Limbic System network
& approach to amnesia
M.S Ramaiah medical college
Border is between the neocortex and the subcortical
Concept of limbic system as an emotional system is the
legacy of McLean (1950’s)
proposed by Papez (1930’s)
anatomical name “limbic” introduced by Broca (1870’s).
The limbic system has evolved to the point that it is not
longer anatomically correct or relevant. It should be
abandoned and replaced by “brain emotional system” or
Limbic Lobe and Papez Circuit together
Distinguishes human emotions and responses to
situations from the stereotypical response of animals
due to reflexive systems involving brainstem
Hippocampus means seahorse in Greek.
Hippocampus aka cornu ammonis.
The term hippocampal formation typically refers to the
hippocampus proper (i.e., cornu ammonis)
Location temporal lobe of each cerebral cortex, medial to the
inferior horn of the lateral ventricle.
Ammon was an Egyptian god, near whose temple ammonia or the
salt of Ammon was prepared.
Ammon’s Horn because the two hippocampi bend around in the
form of the horns of a ram.
fornix is a “C” shaped tract (in sagittal section).
The fornix begins as the bundle of fibers called the alveus.
The alveus is white matter consisting of mylinated afferents
fibers of the alveus travel posteriorly, they aggregate medially
to form the fimbria of the fornix.
Fimbria means fringe and in this case it is the fringe of the
The fimbria looks like a thick rubber band.
The fimbria of each hippocampus thickens as it moves
posteriorly and eventually splits off from the hippocampus
forming the crua or “legs” (singular—crus) of each
The two crua come together and form the hippocampal
commissure. The hippocampal commissure provides one of
two major paths whereby the hippocampi communicate with
After the hippocampal commissure the single fiber bundle
isfornix. The fornix continues in an arc to the anterior
The anterior commissure landmark fornix splits into three
parts and goes to different structures:
1) Split just before the anterior commissure
precommissural fornixseptal nuclei, the ventral striatum, and
the cingulate cortex.
2) Some fibers from the fornixanterior commissure to the
3) Split after the anterior commissurepostcommissural
fornixmammillary bodies of the hypothalamus and the
anterior nuclei of the thalamus.
afferents and efferents of the hippocampus are bundled
together in the same paths.
Two major pathways into and out of the hippocampus are
the fornix and entorhinal cortex (via the cingulate cortex).
The precommissuralconnects to the septal nuclei, preoptic
nuclei, ventral striatum, orbital cortex and anterior
The postcommissuralanterior nucleus of the thalamus and
the mammillary bodies of the hypothalamus.
The mammillary bodies are destroyed in Korsakoff’s syndrome
as profound difficulty forming new memories
mammillothalamic tract also goes to the anterior thalamic
nucleus, the hippocampus can affect the thalamus indirectly as
well as directly.
The anterior thalamic nuclei in turn connect to the cingulate
The cingulate cortex projects back to the entorhinal cortex of
parahippocampal gyrus, completing a “great” loop called the
The Papez circuit like many other areas of the limbic system is
involved in learning and memory, emotion, and social behavior.
The amygdala, along with neocortical areas, are now known to
be centrally involved in emotional experience.
Posterior section: Hippocampus,
Divisions or nuclei of
The hippocampus has direct connections to the entorhinal
cortex (via the subiculum) and the amygdala
The entorhinal cortex projects to the cingulate cortex.
hippocampus can affect the cingulate cortex through the
anterior thalamic nucleus or the entorhinal cortex.
The cingulate cortex, in turn, projects to the temporal lobe
cortex, orbital cortex, and olfactory bulb.
Thus, all of these areas can be influenced by the
Structures and Processes
within the Hippocampus
The hippocampus proper and the dentate gyrus processes
information that passes through the hippocampus.
These two structuresform two interlocking “Cs.”
The term dentate gyrus beaded or toothed small blood
vessels from subarachnoid space that penetrate the dentate
The hippocampus and dentate gyrus arecortex3-layered
cortex rather than 6-layered cortex as in the neocortex.
Because of the smaller number of layers and their location
between the neocortex and diencephalon, these cortices have
been called paleocortex/old cortex/archicortexancient cortex.
