Memory Systems II How Stored: Engram and LTP. Reading: BCP Chapter 25

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1 Memory Systems II How Stored: Engram and LTP Reading: BCP Chapter 25

2 Memory Systems Learning is the acquisition of new knowledge or skills. Memory is the retention of learned information. Many different kinds of information are learned and remembered (e.g., facts, events, skills). Evidence suggests that no single brain structure or cellular mechanism accounts for all learning. Moreover, the way in which information of a particular type is stored may change over time. Where stored Types of Memory Cortical structures How stored Engram Long-term potentiation Long-term depression Consolidation

3 Memory Engram 1 Hebb proposed that the internal representation of an object consists of all of the cortical cells activated by the external stimulus. This group is called the cell assembly. All of these cells are reciprocally connected, and an object is held in short-term memory as long as activity reverberates through the connections of this assembly. If activity persists, then connections are strengthened (consolidated into long-term memory). Neurons that fire together, wire together. Subsequent partial activation causes the whole assembly to fire again.

4 Memory Engram 2 Learning and memory is a two-stage process 1. Acquisition of a short-term memory Physical modification of the brain (altered synaptic transmission) caused by incoming sensory information 2. Consolidation of long-term memory Requires altered protein function and new protein synthesis The development of response selectivity is a hallmark of learning and memory

5 Memory Engram 3 Neural network models illustrate the concept of experience-dependent shifts in neuronal selectivity. How is memory stored in the network? Via a unique pattern or ratio of activity across the neuronal assembly Advantages of a distributed network: No single neuron represents specific memory, thus memories survive damage to individual neurons. Graceful degradation of memories with gradual neuron loss Physical change of memory modification of synaptic weight (some up, others down)

6 Cortical Synaptic Plasticity 1 Memory appears to be dependent on both increases and decreases in synaptic weights. The result is a shift in neuronal selectivity which stores information. It is clear that synapses between axons and dendrites can form in the absence of any electrical activity; for example, most connections are formed during development. However, experience can alter the strength of connections, i.e., synaptic strengths are plastic. Glutamate is most often the transmitter at modifiable synapses, and ionotropic receptors are usually involved in the process. Postsynaptic glutamate-gated ion channels are either AMPA or NMDA type receptors, and they are colocalized at many synapses.

7 Cortical Synaptic Plasticity 2 AMPA receptors are activated by glutamate and conduct sodium ions when open. NMDA glutamate receptors differ from AMPA glutamate receptors in two important ways: the NMDA channel is also voltagegated, due to the action of magnesium (Mg + ) at the channel (i.e., the postsynaptic membrane must be depolarized to dislodge the Mg + block); the NMDA channel also conducts calcium (Ca ++ ) NMDA channels signal the level of pre- and post-synaptic coactivation by the magnitude of their calcium flux (note that it is not strictly necessary that the post-synaptic depolarization elicits a spike, but it often does).

8 Cortical Synaptic Plasticity 3 Synaptic plasticity appears to follow two simple rules dependent on the level of coactivation of pre-and post-synaptic neurons: 1) neurons that fire together wire together and 2) neurons that fire out of sync lose their link. 1 2 Axons carrying activity from open eye Dendrite Cortical neuron Dendrite Axons carrying activity from closed eye Ca +2 Axons from LGN Correlated pattern Noise Ca +2 Internalized AMPA receptors Ca +2 Ca+2 Strong NMDA receptor activation by well-correlated input activity increases number of AMPA receptors (long-term potentiation) Weak NMDA receptor activation by poorly correlated input activity triggers loss of AMPA receptors (long-term depression)

9 Long-Term Potentiation (LTP) Network models indicate that both increases and decreases in synaptic weights can shift neuronal selectivity and store information. The strengthening of synaptic connections is called long-term potentiation (LTP). LTP is measured by comparing the maximum amplitude of EPSPs in a post-synaptic neuron before and after eliciting correlated activity in a bundle of its inputs. EPSPs are larger following the induction of LTP.

