1. SHB 2020
LIMBIC SYSTEM
Robert J. Frysztak, Ph.D.

2. Objectives
Describe and diagram the basic morphology of the structures comprising the “limbic system” (amygdala, hippocampus, septal area, prefrontal cortex, cingulate gyrus, and connections to hypothalamus).
Describe the afferent and efferent connections of each of these areas and their various interconnections.
Understand the basic functions of the limbic structures.
Begin to develop an understanding of the structural and functional basis for clinical and behavioral disorders associated with dysfunction in the limbic system.

3. YOU DO NOT NEED TO KNOW THIS LEVEL OF DETAIL FOR THE EXAM !

4. * * * Papez Circuit – The Limbic “System”
Papez circuit - originally described the CNS areas thought to be involved in emotion; expanded to include amygdala, hypothalamus, prefrontal and associational cortices.
Prefrontal cortex *
Association cortex *
Prefrontal and Associational cortices are described in Dr. Gruener’s cortical lectures.
We will focus on the remaining areas of the hippocampus and the amygdala.
Hippocampus
Each nuclei in the hypothalamus subserves a variety of functions, and most connections are bidirectional.
Many of the neurons specialized as neurosecretory - peptides - with long-lasting actions; results in the modification and modulation of many other control pathways & synapses.
Amygdala *

5. Amygdala
The amygdala is a collection of about a dozen nuclei lying beneath the uncus of the limbic lobe, at the anterior end of the hippocampus and the inferior horn of the lateral ventricle, and is very closely associated with the uncus and the parahippocampal gyrus. The nuclei are subdivided into a medial, central, and basolateral group.
Amygdala
C: Centromedian
BL: Basolateral
*: Medial
PH: Parahippocampal gyrus
Amygdala *

6. Amygdala
The medial nuclei are interconnected with the olfactory system, and are relatively small in humans.
The central nuclei are also small, but their interconnections with the hypothalamus and related brainstem nuclei (e.g., periaqueductal gray) are important in emotional responses.
The basolateral nuclei, the largest part of the human amygdala, are in some ways like a cortex without layers; they contain pyramidal neurons, are continuous with parahippocampal cortex, and are extensively interconnected with other cortical areas. Projections from the basolateral nuclei to the central nuclei provide a key link between the experience of emotions and their expression.
Medial nucleus *

7. Amygdala - Inputs
Much of the input to the amygdala concerns sights, sounds, touches, smells, and tastes. Olfactory information arrives at the medial nuclei, both directly from the olfactory bulb and from olfactory cortex. General sensory information reaches the basolateral nuclei from the thalamus and from unimodal visual, auditory, somatosensory, and gustatory association areas. A second kind of “viscerosensory” input, dealing in a more general sense with levels of physical and emotional comfort and discomfort, also reaches the basolateral nuclei from orbital, anterior cingulate, and the insular cortices. Autonomic sensory inputs reach the central nuclei from the hypothalamus and brainstem sites, such as the periaqueductal gray and parabrachial nuclei.
These inputs arrive via the stria terminalis (hypothalamus & septal nuclei); ventral amygdalofugal pathway (thalamus & hypothalamus, orbital & anterior cingulate cortex); lateral olfactory tract (olfactory bulb & olfactory cortex); and directly from temporal lobe (neocortical areas & hippocampus). *

