brain function and malfunction Flashcards
1
Q
hippocampal sub regions
A
cornu ammonis (CA1-CA3)
dentate gyrus
subiculum
2
Q
the two different hypotheses for hippocampus and memory
A
1 - Immediate storage of incoming information,
Temporary memory buffer ‘consolidating’ information before sent to cortex
2 - Long-term memory storage in hippocampal formation
3
Q
two different forms of long term memory
A
declarative or implicit (non declarative)
4
Q
declarative memory includes
A
episodic (events) or semantic (facts)
5
Q
implicit (non declarative) memory includes
A
priming, habits, skills, implicit emotions
6
Q
episodic memory relies on
A
the hippocampus and associated structures
7
Q
does semantic memory rely on the hippocampus?
A
no
8
Q
common factors behind neurodegeneration
A
genes and environment Age Protein misfolding & aggregation Oxidative stress & calcium dis-homeostasis Inflammation Loss of trophic factors Neuronal death
9
Q
risk of dementia >85 years
A
50% per year
10
Q
AD effects what percentage of the pop.
A
10%
11
Q
end stage AD pathology
A
β-Amyloid (βA) plaques
Tau tangles
Enlarged ventricles
Inflammation
Tissue loss (atrophy), particularly cortical
12
Q
tau based staging method for AD
A
Tau-based Braak Staging
13
Q
Tau-based Braak Staging 5-6
A
Severe AD
14
Q
Mild cognitive impairment Braak staging
A
2-3
15
Q
other than braak post mortem staging for AD?
A
The ABC score
16
Q
The ABC score consists of
A
Composite of the Thal stage (Amyloid deposition),
Braak stage of neurofibrillary tangles (NFTs / Tau),
and the CERAD neuritic plaque score (C).
17
Q
AD dominant inheritance percentage of cases
A
1%
18
Q
AD complex inheritance percentage of cases
A
4%
19
Q
amyloid genetic links are
A
Mutations in APP (chr. 21), Presenilin 1 + 2 (chr. 14 and 1)
Trisomie 21 [Down‘s syndrome]
20
Q
risk genes for AD are associated with
A
Amyloid production, transport & clearance
Inflammation
Metabolic function
Cytoskeletal function
21
Q
which APOE allele increases risk of AD
A
allele ε4 of ApoE (chr. 19
22
Q
homozygous E4 increases risk of AD by
A
14.9x
23
Q
cholinergic hypothesis of Ad is
A
Reduced levels of ChAT (synthesis of ACh)
Loss of cholinergic neurones, especially in nucleus basalis of Meynert
Affected target areas of projections: hippocampus and cortex
Currently the only symptomatic treatment target
24
Q
overall AD pathogenesis is
A
is a diverse and multi-factorial disease with multiple potential initial inducers
25
AD diagnosis
General Physical Examination
Cognitive testing
Brain Imaging
EEG
Genetics
Blood & CSF biomarkers
Post-mortem confirmation
26
stage 1 AD
Occurs in first 3 years. Short term memory, mild amnesia, forgetting conversations
27
stage 2 AD
10 years. Difficulty with speech, forgetting basic tasks (eating, sleeping etc). Emotionally unstable
28
stage 3 AD
8 – 12 years. All intellectual functions decline. Personality loss. Eventually almost vegetative state.
29
benefits of using EEG in Ad diagnosis
```
EEG can measure brain activity and function in ‘real time’
Non-invasive
Inexpensive
Versatile
Fast & simple
Applicable to humans and rodents
```
30
limitations of using Fast Fourier Transformation (FFT) for EEG analysis
Result is heavily contaminated by “noise” and artefacts.
Destroys information about time.
31
benefits of using newer Auto-regressive Spectral Estimation for EEG analysis
(AR-spec)
Data based modelling approach.
Reconstructs a power spectrum free from chaotic activity (noise).
Preserves information about time.
32
resting EEG in AD demonstrates
reduced higher freq. power
| increased low freq. power./
33
reduced higher freq. power in AD infers
Beta-Gamma) changes occur early in the disease.
| Beta + Gamma are features of engaged brain networks
34
increased low freq. power. in AD infers
(delta) waves are an indication of the brain at rest,
| ie not engaging with cognitive processes
35
cerebral cortex for movement neurotransmitters
glutamate/aspartate
36
SNc/VTA to striatum neurotransmitters for movement
dopamine
37
striatum to GPi/SNr neurotransmitters for movement
GABA
| substance P
38
striatum to GPe neurotransmitters for movement
GABA
| enkephalin
39
GPe to STN neurotransmitters for movement
GABA
40
STN to GPi/SNr neurotransmitters for movement
glutamate
41
GPi/SNr neurotransmitter for movement to thalamus
GABA
42
thalamus to cortex neurotransmitter for movement
glutamate
| aspartate
43
Direct pathway steps
cortex->striatum (SNc/VTA influences striatum too) -> GPi/SNr->thalamus
44
indirect pathway steps
cortex->striatum->Gpe->STN-GPi/SNr->thalamus
45
how are the various motor system organised?
into loops
46
some examples of the loop organisations in the cortex?