10 Hippocampus LTP was originally discovered in the hippocampus, a brain region critical for declarative memory formation. The hippocampus consists of two thin sheets of neurons folded onto each other: one sheet called the dentate gyrus; and the other Ammon s horn (Latin: CA, cornu Ammonis). The CA has four divisions including CA3 and CA1. Information flows through the trisynaptic circuit of the hippocampus 1. entorhinal cortex dentate gyrus (perforant path) synapses 2. dentate gyrus CA3 (mossy fiber) synapses 3. CA3 CA1 (Schaffer collateral) synapses

11 Properties of LTP 1 CA1 neurons show small EPSPs in response to intermittent, single electrical shocks of small bundles of their Schaffer collateral excitatory inputs. LTP can be induced in CA1 neurons by brief, high-frequency bursts of electrical shocks (tetanus; shocks/1 sec). LTP is only induced at the active inputs (e.g., input 1); other synaptic inputs onto the same neuron that did not receive tetanic stimulation do not show LTP (input 2). This property is called input specificity, and suggests that NMDA receptors are activated in a spatially restricted manner (within one or other dendritic spine).

12 Properties of LTP 2 In addition to input selectivity, long-term potentiation shows two other properties that can be explained mechanistically by the biophysical properties of the NMDA channels. Cooperativity: This term refers to the fact that in order to achieve the necessary depolarization of the post-synaptic neuron to elicit LTP, one input must fire fast enough to produce temporal summation of its EPSPs or a set of weak inputs must cooperate (fire close enough in time) to produce spatial summation of their EPSPs. Associativity: This term refers to the fact that LTP can be elicited at synapses that are activated by weak, low-frequency, stimuli if their activation is temporally concurrent with an LTPinducing stimulus at another set of synapses on the same cell (the requisite depolarization spreads to the weaker input). This property allows for new associations to develop.

13 Persistence of LTP LTP can be induced by a brief tetanus, lasting less than a second, consisting of stimulation well within the range of normal axonal firing. Remarkably, LTP can last many weeks, possibly even a lifetime. It is this persistence that separates LTP from other forms of synaptic plasticity.

14 Phases of LTP LTP can be divided into three discrete phases, which have distinct mechanistic underpinnings: induction, expression and stabilization. Induction is rapid (on the order of seconds to minutes; expression and stabilization contribute to long-term memory consolidation.

15 Induction of LTP 1 NMDA receptors conduct calcium ions, but only when glutamate binds and the membrane is depolarized enough to displace the magnesium ions that clog the channel. Considerable evidence now links this rise in postsynaptic calcium to the induction of LTP. For example, LTP induction is prevented if NMDA receptors are pharmacologically inhibited, or if rises in postsynaptic calcium are prevented by injection of a calcium chelator. The rise in postsynaptic calcium activates two protein kinases: protein kinase C and calciumcalmodulin-dependent protein kinase II (CaMKII). Current research suggests that kinases: phosphorylate AMPA receptors and thereby increase their ionic conductance promote insertion of (existing, sub-membrane) AMPA channels into the membrane

16 Induction of LTP 2 Evidence indicates that postsynaptic structures can change rapidly following LTP. For example, the addition of AMPA receptors to dendritic spines may cause them to quickly swell or form new buds. Enlarged spine Sprouting of synapses not only increases the size of the responsive postsynaptic surface, but also increases the size of the resultant EPSP and thus the probability that an action potential will be elicited in the postsynaptic neuron. LTP

17 Retrograde Signaling In addition to modifying postsynaptic structures, LTP can also trigger an increase in postsynaptic glutamate release. For LTP in a dendritic spine to induce greater glutamate release from an axon, there must be a retrograde signal. Three such signals have been proposed: A. production of a membrane-permeant diffusible factor (e.g., nitric oxide, arachadonic acid) B. secretion of a factor (e.g., neurotrophins) C. modulation of postsynaptic membrane proteins that are physically linked to presynaptic structures All three forms of presynaptic actions may lead to modulation of transmitter secretion machinery or production of downstream cytosolic factors (X) for long-range retrograde propagation to the nucleus to alter gene expression.