8. Amygdala - Outputs
Fibers leave the amygdala through the stria terminalis and the ventral amygdalo-fugal pathway to reach many of the same areas that project to it (septal nuclei & hypothalamus, olfactory regions, orbital & anterior cingulate cortices). Many ventral amygdalofugal fibers turn dorsally in the diencephalon and reach the dorsomedial nucleus of the thalamus. Finally, some amygdala efferents pass directly to extensive cortical areas in the temporal lobe and beyond. Some reach the hippocampus and related cortical areas, while others extend all the way to primary sensory areas.
B: Brainstem (PAG, PB, etc.)
HC: Hippocampus
Hy: Hypothalamus
S: Septal nuclei
T: Thalamus (DM, others)
VS: Ventral Striatum
Primary, unimodal sensory cortex
Anterior limbic cortex
Some reach the ventral striatum, which in turn projects to the ventral pallidum. The ventral striatum and pallidum are links in a basal ganglia circuit that projects to the dorsomedial nucleus of the thalamus and influence prefrontal and orbital frontal cortex. (This limbic connection with the basal ganglia is presumably a route through which drive related information can influence decisions about movement, and it apparently functions more generally in the neural circuitry that makes associations between stimuli and rewards; virtually anything that is expected to be pleasurable causes increased release of dopamine in the ventral striatum by way of projections from the ventral tegmental area. )
Major outputs from the basolateral (blue), central (red), and medial (green) nuclei of the amygdala (Am). These take three routes:
(1) the stria terminalis, which reaches the septal nuclei (S) and hypothalamus (Hy); (2) the ventral amygdalofugal pathway to the hypothalamus (Hy), thalamus (T; mainly the dorsomedial nucleus), widespread areas of ventromedial prefrontal and insular cortex, ventral striatum (VS), olfactory structures, and various brainstem sites (B); and (3) direct projections to the hippocampus (HC) and temporal and other neocortical areas. Only visual cortical areas are shown, although there are similar projections to most or all primary and unimodal sensory areas. (Modified from Warwick R, Williams PL: Gray's anatomy, Br ed 35, Philadelphia, 1973, WB Saunders.)
Hippocampus
Ventral striatum
Brainstem visceral nuclei
Thalamus
(dorsomedial nucleus)
Hypothalamus *

9. Amygdala – Summary of Connections
* This limbic connection with the basal ganglia is presumably a route through which drive related information can influence decisions about movement, and it apparently functions more generally in the neural circuitry that makes associations between stimuli and rewards; virtually anything that is expected to be pleasurable causes increased release of dopamine in the ventral striatum by way of projections from the ventral tegmental area.
Major outputs from the basolateral (blue), central (red), and medial (green) nuclei of the amygdala (Am). These take three routes:
(1) the stria terminalis, which reaches the septal nuclei (S) and hypothalamus (Hy); (2) the ventral amygdalofugal pathway to the hypothalamus (Hy), thalamus (T; mainly the dorsomedial nucleus), widespread areas of ventromedial prefrontal and insular cortex, ventral striatum (VS), olfactory structures, and various brainstem sites (B); and (3) direct projections to the hippocampus (HC) and temporal and other neocortical areas. Only visual cortical areas are shown, although there are similar projections to most or all primary and unimodal sensory areas. (Modified from Warwick R, Williams PL: Gray's anatomy, Br ed 35, Philadelphia, 1973, WB Saunders.)

10. Amygdala Functions
The amygdala uses its interconnections with limbic and sensory cortex and the hypothalamus both to form and to express associations between objects and the reactions they provoke. While the hippocampus is important for remembering that an event occurred, the amygdala is important not only for remembering whether the event was “good” or “bad,” but also for triggering appropriate responses (“gut feelings”) the next time a similar event occurs. It is also critical to forming “conditioned responses” and the fear response.

