L73. Neuroscience - Limbic System

• The limbic lobe, named by Broca in 1878, includes cerebral cortex on the medial surface of the cerebral hemisphere around the corpus callosum
• The limbic association cortex includes the orbitofrontal cortex, cingulate cortex, and parahippocampal/entorhinal cortex
• The limbic cortex controls learning, memory, and emotions, which is fundamental for cognition and social interaction

Orbitofrontal Cortex

• Cingulate cortex surrounds the corpus callosum
• Parahippocampal cortex is also called entorhinal cortex
• The limbic cortex exchanges information with all areas of the neocortex
• The limbic cortex integrates sensory and motor information to shape cognition and emotional responses.

Phineas Gage Case

• The Phineas Gage case (1848) demonstrated how the orbitofrontal and prefrontal cortices shaped human personality
• Before injury, Phineas was "most efficient and capable foreman... possessed a well-balanced mind... shrewd... very persistent in executing all his plans of operation"
• After injury to orbitofrontal and prefrontal cortices, Phineas was "fitful, irreverent, indulging in profanity, little deference for his fellows, does not follow advice when it conflicts with his desires, obstinate, devises plans for future operation but quickly abandons them. He is no longer Gage."
• Patients with damage to ventral and medial prefrontal cortex (orbitofrontal regions) show impaired emotional responses, especially in the area of social emotions and decision making
• Patients lack autonomic responses (heart rate, sweating) when presented with stimuli (e.g., violent pictures) that normally evoke such responses in control subjects
• Patients lose appropriate behavioral responses to social rules like avoiding punishment, seeking reward, avoiding risk, showing morality; they can describe social rules but don't live by them
• Concussion injuries are prevalent in high-velocity contact sports and are considered a preventable public health issue. Realize that frontal cortex damage in such cases can include the orbitofrontal cortex
• Repeated damage can cause irreversible neurodegeneration and can result in personality changes that include increased violent behaviors and suicidal thoughts.

Hippocampus

• The hippocampus is located deep to the parahippocampal gyrus and adjacent to the inferior horn of the lateral ventrical and posterior to the amygdala
• The hippocampus and its projection pathway, the fornix, form a C-shaped structure
• The hippocampus (G seahorse) is a rolled-up sheet of cortex containing 3 functional areas that resemble a seahorse in cross section
• The hippocampus only contains 3-cellular layers (archicortex) in contrast to the neocortex which has 6-cellular layers

Hippocampal Connections

• The limbic association cortex collects cognitive information and projects to the parahippocampal gyrus, otherwise called the entorhinal cortex
• The entorhinal cortex filters information then relays it to the hippocampus
• Thus, the entorhinal cortex is the main gateway to the hippocampus
• Hippocampal neurons process the information then send it out via the fornix to hippocampal targets
• Bidirectional communication between the Hippocampus and the entorhinal cortex
• The amygdala and septal nuclei project directly to the hippocampus, linking emotions and motivational states to declarative memory formation
• Monoaminergic fibers from the reticular formation project serotonin, dopamine, and norepinephrine information directly to the hippocampus, further altering mood and contributing to emotional aspects of memory formation

Cellular Areas of the Hippocampus

• Dentate Gyrus
• Ammon's Horn (cornu ammonis, CA1, CA3)
• Subiculum
• Much of the information entering the hippocampus comes from the entorhinal cortex via myelinated fibers close to the surface of the cortex
• These fibers perforate the hippocampus broadly, thus the pathway is known historically as the 'perforant pathway'
• Most afferent information goes directly to the dentate gyrus where it is processed by interneurons
• The dentate gyrus sends information to Ammon's Horn (CA regions) and the subiculum for projection center processing
• Hippocampal projection neurons send information to their targets mostly via the fornix, but also project directly back to the entorhinal cortex
• Hippocampal intrinsic circuitry is almost all excitatory and operates by the cellular mechanism of long-term potentiation
• CA fibers in the fornix diverge into the septal area and orbitofrontal cortex via pre-commissural fibers of the fornix when the fornix reaches the level of the anterior commissure
• Subicular fibers in the fornix continue to the mammillary nuclei of the hypothalamus via post-commissural fibers of the fornix

Hippocampal Efferents

• Hippocampal efferent pathway by the fornix as subicular axons travel to the mammillary bodies of the hypothalamus
• A minor pathway is hippocampal CA axons to the orbitofrontal gyrus
• Subicular projections to the mammillary bodies (MB) underlie the Papez circuit, a circuit for declarative memory formation
• MB axons project to the anterior nucleus of the thalamus and then to the cingulate cortex
• Cingulate axons project back to entorhinal cortex to complete the Papez circuit

Clinical relevance of the Hippocampus

• The hippocampus has a primary function in processing information critical to forming declarative memories (facts & events)
• Korsakoff's psychosis is associated with thiamine deficiency that causes degeneration of the medial diencephalon, including mammillary bodies and mammillothalamic tracts
• Patients with Korsakoff's psychosis maintain their intelligence, but lose the ability to form new memories and will often make up answers to compensate for their memory loss, which leads to amnesiac confabulatory syndrome
• Transient global amnesia shows focal lesions of the CA1 (Sommer sector) region of the hippocampus which produce a transient loss of autobiographical memories from the distant past
• A role of CA1 in retrieving long-term memories presumably stored in the neocortex