motor, oculomotor, prefrontal and limbic
47
common stages in the cortex loops
input->striatum->output->thalamus
48
common link with the thalamus for each loop
always feeds back to the input
49
striatal anatomy: limbic and association centres feed into
striosomes
50
associations centres, somatosensory and motor layers feed into
matrix
51
striatal direct pathways ultimately causes
action selection
52
striatal indirect pathway ultimately causes
action suppression
53
striatal anatomy: medium spiny neurones are often found in the
striosomes
54
striatal interneurons consist of
cholinergic interneurons
55
the thalamus relationship with the cortex is
excitatory (glutamate)
56
Gpi +SNr relationship with the thalamus is
inhibitory (GABA)
57
motor cortex relationship with putamen is
excitatory (glutamate)
58
putamen relationship with Gpi Snr is
inhibitory (GABA)
59
sub nuclei direct pathway consists of
2. thalamus (+)
3. motor cortex (+)
5. putamen (-)
1. Gpi/Snr (x)
60
putamen relationship with GPe
inhibitory (GABA)
61
GPe relationship with subthalamic nucleus
inhibitory (GABA)
62
subthalamic nucleus relationship with Gpi-SNr
excitatory (glutamate)
63
sub nuclei indirect pathway consists of
2. thalamus (+)
3. motor cortex (+)
6. putamen (-)
7. GPe (x)
4. subthalamic nucleus (+)
1. Gpi/Snr (-)
64
normally the subthalamic nucleus would be
inhibited preventing it from stimulating Gpi/SNr
65
the reward pathway for the subnuclei is
pre-frontal cortex->SNc->putamen via D2/D1
66
Snc communicates with putamen via
dopamine D1/D2
67
D2 receptor in the putamen stimulates
indirect pathway
68
D1 receptor in the putamen stimulates
direct pathway
69
symptoms of parkinsons
```
Characterised by hypokinesia
Cardinal features include:
Tremor
Rigidity
Bradykinesia (slow movement)
Akinesia (slow initiation)
Postural Instability
loss of facial expression and hypophonia (soft speech)
```
70
how long does parkinsons take to progress
15-20 years
71
other symptoms of parkinsons include
depression, dementia , attention impairments and autonomic dysfunction
72
diagnosis of parkinsons requires
bradykinesia + 1 one the following:
muscular rigidity
4-6hz tremor
postural instability not caused by other organic means
73
pathological hallmark of parkinsons is
loss of the dopaminergic neurones in the substantia nigra pars compacta (SNc)
74
what level of depletion of he dopaminergic neurones in the substantia nigra pars compacta (SNc) is necessary?
80%
75
pathological criteria for diagnosis of Parkinson
α-synuclein protein aggregates: Lewy Bodies
76
parkin mutation impairs specifically
“Ubiquitin-proteasome system”
77
gene mutations for parkinsons accounts for
5%
78
risk factors for PD include
```
pesticides
well water, farming, rural
manganese, copper,
encephalitis lethargica
flu
head injury
```
79
symptomatic treatment for parkinsons
```
Levodopa
Dopamine agonists, e.g. bromocriptine
MAO-B inhibitors, e.g. selegiline
COMT inhibitors, e.g. entacapone
Anticholinergics, e.g. benztropine
```
80
symptoms of Huntington's
Hyperkinesia – abnormal and exaggerated movement, rapid and uncontrollable
Progresses to rigidity and bradykinesia
Difficulty with speech and swallowing, leading to weight loss
Slowed eye movement
Depression, anxiety, psychosis, progressive dementia, altered personality
Death after 10-15 years of onset
81
cause of Huntington's
Autosomal dominant disorder, gene defect on chromosome 4, codes for glutamine in huntingtin protein
82
specific Huntington's mutation
over repetition
of CAG trinucleotide coding
sequence
83
adult Parkinson's cases usually involve how many repeats?
36-50
84
Parkinson's pathophysiology
Brain volume decreases as disease progresses
Caudate nuclei and putamen decrease
Ventricular space increases
85
supportive tx for Huntington's includes
```
Anticonvulsants (Valproic acid)
Dopamine antagonists (Chlorpromazine)
GABA agonists (Baclofen)
Antipsychotics (Risperidone)
Antidepressants (Tricyclic, SSRI’s)
```
86
role of the cerebellum in motor control is
sensory coordination of ongoing movements and modulation
87
does the cerebellum initiate movement?
no - bar nystagmus
88
cerebellum inputs includes
```
position and state of muscle, joints and muscle tone (proprioception)
- spinocerebellar tract-
equilibrium state of the body
-vestibulocerebellar tract-
‘orders’ sent from cerebral cortex
-corticopontocerebellar tract-
```
89
cerebellar cortex is divided based on
source of input
90
cerebrocerebellum receives input from
cortex
91
cerebrocerebellum role
highly skilled spatial and temporal movement sequences
92
spinocerebellum inputs
spinal cord
93
how is the spinocerebellum mapped?
somatopically
94
vestibulocerebellum input?
vestibular nuclei
95
vestibulocerebellum role
regulation of movements underlying posture + reflexes
96
mossy fibres connect to
parallel fibres
97
parallel fibres connect to
purkinje cells (glutamate) and basket/stellate cells)
98
one climbing fibre connects to one
purkinje cell (glutmate)
99
purkinje cells in the cerebellum connect to
deep nuclei nuclear cells (glutumate)
100
basket/stellate cells role
inhibit (GABA) purkinje fibres
101
sensory cortex feedback to the cerebellum arrives via
sensory cortex->inferior olive->cerebellum
102
motor action information is arrives to the cerebellum via
motor cortex->pontine nucleus->cerebellum
103
theories of functions of the cerebellum
Comparator of signal
Damping of movement
Movement initiation (nystagmus)
Control of duration
104
cerebellar dysfunction entails
Asynergia (lack of co-ordination of movements)
Dysmetria (loss of movement accuracy)
Ataxia (unsteadiness of movement, disturbance in gait)
Nystagmus (oscillatory eye movements)
105
non-motor cerebellar functions
Motor learning (nictitating membrane reflex; rotarod test)
Cognition and language (dyslexia)
Cerebellar stimulation is beneficial for intractable epilepsy
106
Pascinian corpuscles
rapidly-adapting mechanoreceptors
respond to vibration or tickle
107
Pascinian corpuscles connect to
large myelinated axons
108
Pascinian corpuscles located in
subcutaneous tissue in palms of hands and soles of feet, joints, genitals and GIT
109
tonic receptors mean
slow adapting receptors that respond during stimulus duration
110
phasic receptors mean
rapidly adapt, fire when stimulus turns on and off
111
Meissner’s corpuscles
rapidly-adapting mechanoreceptors
- respond to tapping
112
Meissner’s corpuscles located
subepidermal location in hands, feet, forearm, lips and tip of tongue
113
Merkel cells
slow-adapting mechanoreceptors
| respond to skin indentation
114
Merkel cells associated with
whiskers
115
Merkel cells located in
basal layer of skin
116
Ruffini’s corpuscle
slowly-adapting, with tonic resting firing rate
117
Hair root nerve endings
- rapidly adapting Aδ fibres
| fire on hair displacement, not on hair release
118
Thermoreceptors located
throughout epidermis
119
Thermoreceptors- cold receptors fibres are
myelinated
120
thermoreceptors hot receptors fibres are
unmyelinated fibres
121
Thermoreceptors
| tonic or phasic?
