Regeneration and Sleep Cycle Flashcards
What is a glial scar?
Hypertrophic glial proliferation (microglia, reactive astrocyte, oligodendrocytes) at the site of lesion which prevents axons from growing across the lesion to innervate distal targets (principally resulting from astrocyte proliferation, only 0.5-2mm)
There is prolonged debris removal from Wallerian degeneration in the CNS compared to PNS
List some inhibitory factors released by the glia:
Inhibitory factors produced by glia:
- Nogo-A (fraction of CNS myelin)
- Chondroitin sulfate proteoglycan (ECM from Astro)
- MAG (Oligo)
- Sema4D (Oligo, trophic factor)
- Ephrin B3
What is a major problem in CNS regeneration?
Caspase mediated apoptosis – commonly resulting from glutamate excitotoxicity (upregulate NMDA receptors) or excessive cytokine stimulation
What does the influx of calcium do in CNS damage / regeneration?
Calcium influx also facilitates a “wash out” of the axonal contents (neurofilaments and microtubules), mitochondrial dysfunction, protease activation –> cytoskeletal damage & chromatolysis –> impeding regeneration via killing the neurons
No good for regeneration.
What is the largest hindrance for spinal cord injury recovery?
Dorsal Root Entry Zone - because of the proliferated astrocytes (glial scar) and produced inhibitory trophic factors at this CNS/PNS border
What is Wallerian Degeneration?
Degradation of the distal axon following transection of the axon (both CNS and PNS), however the basil lamina tube (Bands of Bungner) containing Schwann/oligodendrocyte cells remains providing a structure for the regrowth of the axon following growth cone formation
In the PNS there is also secondary proliferation of Schwann cells (confined by basil lamina)
How is PNS recovery ordered?
First: pressure and crude tough sensation return (Protopathic)
Second: fine touch and fine motor return (could not return) (Epicritic)
- Physical therapy of the affected region has been shown to increase the chance and rate of recovery via increased trophic support
Does method of damage affect recovery potential?
Yes! Recovery of crushed neurons is MUCH more efficient than those sectioned
Axonotmesis: compression injury
Neurotmesis: severing injury
How does stem cell replacement work in regeneration?
Neuron stem cells are supplied from olfactory receptors, taste buds, dentate gyrus of hippocampus (granule cells)
- regeneration occurs but INSUFFICIENT numbers to facilitate functional circuitry :(
Why does a neuroma form?
When the axon attempts to regrow (usually from neurotmesis), it fails to enter a band of Bungner (tube of Schwann cells) and the new nerve ends blindly in tissue; similar situation when axons attempt to cross a glial scar
–> phantom pain
How are neuromas treated?
Treatment involves cutting the end with the neuroma to attempt to initiate functional regrowth across the lesion
What role to CNS cysts play in regeneration?
Cyst formation at the site of the lesion, as in central cavitation, further impedes regeneration
What is reactive synaptogenesis? (collateral sprouting)
Functional method of recovery such that a transected axon that didn’t recover would have an adjacent neuron overgrow into the transected neurons territory of original innervation (also mildly occurs within the CNS)
What is the goal of PNS to CNS grafting experiments?
Hypothetically, allows for CNS neurons to grow from CNS to PNS and then back to CNS (bypassing the initial glial scar and inhibitory factors
- however, once encountering the PNS:CNS barrier the axons did not successfully reinnervate targets
DOESN’T WORK
Pharmacological therapy for regeneration?
- Steroids for antioxidant and anti-inflammatory action
- NMDA antagonists
Causes for ending of the critical period in regeneration?
- plasticity decreases when axonal growth ceases
- synaptic transmission matures
- cortical activation is constrained
What nucleus is the major trigger for sleep via GABA-ergic projection to the tubulomammillary nucleus (TMN)?
Ventral Lateral Preoptic Nucleus (VLPO) of hypothalamus
What does the tubulomammillary nucleus (TMN) do?
Tonically produces histamine for wake state
How do GABA-ergic circuits in the pons also promote sleep (in addition to VLPO)?
Ach inputs to GABA-ergic thalamic neurons
What do orexin neurons in the lateral hypothalamus do?
Stimulate:
- tubulomammillary nucleus to increase histamine production (during sleep) to initiate wakefulness
- brainstem nuclei (Raphe nuclei (5-HT), Locus coeruleus & LTA (NE)) to initiate arousal
List input to the cholinergic nuclei:
- Laterodorsal tegmental nucleus and pedunculopontine nucleus
- Nucleus basalis
- Nucleus of diagonal band
- Medial septal nuclei for initiation of REM
What is narcolepsy and what causes it?
