Limbic system Semmelweis University, Faculty of Medicine 2nd year 1st semester Department of Human Morphology and Developmental Biology Katalin Kocsis 21/10/2014

General view of the limbic brain mammalian brain organized on the base of two major basic theories 1) Modularity theory -specialised functions localized to different brain areas 2) Neuronal network theory complex functions, features - learning, memory, intelligence personality - functional integration - processing of information is in neuronal networks, scattered brain areas

Functions of the limbic system Complex human functions: -personality, behaviour, learning, memory, emotions Basic functions -reproduction, stress

Nomenclature Parolfactory area (subcallosal area) -a small area of cortex on the medial surface of the frontal lobe, immediately in front of and below the subcallosal (=paraterminal) gyrus Gyrus subcallosus = gyrus paraterminalis Septal nuclei -in the septum pellucidum: only a few scattered neurons - nuclei of „true septum” (septum verum) are ventral to the septum pellucidum - extend into the subcallosal gyrus Piriform cortex (olfactory cortex)= rhinecephalon = olfactory brain=nose brain - olfactory bulb, tract, lat. olfactory stria, ant. perf. substance, ant. part parahippocampal gyrus, uncus, amygdala (dorsomed) -paleopallium, oldest part of hemisphere – projections to enthorinal cortex Entorhinal cortex -behind the ant. part of parahippocampal gyrus (piriform cortex) -projections to hippocampal formation (archicortex) Rhinal sulcus (16) -minor sulcus in the parahippocampal gyrus on the ventral-medial margin of the anterior temporal lobe -the rhinal sulcus continuous with the collateral sulcus along the lateral margin of parahippocampal gyrus Isthmus of cingulate gyrus (9) -connects the neocortical cingulate gyrus to parahippocampal gyrus paleocortex archicortex transitional BrainInfo (2007), Neuroscience Division, National Primate Research Center, University of Washington, http://www.braininfo.org.

Pierre Paul Broca (1878) – French neuroanatomist „Limbic lobe” – ring shaped cortical area on the medial surface of hemispheres: - parolfactory area (subcallosal area) - uncus - subcallosal gyrus (paraterminal gyrus) - parahippcampal gyrus - hippocampus - cingulate gyrus („limbic gyrus”) Smell is the main function of the limbic lobe Pierre Paul Broca

-emotional feeling and expression Papez presumed at first (1937): limbic lobe - functions related to the behaviour and emotions , emotions and motivated activity - localized in distinct brain structures Papez proposed: -cingulate gyrus and hippocampus are connected with hypothalamus, anterior thalamic nuclei (limbic thalamus) through neuronal pathways: Papez- circuit -emotional feeling and expression -interconnections constitute a harmonious mechanism -cingulate gyrus is a receptive region for experiencing of emotion Subcortical structures are connected to the limbic lobe: Diencephalon mamillary bodies thalamic nuclei medial and lateral habenular ncll. James Papez (1883-1958) American anatomist

Gyrus parahippocampalis Gyrus uncinatus Uncus Limbus Giacomini Gyrus intralimbicus Gyrus parahippocampalis B

Components of limbic system Cortical areas gyrus cinguli gyrus subcallosus prefrontal cortical areas – anterior part of frontal lobe (rostral to motor areas) piriform cortex –parahippocampal g. anterior part, including uncus, lat. olf. stria entorhinal cortex – parahippocampalis g. hippocampus dentate gyrus subiculum - pre/parasubiculum parahippocampal gyrus Subcortical limbic areas Diencephalon habenula mamillary body(hypothalamus) anterior thalamic nuclei (limbic thalamus) Telencephalon olfactory bulb anterior olfactory nucleus nucleus of the lateral olfactory tract septum nucleus tractus diagonalis nucleus accumbens (ventral striatum) amygdala nucleus stria terminalis Mesencephalon interpeduncular n., raphe dorsalis and medianus n. ventral tegmental nucleus, centr. gray matter

Papez circle

Hippocampal formation: hippocampus, dentate gyrus, subiculum Cortical afferents: ! -from: entorhinal area (fasciculus perforans)- glutamaterg◄amygdala, pr. olfactory c.  - dentate gyrus str. moleculare – granule cells -their mossy fibers activate the dendrites of CA3 pyramidal cells through Schäfer collaterals activate CA1 pyramidal cells (trisynaptic excitatory pathw.) -from contralateral hippocampusból -from cingulate gyrus Subcortical afferents: -medial septal nuclei (cholinerg), caudal hypothalamus, amygdala, midbrain, thalamus Cortical efferents - fornix: -from CA1, CA2, CA3 areas: fibers extend to subiculum (transitional zone between the hippocampus and the bordering entorhinal cortex) and the entorhinal area -from CA3: precommissural fornix to septum -from CA1: postcommissuralfornix to mamillary body – anterior thalamic nuclei – hypothalamus CA3 CA2 Fasciculus perforans CA1 Functional aspects: -memory processing functions -learning -stress -vigilance