- fire constantly and indefinitely
| firing rate dependent on temperature
122
mechanoreceptor nociceptors fibres are
myelinated (Aδ) or unmyelinated (C) fibres
123
nociceptors located
all layers
124
mechanothermal nociceptors fibres are
unmyelinated (C) fibres
125
proprioceptors include
golgi tendon organs
Neuromuscular spindles
joint capsules
flexor reflex afferents
126
nociceptors enable
withdrawal reflex
127
golgi tendon organs enable
stretch reflex
128
Neuromuscular spindles enable
crossed extension reflex
129
Neuromuscular spindles
| are
nerve endings encircle intrafusal muscle fibres
130
sweet stimuli receptor
T1R
131
bitter stimuli receptor
T2R
132
umami receptor
t-mGluR4
133
t-mGluR4 detects
glutamate
134
sodium salt and acid sensation receptor example
MDEG/ENaC
135
t-mGluR4, T2R, T1R are all
7-pass transmembrane receptors
136
types of taste bud
circumvallate, foliate, fungiform
137
variations in taste are due to
heterodimer variation between receptors binding or the amino acid sequence of the receptors or distribution of papillae and receptors
138
taste transduction involves
essentially depolarisation of the cell with intracellular calcium release and then neurotransmitter release.
139
why is taste linked to sensation and mood?
dynamic sensory processing in the brain
Cranial nerve innervate the pontine parabrachial nucleus and the nucleus of the solitary tract in the brainstem.
projections between gustatory cortex and orbitofrontal cortex via the thalamus.
There is also input to gustatory processing from somatosensory and visceral systems
140
Mechanism of odorant signal transduction
odorant receptors activation leads to G protein-mediated activation of adenylate cyclase, which catalyses cAMP production.
cAMP activates calcium channels leading to calcium and sodium influx and depolarisation.
The depolarisation is potentiated by calcium then activating chloride channels, which lets chloride ions out of the cell.
141
how is the odour code "sharpened"
convergence and lateral inhibition not only within the bulb but the cortex.
142
does competition exist between olfactory cells?
yes -After 60 days, the inactive channel-deficient neurons were eliminated unless all channels were inactive
143
osciles in order from external to internal
stapes->malleus->incus
144
sound transduction
cochlear fluid vibrations are transmitted to the basilar membrane.
Movement of the basilar membrane causes displacement of the organ of corti.
Movement of the hair cells due to the vibration of the basilar membrane causes the hair cell cilia to move relative to the tectorial membrane.
Displacement of the hair cells leads to increased or decreased firing of the auditory nerve endings, depending on the direction of movement of the cilia.
145
high pitch sounds vibrate the basilar membrane distally or proximally
proximally
146
low pitch sounds vibrate the basilar membrane distally or proximally
distally
147
do hair cells depolarise in the ear?
no, Instead, the influx of calcium leads to neurotransmitter release from vesicles at the presynaptic membrane. Once in the synapse the neurotransmitter is detected by postsynaptic receptors and a signal is transduced causing ion channels in the postsynaptic neuron to open and depolarise the cell, leading to the propagation of an action potential. The neurotransmitter vesicles in the hair cell are attached to an electron dense body called the synaptic ribbon, or synaptic body
148
vestibular anterior superior horn detects
movement of the head up and down, as done when nodding an affirmative response
149
vestibular lateral (or horizontal) horn detects
sideways shake of the head
150
vestibular posterior canal detects detects
tilting motion from side to side
151
cristae in the ampullae detect
rotation
152
maculaeare in the maculae detect
linear acceleration and head position
153
cristae in the ampullae detect rotation because
endolymph around the gelatinous cupula in a crista causes movement detected by the hair cells
Cells on one side of the head increase firing, while those on the other side decrease firing
154
maculaeare in the maculae detect linear acceleration and head position by
otolith crystals layered on top of the cupula move under gravity, thus triggering hair cells
155
for near vision the lens
round ups up due to the ciliary muscles contracting and pulling the suspensory ligaments
156
for distant vision the lens
ciliary muscles relax
| and suspensory ligaments pull the lens into a flatter shape.
157
long-sightedness (hyperopia) requires
convex lens
158
short-sightedness (myopia) requires
concave lens
159
when light arrives a the retina...
it is detected by rods and cones, the photoreceptor cells at the rear of the retina. These are lined by a pigmented epithelium, which absorbs excess light. Activation of photoreceptors leads to release of pigment and depolarization of bipolar cells. These in turn activate retinal ganglion cells (RGCs), whose axons converge on the optic nerve head and exit the eye into the optic nerve.
160
three types of cones are?
RGB
161
retinal pigment activation elicits
a cGMP-mediated change in release of neurotransmitter and postsynaptic activation of bipolar cells. Convergence of the signal occurs due to many receptors synapsing onto bipolar cells, as well as lateral inhibition mediated by horizontal cells.