Misleadingfalse impression that these cortices are
antiquated remnants left over as the brain evolved and
became more complex.
Actually continued to develop structurally and functionally
The hippocampus and dentate gyrus, like the neocortex,
have a superficial molecular layer and a deep polymorphic
Structures are "inside-out" cortex, the molecular layer is on
the inside and the polymorphic layer is on the outside.
Middle layer of the hippocampus properpyramidal cell
Middle layer of the dentate gyrusgranular layer.
Molecular layer of the hippocampus proper faces the
The area of the hippocampus proper that is capped by the
dentate gyrus is referred to as CA3 (CA for cornu ammonis).
The polymorphic layer alveus and is equivalent to the
white matter of the neocortex.
The subiculum is the transition layer from the hippocampus
to the parahippocampal gyrus and changes gradually from
three to six layers.
A major flow of information through the hippocampus is a
Frontal Lobes of Cortex
Provides Rationale Control of emotional disposition & involved
Injury to frontal lobes causes change in personality
Control of emotions and impulse control
Example of Phineas Gage
Tumors and injury to areas of the brain lead to
Damage to cingulate cortex lead to emotional
disturbances: fear, depression, irritability
Neurons at the pole of the temporal lobe below the cortex on
the medial side
Greek name for almond shape
Has 3 nuclei, basolateral, corticomedial and central
Afferents from all lobes of neocortex & hippocampus and
Input to Amygdala
Basolateral nuclei receive sensory input (visual, gustatory,
auditory and tactile); also projects to cortex for perception of
Corticomedial nuclei receive olfactory inputs
Central nuclei contain output neurons to hypothalamus and
periaqueductal grey in brainstem for physiological responses
Major Output Pathways
of the Amygdala
Ventral amygdalofugal pathway
Directly to the hippocampus
Directly to the entorhinal cortex
Directly to the dorsomedial nucleus of the thalamus
Ventral Amygdalofugal Pathway
"fugal" comes from the word fuge—to drive away—as in
anterior olfactory nucleus,
anterior perforated substance,
anterior cingulate cortex,
The ventral striatum includes
part of the caudate, putamen, and the
nucleus accumbens septi (nucleus that reclines on the
Projections from the ventral striatum are links in a basal
ganglia circuit that are important in stimulus-response
The ventral amygdalofugal pathway also connects to the
hypothalamus and septal nucleus, but the amygdala's major
connection to the hypothalamus and septal nucleus is through
the stria terminalis.
Link motivation and drives, through the limbic
Link responses are learned.
Link associative learning takes place rewards
The stria terminalis is similar in form, function, and location as
the fornix for the hippocampal pathway. Thus by way of
analogy one can say that the stria terminalis is to the
amygdala as the fornix is to the hippocampus.
The stria terminalis connects only to subcortical structures.
(Connection to cortical structures ventral amygdalofugal
The stria terminalis overlaps with the ventral amygdalofugal
pathway in that it also connects to the septal nuclei and
hypothalamus and thus forms a loop.
Similarities to the fornix
Like the fornix, the stria terminalis has
Precommissural to the septal area exactly
postcommissural branches to the hypothalamus
postcommissural branch of the fornix projects to mammillary
bodies of the hypothalamus
postcommissural branch of the stria terminalis projects to the
As with the fornix,
some fibers enter anterior commissure cross to the
Two hippocampi anterior commissure
two amygdala communicate anterior commissure.
The stria terminalis also projects to the habenula, which is part
of the epithalamus.
The central nucleus of the amygdala produces
autonomic components of emotion output pathways to
the lateral hypothalamus and brain stem.
conscious perception of emotion primarilyventral
amygdalofugal output pathway
to the anterior cingulate cortex
orbitofrontal cortex & prefrontal cortex
More on Function of the
Stimulationintense emotion, such as aggression or fear.
Irritative lesions of temporal lobe epilepsy have the effect of
stimulating the amygdala.
Extreme form irritative lesionspanic attack.
Panic attacks are brief spontaneously recurrent episodes of
terror that generate a sense of impending disaster without a
clearly identifiable cause.
