The term second messenger refers to a molecule in a cell that communicates information or change throughout the cell. A first messenger would be a molecule (usually) that communicates information or change from one cell or cell group to another, like a hormone or neurotransmitter. First messengers are outside the cell, whereas second messengers are inside the cell. First messengers attach themselves to receptors on the outside of cell membranes and begin a "cascade" of events that lead to the release of second messengers inside of cells.

The second messenger cyclic Adenosine MonoPhosphate (cAMP) is formed from Adenosine TriPhosphate (ATP) by the enzyme adenylate cyclase. ATP is the molecule that provides cells with the energy they require to function. Adenylate cyclase serves to amplify the signal from the first messenger, because once activated it can convert many ATP molecules into cAMP second-messenger molecules. The other prominent second messengers are cyclic Guanosine TriPhosphate (cGTP), inositol triphosphate, DiAcylGlycerol (DAG) and calcium ion. cGMP acts as a second messenger in the retina and in the Purkinje cells of the cerebellum. Calcium usually acts as a second messenger when its ion is attached to the protein calmodulin.

Calcium-Calmodulin Kinase

Second messengers exert their effects directly and indirectly by attaching them- selves to proteins and causing a conformational change. An example of a direct effect is the protein conformational change due to calcium in muscle which leads to muscle contraction. More commonly, second messengers act indirectly by attaching themselves

cAMP Kinase

DAG Second Messenger

Protein kinases activated by second messengers cause reabsorption of water in the kidney, secretion of digestive enzyme by the pancreas, breakdown of lipids in fat cells, fluid secretion in the intestine and the opening of ion channels in neurons. Protein kinases also induce long-term changes by altering DNA synthesis. For example, antigens act as first messengers to lymphocytes — activating a second- messenger system that leads to protein kinase action on DNA proteins resulting in the production of antibodies specific to the antigen. Normal cell growth is determined by first messengers known as growth factors which alter cellular DNA through second messenger systems to cause cell enlargement and cell division. The activity of protein kinase on the DNA of neurons is the key to structural changes in the nervous system that are associated with long-term memory.

Second Messenger Cascade

When the first messenger attaches to the receptor on the cell membrane, it exerts its effect through a G-protein, ie, a protein which is activated by the attachment of Guanosine TriPhosphate (GTP). When a first messenger attaches to the receptor, it allows GTP to attach to the G-protein. With GTP attached to it, the G-protein can activate the adenylate cyclase to convert many cellular ATP molecules to second-messenger cAMP. The receptor, the G-protein and the adenylate cyclase are all attached to the cell wall membrane. Eventually, a GTPase enzyme will convert the GTP attached to the G-protein to GDP (Guanosine DiPhosphate), thereby stopping the activity of the adenylate cyclase. (GDP remains bound to the G-protein.) The toxin produced by cholera bacteria alters G-protein in the intestine cells so that it cannot be inactivated by GTPase, thereby allowing unlimited production of cAMP second-messenger by adenylate cyclase. The result is continuous fluid secretion in the intestine, leading to diarrhea. Wasp venom acts like GTPase, accelerating the conversion of GTP to GDP and thereby stopping adenylate cyclase activity.

I have attempted to explain second-messenger systems in such excruciating detail because understanding these systems is central to understanding the cellular biology of learning and memory. I can appreciate the fact that these long sequences of molecular events are not intrinsically interesting, but I feel that the risk of being boring and tedious is far outweighed by the benefit of understanding these mechanisms. Second messenger systems are found throughout the body, but they are of particular interest in the synapse of neurons.

Electrical Synapse Gap Junction

The human brain contains at least 100 billion neurons and 100 trillion synapses — which means that the average brain neuron makes about 1,000 synapses. Synapses can be either electrical or chemical. Electrical synapses are referred-to as "gap" junctions, and are not commonly found in the human brain, although gap junctions do connect heart muscle cells. Essentially they are ion channels running through one cell membrane to the cell membrane of an adjoining cell. Gap junctions allow for speed of transmission and bidirectional flow of ions between cells, but do not exhibit plasticity or other properties which give synapses a central role in learning and memory.

Chemical synapses, by contrast, can act like diodes, rectifying a signal to travel in one direction only. A depolarized axon can send an action potential either toward or away-from a cell body, but a synapse can only permit a neurotransmitter to cross from a presynaptic membrane to a postsynaptic membrane on an adjoining neuron (or back to the presynaptic membrane).