162
outer segment of cones and rods contain
disks filled with rhodopsin
163
in darkness rhodopsin is
inactive
cGMP high
ion channels open
tonic release of neurotransmitters to bipolar neurones
164
in light rhodospin is
opsin decreases CGMP
closes sodium channels
hyperpolarises cell
neurotransmitter release decreased in proportion to light
165
identification of shapes and edges are viable because
off centre and on centre visual fields that either excite or inhibit ganglion cells bases on whether light is shined on centre or surrounding
166
precise positional cues for individual axons between RGCs for the retina and tectum is feasible because
Temporal axons, having more receptor, are inhibited from projecting deep into the tectum
Nasal axons, having progressively less receptor, project progressively further into the tectum
Complementary expression of ligands and receptors in the D-V axis provides a 3-D map
167
retinal-tectum 3D map is dependent on
ephrin-A being increased in nasal retina and posterior tectum
EphA being increased in temporal retina and anterior tectum
168
Scotomas mean
defects of central fields
169
early onset schizophrenia tend to
have more disorganized features and worse prognosis for recovery and function preservation
170
positive schizophrenic symptoms
delusion , hallucinations, catatonic behaviours
171
Negative symptoms schizophrenic symptoms
Affective blunting, alogia, anhedonia, avolition, asociality
172
other symptoms of schizophrenia
Cognitive symptoms
- Attention, episodic & working memory, processing speed
Disorganized symptoms – disorganized speech & behaviours
Affective symptoms – Depression, anxiety, anger, hostility, aggression
173
delusion means
fixed, false beliefs that conflict with reality. Despite contrary evidence,
a person in a delusional state can’t let go of these convictions
174
types of delusions
erotomanic, grandiose, persecutory, jealous
175
types of hallucinations
auditory, visual, tactile, olfactory, gustatory
176
Alogia means
decrease in verbal communication, poverty of content and speech, thought blocking
177
Dx of schizophrenia
Two of following symptoms for most of 1 month :
-delusions, hallucinations, disorganizes speech, grossly disorganized or
catatonic behaviours,negative symptoms
organic symptoms ruled out
178
dopamine hypothesis of schizophrenia
PET studies show increased levels D2 of receptors
Drugs which block dopamine reduce psychotic symptoms
179
four dopamine pathways
Mesolimbic pathway
Mesocortical pathway
Nigrostriatal pathway
Tuberoinfundibular pathway
180
Mesocortical pathway
| is between
VTA to prefrontal cortex
| Cognition and executive function
181
Mesolimbic pathway
| is between
VTA to the nucleus accumbens, amygdala and hippocampus
| Regulation of emotional behaviour
182
Mesocortical pathway is associated with what schizophrenic symptoms
Negative symptoms (hypodopaminergic):
Alogia
Affective flattening
Avolition
183
mesolimbic pathway is associated with what schizophrenic symptoms
```
Positive symptoms
(hyperdopaminergic):
Delusions
Hallucinations
Disorganised thought, speech, behaviour
```
184
problems with treating a schizophrenic patient with D2 antagonist antipsychotics
also reduces signalling in the mesocortical pathway
185
an example of a dopamine partial agonist
aripiprazole
186
glutamate hypothesis of schizophrenia entails
1. Hypofunction of NMDA receptors on GABAergic interneurons
2. Diminished inhibitory influences on neuronal function
3. Disinhibition of downstream glutamatergic activity
4. Hyperstimulation of cortical neurons through non-NMDA receptor
5. disinhibition of glutamatergic projections onto midrbain dopamine neurones
6. increased glutamate release
7. increased dopaminergic neuronal activation.
187
when does schizophrenia usually arise
nearly always emerges in late adolescence or early adulthood, with a peak between the ages of 18 and 25, when the prefrontal cortex is still developing
188
does schizophrenia have neurodevelopmental origins?
could include reduced elaboration of inhibitory pathways, and excessive pruning of excitatory pathways, leading to altered excitatory–inhibitory balance in the prefrontal cortex
189
synaptic pruning is important for
is critical for maturation of the frontal cortex, which is involved in so-called executive functions such as planning and decision-making. It makes adolescence and early adulthood a highly sensitive period, during which people are more susceptible to various kinds of mental illness.
190
post mortem schizophrenic brain tissue has implicated what cell?
activated Microglia: primary innate immune cells in the brain
in charge of synaptic pruning
191
microbiome differences in schizophrenia
Patients with schizophrenia had greater abundance of lactic acid bacteria
There were differences in the metabolic pathways controlling glutamate and B12 transport (increased in schizophrenia) and carbohydrate and lipid metabolism (decreased in schizophrenia)
192
does early onset schizophrenia have a stronger genetic component?
yes
193
Dx of major depressive disorder
Sad mood or Loss of interest of pleasure (anhedonia)
Symptoms are present nearly every day, most of the day, for at least 2 weeks
Symptoms are distinct and more severe than a normative response to significant loss
+ 4 other symptoms
194
other symptoms of major depressive disorder
Sleeping too much or too little
Psychomotor retardation or agitation
Poor appetite and weight loss, or increased appetite and weight gain
Loss of energy
Feelings of worthlessness or excessive guilt
Difficulty concentrating, thinking, or making decisions
Recurrent thoughts of death or suicide
195
Tx of MDD
Selective serotonin reuptake inhibitors(SSRIs)
Serotonin-norepinephrine reuptake inhibitors(SNRIs):
Serotonin modulators
Tricyclic antidepressants(TCAs)
Monoamine oxidase inhibitors (MAOIs
atypicals
196
SSRIs mechanism
Block the reuptake of serotonin, increasing serotonin concentrations in the synaptic cleft and postsynaptic neuronal activity
197
SNRIs mechanism
inhibit the reuptake of both serotonin and norepinephrine
198
TCAs mechanism
block the absorption of serotonin and norepinephrine into nerve cells, as well as another neurotransmitter known as acetylcholine
199
MAOIs mechanism
One of the first classes of antidepressants developed ,
| inhibits the action of an enzyme called monoamine oxidase, whose role it is to break down monoamines
200
aetiology of major depressive disorder hypothesis
abnormality in neural circuit (Excitation inhibition imbalance) disturbs neurotransmitter system
Stress causes major changes in the GABAergic system in the prefrontal cortex
reduces levels of GABA, GABA receptors
homeostatic down regulation of glutamate receptors
thus consideration for ketamine treatment
201
psychological Tx of major depressive disorder
```
interpersonal psychotherapy
cognitive therapy
mindfulness
behavioural activation
couples therapy
```
ECT
202
an example of a rare genetic variant for severe schizophrenia and depression
chromosomal translocation between chromosome 1 and chromosome 11 And they found a gene at the breakpoint on the chromosome 1 , and called disrupted in schizophrenia 1, DISC1
203
dentate gyrus in the hippocampus can produce how many neurones a day?