PET scans increase in blood flow to the parahippocampal
gyri, beginning with the right parahippocampal gyrus.
During anxiety attacks blood flow increases
Damage to Amygdala
Decreases emotional response
Kluver-Bucy Syndrome reduced
Some human cannot recognize emotional
expressions on faces that are fearful, anxious
& angry but recognize happy & disgust
Bilateral amygdala removal reduces memory
Lesions of the amygdalaUrbach-Wiethe disease
calcium is deposited in the amygdala.
early in lifewith bilateral amygdala lesions cannot
discriminate emotion in facial expressions, but their ability to
identify faces remains.
The anatomical area for face recognition and memory is in the
multimodal association area of the inferotemporal cortex.
This is a good example of how emotion in one area
(amygdala) is linked with perception in another area
(inferotemporal cortex) to create an intense emotionally
fMRI results showing
amygdala activity in normal
viewing facial expressions
from happy to fearful.
Flatness of affectKluver-Bucy syndrome
Lesions of the amygdalaflatness of affect
Led to the psychosurgical technique of prefrontal lobotomies.
Remember the movie with Jack Nicholson, “One Flew Over
the Cuckoo’s Nest.”
The prefrontal cortex inputs into the amygdala.
Input a flatness of affect is produceddesirable in
schizophrenic patients who were aggressively violent or
amygdala combines many different sensory inputs.
Like the hippocampus it combines external and internal stimuli.
Integrated with somatosensory and visceral inputs—this is
where you get your “gut reaction”.
Link between prefrontal cortex, septal area, hypothalamus,
and amygdala likely gives us our gut feelings.
It is also where memory and emotions are combined.
Reward is particularly sweet last a lifetime.
Trauma and humiliation of punishmentremembered for a
long time too.
Fear Conditioning:Role of the
Amygdala in Learning
The crucial aspect of classical conditioning is that it is a
pairing between two stimuli.
In fear conditioning, an organism hears a noise or sees a
visual stimulus. A few seconds, later it receives a mild shock.
Reactions involve freezing, elevated blood pressure and heart
rate, and it gets twitchy—startles easily
Pathways of fear conditioning
and emotional information.
Expression of different emotional
responses by the amygdala.
Electrical Stimulation of
Cause affective rage when basalateral nuclei is
Corticomedial stimulation reduces aggression
Require the amygdala and work through 2 pathways.
Integrate information from all sensory systems and orchestrate
the physiological and psychological response
Ventral amygdofugal pathway
Autonomic nuclei in the brainstem receive synaptic
input from hypothalamus via
Medial forebrain bundle
Dorsal longitudinal fasciculus
process of laying down a memory begins
with attention (regulated by the thalamus and the frontal
Emotion tends to increase
attentionamygdalasensations derived from an event
The perceived sensationsdecoded in sensory areas of the
cortex combined in the brain’s hippocampus into one single
Hippocampus sorting centre where the new sensations
are compared and associated with previously recorded
oneslong-term memorydifferent parts of the brain
It is also one of the few areas of the brain where completely
new neurons can grow.
stabilizing a memory
synaptic consolidation (which occurs within the first few
hours after learning or encoding)
system consolidation (where hippocampus-dependent
memories become independent of the hippocampus over a
period of weeks to years).
Long-term potentiationallows a synapse to increase in
strength as increasing numbers of signals are transmitted
between the two neurons.
Potentiationsynchronous firing of neurons makes
those neurons more inclined to fire together in the future.
“re-wire” itself by re-routing connections and re-arranging its
neural network, is traversed over and over again, an enduring
pattern is engraved and neural messages are more likely to
flow along such familiar paths of least resistance.
The ability of the connection, or synapse, between
two neurons to change in strength, and for lasting changes to
occur in the efficiency of synaptic transmission, is known
as synaptic plasticity or neural plasticity.
long-term memories widely distributed throughout
After consolidation, long-term memories are stored throughout
the brain as groups of neurons that are primed to fire together
in the same pattern that created the original experience.
