Midsagittal view of the brain showing the limbic system

The Limbic System

The Limbic System

• Functional anatomic system of interconnected cortical and subcortical structures

– between the hypothalamus and cortex

• Role in memory, learning and social interaction

• Paul Broca: limbic means “border”; border between

hypothalamus and cerebral cortex

The Limbic System

• Limbic lobe– Subcallosal gyrus– Cingulate gyrus– Isthmus of the cingulate

gyrus– Parahippocampal gyrus– Uncus– Hippocampal formation

• Originally, the limbic lobe was assigned was assigned a purely olfactory function

• It has been established that only a minor part of the limbic lobe has an olfactory function

• The rest of the limbic lobe, which forms part of the limbic system, plays a role in emotional behavior and memory

•

The Limbic System• Limbic system

– Limbic lobe PLUS all the subcortical and cortical structures related to it

• Nucleus accumbens• Nuclei of hypothalamus (related to

mammillary body)• Amygdaloid complex• Substantia innominata• Anterior and dorsomedial thalamus• Habenular nuclei• Ventral tegmental area• Periaqueductal gray• Prefrontal cortex

Limbic System

1. Emotional behavior2. Memory3. Integration of homeostatic responses such as those

related to preservation of the species, securing food, and the fight or flight response

4. Sexual behavior5. Motivation

- The underlying mechanism for these different funtionc are very complex & inaqequately understood

The Limbic System

• Main efferent fiber bundles of the limbic system– Fornix

• Hippocampus and subiculum

– Stria terminalis and Ventral amygdalofugal pathway

• Amygdaloid complex

– Mammillothalamic tract• Medial mammillary nucleus

Cytoarchitectural Definitions of The Limbic Cortex

• Most cortices : neocortex with 6 layers– Primary sensory, motor and association cortices

• Allocortex: < 6 layers – Most structures of limbic system

• Paleocortex/paleopallidum/periallocortex : 3 to 5 layers– Parahippocampal gyrus (entorhinal cortex), Uncus (piriform

cortex), Lateral olfactory stria (gyrus)• Archicortex /archipallidum/allocortex: 3 layers

– hippocampus and dentate

Cytoarchitectural Definitions of The Limbic Cortex

• Transition from one cortex to another– Funnel input from association areas of neocortex into

allocortex– Temporal pole, parts of insula, portions of

parahippocampus, cingulate gyri

Papez CircuitEmotion mediated through hypothalamus is controlled and modulated by fibers from fornixCortical control of emotional activity originate from cingulate and hippocampusCircuit ends in the cingulate gyrus

Hippocampus → fornix →

mammillary bodies → anterior

thalamic nucleus → cingulate gyrus →

hippocampus• Areas of cerebral cortex recruited through connections of the cingulate gyrus• Reciprocal connections with premotor, prefrontal areas, visual/auditory/somatosensory

association cortices

• Areas of cerebral cortex recruited through connections of cingulate gyrus

• Reciprocalconnections with premotor, prefrontal areas, visual/auditory/somatosensory association cortices

Neural circuit for emotion proposed by James Papez and extended by Paul MacLean

The Circle of Willis

Blood Supply to the Limbic System

• Internal CarotidArtery– Anterior choroidal artery

• Hippocampal formation, parts of amygdaloid complex, stria terminalis

• Anterior Cerebral Artery– Subcallosal area, rostral cingulate gyrus– (branch) Pericallosal artery: most of cingulate gyrus

• Anterior Communicating Artery– (+ branches from ACA): rostral hypothalamus

Blood Supply to the Limbic System

• Middle Cerebral Artery– (+ branches from PCA): uncus

• Posterior Cerebral Artery– (+ branches from Pcom): posterior hypothalamus– Thalamoperforating artery: anterior nucleus of

thalamus– Temporal branches: parahippocampal gyrus

Hippocampal Development

Dorsal to the corpus callosum early in brain developmentPulled down into the temporal lobeForms by infolding of cortex, dentate & subiculum fuse

Hippocampal Development• Remnants of hippocampal formation remaining dorsal to corpus callosum

– Medial and lateral longitudinal striae– Indusium griseum (gray matter)

The Hippocampal Formation

Hippocampal Formation

• 1. Hippocampus- largest• 2. Dentate gyrus: interval between the

hippocampus & subiculum• 3. Subiculum- in direct continuity with the

hippocampus

DENTATE GYRUS – toothed or beaded surface-- occupies the interval between the hippocampus and the subiculum part of the parahippocampus

