Limbic System

Functional Neuroanatomy of the Limbic System Alex Dranovsky, M.D., Ph.D. Assistant Professor of Clinical Psychiatry Columbia University

Why Functional and Why a Psychiatrist? 1. How to conceptualize the limbic system - a Psychiatrist’s perspective •

Hypothalamus and basic drives

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Amygdala and emotional salience

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Hippocampus and the integration of novelty

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VTA - Accumbens and reward contingency

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Other structures

Limbic System •

MWD - Limbic system noun Date:1952: a group of subcortical structures (as the hypothalamus, the hippocampus, and the amygdala) of the brain that are concerned especially with emotion and motivation

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WIKIPEDIA ­

The limbic system is a term for a set of brain structures  including the hippocampus and amygdala and anterior thalamic  nuclei and a limbic cortex that support a variety of functions  including emotion, behavior and long term memory. 

What defines the Limbic System? • Limbic Lobe - “a ring of cortical tissue that surrounds the brain stem” - Paul Broca 1800’s

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Definition II • Klüver and Bucy – Removal of Temporal lobes in Rhesus Monkeys results in • • • •

Indiscriminant hypersexuality Complete loss of fear Dulling of emotional expression Increased oral exploration » Arch of Neurol Psych 1939

• Bilateral temporal lobe damage in humans • Hypersexuality, inappropriate oral and tactile exploration, memory deficits, flattened emotions, and bulimia

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Arch Neur Psych, 1937

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A Psychiatrist’s Perspective • A Structural Model

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– ID - Instinctual Needs/Drives – Superego - Moralizing Conscience – Ego - An organizing mediator

Why Functional and Why a Psychiatrist? 1. Hypothalamus and basic drives 2. Amygdala and emotional salience 3. Hippocampus and the integration of novelty 4. Nucleus Accumbens and reward contingency 5. Cingulate and higher cortical function

Hypothalamus as the center for drives • • • • • •

Sex Feeding Osmoregulation Sleeping Pair bonding Stress response

Hippocampus •

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Deep temporal lobe structure that runs anterioposterior parallel to the parahippocampal gyrus.

Major inputs – Perforant pathway from the entorhinal cortex – Fornix - Septohippocampal tract afferents

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• Cholinergic (EXC) - med septal nuc -> throughout • GABAergic (INH) - msn -> to GABA interneurons

– Modulatory systems -> throughout • LC, Raph, VTA • Posterior hypothalamus - GABA, Histamine

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Major outputs – Subiculum - throughout neocortex and other cortical regions – Fornix MAJOR OUTPUT PATHWAY • Contralateral hippocampus • Septum • Hypothalamus (mammillary bodies)

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Intrahippocampal circuitry • Tri-synaptic circuit with collateral and contralateral connections • Highly organized subregions with dense and redundant connections • Especially adapted for pattern separation.

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Hippocampal Plasticity • Changes in the external world result in SUSTAINED molecular, cellular, and physiologic changes in the hippocampus in rodents – Positional changes -> changes in ensemble representations – Chronic Stress -> dendritic shrinkage and decreased neurogenesis – Antidepressant treatment -> dendritic complexity and increased neurogenesis – Learning -> LTP

Hippocampal Function I • Temporal lobectomy disrupts recent memories (HM) – Distant memory is in tact – Procedural memory is in tact

• Depression, PTSD, Schizophrenia – Decreased hippocampal volume – Decrease is proportional to time spent in disease state

• Stress – Decrease volume – GR and MR receptors in all subfields – Direct regulation of the hypothalamus stress response

Hippocampal Function II • Identification of sensory stimuli as NOVEL is one function of the hippocampus that ties together its role in memory, learning, stress response, and place representation

Amygdala QuickTimeª and a Video decompressor are needed to see this picture.

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Complex of nuclei deep to the piriform cortex in the rostral end of the temporal lobe

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Structure-function groups of nuclei – Corticomedial – Basolateral – Central

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Contralateral connectivity via the stria terminalis and the anterior commissure

Inputs and outputs

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Amygdala Function I • Fear – Klüver and Bucy Complete loss of fear – Necessary for fear learning in rodents • FC potentiates dorsolateral synaptic plasticity

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How can you prove that Amygdala mediates fear learning? •

Classical Conditioning – UCS -> UCR – UCS+CS -> UCR – CS -> CR

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The ability of a neutral CS to produce an emotional CR serves as a model for emotional learning

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Amygdala Function II (It’s not just for fear…) •

Rodent models – The same holds true for appetitive memories – ITS NOT THE VALENCE, IT’S THE SALIENCE

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Urbach-Wiethe disease (Lipoid Proteinosis) – No enhancement of memory by emotional content – ITS NOT THE VALENCE, IT’S THE SALIENCE

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Amygdala Function III The assignment of salience • fMRI hyperactivity to emotional faces – in patients with Social Phobia – in patients with PTSD – compared to neutral faces in normal controls

• fMRI hypoactivity to emotional faces – In patients with Autism

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Modulators of emotional learning • Norepinephrine release in the amygdala potentiates formation of fear memories – Beta adrenergic receptor blockers diminish FC – Beta adrenergic receptor blockers diminish fMRI signal – Clinical implications

• Extinction - repetitive presentation of CS without UCS results in loss of CR – D-cycloserine administration in the amygdala potentiates extinction of fear memories – Clinical implications

Dopamine comes from the VTA • Cell bodies of dopaminergic neurons reside in the VTA of the midbrain – Tuberoinfundibular – Mesocortical – Mesolimbic

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Mesolimbic projections • Outputs – A major tract to the nucleus accumbens – Projections to other limbic structures

• Inputs – Medial forebrain bundle major tract from the forebrain – Inputs from Amygdala, Hippocampus, Hypothalamus, Thalamus and many other brain regions

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What’s in this for me? • upon evaluating sensory information and performing associative learning the brain must compute a reward contingency before performing a motor output

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Drugs of Abuse • Almost all compounds that have the ability to stimulate the VTA -> NA pathway are substances of abuse across species • Electrical stimulation can induce selfadministration • MFB stimulation can directly induce relapse “best feeling ever”

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VTA -> NA

• Manipulating reward contingency is the greatest molder of behavior

Other tidbits • Brain stem nuclei produce all of the brain’s serotonin, norepinephrine, and dopamine • Septum – Major relay for hippocampal projections to the anterior thalamic nucleus – Also meeting point for anterior comissure – Overlying hypothalamus – ? Relay station for generalization

• Major cortical projection areas – Cingulate gyrus • Anterior region is hyperactive in depression • Current focus of brain stimulation research

– Medial orbitofrontal area

Putting it all together: physiology • A Structural Model – ID - Instinctual Needs/Drives – Superego - Moralizing Conscience – Ego - An organizing mediator

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Putting it all together: disease

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• Anxiety disorders • Depression • Substance abuse

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Autism Schizophrenia Alzheimers disease Personality disorders