Actively reconstructed from elements scattered throughout
various areas of the brain by the encoding process. Memory
storage is therefore an ongoing process of reclassification
resulting from continuous changes in our neural pathways, and
parallel processing of information in our brains.
ultra-short-term memory (200 - 500 milliseconds)
ability to retain impressions of sensory information after the
original stimuli have ended
ability to look at something and remember what it looked like
with just a second of observation is an example of sensory
sensory memory for visual stimuli iconic memory,
memory for aural stimuli echoic memory
Touch haptic memory.
Smell closely linked to memory olfactory bulb and
olfactory cortex are physically very close - separated by just 2
or 3 synapses - to the hippocampus and amygdala.
Information is passed from the sensory memory into short-term
memory process of attention effectively filters the stimuli
to only those which are of interest at any given time.
SHORT-TERM (WORKING) MEMORY
“scratch-pad” for temporary recall of the information which is
being processed at any point in time, and has been referred to
as "the brain's Post-it note"
typically from 10 to 15 seconds, or sometimes up to a minute).
the beginning of the sentence needs to be held in mind while
the rest is read, a task, which is carried out by the short-term
Central executive part of the prefrontal cortexplay a
fundamental role in short-term/working memory.
Central executive controls two neural loops,
one for visual data (near the visual cortex of the brainvisual
one for language (the "phonological loop", which uses Broca's area
as a kind of "inner voice" that repeats word sounds to keep them in
limited capacity-George Miller in 1956 Memory span is between
5 and 9 (7 ± 2“magical number”/Miller's Law).
spontaneously decays10 - 15 seconds
Displacement New contentgradually pushes out older content
Short-term memories can become long-term memory through the
process of consolidation
Physiologically, the establishment of long-term memory involves a
process of physical changes in the structure of neuronslong-
Whenever something is learned, circuits of neurons in the brain,
known as neural networks synapses.
short-term memory is supported by transient patterns of neuronal
communication in the regions of the frontal, prefrontal and parietal
lobes of the brain.
long-term memoriesmore stable and permanent changes in
neural connections widely spread throughout the brain.
The hippocampus temporary transit point for long-term
memories, and is not itself used to store information.
Essential to the consolidationshort-term to long-term
memory, changing neural connections for a period of three
months or more after the initial learning.
Taxonomy of Long-term Memory Systems
Squire L, Zola S PNAS 1996;93:13515-13522
Adapted from Squire, Knowlton 1994
DECLARATIVE (EXPLICIT) &
PROCEDURAL (IMPLICIT) MEMORY
Declarative memory (“knowing what”)facts and events,
consciously recalled (or "declared”)
Declarative memoryepisodic memory and semantic memory.
Procedural memory (“knowing how”) is the unconscious memory of
skills and how to do things
Declarative memories are encoded by hippocampus, entorhinal
cortex and perirhinal cortex (medial temporal lobe of the brain)
consolidated and stored in the temporal cortex and elsewhere
semantic memory mainly activates the frontal and temporal
episodic memory activity is concentrated in the hippocampus,
at least initially.
Once processed in the hippocampus, episodic memories are
then consolidated and stored in the neocortex.
The memories of the different elements of a particular event
are distributed in the various visual, olfactory and auditory
areas of the brain, but they are all connected together by
the hippocampus to form an episode, rather than remaining a
collection of separate memories.
Procedural memoriesdo not appear to involve the
hippocampus at all
Encoded and stored by the cerebellum, putamen, caudate
nucleus and the motor cortex, all of which are involved in
Learned skills such as riding a bike are stored in the putamen;
Instinctive actions such as grooming are stored in the caudate
cerebellum is involved with timing and coordination of body
Without the medial temporal lobeperson is still able to form
new procedural memories (such as playing the piano), but
cannot remember the events during which they happened or
Highly processed information from association cortex
areas enter hippocampus
Hippocampus integrates them—ties them together
and then output is stored in other cortical areas
Allows you to retrieve all the information about an
Cannot form any new types of memories so always live
at time of injury
Cannot recall stored memories for a specific time
Had bilateral mediotemporal lobes removed due to
Removed amygdala, anterior 2/3 of hippocampus,
Had anterograde amnesia
Studied by Brenda Milner
Could learn by procedural memory but had no
recollection of having learned task
Squire & Mishkin
Neuroscientists create an animal model for
Lesioned amygdala, hippocampus and
perirhinal cortex in temporal lobe of monkeys
and found that they could no longer perform in
recognition memory tests
Later showed that perirhinal cortex is most
important for new memory; temporary
storage? Memory consolidation?