Chemical synapses can be excitatory or inhibitory. Whether a synapse is excitatory or inhibitory depends entirely on the receptors on the postsynaptic membrane, not on the presynaptic membrane or the chemical released at the synapse (apart from the fact that the receptor is built to detect a certain transmitter). An excitatory receptor results in an Excitatory PostSynaptic Potential (EPSP) and drives the postsynaptic neuron closer to the depolarization threshold which makes the cell "fire" an action potential. An inhibitory receptor results in an Inhibitory PostSynaptic Potential (IPSP) and drives the postsynaptic neuron further from the depolarization threshold. The neurotransmitter acetylcholine is excitatory at so-called nicotinic receptors, such as are found at the junction between motor neuron synapses and muscle cells (the neuromuscular junction). But acetylcholine is inhibitory at so-called muscarinic receptors, such as are found at the junction of the vagus nerve and the heart.

In the brain, the receptors for glutamate are typically excitatory, whereas the receptors for Gamma AminoButyric Acid (GABA) are typically inhibitory. The postsynaptic membrane of a neuron often has receptors for both glutamate and GABA. Excluding neuropeptides, any given neuron will release only a single neurotransmitter. Thus, axon terminals from many neurons can connect to a given neuron and release a variety of neurotransmitters which impinge on excitatory and inhibitory receptors to produce EPSPs and IPSPs. The postsynaptic neuron acts like a tiny computer, summing the EPSPs and IPSPs which determine whether or not it will "fire".

Synapse Transmitter Release

Even without the IPSPs, the firing of a brain neuron is a complex event. A single impulse to a neuromuscular junction is generally adequate to cause contraction of the postsynaptic muscle cell. But in the spinal cord, the EPSP will typically be 0.2-0.4 milliVolts in amplitude, as compared to the 10mV depolarization threshold the postsynaptic motor neuron requires to fire. Thus, inputs from at least 75 afferent neurons are required to produce firing. This picture is further complicated by variation in time constant between neurons — some cells can experience their EPSPs over a wider period of time than others. Moreover, the length constant of a neuron will determine how physically close presynaptic terminals must be before an action potential is generated in the postsynaptic neuron. Thus, chemical synapses make for a signalling complexity that is many orders of magnitude greater than the 100 trillion synapses alone would imply. A cryonicist could easily despair of ever preserving such a complex system. But it is important to remember that many changes have occurred to our synaptic networks over the course of our lives, and in the process of accumulating memories. Stroke victims have lost relatively large areas of their brains without losing their identity.

The sequence of events in the presynaptic terminal leading to transmitter release is the arrival of a presynaptic action potential which opens calcium ion channels, allowing calcium ions (Ca²⁺) to flow into the terminal. (The calcium ion concentration in the extracellular space is over 10,000 times as great as it is in the presynaptic cytoplasm.) The calcium ions cause vesicles containing neurotransmitter to fuse with the presynaptic membrane and release neurotransmitter into the synaptic cleft. The vesicles are typically bound together in a network connected by a protein named actin, which is dissolved by calcium ions. Moreover, vesicles tend not to be distributed randomly along the presynaptic membrane, but are concentrated into specialized regions known as active zones. These active zones contain dense projections for the attachment of neurotransmitter vesicles. It is known that calcium channels tend to be concentrated near the active zones. Rows of particles on either side of the dense projections, as seen in electron micrographs, are thought to be calcium channels. Calcium ion influx is ten times greater at the active zones than it is elsewhere in the terminal.

Calcium Influx Effect

Synapse Membrane Structure

Calcium Causes Vesicles Containing Neurotransmitter to Fuse with Post-Synaptic Membrane

Ion channels on the postsynaptic membrane can be classified as directly-gated or indirectly-gated. Directly-gated ion channels are directly connected to neurotransmitter receptors which control whether they are open or closed. Indirectly-gated ion channels are not connected to receptors on the cell membrane, but are controlled through second messengers. Nicotinic receptors for acetylcholine at the neuromuscular junction control directly-gated ion channels, whereas muscarinic acetylcholine receptors on the heart control indirectly-gated ion channels. The neurotransmitters GABA and glycine tend to have direct-gating receptors, whereas noradrenaline, dopamine and serotonin tend to have indirect-gating receptors. One glutamate receptor, the NMDA receptor, controls its ion channel through both direct and indirect gating.