SUBICULUM PART OF THE PARAHIPPOCAMPUS – direct continuation of the hippocampus

Schematic diagram showing the components of hippocampal formation

The Hippocampus• 3 layers

– Molecular• Axons and dendrites

– Pyramidal• Cells are principal neurons• Axons are only outflow tract, forming alveus and fimbria

(fuse to become fornix)– Stratum oriens/ Polymorphic layer

• Intrinsic neurons – basket cells; “GABAergic” • Glial elements• Axons of pyramidal cells

Dentate Gyrus

• 3 layers– Molecular- continuous with the hippocampus– Granular

– Small densely packed granule cells– Axon forms the mossy fiber system which links the dentate

gyrus and the hippocampus– Polymorphic

• Pyramidal and basket cells

Unlike the hippocampus, the output of the dentate gyrus does not leave the hippocampal formation

Hippocampus: Subiculum• Transitional area• 3 layers

– Molecular– Pyramidal

• Axons contribute to output of hippocampal formation– Polymorphic

• Parts– Prosubiculum– Subiculum proper– Presubiculum– parasubiculum

The Hippocampus

• 4 fields– Cornu Ammonis (CA) 1/ Sommer’s sector/ vulnerable

sector• Largest; between hippocampus and subiculum• Pyramidal neurons sensitive to anoxia and ischemia• TLE trigger

– Cornu Ammonis (CA) 2– Cornu Ammonis (CA) 3– Cornu Ammonis (CA) 4/ Bratz sector

• Between hippocampus and dentate• Medium vulnerability to hypoxia

Parahippocampal Gyrus

• Major input to hippocampus• Gateway between cerebral cortex and

hippocampus– 2 routes

• Perforant Pathway– Main input– Travels through

subicular area• Alvear Pathway

– Via ventricular surface, where alveus is formed

Entorhinal Area (Brodmann’s Area 28) of the parahippocampal gyrus

• The entorhinal area serves as an important gateway between the cerebral cortex and the hippocamus

• Information from many cortical areas (limbic, modality-sensory specific, & multimodal association cortices) in the frontal, temporal, parietal, and occipital lobes conveying visual, auditory, and somatosensory information converges on the enterohinal cortex & the posterior parahiccocampal gyrus

• The enterohinal cortex is the most heavily damaged in Alheizer’s disease & is the site of early onset of the disease.

Hippocampal Circuit

Limbic association areas

Entorhinal cortex

Dentate Granule Cells

Mossy fibers (granule cell axons)

CA3 pyramidal cells CA1 pyramidal cells

Alveus

Fimbria

Outflow of Hippocampus

• Cells of Subiculum and Pyramidal cells of hippocampus– Axons enter alveus

• Glutaminergic• Traverse extent of fornix, some enter

hippocampal decussation – Anterior to splenium of Corpus Callosum

Outflow of Hippocampus• Fornix divides at level of anterior commissure

– Postcommissural • Fibers from subiculum

– Medial mammillary nucleus (majority)– Anterior nucleus of the dorsal thalamus– Ventromedial nucleus of hypothalamus

– Precommissural• Fibers from hippocampus

– Septal nuclei– Medial areas of frontal cortex– Preoptic and anterior nuclei of hypothalamus– Nucleus accumbens

Schema of Fornix

Hippocampal Afferents & Efferents

The Hippocampus• A temporary depository for long term memory.• Ultimately, transfers the learned information to the other areas, the cerebral

cortex. The key components of the medial temporal lobe important for memory storage can be seen in the medial (left) and ventral (right) surface of the cerebral hemisphere

The Hippocampus• Functions as a waystation for the long term

memory or a facilitation system that is essential for the storage of memory elsewhere in the brain.

The Anatomical Organization of the hippocampal formation

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Unimodal and polymodal

Association areas(frontal, temporal, and

parietal lobes)

Parahippocampalcortex

Perirhinalcortex

EntorhinalCortex

Dentategyrus

HippocampusCA3

HippocampusCA1

Subiculum

MossyFiber

pathway

Schaffercollateralpathway

Perforantpathway

The input and output pathways of the hippocampal formation

SUPERIOR DISSECTION OF THE HIPPOCAMPUS AND AND FORNIX

Efferent PathwayHIPPOCAMPUS

SUBICULUMFORNIX

VENTRAL STRIATUM

HYPOTHALAMUS

MEDIAL FRONTAL CORTEX

SEPTAL NUCLEI

ENTORHINAL AREA

LIMBICSENSORY SPECIFIC andMULTIMODAL ASSOCIATION CORTICES

ANTERIOR NUCLEUS OF THALAMUS

MAMILLARY BODY

PRECOMISSURAL FORNIX

POSTCOMISSURAL FORNIX **major component

Axons of pyramidal neurons in the subiculum and hippocampus which gather at the ventricular surface of the hippocampus as ALVEUS