Dorsal medial thalamic
Receives input from temporal lobe structures including
amygdala & inferiortemporal cortex
Projects to all frontal cortex areas
Air Force technician injured by fencing foil –penetrated
the dorsalmedial thalamus
Developed retrograde amnesia of previous 2 years
and severe anterograde amnesia
Supports role of thalamus in memory
Lashley: 1920s studied rats in maze after cortical
Found that all cortical areas are involved in memory
Hebb, Lashley student
suggested CELL ASSEMBLY = all cells that respond
to an external stimulus & are reciprocally
Neurons that fire together, wire together
1949 Organization of Behavior
Sensory cortex also stores memory
Led to neural networks computer modeling
Circuit using limbic
Hippocampal output axons travel as a bundle, the
fornix, to the mammillary bodies of the hypothalamus
Mammillary body axons project to anterior thalamic
Memory based on Vision
Should be found in cortical area involved in vision
inferiortemporal cortex: higher order processing of
visual information—stores memory of previously seen
Allows recognition of visual objects
Remember Kluver-Bucy pyschic blind monkeys
Neurosurgeon in the 1950’s removed epileptic foci
Found that stimulation of temporal lobe in awake
patients caused halucinations or memory retrieval
LIMBIC SYSTEM - CLINICAL IMPLICATIONS
TEMPORAL LOBE EPILEPSY
Form of focal epilepsy, a chronic neurological condition, Characterized by
Recurrent epileptic seizures arising from one or both temporal lobes
Two main types
Mesial temporal lobe epilepsy (MTLE)
Lateral temporal lobe epilepsy (LTLE)
Mesial temporal sclerosis –
47-70% of all TLE
Severe neuronal loss in CA1, May spread to involve CA3 and CA4,
CA2 and dentate are only mildly involved
Specific pattern of hippocampal neuron cell loss
Associated with hippocampal atrophy and gliosis
Dispersion of granule cell layer in dentate gyrus
Pts classically describe fear, déjà vu, jamaisvu, elementary
and complex visual hallucinations, illusions, forced
thinking, emotional distress.
An inflammatory process involving the hippocampi, amygdala and less frequently
frontobasal and insular regions of the limbic system and other parts of the brain.
severe impairment of short-term memory (cardinal sign),
psychiatric symptoms (changes in behavior & mood –
60%paraneoplastic in origin
Paraneoplastic limbic encephalitismost commonly associated with small cell
Neurodegenerative changes in limbic
Amyloid proteins build up and form
amyloid plaques (outside cells)
Neurofibrilllary tangles (inside cells),
leads to neuronal death
Hippocampus is one of first areas to
degenerate, leads to anterograde
Cortex also degenerates early, leads
to retrograde amnesia and dementia
Neurobehavioural syndrome associated with bilateral lesions in the
medial temporal lobe , particularly amygdala
Facial Blunting (may not respond appropriately to stimuli)
Hyperphagia (extreme weight gain without a strictly monitored diet)
Hyperorality (marked tendency to examine all objects orally)
Hypermetamorphosis (an irresistible impulse to attend& react to visual
Inappropriate Sexual Behavior (Hyper sexuality) atypical sexual
behavior, mounting inanimate objects.
Visual Agnosia/ "psychic blindness" (inability to visually recognize
Amnestic syndrome, caused by thiamine
Associated with poor nutritional habits of
people with chronic alcohol abuse, gastric
carcinoma, haemodialysis etc.
Leads to damage to mammillary bodies and
dorsomedial nucleus of thalamus
Amnesia, confabulation, attention deficit,
disorientation, and vision impairment, change in
personality like -lack of initiatives, spontaneity,
lack of interest or concern, Executive function
Recent memory more affected than remote,
Immediate recall is usually preserved