1400
204
DISC1 can impact
axonal targeting, cell positioning, GABA action switch, synaptic development and cell morphology
205
the progression of cells involved in cortical development for mice
```
Neuroepithelial cells
Radial Glial cells (RGCs)
Intermediate progenitor cells (IPCs)
Neurons
Astrocytes
Oligodendrocyte progenitor cells
```
206
difference in morphology between human and mice brain aside from size
human brains are gyrencephalic whereas mouse brains are lissencephalic
207
Neuroepithelial cells can selfrenew to generate more
| neuroepithelial cells through what form of division
vertical
208
Radial glial cells generate
| neurons through
vertical
divisions and Notch signalling is involved in
the cell division.
209
outer radial glial cells are made through
Radial glial cells generate outer
radial glial cells by undergoing a
horizontal division.
210
outer radial glial cells propagate through
horizontal division
211
layers of a developing cortex
```
Marginal zone
Cortical Plate
Intermediate zone
Outer subventricular zone
Inner subventricular zone
Ventricular zone
```
212
how does the cortex develop in terms of the cellular progression (outside in or inside out?)
inside out, new cells pass through layers to reach the external surface before settling
213
difference between mouse brain and human brain in cellular content?
human brains contain (?more) outer radial glial cells compared to mice
214
development of the dentate gyrus involves
Neural stem
cells at the dentate
neuroepithelium start to migrate
away during early development
The migrate in the dentate
migratory stream
```
They populate the subgranular
zone of the dentate gyrus and
remain there throughout life
while retaining the capacity to
generate neurons.
```
215
in the developing dentate gyrus what is the main form of cellular division
the NSCs switch from vertical to horizontal
216
the dentate gyrus is part of the
hippocampus
217
the neural stem cells in the dentate gyrus are
radial glial like cells (RGLs) and are multipotent NSCs and usually quiescent
218
the dentate gyrus forms part of what pathway
hippocampal tri-synaptic pathway
219
dentate gyrus receives input from
Entorhinal cortex
220
the new-born neurones of the dentate gyrus project to
send axons to CA3
| of the hippocampus
221
the new neurones of the dentate gyrus is essential for
are important for
| learning and memory.
222
what cells are the most important for human cortical development and upper layer expansion
Outer radial glial cells
223
progression of cortical human development
Neuroepithelial cells
Radial Glial cells (RGCs)
Intermediate progenitor cells (IPCs) form:
Neurons
Astrocytes
Oligodendrocyte progenitor cells
224
what factors are used to reprogram fibroblasts
the Yamanaka factors
225
Outer and ventricular Radial Glial Cells marker
SOX2+
226
Seckel syndrome inheritance
autosomal recessive
227
Seckel syndrome causes
intellectual disability
| Microcephaly
228
Seckel syndrome mutation
CPAP
229
neural stem cell marker
nestin
230
Seckel syndrome study into cortex found
thinner ventricular zone
231
seckel organoids also revealed what change in cell division
increased horizontal division
232
CPAP mutation thus causes
long cilia, retarded cilia
disassembly
Thinner VZ
Disrupted division plane
233
seckel syndrome primarily effects what cells then
radial glial cells
234
zika virus spread
```
Primarily spread by female
mosquitos.
• Can be passed on by sex and
blood transfusion and through
pregnancy.
```
235
zika virus usually causes
Usually causes mild fever,
| sometimes asymptomatic.
236
rare risk with zika virus and pregnancy
```
5%-14% give birth to children
with signs of congenital Zika
syndrome
• 4%-6% subset have children with
microcephaly.
```
237
what cortical cells does zika virus infect
neural stem cells and not neurones which induces death and reduces proliferation
238
zika ultimately causes what to happen to the cortical layers then?
reduced thickness of
the ventricular zone and neuronal
layer.
239
zika virus then usually affects what cortical developmental cells then?
radial glial cells and outer radial glial cells
240
SARS-CoV-2 infects what cerebral cells
Choroid plexus epithelial cells
241
what mutation can be used to replicate macrocephaly in organoids
RAB39b–PI3K–mTOR
242
what happens to the cortical layers in macrocephaly
Over proliferation of NPCs
• Thicker VZ
• leading to an increased overall size
243
macrocephaly ultimately effects what cells
radial glial cells
244
Miller Macrocephaly-Dieker -Syndrome causes
Lissencephaly
245
Miller Macrocephaly-Dieker -Syndrome induces what change in the ventricular zone
increased apoptosis
246
Miller-Dieker Syndrome then ultimately affects what cells
Neuroepithelial cells
Radial Glial cells (RGCs)
Outer Radial Glial cells (RGCs)
247
what occurs in the dentate gyrus in AD
Patients suffering from
Alzheimer's disease have
fewer newborn neurons
248
seizures during development alter the dentate gyrus by
casing aberrant neurogenesis leading to the question of does inhibiting neurogenesis stop the seizure rusk
249
classic pathology and natural history of spinal muscular atrophy
degeneration of lower, alpha motor neurones in the ventral horn with progressive denervation and atrophy ogf skeletal muscle proximally with eventual paralysis
250
SMN in in relation to spinal muscular atrophy (SMA) refers to
survival motor neurone protein
251
genetics of SMA are
autosomal recessive
252
why does missing SMN not be fatal in humans
we have two copies (SM1/SM2)
253
what is the issue with SMN2
single point mutations in exon 7 results in unstable protein production
254
what are the classifications of SMA?