FIMBRIAE (flattened ribbon of white matter)

CRUS OF THE FORNIX(under the splenium of the corpus

callosum)

ANTERIOR COLUMNS (flattened ribbon of white matter)

BODY OF THE FORNIX(attached to the inferior surface of

the septum pellucidum)

MAMILLARY BODIES – 75%ANTERIOR NUCLEUS OF THE

THALAMUS – REST

Amygdala –” almonds”; located at the tip of the temporal lobe beneath the cortex of the uncus and rostral to the hippocampus and inferior horn of the lateral ventricle

The Amygdaloid Complex

Amygdaloid Nuclei

• 2 Main Groups– Corticomedial-central group :related to olfaction– Basolateral group : Connections with cortical structures

The Amygdaloid Complex: Afferents

• Basolateral cell group– Dorsal thalamus– Prefrontal cortex– Cingulate and parahippocampal gyri– Temporal lobe– Insular cortex– Subiculum

• Supply somatosensory, visual and visceral information

The Amygdaloid Complex: Afferents

• Corticomedial-central cell group– Hypothalamus (VM, lateral)– Dorsal thalamus (DM, medial)– Brainstem nuclei related to visceral functions (parabrachial

nuclei, solitary nucleus, periaqueductal gray)• Olfactory input

The Amygdaloid Complex: Efferents• Stria terminalis

– From corticomedial nuclei– Between caudate and

dorsal thalamus– Associated with “bed

nucleus of the stria terminalis”

– Connects to hypothalamus, nucleus accumbens, septal nuclei, rostral caudate nucleus, putamen

Ventral amygdalofugal pathway Major efferent bundle From basolateral group and

central nucleus hypothalamus, septal nuclei substantia innominata

Diffuse cholinergic projection to cortex

“cortical activation” Prefrontal/frontal, cingulate,

insular & inferior temporal cortices

Schematic diagram of the major efferent connections of the amygdala

2 main output pathways from the amygdala:

STRIA TERMINALIS• Arises predominantly from the corticomedial group•Supplies the septal nuclei•Anterior,preoptic, ventromedial nuclei of the hypothalamus

VENTRAL AMYGDALOFUGAL• originates from the basolateral and central amygdalar nuclei• Projects to thalamus (DM nucleus)•Prefrontal, entorhinal area, cingulate•Nucleus basalis, septal area, hypothalamus

The Amygdaloid Complex: Efferents

• Stria medullaris thalamiHippocampus and amygdala

Septal nuclei

Habenular nuclei

Midbrain: Interpeduncular nuclei, ventral tegmental area, periaqueductal gray

Habenulointerpeduncular tract

Septal Nuclei

• Found adjacent to septum pellucidum• Afferent pathways

– Hippocampus – Amygdaloid complex– VTA of midbrain– Hypothalamus

Septal Nuclei

• Efferent pathways– Septohippocampal fibers (via fornix)– hypothalamus– Habenular nuclei– Medial thalamic nuclei (stria medullaris thalami)– VTA

• Via medial forebrain bundle– Conveys inputs to hypothalamus then septal area– Major conduit through which septal nuclei and portions of

hypothalamus communicate with brainstem– Dopamine containing fibers = “pleasure”

Nucleus Accumbens• Inputs

– Amygdaloid complex (via ventral amygdalofugal pathway and stria terminalis)

– Hippocampal formation (through precommissural fornix)

– Bed nucleus of stria terminalis– VTA (via medial forebrain bundle)

• Outputs– Hypothalamus– Brainstem nuclei– Globus pallidus

Functions of the Limbic System

• Aversion and gratification centers– Hippocampus and amygdala: aversion predominant– Nucleus accumbens: gratification predominant

• Role in addiction

• Modulation of– Aggressive behavior– Certain forms of learning and memory

Aggression and Rage• Experimental studies in animals

– Activation of the part of the hippocampal formation closest to the amygdala facilitates predatory attack behavior

– Activation of the HF near the septal formation suppresses the aggression

• In humans, published reports linking lesions, tumors, and epileptogenic activity of the hippocampal formation with aggressive reactions ( varied; hostility and explosive acts of physical violence)

MEMORY

Explicit“Knowing that”Explicit“Knowing that”