11. Amygdala Lesions
Bilateral lesions to the tips of the temporal lobes, originally done to relieve intractable seizures, resulted in the following constellation of deficits called the Klüver-Bucy syndrome (the list of symptoms differs somewhat by source) :
Docility. Characterized by exhibiting diminished fear responses or reacting with unusually low aggression. This has also been termed "placidity" or "tameness."
Dietary changes and/or Hyperphagia. Characterized by eating inappropriate objects and/or overeating.
Hyperorality. An oral tendency, or compulsion to examine objects by mouth.
Hypersexuality. Characterized by a heightened sex drive or a tendency to seek sexual stimulation from unusual or inappropriate objects.
Visual agnosia. Characterized by an inability to recognize familiar objects or people.
The Kluver-Bucy syndrome has been fractionated to some extent: the placidity and hypersexuality result from destruction of the amygdala, and the visual agnosia from damage to visual association areas on the inferior surface of the temporal lobe. The composite syndrome is tremendously detrimental. (“A monkey which approaches every enemy to examine it orally will conceivably not survive longer than a few hours if turned loose in a region with a plentiful supply of enemies. We doubt that a monkey would be seriously hampered under natural conditions, in the wild, by a loss of its prefrontal region, its parietal lobes or its occipital lobes, as long as small portions of the striate cortex remained intact." (Kluver H, Bucy PC: Arch Neurol Psychiatry 42:979, 1939.) Leaving aside the visual agnosia, it is as though all the behavior patterns central to satisfying basic drives are intact, but the animal can no longer tell when and in what context to use them.
Klüver–Bucy syndrome was first documented among certain humans who had experienced temporal lobectomy in 1955 by H. Terzian and G.D. Ore. It was first noted in a human with meningoencephalitis in 1975 by Marlowe et al. Klüver–Bucy syndrome can manifest after either of these (lobectomies can be medically required by such reasons as accidents or tumors), but may also appear in humans with acute herpes simplex encephalitis or following a stroke. Other conditions may also contribute to a diagnosis of Klüver–Bucy syndrome, including Pick Disease, Alzheimer's Disease, ischemia, anoxia, progressive subcortical gliosis, Rett syndrome, porphyria and carbon monoxide poisoning, among others.
It is rare for humans to manifest all of the identified symptoms of the syndrome; three or more are required for diagnosis. Among humans, the most common symptoms include placidity, hyperorality and dietary changes. They may also present with an inability to recognize objects or inability to recognize faces or other memory disorders. *

12. Fear
Blame the amygdala

13. Hippocampus
The hippocampus is a distinctive area of cerebral cortex folded into the temporal lobe. It is made up of the dentate gyrus and the hippocampus proper (two interlocking strips of three-layered cortex) together with the subiculum (a transition zone between the hippocampus proper and temporal lobe neocortex).
Hippocampus
Fornix
Amygdala *

14. Hippocampus (cornu ammonis)
Fornix
Fornix
Fornix
Dentate gyrus
3-Layered
Sub-Cortical Structure
(NOT 6)
Hippocampus (cornu ammonis)
CA1 – CA3
Structure of the hippocampus. A, Three-dimensional reconstruction of the hippocampi and fornix. B, Arrangement of the dentate gyrus and hippocampus proper (cornu ammonis) as two interlocking C-shaped (in cross section) cortical structures. C, Coronal section through the dentate gyrus, hippocampus proper, and subiculum. D, Schematic diagram showing the general arrangement of cells and fibers in the hippocampus. A few hippocampal efferents arise from pyramidal cells of the hippocampus proper (CA), but most, as indicated, arise from the subiculum. Note that the major route of information flow through the hippocampus is a one-way circuit, starting with inputs from entorhinal cortex (1) and then passing successively through the dentate gyrus (2), two sectors of hippocampal pyramidal cells (3, 4), and the subiculum. Finally, subicular neurons project either through the fornix (5) or directly back to entorhinal cortex (6). As discussed later in this chapter, a small population of neural stem cells is located in deep parts of the dentate gyrus. (8, modified from Duvernoy HM: The human hippocampus: functional anatomy, vascularization and serial sections with MRI, ed 3, Berlin, 2005, Springer-Verlag. C, modified from Nolte J, Angevine JB Jr: The human brain in photographs and diagrams, ed 3, St. Louis, 2007, Mosby.)
Numbers refer to the flow of information through the hippocampus (wiring diagram).

15. Hippocampus

16. Hippocampus
The anterior part of the parahippocampal gyrus (entorhinal cortex) is the major interface between the hippocampus and vast areas of association cortex, allowing the hippocampus to serve as a key link underlying declarative memory. Bilateral damage to the hippocampus and neighboring areas of cortex, or to the diencephalic areas they are interconnected with, causes anterograde amnesia, in which new memories for facts and events cannot be formed. Retrograde amnesia following such damage is limited to a few hours or days, indicating that long-term memories mostly live outside the hippocampus. *

