Where are the hippocampus and limbic system?
Medial parts of the temporal lobe
3 C-shaped structures and pathways of the limbic system
1) Limbic association cortex: cingulate and parahippocampal gyri
2) Hippocampus and fornix
3) Amygdaloid complex and stria terminalis
Limbic cortical areas
Medial orbital gyri of frontal lobe
Cingulate gyrus of frontal and parietal lobes
Parahippocampal gyrus of temporal lobe
All receive input from higher order sensory and association areas
How is the medial prefrontal cortex related to the limbic system?
Can influence various cortical and subcortical parts of the limbic system:
Some brainstem nuclei
What structures are in the medial part of the temporal lobe?
(both underneath the parahippocampal gyrus!)
Continuation of cingulate gyrus on inferior surface of the brain
Cortex of parahippocampal gyrus includes subiculum and entorhinal cortex (both functionally related to hippocampus)
Rostrally, parahippocampal gyrus expands to form uncus (amygdala and anterior part of hippocampus underlie the uncus)
Diverse functions of the limbic system
Control of visceral function
Outdated, but a good model
Mammillary body --> anterior thalamic nucleus -->cingulate gyrus --> cingulum --> hippocampus --> hippocampus and subiculum --> fornix --> mammillary body
Collection of several distinct nuclei, so called amygdaloid complex
In temporal lobe just beneath cortex of uncus (or parahippocampal gyrus!), immediately rostral to hippocampal formation
3 major divisions of amygdaloid complex
Don't need to know
Basolateral nuclei: largest group; connections with cerebral cortex, particularly sensory association areas, limbic association cortex (cingulate cortex, orbital and medial prefrontal cortex), and thalamus (MD nucleus); general function = emotion/experience
Central nuclear group: connections with brainstem and hypothalamic regions that include viscerosensory areas such as the nucleus of the solitary tract and autonomic nuclei such as the dorsal motor nucleus of the vagus; general function = visceral control
Medial group: connections with olfactory bulb, olfactory cortex and hypothalamus; general function = olfaction
Efferent pathways of the amygdala
Stria terminalis: from medial group to parts of hypothalamus and septal areas
Ventral amygdalofugal system: diffuse but connects frontal cortex to brainstem
Interconnections among amygdaloid nuclei: connect cortical regions that provide highly processed sensory info (sensory association areas) with hypothalamic and brainstem regions that serve as effector systems
Function of amygdala
Sensory events connected to emotional significance
Emotion-related aspects of learning
Learning about fearful stimuli
Evaluating the emotional significance of events in the environment
Overview of function of hippocampal formation
Important role in memory
Bilateral damage causes loss of ability to consolidate short-term memory to long-term memory
3 regions of hippocampal formation
1) Dentate gyrus
2) Hippocapmus (Ammon's Horn or Cornu Ammonis)
Cells of the dentate gyrus vs. cells of the hippocampus
Granule cells major cell of dentate gyrus
Pyramidal cells major cell of hippocampus
3 layers of cells of the dentate gyrus
1) Molecular layer = dendritic layer
2) Granule cell layer = cell body layer
3) Polymorph layer/hilus = axonal layer
In general, dendrites of granule cell layer extend into relatively neuron-free region above granule cell layer and layer of polymorph cells below or within granule cell layer
3 layers of hippocampus
1) Stratum radiatum = dendritic layer
2) Pyramidal cell layer = cell body layer
3) Stratum oriens = axonal layer
Interneurons in each layer but most prominent within or immediately below granule cell/pyramidal cell layers; many of the interneurons are basket cells that use GABA and inhibit input to cell bodies of principal cells
In general, dendrites of pyramidal cell layer extend into relatively neuron-free region above pyramidal cell layer and layer of polymorph cells below or within pyramidal cell layer
One type of GABA interneuron
Inhibit cell bodies of principal cells of dentate gyrus (granule cells) and hippocampus (pyramidal cells)
Neuronal cell bodies and axon terminals in dentate gyrus
Trisynaptic circuit through hippocampal formation (most classical hippocampal pathway)
Info from all over the cortex --> entorhinal cortex --> across hippocampal fissure (perforated path) --> dentate gyrus (and also small input to hippocampus) --> granule cells send axons to CA3 of hippocampus ONLY --> pyramidal cells send projection to CA1 field (but some from CA3 leave hippocampus via fornix) --> most sent to subiculum --> entorhinal cortex --> cortical association areas
Summary: entorhinal cortex through perforant path to dentate gyrus --> mossy fibers to CA3 --> Schaffer collaterals to CA1 --> subiculum --> entorhinal cortex
Links in hippocampal pathways
Perforant path: major projection from entorhinal cortex to dentate gyrus and hippocampus; crosses or "perforates" hippocampal fissure to reach dentate
Mossy fibers: axons of granule cells of dentate gyrus that have large, characteristic terminals that contact CA3 neurons
Schaffer collaterals: axon collaterals from CA3 neurons to CA1
Where does the hippocampus send info via fornix?
Hippocampus sends info to mammillary bodies and septal region through the fornix
What NT is used in the basic hippocampal circuitry fron entorhinal cortex --> dentate gyrus --> CA3 --> CA1?
Glutamate (excitatory) used in this circuitry!!
Mossy fibers which project from dentate gyrus to CA3 also contain high levels of zinc and other neuropeptides
Where is acetylcholine used?