Synapse Ion Channel

For a typical indirectly-gated ion channel, a neurotransmitter will attach itself to a receptor, causing a G-protein to exchange GDP for GTP. The GTP-containing G-protein then activates adenyl cyclase to convert ATP to second-messenger cAMP. cAMP then binds to the regulatory units of cAMP protein kinase, thereby releasing the catalytic units to phosphorylate the ion channel — which opens and allows potassium ions (K+) to exit. Although second messenger systems are slower and seem unnecessarily complicated, they have several advantages over direct gating. Indirect gating allows for considerable amplification of the input signal. Amplification can occur at each step of the "cascade". G-protein activated adenylate cyclase generally produces many cAMP second messengers before being inactivated. Moreover, second messengers can induce changes throughout the postsynaptic neuron cytoplasm, not simply at the ion channel. Second messenger systems produce the structural alterations which are necessary for long-term memory.

Not only can the catalytic subunits of protein kinase phosphorylate the ion channels, but they can enter the cell nucleus and phosphorylate transcriptional activator proteins that bind to a specific regulatory region of DNA (called the cAMP-Response Element, or CRE). Transcription of DNA results in messenger RNA (mRNA) that enters the cytoplasm to direct the manufacture of proteins. These proteins may make more lasting alterations to the ion channels or produce other structural changes throughout the cell.

Indirectly-Gated Ion Channel Leading to DNA Transcription

Aplysia californica

The cellular physiology of learning and memory is known in the greatest detail for the sea slug Aplysia californica. Aplysia has about 20,000 neurons in the nervous system consisting of nine ganglia — four pairs of symmetrical ganglia and one large abdominal ganglion consisting of two lobes (misrepresented in the illustration).

Interneurons in Habituation

Perhaps the simplest form of learning occurs when an organism learns to ignore an innocuous stimulus, a form of learning known as habituation. If a soft jet of water is applied to the siphon of Aplysia, it withdraws its gill. With repeated jets of water to the siphon, Aplysia soon greatly reduces the extent to which it withdraws its gill. A fairly simple "wiring diagram" shows the neurons involved in this phenomenon. Experiment has shown that habituation occurs at the synapse of the axon originating from the sensory neuron and terminating at the motor neuron. Habituation can be short-term or long-term. The application of 10 siphon stimulations at one minute intervals leads to habituation that lasts no more than a couple of hours. This is short-term habituation. The application of 10 siphon stimulations at one minute intervals on 4 consecutive days leads to habituation that lasts for 3 weeks. This is long-term habituation. Forty applications on a single day does not result in long-term habituation — no habituation is observed within one day following the applications.

Short-term habituation is correlated with two observable physiological changes in the presynaptic terminal: (1) less calcium ion enters the cell upon stimulation after short-term habituation. This is thought to be due to a decreased activation of a calcium-channel. (2) only 11% of neurotransmitter vesicles are within 30 nanometers of the presynaptic active zone membrane in short-term habituation, as opposed to 28% in normal terminals.

Long-term habituation shows more significant changes: (1) 10% of terminals have active zones as opposed to 40% in normals (2) the mean area of active zones is smaller (3) the number of vesicles within 30 nanometers of the presynaptic membrane is smaller and (4) the total number of synapes per neuron is smaller.

Sensititization by Interneuron Axo-Axonic Synapse

Sensitization is a more complex form of learning than habituation. A rough analogy might be being alone in a large house at night and suddenly hearing a loud crash. Immediately following the crash you would probably become acutely sensitive to subsequent sounds, sights, odors or tactile stimuli. In Aplysia the sensitizing stimulus is a strong shock to the tail. Following the shock, a soft jet of water applied to the siphon results in a stronger-than-normal withdrawal of the gill. The "wiring diagram" shows the relevant neurons and connections. As with habituation, all the physiological changes occur at the synapse of the axon originating from the sensory neuron and terminating at the motor neuron. The critical difference is that a facilitating interneuron forms an axo-axonic synapse on the presynaptic membrane. The sensitizing stimulus causes the facilitating interneuron to release serotonin (5-HydroxyTryptamine, 5-HT) at the axo-axonic synapse. The presynaptic membrane of the sensory-motor synapse has serotonin receptors connected to second messenger systems. As with habituation, short-term and long-term sensitization can be observed.

