Limbic System George R. Leichnetz, Ph.D. OBJECTIVES 1. To define "limbic system" and its network of interconnected structures that subserve affective behavior (emotion), motivation and reward, and memory. 2. To know the afferent and efferent connections of the principal limbic structures: hippocampus, amygdala, and septum/basal forebrain, (Hypothalamus is covered in a separate lecture) 3. To recognize how the connectivity of these limbic structures support their functions and suggests involvement in emotional components of memory, reproductive, or other behaviors. I. INTRODUCTION: Definitions

Limbic Lobe - first defined by Broca (1878), included the subcallosal gyrus, cingulate gyrus, parahippocampal gyrus, and hippocampal formation.

From Carpenter and Sutin, Human Neuroanatomy

Central Circuit of Emotion (Papez Circuit) - (see hippocampus section for illustration) Papez (1937) described a "central circuit for emotion," now referred to as the classic “Papez Circuit”, consisting of the hippocampal formation, fornix, mammillary bodies, mammillothalamic tract, anterior nucleus of the thalamus, cingulate gyrus, and cingulum bundle. Recent evidence suggests these structures also play a role in the memory process. Limbic System By contemporary definition, this broader term includes all structures which have connections with the septo-mesencephalic limbic continuum, a longitudinal system of gray matter on the base of the brain extending from the precommissural septum through the

hypothalamus to the paramedian midbrain reticular formation (midbrain limbic area). This whole continuum is interconnected by the ascending and descending fibers of the medial forebrain bundle. Traditionally, the term “limbic” has carried the connotation of having to do with emotion, but since “affect” and “emotion” are part of a broad range of human behaviors (e.g. memory, motivation and reward, reproductive, feeding) many cortical and subcortical systems entertain limbic connections. * Link to Netter Image 111.75

From Nieuwenhuys et al, The Human Central Nervous System

II. HIPPOCAMPUS The hippocampus is also called Ammon's Horn (cornu ammonis) after Egyptian God Ammon (ram's head). It is the oldest cortex (archicortex). Hippocampal Formation = hippocampus proper, dentate gyrus, and subiculum. The hippocampal formation is rolled inside the parahippocampal gyrus in the ventromedial temporal lobe. The subiculum is a transitional region between the paleocortical entorhinal cortex and archicortical (tri-laminar) hippocampus. The hippocampus proper consists of CA1-CA3 subfields. The CA1 region is vulnerable to ischemic injury and is known to neuropathologists as Sommer's Sector. The dentate gyrus is made up of the CA4 subfield, (polymorphic cell layer) plus the dentate fascia (molecular and granular layers). Since bilateral temporal lobe lesions involving hippocampus result in anterograde amnesia (loss of recent memory), the hippocampus is thought to be involved in processing information for memory storage elsewhere in the cortex. * Link to Netter Image 1.31A * Link to Netter Image 1.31B * Link to Netter Image 1.31C * Link to Netter Image 111.76

A. AFFERENTS The principal source of direct input into the hippocampus is the entorhinal cortex ("gateway of the hippocampus") which is the cortex on the ventral surface of the rostral parahippocampal gyrus adjacent to the hippocampus. It receives multimodal sensory input regarding ongoing sensory information for possible incorporation into memory.

From: Niewenhuys, The Human Nervous System

The entorhinal cortex projects into the hippocampal formation through two systems: the perforant and alvear paths. The alvear path terminates in the hippocampus. The perforant path terminates in the dentate gyrus.

From: Carpenter, Human Neuroanatomy

* Link to Netter Image 111.77

The entorhinal cortex is the main relay and staging area for multimodal sensory information being conveyed to the hippocampus for memory processing. It receives direct olfactory input from the olfactory bulb, and somatosensory, visual and auditory imput from multimodal convergence areas of the association cortex (prefrontal, temporal, parietal). The entorhinal cortex shows substantial shrinkage (with cell loss) early in Alzheimer’s disease, and has become a diagnostic tool before the onset of memory loss. B. INTRINSIC HIPPOCAMPAL PROCESSING Mossy fibers (axons) of dentate granule cells project to the CA3 subfield. CA3 pyramidal cell axons project back to CA1.

C. EFFERENTS Fornix – the principal efferent tract of the hippocampus; originates from both the subiculum and hippocampus proper, and projects via the precommissural fornix to the septum/basal forebrain, and via postcommissural cornix (fornix columns) to the anterior nucleus of the thalamus, hypothalamus (mammillary bodies) and midbrain limbic area. It represents the first segment of Papez Circuit.

From: Noback et al., The Human Nervous System

Papez Circuit - hippocampus (via fornix) to mammillary body (via mammillo-thalamic tract) to anterior nucleus of the thalamus to cingulate gyrus (via cingulum) to hippocampus. Originally thought to be a reverberating circuit of emotion, now thought to subserve memory processing.