- Lesion to orexin neurons or deficiency of hypocretin will lead to lack of waking stimulus
- (REM sleep attacks) causing excessive daytime sleepiness, cataplexy (sudden REM paralysis, hypnagogic hallucinations (graphic dreams), sleep paralysis
- seen in 1/1000 in US (genetic)
What will a lesion to the VLPO cause?
Insomnia due to lack of GABA-ergic input to TMN
What is an electroencephalogram of sleep?
Recording of the underlying neuronal activity within the cortex
- Synchronous activity is REQUIRED for good recording of the activity and this is seen in the deep sleep stages when synchrony is at its highest
Magnetoencephalography (MEG) is also a method of cortical activity recording
What do K complexes and Spindles in stage 2 sleep result from?
The thalamocortical inputs for synchronization and inhibition of afferent input to cortex
- Rhythms also result from shared timing function of excitatory and inhibitory neurons within the cortex
Awake state on an electroencephalogram of sleep?
Alpha (quiet-awake) and Beta rhythms (activated cortex)
REM sleep on an electroencephalogram of sleep?
Beta rhythms (fastest, >14Hz, asynchronous, sharp/frequent eye movements for 30-50min)
Stage 1 on an electroencephalogram of sleep?
Alpha rhythms irregular and wane (few minutes)
Stage 2 on an electroencephalogram of sleep?
Theta rhythms with K complexes and Spindles from thalamic pacemaker
Stage 3 on an electroencephalogram of sleep?
Delta rhythms (hallmark of deep sleep)
Stage 4 on an electroencephalogram of sleep?
Delta rhythms (VERY low frequency = less than 2Hz, high amplitude), ascends to stage 2 for 10-15min. before REM onset
Briefly describe the sleep stage cycle.
There are 4-5 cyclic episodes of the sleep cycle, with more time in REM for each episode; with each episode of REM there is an increased HR, respirations, and penile/clitoral erection is experienced
How does the cycle differ for the very young? Teenagers? The elderly?
- The very young experience a VERY FAST progression to stage 3 sleep and a very fast return to REM but there are SHORT periods of REM compared to later years
- Teenagers have a difficulty falling asleep but REM stages are expanded and more cyclic than in the very young
- The elderly experience mostly stage 1 and 2 sleep with periods of REM, this lighter sleep often causes fitful awakenings
Sleep deprivation. Is it good for your memory?
Hell no. Memory is affected first and to the largest degree during deprivation.
Briefly describe REM sleep.
- Body is paralyzed resulting form spinal cord motor inhibition via medullary glycinergic input to alpha motor neurons
- Sensation is present BUT is a result of internally generated stimuli
- Dominated by sympathetic activity
- Half the night REM sleep is in the last 1/3 of the night
- Functions to integrate and consolidate memories
- Characterized by PGO waves
What are ponto-geniculo-occipital waves (PGO)?
Phasic field potentials from pons, LGN, and occipital cortex via Ach which appear during REM providing for the vividness of the dreaming experience and activate phasic eye movements
What is sleep apnea? Treatment?
Due to interruptions of breathing from relaxation of pharynx and airway compromise; patients never enter deep stages of sleep and do not feel rested after a night of sleep
TX: positive pressure breathing apparatus (C-pap)
What is restless leg syndrome?
Unpleasant tingling in the legs and feet affecting 12M in US (mostly elderly), treatment with dopamine antagonist
What is REM sleep behavior disorder?
- States in which there is functionality of the muscle during REM sleep; seen commonly in elderly males leading them to act out their dreams (often from lesion to brainstem inhibition of spinal motor neurons)
- During this time there may be inappropriate or dangerous activities engaged in due to the lack of inhibition on muscle movements
What is somnambulism?
Sleepwalking which typically occurs during the 1st stage 4 non-REM period of the sleep cycle
How do the following drugs affect sleep?
- Benzodiazepines
- Caffeine
- Anti-histamines
- Benzodiazepines – GABA-ergic agonist which leads to more superficial sleeping states
- Caffeine – serves as an anti-adenosine agent (adenosine typically puts you to sleep)
- Anti-histamines – induces sleep due to mimicking the action of the VLPO
How is melatonin secreted? What does it do?
Retinal ganglion cells (with input from photoreceptors responsible for signaling circadian light changes) input to the SCN –> IML cell column –> Superior cervical ganglion (SY) –> pineal gland for conversion of serotonin to melatonin
Results in peripheral expression of seasonal rhythms and physiological/behavioral expression of circadian rhythms
What is REM rebound?
Increased REM sleep fraction following deprivation of REM sleep
What is neurapraxia?
Focal demyelination occurs without axonal degeneratiom
- loss of conduction, but recovery is expected