Axo-Axonic Synapse

Short-term sensitization is correlated with three observable physiological changes: (1) a cAMP second-messenger cascade leads to phosphorylation of a potassium ion (K+) channel — closing the channel. Reduced K+ outflow from the cell prolongs the action potential and allows more calcium to enter (2) serotonin and cAMP directly increase the number of transmitter vesicles within 30 nanometers of the presynaptic membrane and (3) serotonin and cAMP directly influence another type of calcium channel to allow more Ca²⁺ into the cell. Protein Kinase C (PKC) is also activated by serotonin.

Long-term sensitization doubles the number of synaptic terminals and increases the proportion of terminals with active zones from 40% to 65%. Catalytic units of cAMP-dependent protein kinase activates nuclear genes to produce two classes of proteins. One class led to the growth of new synapses. The other protein is an enzyme which disables kinase regulatory subunits, allowing for more persistent kinase activity.

Synapses in Habituation and Sensitization

Aplysia has also been subjected to a form of classical conditioning. In Pavlov's classical experiments with dogs, a bell was rung immediately prior to presenting the dogs with meat powder. The dogs learned to salivate upon hearing the bell ring. In Aplysia a shock to the tail follows a soft jet of water applied to the siphon so that Aplysia "learns" to expect a shock after a siphon stimulus, and withdraws its gill accordingly. The stimuli are identical to those seen with sensitization, except that the order of application is reversed. Moreover, the physiological responses are very similar to those seen in sensitization. Critics have noted this and denied that Aplysia is demonstrating classical conditioning. The fact that stimulating the siphon results in gill withdrawal in an untrained animal makes it seem less of a novel stimulus for the response than ringing a bell to produce salivation. Defenders claim that all responses are pre-wired, and that classical conditioning only unmasks a subthreshold connection causing dogs to salivate in response to a bell.

Nonetheless, Aplysia does exhibit what appears to be conditioning in the form of a more prolonged gill withdrawal in response to soft stimulation of its siphon. Moreover, a distinct physiological phenomenon is seen: the arrival of the action potential from the siphon stimulation allows calcium ion into the terminal prior to the binding of serotonin due to the tail-shock. Calcium causes calmodulin to bind to adenyl cyclase in conjunction with the G-protein. This causes the adenyl cyclase to produce more cAMP second messenger than would have been produced without the calmodulin.

Second Messengers in Sensitization

Habituation has been demonstrated in spinal cord preparations of frogs and cats, but the presence of interneurons and other technical difficulties have thus far presented insuperable barriers to the elucidation of cellular physiology. Goldfish trained to avoid an electric shock by pairing the shock with light have shown that protein synthesis is essential for establishing long-term memory, but not for short-term memory.

Most of what is known about the basis of learning and memory in the vertebrate brain involves correlating activity of certain types of neuron groups with certain types of learning. Details of cell physiology are rarely obtainable by current methods.

There are evidently many different areas in the human nervous system where learning occurs — and many means by which learning occurs. Preserving many or even any of these mechanisms may not be essential to the preservation of identity — or even to the preservation of memory. Preserving long-term habituation of spinal reflexes does not seem crucial for maintaining identity.

Pathways of Interpositus and Red Nucleus

The cerebellum seems to be important in learning certain types of motor skills, especially those involving balance and co-ordination — like riding a bicycle. Cats have been trained to associate a tone with an electric shock to the forearm — to withdraw the forearm upon hearing the tone. The interpositus nucleus of the cerebellum and the red nucleus of the midbrain are the critical intermediaries in a circuit linking the cerebellum to the cerebral cortex in this classical conditioning experiment. New synapses are apparently formed in the red nucleus in association with this learning.

Rats raised in an environment where they could exercise and be active showed 23% more spines on the dendrites of Purkinje cells of the cerebellum than rats in cages allowing only enough space for access to food and water. Similarly, rats raised in an "enriched" environment allowing for exploration showed increased branching of dendrites in the primary visual area of the cerebral cortex.

Basal Ganglia in Learning

Operant conditioning is similar to classical conditioning, except that learning occurs through reward or punishment of spontaneous behaviors, rather than through the induction of conditioned reflexes to novel stimuli. A laboratory animal that learns to press a lever to get a food pellet is demonstrating operant conditioning. The basal ganglia are evidently very important in learning that links rewards with motor activity. The caudate nucleus and the putamen are basal ganglia that receive inputs primarily from the cerebral cortex — the caudate nucleus from the association areas and the putamen from the somatosensory and somatomotor gyri. These two nuclei are collectively called the striatum.