Conscious retrieval of information

Supports the learning and retention of facts and the conscious recollection of prior events

MEMORY

Explicit“Knowing that” Explicit“Knowing that”

EPISODIC (UNIQUE)memory of personally experienced facts and events

SEMANTIC (GENERIC)memory of culturally and educationally acquired encyclopedic knowledge eg math, historical information etc

SHORT TERM MEMORY/ WORKING MEMORY memory of limited amount of information eg 7 digit phone number - decays in seconds if not refreshed continuously

LONG TERM /REMOTE MEMORY memory that can be retrieved after delays

MEMORY

Implicit“Knowing how” Implicit“Knowing how”

Supports learning and retention of skills

Memory of experience-affected behaviors that are performed unconsciously

PROCEDURAL MEMORYrepeated performance of motor act eg biking, enhances and automates future skill of the same act resistant to forgetting

PRIMING short lived enhancement of perceptually based performance ff recent exposure to visually similar object

Anatomic Correlates of Memory• EPISODIC MEMORY

– Mesial temporal cortex( hippocampus and parahippocampal gyrus) are critical for this type of memory

– Unable to acquire new explicit memory (anterograde amnesia)

– No new information is retained beyond the span of 40-60 sec

– Other brain structures implicated in episodic memory• Hippocampus-mamillary body-anterior and medial thalamic

nuclei via the fornix and mamillothalamic tract• Cortico-cortical connections from the anterior and posterior

neocortices to the entorhinal cortex• Basal forebrain cholinergic nuclei

Long Term Potentiation and Memory

• Underlies memory consolidation

Mg2+ Glutamate Calcium

AMPAreceptor

Presynaptic neuron

Postsynapticneuron

NMDAreceptor

Na+

[Ca2+]

Hippocampus and Memory• Consolidation of immediate and short term

memory to long term memories• Case of H.M.

– Temporal lobe epilepsy underwent removal of both medial temporal lobes after the surgery, lost the capacity for consolidating short term memory to long term memory

• May be seen also in patients after a hypoxic/anoxic event– Sommer sector involvement

• May have epilepsy

Hippocampus and Memory

• Alzheimer’s Disease– Subiculum and EC first affected by plaques and

tangless

Hippocampus and Memory

• Korsakoff syndrome– Thiamine deficiency– Primarily affects mammillary bodies, DM nucleus

of the thalamus, – Columns of the fornix, hippocampal formation– Dementia with confabulation

• Wernicke-Korsakoff Syndrome– If with gaze palsies and ataxia

Kluver Bucy Syndrome

• Bilateral temporal Lobe injuries involving amygdaloid complex

• Behavioral Dysfunction– Visual agnosia (+/- tactile and auditory agnosia)– Hyperorality– Hypermeetamorphosis– Hypersexuality– Docility– Lack of emotional response, blunted affect– Memory deficit

Temporal Lobe Seizures

• Spread to adjacent TL or both TL• Uncus involvement

– Uncinate fits– Olfactory or gustatory

• Complex partial Seizure

Temporal categories of memory• Immediate memory

– Recall of a memory trace after few seconds• Short-term memory

– Ability to hold information in mind for periods of seconds to minutes once the present moment has passed

• Working memory– Ability to hold things in mind long enough to carry out

sequential actions• Long-term memory

– Retention of information for days, weeks, years or even a lifetime

Clinical subdivisions of memory

• Immediate memory• Recent memory

– Ability to learn new material and to retrieve that material after an interval of minutes, hours, or days

• Remote memory– Recollection of facts and events that occurred

years previously

The Major Temporal Categories of Human Memory

Long term memory

(days-years)

FORGETTING

Short term memory(seconds-minutes))

Immediate memory or sense of the

Present (fractions of a

second-seconds)

Immediate memory or sense of the

Present (fractions of a

second-seconds)

Understanding Memory

• Removal of the medial temporal lobes left him with a devastating memory deficit; but:

…. normal short-term memory…. perfectly good long-term memory for events…. perfectly good command of language…. IQ of bright-normal.

His main defect was the ability to transfer new short-term memory into long-term memory

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Understanding Memory

• Patients with bilateral medial temporal lobe lesions can perform tasks and other forms of simple reflexive learning, including habituation, sensitization, classical conditioning and operant conditioning.

…. tasks that have 2 things in common– tasks tend to be reflexive rather than reflective– they do not require conscious awareness or complex cognitive

processes.