Amygdala

• The Amygdala (G almond) is shaped as an almond-shaped nucleus derived from the telencephalon.
• The amygdala is positioned anterior to the hippocampus in the medial temporal lobe
• The amygdala is surrounded by cortex of the medial temporal lobe that resembles a pear shape, which is called the piriform cortex
• The "uncus" is a gross anatomy term used to designate the physical bump made by the piriform cortex and underlying amygdala

Amygdala Afferents

• Olfactory axons play a role in motivational behaviors for feeding and reproduction
• The solitary nucleus of the medulla provides information from major body organs to integrate autonomic nervous system functions with emotions
• The limbic association cortex sends information about the environment; visual information is especially important for amygdala function
• Monoaminergic fibers from the reticular formation provide serotonin, dopamine, and norepinephrine that are important for emotional tone/mood

Information Processing in the Amygdala

• Olfactory information for feeding and reproductive behaviors
• Information related to the viscera and autonomic nervous system
• cognitive information from the limbic association cortex, hippocampus, and basal forebrain (septal nuclei & nucleus basalis)

Amygdala Efferents

• Vast connections with the hypothalamus for feeding, thirst, reproductive, and endocrine functions
• Projections to autonomic centers in the brainstem and spinal cord for parasympathetic and sympathetic systems
• Sends information to the hippocampus to allow emotions to influence memory formation
• Reciprocal connectives with dorsomedial thalamus and limbic association cortex for integration of cognitive and sensory information about the environment

Amygdala Function

• The amygdala is an "aversion center" that analyzes environmental cues signifying danger
• The amygdala influences learning and memory, especially under circumstances that elicit a strong emotional response for survival mechanisms
• Stimulation of the amygdala induces attention related to the induction of fear and defense mechanisms and sympathetic autonomic responses (increased heart rate, respiration)
• In humans, the amygdala activates the expression of "fear"
• The amygdala function is missing in Urbach-Wiethe disease where the amygdala degenerates bilaterally
• Destruction of the amygdala in lower animals/primates results in a loss of significance of threatening objects
• Neurotransmitter imbalance of the amygdala underlies anxiety and panic disorders
• Kluver-Bucy Syndrome accompanies bilateral damage of the medial temporal lobes in the area of the amygdala
  • Visual Agnosia: can't recognize items by sight
  • Hyperorality: tendency to examine objects by mouth
  • Hypermetamorphosis: intense examination of all objects in immediate environment and overreaction to visual stimuli
  • Placidity: failure to show fear or anger
  • Hyperphagia: eats excessive amounts of anything (including non-food items)
  • Hypersexuality: suggestive behavior and talk, ill-conceived attempts at sexual contact
  • Also amnesia, dementia, and aphasia.

Basal Forebrain & Nucleus Accumbens

• The basal forebrain & nucleus accumbens is ventral area located between orbitofrontal cortex and hypothalamus
• An old name for this region is substantia innominata ("unnamed substance")
• At the gross brain level, this region is called the anterior perforated substance, named for the many blood vessels that enter the ventral surface of the telencephalon just rostral to the optic chiasm

The Two Basal Forebrain Nuclei

• Septal Nuclei: hang ventrally from the septum pellucidum
• Nucleus Basalis (of Meynert): located ventral to the anterior commissure

Basal Forebrain Afferents

• Hippocampus (precommissural fornix fibers from CA regions)
• Amygdala
• Limbic association cortex
• Reticular Formation
• Olfactory axons (medial stria) innervate the septal nucleus.

Basal Forebrain Efferents

• Septal nucleus projects to the hippocampus via the fornix (against normal output traffic flow)
• Nucleus basalis projects to the cerebral cortex (neocortex) via the external capsule

Basal Forebrain Function

• The basal forebrain functions mainly as a gratification center
• Rats with electrodes in the septal nuclei self-stimulated to receive a pleasurable feeling
• Various pleasurable sensory stimulations converge on the basal forebrain
• Examples include olfactory sensations such as sweet smells
• Septal Nuclei and Nucleus Basalis send cholinergic axons to hippocampus and cerebral cortex, which help strengthen memory formation and retrieval
• This mechanism may relate to pleasurable experiences, which is one of many ways memories are easier to recall than negative experiences

Nucleus Accumbens (NAC)

• A ventral part of the striatum, the Nucleus Accumbens, functions in regulating behaviors associated with addiction, such as drug use, smoking, and gambling
• Similar to the striatum, the NAc receives dopamine and glutamate afferents and functions along with the basal forebrain in mediating behaviors associated with pleasure and reward
• Glutamate afferents mainly come from limbic association cortex
• Dopamine afferents originate from ventral tegmental area (VTA)
• The nucleus accumbens involves dopamine and opioid mechanisms for substance abuse
• Parkinson's patients on long-term DA replacement therapy exhibit a high propensity to develop a gambling disorder through maladaptive DA receptor mechanisms resulting from long-term DA decline and artificial replacement via L-DOPA