Somatomotor Cortex and Basal Ganglia in Operant Conditioning

Operant conditioning, however, has been demonstrated on a single neuron of the somatomotor cortex. A microelectrode was implanted on a single motor neuron of a monkey, and the monkey was rewarded with drops of fruit juice when the firing of that neuron exceeded a preset level. With conditioning, bursts of impulses from the neuron became more frequent and more intense. [E.Fetz and M.A.Baker, J.NEUROPHYSIOLOGY, Vol.36, p179-204 (1973)]

A form of short-term memory referred to as working memory is associated with the ability to store contemporary representations of the outside world. The apparent locus for working memory is in the prefrontal area of the cerebral cortex. Monkeys shown that food is hidden behind an obscuring object, but who are restrained from immediately taking the food, maintain knowledge of the food behind the obscuring object. The monkeys will take the food after a delay, when restraints have been removed. Monkeys with areas of their prefrontal cortex surgically removed will forget about the food immediately after they can no longer see it ("out of sight, out of mind"). Dopamine seems to be the most important neurotransmitter for neurons involved in working memory.

Chronic alcoholics show learning-deficit symptoms of "Korsakoff's syndrome" as a consequence of damage to the mammillary bodies of the hypothalamus and the dorsomedial nucleus of the thalamus. Such patients have difficulty discriminating objects and words. Acquisition of new knowledge based on discrimination is very slow and short-term memory is poor, but long-term memory is not so impaired.

Limbic System Structure in the Brain

The term "limbic system" is an umbrella term to describe the cingulate gyrus, the hippocampus, the septal nuclei and the amygdaloid nuclei. Sometimes the mammillary nuclei and anterior thalamic nuclei are also included. Although the limbic structures have been described as the "emotional brain", the functional unity of these structures remains to be proven. The cingulate gyrus seems to be the channel through which the cerebral cortex influences autonomic functions like respiration and heart rate (often linked to emotion). Removal of the cingulate gyrus from monkeys makes them more tame, but also more indifferent to social interaction. Lesions to the cingulate gyrus to humans reduce the experience of pain. Artificial stimulation of the amygdala causes animals to demonstrate signs of strong fear or rage. Monkeys whose amygdala have been lesioned can learn to recognize objects, but have difficulty associating objects with reward or punishment. Lesions to the septal nuclei reduce aggression and alter sexual behavior.

H.M. lost Hippocampus, Amygdala and parts of Parahippocampal Gyrus of the Limbic System

In 1953 a 27-year-old patient referred to as "H.M." was subjected to surgery to relieve extreme epilepsy. H.M. lost his hippocampus, amygdala and parts of his parahippocampal gyrus on both sides of his brain. Thereafter, H.M. lost his ability to form new memories of facts. He only remembered facts acquired some time before his operation. He could acquire new skills, but had no memory of having acquired them. Nor were these simply motor skills. By repeated practice, he improved his ability to solve the Tower of Hanoi problem. He also learned to read and form letters through a mirror (a type of learning reportedly mediated by the striatum). He could not recall people whom he met on a regular basis, but had not known prior to his operation. Shortly after having finished a meal, he could start another one without remembering he had just eaten. (His feelings of hunger and satiety were also diminished.) H.M. once described his life with the words, "Every day is alone, regardless of the pleasures I have had or the sorrows I have had."

Limbic System connections

H.M. seems the archetypal case of a person who is capable of memory, but not of learning. For a cryonicist, this raises the question, "Is the hippocampus essential for the preservation of identity?". The loss of an eye or a hand would be tragic, but it would not mean loss of identity. A future technology may yet provide us with a new eye or a new hand — or perhaps a new hippocampus.

The hippocampus has proven to be a boon to neuroscience. Not only does it seem to be a central organ of learning, but its physiology is very amenable to laboratory study, thanks to its lamellar structure. Nonetheless, although many suggestive correlations are seen between the hippocampal anatomy&physiology and hippocampal function, there is not the causal connectedness that is seen with Aplysia experiments.