17. Hippocampus - Inputs
Inputs to the entorhinal cortex, and from there to the hippocampus, come from widespread unimodal, multimodal, and limbic cortical areas. In addition, modulatory cholinergic inputs from the septal nuclei* reach the hippocampus directly by traveling "backward“ through the fornix, which is the major output route from the hippocampus (MB). Finally, there are direct projections from the amygdala to the hippocampus (the amygdala is important for marking the emotional significance of situations and events); this connection affects the probability that something will be recorded as a declarative memory, depending on our emotional reaction to it.
*Septal nuclei have extensive connections with most structures in the limbic system and olfactory bulb. Along with the nucleus accumbens, the septal nuclei play a role in reward and reinforcement along with the nucleus accumbens. In the 1950s, Olds & Milner showed that rats with electrodes implanted in this area will self-stimulate repeatedly (i.e. press a bar to receive electrical current that will stimulate the neurons).
Afferents to the hippocampus. The major source is the entorhinal cortex, which in turn collects inputs from widespread association areas and from the olfactory bulb. Entorhinal cortex projects to the dentate gyrus (D), which projects to the hippocampus proper (CA). Other hippocampal inputs arrive directly from the amygdala (Am) and via the fornix from the septal nuclei (5) and contralateral hippocampus (not shown). Other modulatory inputs, such as those from the locus ceruleus, are not indicated. For simplicity, all neocortical inputs are shown projecting only to entorhinal cortex, although some reach parts of the hippocampus directly. Similarly, all inputs from the amygdala are shown projecting only to the hippocampus proper, although some reach entorhinal cortex and other nearby areas. (Modified from an Illustrationn in Warwick R, Williams PL. Gray s anatomy, 35, Philadelphia, 7973, WB Saunders.) *

18. * Hippocampus - Outputs
The hippocampus projects back, by way of entorhinal cortex, to widespread unimodal, multimodal, and limbic cortical areas. Hippocampal outputs also reach limbic cortex indirectly, by way of projections to the mammillary bodies through the fornix. The fornix curves around with the lateral ventricle; it separates from the hippocampus near the splenium of the corpus callosum, travels forward along the inferior edge of the septum pellucidum, turns downward in front of the interventricular foramen, and enters the hypothalamus. The mammillary bodies project to the anterior nucleus of the thalamus through the mammillothalamic tract, and this link forms part of the Papez circuit.
Efferents from the hippocampus. One major efferent pathway is the fornix, through which fibers reach an assortment of anteriorly situated forebrain structures, including the anterior nucleus of the thalamus (A), the mammillary body (MB) and other parts of the hypothalamus (Hy), the septal nuclei (S), and the ventral striatum (VS). Some fibers of the precommissural fornix spread beyond the septal nuclei and ventral striatum and reach orbital and anterior cingulate cortices. In addition, many fibers pass directly from the subiculum to the entorhinal cortex, to the amygdala (Am), or backward along the cingulum to the posterior cingulate gyrus. For simplicity, the entorhinal cortex and subiculum are lumped together, although they have distinctive but overlapping connections (e.g., the subiculum projects mostly to entorhinal cortex but also has some outputs to other cortical areas). *, anterior commissure; CA, hippocampus proper; D, dentate gyrus. (Modified from an illustration in Warwick R, Williams PL: Gray's anatomy, Br ed 35, Philadelphia, 7973, WB Saunders.) *