type 1 (severe) - type 4 (mild)
255
severity of SMA is dependent on
milder SMA means more copies of SMN2 gene
256
the classification of SMA focuses on
inability to gain function
257
type 1 SMA maximum function
unable to sit
258
most variable staging of SMA is
type 2
259
type 2 SMA maximum function
sit, never walk
260
type 4 SMA maximum function
walking during adulthood
261
Do other species have multiple copies of SMA
no
262
roles of SMN
role in RNA processing and splicing but this couldn't be linked to disease severity
interacts with ribosomes altering their location and function
263
what has recent data about SMA and ribosomes revealed
these are concentration dependent, vary in different tissues and at different stages of development, and act on specific disease-relevant pathways in neurons
264
SMA axonal pathology at birth
Motor systems are normal at birth, pathology arises post-natally
265
mechanisms and details of SMA axonal pathology
impaired axon-genesis and synaptic maintenance may be responsible
266
is restoration of SMN to muscle alone sufficient to ameliorate disease?
no despite defects independent of denervation also present in the skeletal muscle
267
non-muscular pathology of SMA
Cardiac arrhythmias and heart defects in patients
Digital and peripheral necrosis in artificially ventilated patients and drug treated mice
Independent vascular defects in skeletal muscle, spinal cord and retina
Now, bone, pancreas, liver, spleen and kidney are reported to be defective in SMA mouse models
268
what therapies exist for SMA
gene therapy
| HDAC inhibitors
269
SMA gene therapy entails
self-complimentary adeno-associated viruses
270
SMA gene therapy name
Zolgensma
271
SMA gene therapy efficacy
mice lifespan from 13-250 days (controversial because of cost)
272
Histone deacetylase inhibitors are
non-specific regulators of transcription
273
Histone deacetylase inhibitors role in SMA is to
increases SMN2 promoter activity
274
Histone deacetylase inhibitors efficacy in SMA
12-38 days is the best recorded outcome in treated severe mouse models
275
ASO treatment in SMA refers too
antisense oligonucleotides
276
antisense oligonucleotides role in SMA
bind to intronic splice silencers to promote inclusion of exon 7 in SMN2 transcripts, therefore generating increased amounts of full length functional SMN protein
277
ASO efficacy in SMA
increase lifespan 10-248 days
278
ASO most efficacious for SMA when delivered
pre-symptomatic, systemic administration
279
Zolgensma is approved for
Approved for Type 1 and patients with ≤3 copies of SMN2 as a single dose therapy
280
Risdiplam is a
Daily, liquid, orally-delivered SMN2 splice modifier
281
an example of non SMN pathways in SMA
Ubiquitin-dependent pathways regulate neuromuscular pathologies in SMA
282
is there any therapy for non SMN pathways in SMA
Therapy with quercetin can ameliorate neuromuscular symptoms
| But: these more healthy mice do not live longer
283
in hippocampus (learning and memory) each astrocyte defines a
unique 3-D spatial domain, with minimal peripheral overlap
284
all synapses in a confined volume may be controlled / modulated by
one astrocyte
285
how do astrocytes communicate with one another?
using waves of Ca2+
286
can astrocytes signal in response to neurones AP
yes
287
Astrocytes regulate synaptic transmission via
tripartite” synapses
288
do astrocytes have neurotransmitter receptors?
yes
289
astrocyte Ca2+ waves can release
neuromodulators: gliotransmitters such as glutamate, D-serine, ATP
290
astrocytes can therefore locally regulate
neurotransmission and local blood flow
291
Dendritic spines, synapses and astrocyte sheaths :
| ..…may ALL change shape
over minutes – coordinately
292
astrocytes are coupled across the brain via
gap junctions
293
CA2+ astrocytes signalling wave works through
Ca2+ dependent release of ATP and of glutamate
ATP spreads to neighbours - activates P2Y receptors and increases Ca2+ - spreads to more neighbours like ripples on a pond.
294
in the hippocampus astrocyte Ca+ waves increase
glutamate release –
| this helps sychronize firing of clusters of pyramidal neurons
295
whisker stimulation, visual stimuli and running : all increase and is mediated by what in regards to astrocytes
Ca2+ in sensory cortex astrocytes - mediated by mGluR
296
photoactivation of specific astrocyte in visual cortex causes Ca2+ waves AND
changes neuron-specific responsiveness to orientation preferences
changes the basal firing rate of specific neurons and somehow modifies neuronal orientation responsiveness
So - astrocytes alter integration of sensory information processing
297
how could astrocytes produce higher order organization of information
astrocyte modulation of synapses + coupling of large domains of synapses, introduces a code above and beyond a binary, synapse specific coding
Astrocytes produce slower signals and carry large
amounts of information over long distances
298
Astrocytes key roles in development
radial glial cells assist in laying down guidelines for neurone migration and become astrocytes
299
how can astrocytes control synapse number?