Hippocampal formation:hippocampus, gyrus dentatus, subiculum

Sulcus fimbriodentatus Sulcus collateralis

Hippocampus and episodic memory -epizodic memory (what–where-when) – memory of experienced events within spatiotemporal context -„object-place memory task”– single specific event („object”) - particular occasion („place”) -participants are instructed to remember of objects in a short time period, and asked to recall the arrangement of the objects after a delay period „theta rhythm” (regular oscillation of the local field potential at frquencies of 3-12 Hz) EEG theta oscillation increases during a successful recall -theta oscillation is not a localized neuronal process, but distributes over the enthorhinal-hippocampal network 1)Θ osc. Generated in enthorinal cortex superficial II and III- layers 2)Extends into dentate gyrus, then through the mossy fibers 3)A Θ osc. into hippocampus CA3 zone 4)From CA3 Schafer collateráls into CA1 zóne This network enables on-line real-time formation of memories of novel experiences Sato and Yamaguchi, 2007 -some hippocampal cells have preferred positions: „place cells” their preferred positions are called „place fields” „in place field” -a given position in the environmental space is represented precisely by the firing rates of „place cells” -the population of active „place sejtek” continuously changes according to the running behavior in an environment

Prefrontal cortex - human Complex functions: -working memory, attention, cognition, emotion -executive control -regulates behavioral inhibition -jugdment, foresight Prefrontal cortex - human Dorsomedial prefrontal cortex -extensive connections with sensorimotor and association neocortex (contemporary and past sensory experiences) Orbitofrontal cortex -strong connections with amygdaloid complex -project heavily to subcortical limbic structures: hypothalamus and septum influences on behavioral and autonomic functions Reciprocal relationship between dorsal and ventral prefrontal cortex cognitive - emotional interactions

Amygdaloid complex Basolateral nuclei (younger) Extraordinarily complex Involved in many aspects of behavior but: there is no single high level function Swanson and Petrowich: „neither a structural nor a functional unit” Amygdaloid complex -implicated in emotional processing -critically involved in mediating the stress on hippocampal memory processes – amygdalo-hippocampal interactions Basolateral nuclei (younger) -extensive reciprocal relations: sensory assotiation cortex (parietal, temporal), frontal lobe and ventral striatum (putamen, and caudate n. ventral parts) n. accumbens, Meynert’s n. basalis, dorsal thalamus -projections from olfactory bulb, entorhinal cortex, cingulate gyrus, subcallosal area Corticomedial nuclei (older) -descending pathways to n. dorsalis n.vagi, brainstem cardiovascular centers, locus coeruleus, n. raphe dorsalisventral tegmental nucleus -peptidergic neurons(enkephalin, CRH, somatostatin, cholecystokinin) -HYPOTHALAMUS – tractus amygdalo-hypothalamicus ventralis + stria terminalis - reciprocal Many authors have attempted to divide this complex into clear functional units, largely without succes corticomediális, basolaterális subnuclei

Nucleus accumbens (limbikus striatum) N. accumbens functional aspects: -responsible for motivated, goal-directed behaviors -(compulsive drug seeking in cocaine addicts) -interface between limbic and motor system Normally descending projections from prefrontal cortex to n. accumbens, as well as other limbic regions, exert inhibitory control over reward-seeking behaviors

Changes of „award” system in heroin abuse GABA (inhibitory) terminal dopaminerg terminal , Heroin modifies the action of dopamine in the nucleus accumbens and the ventral tegemental area – (‘reward pathway’). Crossing the BBB, heroin is converted to morphine, which acts as a powerful agonist at the mu opioid receptors inhibiting the release of GABA from the nerve terminal, reducing the inhibitory effect of GABA on dopaminergic neurones. The increased release of dopamine results in sustained activation of the post-synaptic membrane. Continued activation of the dopaminergic reward pathway leads EUPHORIA. Addiction uses same interneuronal connections as the learning and memory formation

limbic system scheme: afferentation nucl. ant. thalami limbic system scheme: afferentation

limbic system scheme: Papez circle nucl. ant. thalami limbic system scheme: Papez circle

limbic system scheme: efferentation nucl. ant. thalami limbic system scheme: efferentation

Papez circle hippocampus

Pathology Wernicke-Korsakoff- encephalopathy Before treatment 7 days thiamin treatment Symptomes: apatia, confabulation, confusion, memory loss, inability to stand or walk without assistance abnormal hyperintensity mamillary body and periaqueductal gray matter Etiology: vitamin B1 deficiency

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