Hippocampus Structure	Hippocampus Connections

The hippocampus is distinguished by 3 distinctive regions composed of 3 distinctive kinds of cells: the dentate gyrus, which is composed of granule cells and the CA3 and CA1 regions, which are composed of pyramidal cells having different properties. A rough description of the pathway of signals through the hippocampus would be: from the entorhinal cortex to the dentate region, from the dentate gyrus to the CA3 region, from the CA3 region to the CA1 region, and from the CA1 region back to the entorhinal cortex. Nonetheless, within CA3 and CA1 there is a massive input from collateral fibers. Of the roughly 16,000 synapses seen on a typical CA3 neuron, approximately 12,000 of those synapses will be inputs from other CA3 neurons. CA1 neurons, though also having many internal collaterals, primarily receive input from CA3 neurons. Inputs to the hippocampus from the septal nuclei are neuromodulatory — they bathe groups of neurons in acetycholine, thereby increasing their excitability.

All the 3 groups of neurons in the hippocampus exhibit a phenomenon known as long-term potentiation (LTP), although in different ways. In 1973, microelectrodes were applied to the perforant path leading to the dentate gyrus of rabbits, and trains of electrical stimulation were administered at the rate of roughly 15 cycles per second for 10-15 seconds. One or two such exposures was enough to "condition" (potentiate) an increased response to the perforant path for up to 10 hours. It was later discovered that optimal LTP training is at a frequency of 5 cycles per second — the frequency of so-called theta waves. Animals exploring an environment display hippocampal EEG rhythms in the theta range. Rats exposed to an enriched environment show substantial potentiation of the perforant path.

Induction of LTP in the CA1 pyramidal cells increased the number of shaft synapses seen in electron microscopy by one third. The physiology of LTP in the CA1 synapses has been subject to the most research because of the presence of glutamate receptors known as NMDA receptors. Although NMDA receptors are widely distributed in the brain — especially concentrated in the cerebral cortex and basal ganglia — NMDA receptors are particularly concentrated in the CA1 region of the hippocampus. It is worth noting that NMDA receptors are not present in CA3 synapses, and the mechanism of LTP there remains unknown.

At least four types of glutamate receptors can be distinguished in the brain. Two glutamate receptors are directly gated and control ion channels that pass sodium (Na+) and potassium (K+) ions. NMDA receptors (so-called because they are selectively stimulated by N-Methyl-D-Aspartate) are directly gated and control ion channels that pass Na+, K+ and Ca²⁺ (calcium ions) as well. Moreover, NMDA receptors are normally blocked by Mg²⁺ (magnesium ion) and do not function effectively unless they are bound by glycine. NMDA receptors are also distinguished from other glutamate receptors by the fact that they are selectively blocked by the drug APV and are inhibited by the hallucinogenic drug PCP ("angel dust"). The fact that NMDA receptors are directly gated, but pass calcium ion, allows them to induce a second-messenger system that is not mediated by G-protein (probably Ca2+/Calmodulin Kinase) resulting in long-term structural changes to the post-synaptic cell. Moreover, the activation of kinase is thought to induce synthesis of the molecule nitric oxide (NO), which is so small that it effortlessly passes through cell membranes — acting as a "retrograde second messenger" to induce the presynaptic neuron to enhance transmitter release.

Glutamate Receptors

NMDA Receptors

CA1 postsynaptic membranes contain NMDA glutamate receptors as well as non-NMDA (directly-gated) glutamate receptors. During normal low-frequency stimulation, only the non-NMDA channels will open, due to Mg²⁺ blockage of the NMDA ion channels. But high- frequency presynaptic input resulting in depolarization of the postsynaptic membrane displaces the magnesium ions, making the NMDA receptor sensitive to subsequent release of glutamate neurotransmitter.

It seems plausible that LTP mechanisms allow for a kind of learning involving a single episode, rather than repeated trials. It is speculated that associations formed in the CA3 matrix of neurons are built into more economical form in the CA1 neurons. And, in fact, the hippocampus itself probably functions by building more economical storage (long-term memory) in the cerebral cortex. Inputs to the entorhinal cortex (and on to the hippocampus) originate only in so-called multi-modal association areas, which integrate information from several sensory modalities. Outputs from the entorhinal cortex are similar multi-modal association areas. In this view, the hippocampus functions as a transient intermediary in the formation of long-term memories in the association areas of the cerebral cortex.