Thrombospondin 1 and 2 are released by astrocytes and cause a three fold increase in synapse numbers
Antibodies to thrombospondins inhibit this
300
what time frame does astrocytes best regulate synapse numbers
Time window of astrocyte release : high in brain postnatal week 1,
as synapses are forming and drops off by postnatal week 3
301
Time window of astrocyte synapse regulation infers
astrocytes down regulate their own ability
| to increase synapse numbers developmentally
302
dendrites in contact with astrocytes have
a longer lifetime and are morphologically more mature
303
how is dendritic maturation regulated by astrocytes
there is local activation of Ephrin A receptors on dendritic spines by astrocytic ephrin-A3 ligand
304
astrocyte regulation of neurogenesis is by
infusion of ephrin B2 into the lateral ventricles causes an increase in stem cell proliferation in the SVZ
ephrin B2 on hippocampal astrocytes promotes differentiation of sub granular zone neural stem cells in adult mouse
305
So activation of astrocyte CB1R by cannabinoids induces
LTD in hippocampus and impairs spatial working memory
306
what happens when human astrocytes are grafted into mice
they stay bigger and cortex and hippocampus is colonized in 4 – 12 months.
Gap junction coupled, grafted human astrocyte Ca2+ waves are 3 x faster than mouse
mice with human astrocytes are much faster to learn maze and fear conditioning
307
how may Fragile x pathology relate to astrocytes
mutation in gene FMR1
FMR protein lost
FMRP is an RNA binding protein that associates with polyribosomes
hippocampal neurons grown on FMR1 deficient astrocytes – have stunted dendritic arborisation, but are OK on WT astrocytes - so astrocytic involvement.
308
how may Rett syndrome pathology relate to astrocytes
loss of transcriptional repressor methyl CpG binding protein 2 (MeCP2)
MeCP2 is present in neurons and astrocytes
hippocampal neurons cultured with conditioned medium or on astrocytes from MeCP2 deficient mice have stunted dendrites
309
can Astrocyte calcium waves signal injury?
yes
310
how does a propagating astrocyte calcium wave signal long range injury
Calcium waves in gap junction coupled astrocytes increase NSC division and migration
through notch signalling
311
transcranial stimulation induced what in astrocytes?
induced large amplitude synchronous Ca2+ surges in astrocytes
thus Astrocytes may be involved in synaptic plasticity induced by tDCS
312
Activation of target designer receptors
| in hippocampal astrocytes caused:
1. increased Ca2+ signals/waves
2. increased transmitter release from CA1 neurones
3. potentiated synaptic transmission at CA3 to CA1 synapses and LTP
313
thus astrocyte activation in the hippocampus is associated with
improved memory
314
neural tube arises from
dorsal ectoderm
315
spinal cord embryologically formation
neural plate->neural fold->neural tube->spinal cord
316
secondary neurulation involves
Tail bud cells condense and epithelialize then hollow out to form a secondary neural tube caudally- region of the coccyx and cauda equina
317
primary neurulation occurs around
Primary neurulation
| Days 22-26
318
secondary neurulation occurs around
Secondary neurulation
| Days 26-42
319
dorsal root ganglia is formed by
After fusion, neural crest cells migrate away from the dorsal side of the neural tube to form the sensory neurons of the dorsal root ganglia (DRG).
320
the three layers of the neural tube are
ventricular layer
mantle layer
marginal layer
321
ventricular layer of the neural tube consists of
undifferentiated, proliferating cells, forms the lining of the central canal
322
mantle layer of the neural tube consists of
differentiating neurons that will form the grey matter of the spinal cord
323
marginal layer of the neural tube consists of
nerve fibres and will be the white matter
324
dorsal portion of the neural tube is termed the
alar plate and forms the sensory area
325
the ventral portion of the neural tube is termed the
basal plate and forms the motor area of the spinal cord.
326
dura mater
tough outer membrane
327
epidural space
protective pad of loose connective and adipose tissue
328
arachnoid mater
middle layer of meninges
329
subarachnoid space
between arachnoid and pia mater
330
pia mater
attached to surfaces of brain and spinal cord
331
order of the meninges
```
dura mater
epidural space
arachnoid mater
subarachnoid space -
pia mater
```
332
impulse conduction via the cord occurs through
white matter
333
reflex integration occurs via the
grey mater
334
two spinal enlargements are
cervical C3-T2
| lumbar T9-T12
335
spinal nerve pairs
31
336
4 nerve plexuses
cervical
brachial
lumbar
sacral
337
central pattern generators can
can produce rhythmic network activity in the absence of external timing cues- without rhythmic sensory feedback or rhythmic activation by descending neurons
338
central pattern generator (CPG) examples
stepping, scratching, swimming, flying, respiration
339
Central pattern generators are coordinated by
coordinated via propriospinal neuron pathways (PNs)
340
what could trigged a CPG?
spontaneous or triggered by stimulation (tactile, electrical, pharmacological)
341
how can a CPG be refined?
dynamic interaction of supraspinal signals (motor cortex) and sensory feedback to the spinal network
342
do we know the physical location of all CPG's yet?
no
343
neural tube defects
craniorachischisis. anencephaly, encephalocele, iniencephaly, spin bifida occulta, closed spinal dysraphism, meningocele, myelomeningocele
344
craniorachischisis -
completely open spinal cord and brain
345
anencephaly -
open brain and lack of skull vault
346
iniencephaly -
occipital skull and spine defects with extreme retroflexion of the head
347
encephalocele -
herniation of the meninges
348
closed spinal dysraphism -
deficiency of at least two vertebral arches
349
spina bifida prevention is with
Supplement maternal diet with folic acid, a naturally occurring, water soluble B vitamin (B9)
350
what alternative preventative treatment for spina bifida for highly predisposed women exists>
Inositol
351
traumatic causes of spinal injury
Hyperflexion: bending the spine forwards
Hyperextension: stretching the spine backwards
Rotation: twisting the spine sideways
Vertical/axial compression : squashing the spine.
352
non-traumatic causes of spinal injury
cord compression
infection
cyst or tumour
lack of blood flow
353
initial injury to the spine in trauma usually is
compression
354
initial injury site of the spine is
central
355
why is spinal trauma injury site usually central?
