structure

purves et al. Ch 29 Neuroscience 1997 ; Schacter Ch 7,15 Memory Distortion 1996; Dudai Ch 10,11,15 Memory 1989; other sources (carpenter 1984)
oct 31
Limbic circuit (temporal lobe, hippocampal region, medial diencephalon)
I. How do we know that the limbic system is involved.
A. Humans exhibit amnesia (loss of memory). This conditioning has a variety of etiologies (causes ) such as head injury, stroke, ischemia, anoxia, surgery, brain tumors, degenerative processes due to heredity, malnutrition, infection, intoxication, aging and/or disease.
    H.B. R.B., and N.A. are examples of individuals who have developed amnesia as a result of an acute trauma. Their amnesia was specific or dissociated in that these patients demonstrated a deficit in the ability to verbally recall events but were not impaired in other cognitive functions. This deficit related to material experienced after the traumatic even as well as for material experienced a short period before. This inability to recall events that occur after the damage is done is referred to as anterograde amnesia. In contrast to anterograde amnesia there is retrograde amnesia which this patient can also show evidence of but only for events in the recent past (relative to the experience that damaged the temporal lobe structures). It is unsure if this problem is due to faulty storage or due to problems in retrieval.
    Scans (MRI, NMR) of these patients brains demonstrates damage to the medial temporal lobe in H.M, area CA1 in R.B and in N.A. unilateral damage to the thalamus, medial temporal lobe, and bilateral damage to the mammilary bodies. In only the case of R.B are we actually sure of the pathology of the brain because the other two are still alive.
    In these patients it could actually be shown that although they do not remember having had an experience they do adjust their behavior based on what had occurred in the past. For instance, while H.M. could not remember having done a particular task (Tower of Hanoi) he could still accomplish the task at a rate that would suggest that he had in fact previously experienced the task. In another instance a pianist was taught a new piece on one day and was able to play it the day after . However, on the day after he was unable to say where he acquired the relevant information. This type of spared learning and the associated memories are referred to as procedural memory and contrast with memories that are impaired. The impaired memories are referred to as declarative memories and were discussed above. Another example of spared learning ability is demonstrated by the example where a physician who is treating an amnesic pricks the amnesiac with a pin while shaking hands with her. The next day when the physician entered the room and introduced himself and motioned to shake hands the amnesiac withdrew rather than presented her hand. When asked why she could give no justification other than the general comment that sometimes things are hidden in people's hands. Thus it was concluded that amnesiacs were capable of classical avoidance conditioning.
B. A symptom of chronic alcoholics is severe memory loss. These patients show bilateral loss of brain tissue in the medial thalamus and mammillary bodies as a result of thiamine (vitamin B1 deficiency). Unfortunately whether this damage is the cause of the memory dysfunction is not so clear cut because this disease also causes many other physiological problems. None-the-less this finding by Korsakoff does support the idea that the limbic circuit is involved in the organization, formation and retrieval of memories.
C. A side effect of a seizure that originates in the temporal lobe is the erasure of memories (retrograde amnesia) and the inability to remember events that occur immediately after the seizure (anterograde amnesia). This phenomena is replicated in profoundly depressed patients who have electroconvulsive therapy.
D. Direct brain stimulation also implicates the temporal lobe in the storage of retrieval of memories. Penfield - in dudai Ch 10.
E. Various visualization techniques demonstrate that the hippocampus is very metabolically active in tasks that are clearly memory dependent. 2 deoxyglucose positron emission tomography (PET), along with electroencephalography (EEG) and magnetic resonance imaging (MRI) have been used for this purpose.

Nov 3
F. Animal studies would allow for the most accurate description of the system involved with declarative memory however, animals don't speak and therefore it is difficult to perform tasks that involve a declarative component. Fortunately various tasks have been found that are disrupted by lesions of the hippocampal region, and/or medial diencephalon. Such tasks include the 8-arm radial maze, water maze and non matching to sample paradigm. The mazes are generally used with rats and have lead to the concept of the hippocampus as a place where spatial relations are stored (spatial memory). The non-matching to sample paradigm is used with monkeys as well as rats and lead to the the idea that the hippocampus is involved in providing flexibility to the behavior repertoire i.e. the hippocampal region is involved in breaking out of a previously learned pattern of behavior (possible connection to obsessive compulsive disorder).

II. Circuitry
A. information from the senses is passed to various regions of the brain. At some point this information reaches the primary sensory regions of the neocortex. From there the information is sent to association cortices. One of the regions that receives multimodal information is the perirhinal and parahippocampal cortices. These areas project to layer V and IV of the entorhinal cortex (EC). Other regions that project to the EC include the orbitofrontal cortex, cingulate cortex, superior temporal gyres, and insular cortex, primary olfactory cortex.
larger image of hippocampal region
B. Cells in layer II of the EC project into the dentate gyrus.
C. Granule cells in the dentate gyrus project to the CA3 region of the hippocampus. The CA3 region of the hippcampus then projects predominantly to the CA1 region. CA1 projects projects to the subiculum and the subiculum projects to the entorhinal cortex and mammillary bodies.
D. Some CA3, CA1 and subicular axons form a bundle called the fornix. Fibers in the fornix travel anterior and ventral before diving dorsally. At the point where the fibers start to dive dorsally they divide around the anterior commissure into the precommissural fornix which synapses on the nuclei of the lateral septum, and the postcommissural fornix which synapses in the mammillary body mainly in the medial nucleus. Some fibers traveling in the fornix also synapse in the anterior and interlaminar nuclei of the thalamus. Those fibers that make up the postcommissural fornix mostly originate in the subiculum.