19. Fornix
Fornix

20. Hippocampus
In Alzheimer's disease, the hippocampus is one of the first regions of the brain to suffer damage; memory loss and disorientation are included among the early symptoms. Damage to the hippocampus can also result from oxygen starvation (hypoxia), encephalitis, or medial temporal lobe epilepsy. Bilateral lesions/removal of the temporal lobes results in striking memory deficits. Following this type of lesion, patients are unable to form new memories (anterograde amnesia); there is typically some retrograde amnesia to semantic memories immediately prior to the event. This only applies to “declarative” memories and NOT to skills or procedures (nondeclarative). Patients could learn to assemble a puzzle with greater skill on each attempt, but not remember having ever seen the puzzle before. The function of laying down or consolidating memories has been attributed, therefore, to the hippocampus. The memories themselves, however, are stored elsewhere. The hippocampus functions like an index, keeping track of where all the pieces of a memory are stored. Other areas where the hippocampus appears to play a role include: aging, stress, epilepsy, schizophrenia and transient global amnesia.
Long-term Memory
Hippocampus contains highest concentration of glucocorticoid receptors in brain and exerts an inhibitory control over plasma corticosteroid levels.
Aging leads to loss of hippocampal neurons and their glucocorticoid receptors, explaining why the aged cannot promptly terminate
stress-related secretion of corticosteroids once stress has ended.
Hippocampal Functions: Patient HM
Permanent Anterograde Amnesia
HM underwent bilateral medial temporal lobectomy in 1953 to treat complex partial seizures. After surgery he suffered from permanent anterograde amnesia, being unable to form any new memories.
His amnesia related to declarative memory, or episodic memory, which refers to statements such as “I had cereal for breakfast this morning.”
HM also suffered from some retrograde amnesia (loss of old memories) covering the 11 years prior to his surgery, probably the result of seizures or antiseizure medication.
Brenda Miller at McGill University, Montreal studied his case for 3 decades. She learned that the temporal lobe damage did not affect HM’s ability to learn new skills, leading Dr. Milner to propose that procedural memories are formed in different brain structures, and that there are multiple systems for acquiring different types of new memories.
Declarative

21. * Hippocampus Damage to hippocampal targets has clinical consequences:
Mammillary nuclei of the hypothalamus:
Massive input from hippocampal formation via the fornix.
Sends unilateral, collateral projections to: thalamus (via mammillothalamic tract), midbrain tegmentum, and reticular nuclei associated with cerebellum/vestibular inputs.
Unique in hypothalamus in that mammillary n. have highly restricted inputs/outputs
Critical for spatial memory/position of head in space.
Wernicke-Korsakoff Syndrome:
Disabling degenerative brain disorder. Lack of thiamine (vitamin B1) due to alcohol abuse, dietary deficiencies, prolonged vomiting, eating disorders, or the effects of chemotherapy.
Symptoms: mental confusion, confabulation, attention deficit, memory impairment (both anterograde and retrograde), vision impairment, stupor, coma, hypothermia, hypotension, and ataxia.
Wernicke’s encephalopathy represents the “acute” phase of the disorder;
Korsakoff’s Amnesic Syndrome represents the “chronic” phase (memory disorder, confabulation). *

22. Septal Nuclei
Afferents: Hippocampus, Amygdala & Preoptic area of hypothalamus
Efferents: Hippocampus, Amygdala, Preoptic area of hypothalamus, Mammillary body & Median eminence
Functions:
• Regulates gonadal hormone secretion and various reproductive and sexual behaviors by way of its gonadotropin-releasing hormone projections to median eminence.
• Facilitates memory formation via its massive cholinergic projection back to the hippocampus.
• Lesions in animals produce septal syndrome of general behavioral overreaction, particularly evident as "septal rage" after trivial stimulation.
Mammillo-Thalamic Tract
Fornix
Dorso-Medial Nucleus
Olfactory Bulb
Medial Olfactory Stria
Anterior nucleus
Stria Medullaris Thalami
Diagonal Band of Broca
Olfactory Tract
SEPTAL NUCLEI
Column
of the Fornix
SEPTAL NUCLEI
Anterior Perforated Substance
Stria Terminalis
Anterior nucleus
Anterior Perforated Substance
Lateral Olfactory Stria
Habenular Nucleus
Stria Medullaris Thalami
Amygdala
Medial Olfactory Stria
Body
of the Fornix
Habenulo-Peduncular Tract
Mammillo-Thalamic Tract
Olfactory Bulb
Dentate Gyrus
Mammillary Body
Stria Terminalis
Habenular Nucleus
Olfactory Tract
Lateral Olfactory Stria
Hippocampus
Hippocampus
Crus
of the Fornix
Fimbria
of the Fornix *
Diagonal Band of Broca
Mammillary Body
Amygdala
Dentate Gyrus

23. Summary
Limbic Structures *

24. A little “hippocampus humor” from PBS . . . . .

25. Deer hunting season opened this past weekend,
and Dr. D. was spotted at his deer stand in Channahon

26. Merry Christmas and Happy Holidays from Rey and Pirate!
Wishing you luck on the Final Exam !
Merry Christmas and Happy Holidays from Rey and Pirate!