Greatest deformation of a gel inside a compressed tube is at centre
Forces at the centre produce a haemorrhage
Gray matter is more vascularized than white matter, so more vulnerable
A “rind” of white matter is spared at the periphery
356
secondary spinal injury mechanics
cell death in grey matter
Wallerian degeneration in white matter
localised breakdown of nerve followed by “die back” of the distal portion- influx of calcium
357
chronic cellular consequences of spinal injury
fibroglial” scar formation- invasion by
collagen-producing fibroblasts
Astrocytes- activated microglia
macrophages- cavities
358
spinal microlesion description (cellular)
BBB minimally disrupted
astrocytes produces CSGS and KSPGs along injury
Axons cannot regenerate
macrophages invade
359
contusive injury spinal description
```
BBB disrupted but meninges intact
cavitation as epicentre
altered astrocyte alignment
Gradient astrocytic production of ASPGS and KSPGs
penumbra
macrophage invasion
dystrophic axons
```
360
large spinal stab injury description
```
BBB disruption
cavitation
astrocyte alignment altered
CSPG and KSPG gradient
fibroblasts invade and express SEMA3
macrophages invade and release inflammatory cytokines
dysrohic neuones repelled by lesion
```
361
C4 injury
quadriplegia
362
C6 injury
partial paralysis of hand and arms as well as paralysis of lower body
363
T6 injury
paraplegia below chest
364
L1 injury
paralyses below waist
365
ASIA A grade
complete
366
Asia B
no motor function S-S5 and below
367
ASIA C
motor function below injury have grade <3
368
ASIA D
motor function above injury >3
369
Asia E
normal
370
complications of spinal cord injury
pressure sore
infection
spasticity
autonomic dysreflexia
371
autonomic dysreflexia can cause
over activity of the autonomic nervous system causes a life threatening increase in blood pressure
mainly when injury is T5 or higher
caused by irritating stimulus below the level of SCI
372
barriers to spinal cord injury recovery
Scar is non-permissive for regeneration
Spared cells in white matter are demyelinated
Retained remnants of degrading myelin prevent axonal growth
373
why is a spinal scar Scar is non-permissive for regeneration
Fibroblasts and their matrix deflect growth
E.g. semaphorin-3A
Astrocytes provide chemical inhibitory signals
chondroitin sulphate proteoglycans (CSPGs), tenascin
374
what Retained remnants of degrading myelin prevent axonal growth
Nogo-A, myelin-associated glycoprotein (MAG) etc can be retained for at least a year
375
what limits non-neuronal lesion core/peripheral spinal neuronal regeneration
inadequate facilitators:
intrinsic growth potential
matrix support
chemoattractant
376
spinal lesion compartments consist of
Lesion compartments
Non-neuronal core- residual inflammatory cells that remain after debris clearance
Astrocyte scar at periphery restricts inflammation
Spared but reactive neural tissue undergoing circuit reorganisation
377
targets for SCI repair
1) Damaged nerves/support cells must survive or be replaced- prevent secondary injury
adult nerves don’t usually divide, so unlikely to get significant recovery without intervention
2) Surviving neurons must regrow axons, despite scar tissue and inhibitory molecules
3) Axons must migrate toward appropriate targets
4) Axons must form effective synapses
5) Target cells must be able to respond to neurotransmitters (no major muscle fibre loss)
6) Neural circuitry must compensate for changes in spinal cord circuitry following injury
378
incomplete SCI treatment requires
Stimulate reorganisation of spared circuitry
379
anatomically complete SCI requires
neuron grafts or stimulate regrowth across lesion
380
does sciatic nerve bridges work?
peripheral nerves graft enable axonal growth but issue when entering a hostile CNS
381
other acute injury treatments for SCI
Cooling injury site
Acute intermittent hypoxia
Methylprednisolone
382
acute SCI cooling site injury risks
reduces swelling and necrosis due to hypoxia
| but cause additional damage to cord- dangerous surgery for collar
383
Acute intermittent hypoxia for SCI entails
1.5 min AIH, @ 1 min intervals, 15 x daily, 5 consecutive days
Improves walking inpatients with chronic SCI
384
SCI Methylprednisolone must be administered within
8 hours
385
for SCI is Methylprednisolone administered anymore?
no
386
transplants and implants for SCI include
Foetal spinal cord transplants, alone or in combination with:
growth factors
anti-apoptotic agents
molecules that counteract inhibition by myelin-associated proteins (Nogo-A and MAG, CSPG’s)
polymer scaffolds (± stem cell seeding)
387
other strategies for treating SCI include
modulate cAMP levels
stem cells
extracellular DC voltage gradients
388
modulate cAMP levels for SCI involve
increased cAMP overcomes MAG inhibition of axon growth
| improve regeneration in adults using drugs that elevate cAMP?
389
what stem cell research was being conducted for SCI
oligodendrocyte precursors injected into lesion site- aimed to remyelinate axons
390
extracellular DC voltage gradients for SCI involve
```
electric fields (EFs) in developing and regenerating systems
neurons grow directionally in electric field in vitro
```
391
EF with cathode distal to SCI lesion prevents
die back
392
EF with cathode proximal to lesion enhances
die back
393
Chronic electrical stimulation of motor cortex enhances
sprouting of spared corticospinal tracts
394
some ideas as to why electrical stimulation encourages nerve growth
Induces action potentials in neurons
Calcium transients
via voltage gated channels
via mechanosensitive channels
Increases transcription of regeneration associated genes (RAGS)
395
most improvement for a SCI occurs when?
6 months after trauma
396
Electrotherapy plus physical therapy can
improve symptoms with return to bipedal locomotion with support but only during electrical stimulation
397
why does Electrotherapy plus physical therapy work?
likely by stimulating central pattern generators