The septal nuclei project, among other places, back to the hippocampus. The mammillary bodies project to the the anterior nucleus of the thalamus and the ventral and dorsal tegmental nuclei (nuclei which have discussed with respect to motivation and reinforcement.
The anterior nucleus of the thalamus projects to the cingulate gyrus which projects to the entorhinal cortex (forming a large loop).

Nov 5

Review of large and small loop that might be involved in declarative, spatial or contextual memory: Introduction of serial processing. This type of processing is subserved by feedforward excitatory connections.

Introduce idea of parallel processing. An example of such a process is seen in the parallel inputs from the entorhinal cortex to the CA regions. Cells in Layer II of the entorhinal cortex project to the CA1 regions through the connections described in the small loop i.e. they project to CA3 through dentate gyrus cells and to CA1 through DG and CA3. Layer III cells in the entorhinal cortex project directly to CA1 and CA3. to CA regions which originate in layer III of the entorhinal cortex.

Within region processing is of two major types: 1) inhibitory feedback and feedforward inhibition and 2) excitatory feedback eg. CA3 cells. The former is mediated by interneurons that are found in all regions discussed above and are mostly GABAergic. They remain within a given region and have many shapes and sizes. Some examples are the basket cells, O/A interneurons, and L/M interneurons. eg.interneurons in CA1. The latter can be best described by using a specific example i.e. CA3.

CA3 cells also receive input from other CA3 cells (recurrent excitation). The probability of a given CA3 cell contacting another CA3 cell is 5%. Although this seems very small in the rat there are 160,000 CA3 cells thus one CA3 cell makes excitatory contact with 8000 other cells. It is known from simulations using recurrent excitatory networks (autoassociative networks) that these networks can be used to perform such tasks such as object completion.

Information processing is also affected by the positioning of specific inputs along the dendrites of cells.

Inputs to various regions are segregated along the dendrites of cells with which they synapse. Thus providing variable excitatory drive depending on where they synapse relative to the soma. e.g.. Perforant path fibers from the lateral entorhinal ctx (olfactory infor) synapse on the distal third of the granule cell dendrites while fibers originating in the medial entorhinal cortex (multimodal info) synapse in the middle third. The inner third is occupied by axons originating in the ipsilateral hilus, and contralateral dentate gyrus. A small region of the dendrite, very proximal (near the soma) is occupied by input from the septal nucleus. Segregation of this sort can also be seen on CA3 cells with mossy fibers synapsing proximally, perforant path fibers synapsing distally and CA3 axons from other CA3 cells synapsing in between.
CA1 inputs demonstrate both segregation and parallel processing. Layer II cells from the entorhinal synapse on dentate granule cells which synapse on CA3 cells which synapse in the middle portion of CA1 pyramidal cells (stratum radiatum). Layer III cells from the EC synapse directly on CA1 pyramidal cells. The Layer III input seems more modulatory and therefore is not considered part of the small loop. However, it can still be said that the segregation of inputs onto CA1 cells suggests a specific processing pattern and that since the information carried in these two systems originates in the same structure (but doesn't follow the same path to) that this is a demonstration of parallel processing.

Miscellaneous tidbits

The fibers that travel from layer II and III of the entorhinal cortex to the dentate gyrus and CA regions are referred to as perforant path fibers because they 'perforate' the subiculum on their way to their terminus.
the CA3 axons that synapse on CA1 apical dendrites are called the Schaffer collaterals.
mossy fiber (axons of the granule cells) terminals contain a high concentration of zinc and therefore can be visualized with a Timm stain.

Summary of some of the connections

CA3 axons project to two main regions: 1) CA1, and 2) medial septal nucleus
CA1 cells project to three main areas: 1) Subiculum, 2) medial septal nucleus, 3) entorhinal cortex (synapse in layer IV,V).
Subicular axons 1) travel in the postcommissural fornix and synapse in the mammillary bodies and 2) project to the entorhinal cortex (layers IV,V).

All of this activity influences what is stored in the neocortex because Entorhinal cells projects back to neocortical regions. Thus allowing for information that has been processed by the temporal lobe/medial diencephalic structures to influence what and how information is stored in the neocortex.

III. Spatial Maps dudai pg 189-190
A. Phenomenon - cell firing activity will correlate with the relationship between various aspects of the environment.

IV. What have we learned?
A.Temporal lobe and medial diencephalic structures are involved in declarative memory.
B. Those same structures seem to be involved with 1) discrimination reversal, 2) delayed non-matching to sample, 3) contextual or spatial memory as studied in animals. Also there is speculation that the role of the hippocampus may be in providing a place for working memory (we will hear more about working memory in the next section).
C. It has been proposed that that connection is one of relations i.e. the temporal lobe is involved in relational memory (Eichenbaum,H. and Cohen, N.)

V. Speculation on how all of this comes together to produce learning.
CA3 and CA1 are quickly integrate information about the world and tie disperate facts together. We can see the results of this process by observing the firing patterns of cells in the hippocampus during exploration (place cells). The process of integrating information and producing cognitive maps is done by taking advantage of the various loops, the autoassociative network in CA3 and the fact that plasticity is easily produced in various sets of connections. The integrated information is then feed back to the neocortex through the entorhinal cortex where it facilitates in the process of slowly linking and storing the relevant information into a more permanent engram.