* Link to Netter Image 111.78

D. CLINICAL SIGNIFICANCE Bilateral lesions of the hippocampal formation produce anterograde amnesia (a loss of recent short-term memory); inability to form new memories. Subregion CA1 (Sommer's Sector) is particularly vulnerable to vascular injury (supplied by small caliber ant. choroidal arteries)

The hippocampal system is involved in declarative memory - memory of facts and events. The medial temporal lobe is the target of highly processed information originating from a variety of cortical regions. The hippocampal system may serve to bind together disparate aspects of memory and distill them into a coherent memory trace that can subsequently be accessed by many routes. Postulated Memory Circuit (Kornhuber): proposed that Papez circuit constitutes a "limbic system selection unit" in which behaviorally relevant information is selected for memory storage.

Korsakoff’s Syndrome (component of Wernicke’s encephalopathy) - anterograde amnesia; vitamin B1 deficiency, produces petechial hemorrhages in structures within Papez Circuit, such as mammillary bodies and anterior thalamic nucleus.

III. AMYGDALA The amygdale is located in rostral ventromedial lobe, deep to the cortex of the rostral parahippocampal gyrus.

The amygdala is a complex of subnuclei involved with affective behaviors (emotion), applying an “emotional tag” (emotional salience) to sensory experience. The lateral group of nuclei primarily receive multimodal sensory input from visual, auditory, and somatosensory associational cortex relayed in adjacent temporal cortex, and gives rise to efferents (feedback) to these same cortical associational areas to apply emotional salience to sensory experience. The medial group of nuclei receive direct olfactory input (from the olfactory bulb), and give rise to subcortical efferents through the stria terminalis and ansa peduncularis to the basal forebrain (eg. nucleus accumbens), hypothalamus, and brainstem autonomic nuclei.

A. AFFERENTS

Sensory Inputs - receives direct olfactory input from the olfactory bulb, plus multimodal sensory input (visual, auditory, somatosensory) via relay in adjacent temporal associational cortex, which affects its role in emotion. Ongoing sensory experience is given an "emotional tag". Limbic Inputs - from hypothalamus and mediodorsal nucleus of the thalamus in reverse direction through its main efferent tracts, the ansa peduncularis and stria terminalis.

* Link to Netter Image 111.79 B. EFFERENTS: 1. Cortical Efferents

primarily from the lateral group, the amygdala provides feedback projections to visual, auditory, and somatosensory associational areas to bring “emotional salience” to ongoing sensory experience, including directing one’s attention to events which are threatening or “emotionally-charged.” Amygdaloid projections to prefrontal associational cortex affect working memory, social behavior, and higher cognitive (executive) functions. Example: Feedback projections to visual associational cortex

2. Subcortical Efferents Primarily from the medial group, the amygdala give rises to two principal efferent tracts: the stria terminalis and the ansa peduncularis, which target the septum/basal forebrain (eg. nucleus accumbens for “reward”), hypothalamus (affects on appetite, reproductive behavior, etc.), and brainstem autonomic nuclei (direct “emotional” affects on autonomic visceromotor function).

From: Noback et al., The Human Nervous System

• Link to Netter Image 111.80

Table 1: FUNCTIONAL SIGNIFICANCE OF AMYGDALOID TARGETS "Tagging" behaviors with emotion Nucleus accumbens - (addiction, "reward system") Nucleus basalis of Meynert - cholinergic effects on memory process Hypothalamus - feeding/appetite, reproductive behaviors; endocrine releasing factors Brainstem autonomic nuclei - autonomics (cardiac, respiratory) MD thalamus - relay to prefrontal cortex Prefrontal Cortex - direct input, effects mood, personality, social behavior, working memory

C. CLINICAL SIGNIFICANCE The amygdala is involved in emotionality. Temporal lobe lesions involving the amygdala result in Kluver-Bucy Syndrome (lack of emotionality, docility, hypersexuality). The amygdala is essential for decoding emotional expression on faces. It receives input from adjacent inferior temporal (visual association) cortex concerned with facial recognition. The amygdala receives multimodal sensory input that may trigger fear, input from the hippocampus ( or subiculum) related to mnemonic (remembered) aspects of emotional experience, and input from the associational cortex related to subjective cognitive aspects of emotional experience, and then orchestrates emotional responses through its hypothalamic (limbic) and autonomic connections. In addition, it is involved with the affective (emotional) component of other behaviors. Its olfactory inputs and projections to areas of the hypothalamus related to appetite (VM hypothalamus) suggests a role in feeding behavior. It also has a role in reproductive behavior (gonadotrophin release and ovulation) through its projections to the ventromedial hypothalamus (possible median eminence) eliciting release of FSH or LH releasing hormones into the hypothalamo-hypophyseal portal system.