ACh is major NT of neurons from septal nuclei to hippocampal formation; part of group of cholinergic neurons in basal forebrain; remember basal nucleus of Meynert project to all areas of cerebral cortex
Choliergic neurons in septal nuclei project to hippocampal formation through fornix
Why is cholinergic innervation of the hippocampus special?
1) Cholinergic neurons that innervate hippocampus (from septal nuclei, through fornix) are severely depleted in Alzheimer's disease
2) Nerve growth factor (NGF) has been found to influence survival of cholinergic neurons in CNS
What NT is used by intrinsic neurons within the hippocampus and dentate gyrus?
GABA used by many intrinsic neurons (one example is basket cells)
(There are also GABA neurons in septum that project to hippocampus)
Which neuropeptides are found in interneurons in hippocampus?
Somatostatin, CCK, VIP
Co-localized with other neuroactive substances such as GABA
What diseases show selective vulnerability of neurons in hippocampal formation?
Ischemia: CA1 field of hippocampal formation; excitotoxicity involved (get loss of short term memory)
Temporal lobe epilepsy: CA1 field and hilus of dentate gyrus, and CA3 field; hippocampus becomes shrunken (hippocampal sclerosis); granule cells of dentate gyrus and CA2 field are spared
Alzheimer's disease: entorhinal cortex and CA1 field; however other brain regions involved, such as cerebral cortex and basal forebrain
Neurogenesis in the adult brain
Occurs in dentate gyrus and subventricular zone
New granule cells generated from dividing progenitor cells: new neurons generated near base of granule cell layer, differentiate, extend axons and are incorporated into existing circuitry of hippocampus
Environmental factors and stimulation can influence rate of neurogenesis
Do axons of the CNS regenerate?
Not over long distance, and is limited
However, axonal reorganization or "sprouting" does occur!
Undamaged neurons form new synaptic connections in response to either loss of normal targets or deafferentation of nearby neurons
Axon collaterals of remaining neurons occupy synaptic sites that have been vacated by damaged neurons
Reorganization of mossy fibers of dentate gurys in patients with temporal lobe epilepsy
Normally, mossy fibers confined to hilus of dentate gyrus and CA3 field, but in epilepsy patients, putative mossy fibers or collaterals occupy inner part of molecular layer
1) Hilar (polymorph, PM) neurons normally innervate inner molecular layer of dentate gyrus
2) Hilar neurons (and CA3 neurons) depleted in epilepsy patients, so granule cells lost major sites of termination
3) Loss of hilar neurons led to vacated synaptic sites in inner molecular layer
4) Granule cells send axon collaterals into inner molecular layers and innervate vacated synaptic sites --> leads to hyperexcitability, increased synchronization of firing of granule cells, epileptiform activity
Do similar types of neuronal reorganizaton occur in other neurological disorders?
Yes! Just not shown in humans yet
Spinal shock to hyperreflexia after spinal cord injury may be explained by axonal sprouting
Spasticity after stroke may be explained by reorganiation of axons from remaining neurons
Also axonal reorganization could have beneficial effects and contribute to recovery of function in neurological disorders
Located rostrally in the brain, where caudate and putamen meet at the bottom (is in the "ventral striatum")
Ventral tegmental area of the substantia nigra projects up to nucleus accumbens using dopamineric neurons
Implicated in the reward system
Regions involved in emotion
Orbital and medial prefrontal cortex (ventral basal ganglia)
MD nucleus of thalamus
What happens if you lose the amygdala on both sides?
Can't recognize fearful expressions
Amygdala and emotional response
Receives wide variety of sensory inputs
Strong connections with cerebral cortex and hypothalamus
Involved in emotion-related aspects of learning (if something is good or bad; strong emotion --> strong memories)
Involved in associating sensory experience with emotional significance
Flow of information into the hippocampus--where does this info come from?
Information comes from many areas of the cortex into the cingulate gyrus --> through fibers of the cingulum --> feeds into entorhinal cortex
What are CA1, CA2, CA3?
Just different regions of the hippocampus
What do we use to control the very excitatory hippocampal pathway that uses glutamate only?
GABAergic interneurons (one example is basket cells)
Also cholinergic input is important for controlling the system
Where exactly are the septal nuclei?
Gray matter area along the base of the septum pellucidum (between lateral ventricles)
In patient RB who had global ischemia, what happened?
CA1 cells were damaged (they were selectively vulnerable)
Loss of these CA1 cells interrupted the hippocampal loop and that caused deficit where patient had anterograde amnesia (couldn't form new memories)
How could excitotoxicity kill cells?
Excitotoxicity is abnormal excessive accumulation of glutamate that can "excite" neurons to death
NMDA receptors probably involved here because they can let too much Ca2+ in
Extensive cell loss but selective (hilus of dentate, CA3, CA1)
Preservation of granule cells of dentate gyrus and CA2
Example of selective vulnerability
What can affect neurogenesis?
Increased neurogenesis: severe acute seizure activity, exercise, SSRIs, enriched environment
Decreased neurogenesis: chronic stress
What happens when granule cells are interconnected?
Normally, granule cells are not interconnected--they just form their own little path out
If they lost places they need to project (hilar cells) and lost things that should innervate them (hilar cells), they form interconnections and innervate each other
Consequences: synchronous firing of granule cells; lose inhibitory interneurons that usually control this region