theta-frequency synaptic activity augments the induction of L-LTP
Elk-1 phosphorylation increases with L-LTP-inducing stimulation, a mechanism which likely triggers SRE-mediated changes in gene expression. One specific candidate target for this pathway is the transcription factor zif268
NFkB is a transcription factor that normally resides in the cytoplasm, bound to an inhibitory partner IkB (inhibitor of kappaB). NFkB is activated when the kinase IKK phosphorylates IkB, which leads to loss of IkB by ubiquitin-mediated proteolysis. The free, active, NFkB can then translocate to the nucleus and affect transcription of its target genes
Zif268 (aka krox24 and NGFI-A)
fos/jun regulation may be more of a general activity-related read-out as opposed to a specific signal associated with memory per se
Late (several hours post-training) elevation of C/EBP is necessary for memory consolidation
BDNF, which couples to the ERK/CREB cascade, could trigger a self-perpetuating feedback mechanism for perpetually maintaining increased synaptic strength
t-PA is a secreted protease that has the capacity to modulate the extracellular matrix structure. Potentially, t-PA could serve in a long-term regulatory role through increasing active products in the extracellular space via its known role of converting pro-hormones into hormones
AMPA receptor
The metabotropic receptor scaffolding protein HOMER
Arc mRNA is rapidly induced by LTP-inducing stimulation and memory formation. This mRNA is selectively localized to recently-active synaptic regions, and is subject to selective expression by local protein synthesis mechanisms
+ - 11 Inherited disorders of human memory-mental retardation syndromes
+ - 12 Aging related memory disorders-Alzheimer's disease
Appendix