Table 2: AMYGDALOID LESIONS

Temporal lobe lesions which involve the amygdala result in Kluver-Bucy Syndrome

Lack of emotion; lack of fear; inability to discriminate between threatening * non-threatening stimuli, normal food from non-food objects; hypersexuality The amygdala plays a central role in facilitating the significance of environmental stimuli in selection of appropriate food, or a mate, or avoidance of dangerous situations or substances “Emotional decoding” of facial expressions

IV. SEPTUM/BASAL FOREBRAIN The precommissural septum is a region of modified cortex in the caudal medial frontal lobe that extends inferiorly from the septum pellucidum, rostral to the anterior commissure, contiguous inferiorly with the caudal basal frontal lobe, called the basal forebrain. It is useful functionally to consider them as a unit, although they contain numerous separately named cell groups, including numerous cholinergic cell groups (Ch 1 - Ch 4). One of the most important nuclei is the nucleus accumbens, located ventromedial to the internal capsule. Its proximity to the caudate and putamen have led to it being referred to as the "ventral striatum." The nucleus accumbens is thought to be the center of addiction. It receives mesolimbic DA projections (reward systems) from the ventral tegmental area of the midbrain. Its neurons have both DA and opiate receptors and mediate cocaine and heroin addiction. It is activated by drugs of abuse and any pleasurable experience (e.g. food, sex, music).

* Link to Netter Image 111.50 The heavily cholinergic region contains the Ch1-Ch4 cell groups all of which give rise to projections to the cortex. The most well known of these nuclei, the nucleus basalis of Meynert, corresponds to Ch 4 which is the principal source of ACh innervation of the cerebral cortex.. Loss of its constituent neurons is implicated in the cognitive deficits associated with Alzheimer's disease.

A. AFFERENTS:

1. Medial Forebrain Bundle - carries both afferents and efferents of the septum. It consists of both ascending and descending components. The septum, lateral hypothalamus and midbrain limbic area (interconnected through MFB) form a septo-mesencephalic limbic continuum, regarded as the central core of the limbic system. Some of its ascending fibers from the brainstem are noradrenergic (NE), dopaminergic (DA) (reward system) and serotonergic (5-HT). The mesolimbic DA projection (reward system) within the MFB originates from the ventral tegmental area (A10) and terminates in the nucleus accumbens of the septum/basal forebrain.

2. Stria terminalis and ansa peduncularis - from amygdala. 3. Fornix (precommissural) - from hippocampus.

B. EFFERENTS:

Medial Forebrain Bundle - fibers originating in the septal nuclei or basal forebrain (many very likely from cholinergic cell groups) descend to the hypothalamus and brainstem reticular formation Efferents in stria terminalis, ansa peduncularis, and fornix - reciprocal feedback to amygdala and hippocampus

From Niewenhuys, The Human Central Nervous System

V. LIMBIC-RELATED NUCLEI OF THE THALAMUS

The anterior nucleus and dorsomedial nucleus of the thalamus have been referred to as "limbic" thalamic nuclei because their connections are predominantly with limbic structures (receive input from amygdala, hippocampus and project to cingulate and prefrontal cortex). The anterior nucleus - receives input from the hippocampus (fornix) and mammillary bodies (mammillothalamic tract) , and projects to the cingulate cortex (limbic lobe cortex). The dorsomedial nucleus - receives input from the amygdala and hypothalamus and projects to the prefrontal cortex (the neocortical representative of the limbic system; see below)

VI. PREFRONTAL CORTEX

The prefrontal cortex has been referred to as the "neocortical representative of the limbic system." It is concerned with mood and personality, social behavior, working memory, and higher cognitive (“executive”) functions, and receives major direct limbic input from the amygdala, dorsomedial thalamic nucleus (relays amygdala output), and mesocortical dopaminergic projections from the ventral tegmental area of the midbrain.

Lesions of prefrontal cortex produce impairments in the classical “delayed response” test; switching performance strategy when there is a delay between stimulus and response (cannot hold essential information in temporary “working” memory).

Patients have difficulty modulating social behavior appropriate to the context of ongoing events, anticipating the consequences of unacceptable behavior and in developing strategies in unfamiliar new situations.

Phineas Gage Case Report In 1848 a 25 year old railroad construction worker accidently detonates powder. Explosion drives 3 cm. thick tamping iron through forehead. No impairment of speech or movement. Profound changes in personality (irreverent, capricious, profane, lost sense of responsibility). No autopsy, but skull was retained. Measurements and modern neuro imaging allowed Damasio et al to reconstruct the injury to prefrontal cortex. Defect in rational decision-making and processing emotion.

A Self-Assessment is available for this lecture. * Netter Presenter Image Copyright 2004 Icon Learning Systems. All rights reserved.