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Two forms of memory

Implicit memory ( non-declarative memory)• a memory that is recalled unconsciously• involved in training reflexive motor or perceptual skills• rigid and tightly connected to the original stimulus

Explicit memory ( declarative memory)• factual knowledge of people, places and things and what these facts

mean• recalled by a deliberate conscious effort• highly flexible and involves the association of bits and pieces of

information.

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Various Forms of Memory

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Two forms of long term memory

Explicit(declarative)

Implicit(nondeclarative)

Facts Events

Medial temporal lobe Neocortex Striatum Amygdala Cerebellum Reflexpathway

Priming Procedural(skills and habits)

Associative learning:Classical andOperant conditioning

Nonassociative learning:Habituation andsensitization

Emotionalresponse

Skeletalmusculature

Human Memory

Declarative (available to consciousness)

Procedural(generally not available to consciousness)

Daily episodes

Words and their meanings

Words and their meanings

MotorSkills

AssociationsAssociationsPriming

Cues

PuzzleSolving

Skills

Qualitative categories of memory

• Declarative memory (explicit)– Storage and retrieval of material that is available to the

conscious mind and which therefore be encoded in symbols and expressed by language

– Memory for facts, eventsa. Episodic memory - explicit recollection of specific personal events

b. Semantic memory – general knowledge of facts & concepts not specified in time & space

Semantic Memory

• Our experience of knowledge as a seamless orderly and cross-referenced data base is the product of integration of multiple representations in the brain at many distinct anatomical sites.

• There is no general semantic memory; semantic memory is not stored in a single region.

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Semantic Memory

• Type of long-term memory that embraces knowledge of objects, facts and concepts, words and their meaning.– includes naming of objects, definition of spoken words and

verbal fluency.

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EPISODIC MEMORY

• Episodic (autobiographical) knowledge involves the prefrontal cortex.– the areas of the neocortex for long-term storage of

episodic knowledge are the association areas of the frontal lobe.

– Source amnesia – forgetting how information was acquired.

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Explicit knowledge involves four distinct processes:

1. Encoding – the process by which newly learned information is attended to and processed when first encountered.

– memory storage is stronger when one is well-motivated.

2. Consolidation – those processes that alter the newly stored and still labile information so as to make it stable for long-term storage.

– involves the expression of genes and synthesis of new proteins leading to structural changes that store memory stably over time.

3. Storage refers to the mechanisms and sites by which memory is retained over time.

4. Retrieval refers to those processes that permit the recall and use of the stored information.

…. most effective in the presence of some cues.

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How is explicit memory recalled and brought to consciousness?

The initial encoding and ultimate recall of explicit knowledge are thought to require recruitment of stored information into a

special short-term memory store called WORKING MEMORY.

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Components of working memory

1. Attention control system ( central executive) located in the prefrontal cortex.- regulates the information flow to two rehearsal systems that are thought to maintain memory for temporary use: the articulatory loop for language and the visuo-spatial sketch pad for visions and action.

2. Articulatory loop is a storage system with a rapidly decaying memory trace where memory for words and numbers can be maintained by subvocal speech.e.g. remembering a telephone number

3. Visuo-spatial sketch pad represents both the visual properties and spatial location of objects to be remembered.

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IMPLICIT MEMORY

1. Does not depend on conscious processes

2. Does not require a conscious search for memory

3. Builds up slowly through repetition over many trials

4. expressed primarily in performance, not in words.Examples.perceptual and motor skillslearning of certain types of procedures and rules

5. Acquired through different forms of learning and involved different regions.

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Hippocampus and Memory

• Alzheimer’s Disease– Subiculum and EC first affected by plaques and

tanglesAmyloid plaques

Neurofibrillary tangles (NFT)

Hippocampus and Memory• Korsakoff syndrome

– Thiamine deficiency– Primarily affects mammillary bodies, DM nucleus of

thalamus– Columns of fornix, hippocampal formation– Dementia with confabulation

• Wernicke-Korsakoff syndrome– If with gaze palsies and ataxia

Cingulate Gyrus

• Bilateral lesions of anterior part– Akinetic mutism– Immobile, mute, unresponsive– Not in coma– Memory affected

Kluver Bucy Syndrome• Bilateral temporal lobe injuries involving

amygdaloid complex• Behavioral dysfunction

– Visual agnosia (+/- tactile and auditory agnosia)– Hyperorality– Hypermetamorphosis– Hyperphagia– Hypersexuality– Docility– Lack of emotional response, blunted affect– Memory deficit

Temporal Lobe Seizures

• Spread to adjacent TL or both TL• Uncus involvement

– Uncinate fits– olfactory or gustatory aura

• Complex partial seizures