Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_24_библиотеки_им_акад_М_И_Перельмана
.pdf
38 Role ofUnipolar Brush Cells intheVestibulocerebellum
https://t.me/medicina_free
247
UBCs can also receive glycinergic inhibitory postsynaptic currents (IPSCs) as well as different sets of GABAergic
IPSCs (Dugue etal. 2005; Rousseau etal. 2012) from Golgi
cells (Rousseau etal. 2012), basal interstitial nucleus cells
(Jaarsma etal. 2018), and Purkinje cells (Guo etal. 2021a).
The slower glycinergic IPSCs may provide an inhibitory
tone, setting the gain of the mossy ber to UBC relay,
whereas the fast and large GABAergic IPSCs may control
spike timing (Rousseau etal. 2012). While the excitatory and
inhibitory inputs to the UBCs determine the state of their
membrane potential, this state in turn will inuence the type
of their response in that the level of depolarization or hyperpolarization will determine to what extent mossy bers elicit
tonic or burst responses, respectively (Diana et al. 2007;
Birnstiel etal. 2009). Indeed, UBCs often show a bimodal
ring pattern, depending on the fast and slow calcium currents as well as metabotropic glutamate receptors that are
activated (Birnstiel etal. 2009; Guo etal. 2021b).
At the output level, UBC axon terminals are void of
GABAA and glycine receptors (Mugnaini et al. 1994) and
strictly glutamatergic (Nunzi etal. 2001). UBCs can therefore pass on a largely amplied signal to the cells downstream, forming an excitatory feedforward network within
the cerebellum (van Dorp and De Zeeuw 2014). The nding
that UBCs are relatively sensitive to the duration, rather than
the frequency, of stimulation (Borges-Merjane and Trussell
2015), raises the possibility that UBCs and their feedforward
mechanisms serve to introduce temporal patterning and
delays in the cerebellar network (Gao etal. 2012). Together,
the synaptic and intracellular mechanisms engaged by UBCs
are likely to enrich the diversity of temporal patterns in the
granular layer of the cerebellar cortex, adding to its expansion coding (D’Angelo and De Zeeuw 2009).
38.5 A Continuum ofSubtypes
UBCs show a continuum of different cell-intrinsic temporal
responses, which correlate with differential expression levels
of a variety of proteins (Guo etal. 2021b; Kozareva etal.
2021). At the outer parts of the continuous spectrum, there
are two dominant subtypes, which were initially called type
I and type II UBCs, based upon the relatively prominent
expression of calretinin (CR) and metabotropic glutamate
receptor 1-alpha (mGluR1α), respectively (Floris etal. 1994;
Nunzi etal. 2002; Kim etal. 2012; Sekerkova etal. 2014).
Nowadays, type I and type II UBCs are often referred to as
OFF-UBCs and ON-UBCs, as they show inhibitory and
excitatory responses upon activation of the glutamatergic
mossy bers (Martina and Sekerková 2016; Balmer and
Trussell 2019; Guo etal. 2021b) (Fig.38.3a–c), analogous to
those of the OFF- and ON-bipolar cells that have been
described for the retina (Euler etal. 2014). While the typical
ON-UBC is relatively silent without active mossy ber input
(Kim etal. 2012), the OFF-UBCs can show a regular, intrinsic ring frequency of up to 35 Hz (Simpson et al. 2005;
Ruigrok et al. 2011; Hensbroek et al. 2015). Accordingly,
whereas ON-UBCs usually re in bursts upon stimulation,
generating an amplication of signals, OFF-UBCs tend to
show a more monotonic signal almost linearly following that
of the mossy bers (Kim etal. 2012).
The continuum in the heterogeneity of the UBC response
patterns to mossy ber stimulation results to a large extent
from the large variation in metabotropic signaling in the
UBC population (Rodrigues etal. 2019; Guo etal. 2021b;
Kozareva et al. 2021). Indeed, the expressions of proteins
involved in the excitatory mGluR1 and inhibitory mGluR2/3
pathways are inversely related to each other and correspond
to the typical ON-UBC and OFF-UBC highlighted above
(Knoach and Kemp 1998; Nunzi etal. 2002; Chung etal.
2009a, b; Kim et al. 2012), but all these expressions are
graded (Guo etal. 2021b; Kozareva etal. 2021). As a consequence, proteins in these different pathways co-exist in varying degrees in many UBCs, and co-activation of them leads
to a continuum of response patterns to mossy ber stimulation in the population of UBCs, supporting learning over
multiple timescales. For example, since many of the UBCs
prominently express both mGluR2/3 and mGluR1, many
UBCs will show a sequence of inhibition and excitation with
particular durations, dependent on the expression levels of
the faster mGluR2/3-currents and the slower mGluR1currents, respectively (Guo etal. 2021b) (see e.g., Fig.38.3c).
Various other proteins, which are also expressed at different
levels in UBCs (Kozareva etal. 2021), further enrich the continuum of response patterns (Fig.38.3d). The level of expression of DAG-kinase correlates with the duration of the
mGluR1 response (Guo et al. 2021b), and that of the G
protein- coupled inwardly rectifying potassium channel
(GIRK) correlates with the strength of the hyperpolarizing
impact of activated mGluR2 receptors (Borges-Merjane and
Trussell 2015). Likewise, the expression levels of GABAa
and GABAb receptors will further shape the duration and
strength of the inhibitory postsynaptic currents (Dugue etal.
2005; Rousseau etal. 2012; Guo etal. 2021a). Interestingly,
as such the heterogeneity of protein composition of UBCs
may also provide a cellular basis for the notion that the mean
of the latency of the UBC peak responses correlates linearly
with their variability (Fig.38.3d), i.e., they behave according
to Weber’s law (Guo etal. 2021b). Thus, a continuum of subtypes of UBCs provides a cell-autonomous basis in the input
layer of the vestibulocerebellum, allowing for temporal integration and learning of compensatory movements over multiple and expanded time scales (Gao etal. 2012; Guo et al.
2021b).
248
https://t.me/medicina_free
R. N. Koops et al.
a
b
c
d
Fig. 38.3 A continuum of UBCs with two predominant subtypes at the
outer parts of the spectrum. (a) Schematic representation of an invitro
whole cell recording of a unipolar brush cell (UBC; in pink), while
stimulating an external mossy ber (blue) and applying a puff of glutamate. (b) Voltage clamp (VC) and current clamp (CC) recordings of a
response of a typical ON-UBC in the presence of a 1mM glutamate
puff (indicated by red arrows). The VC recording shows an inward
biphasic excitatory postsynaptic current (EPSC) and a fast EPSC followed by a long slow component; the CC recording shows that this
stimulation results in a prolonged ring activity. (c) VC and CC recordings of a response of a typical OFF-UBC in the presence of a 1mM
glutamate puff (indicated by red arrows). Glutamate release results in
an initial fast inward EPSC followed by a large outward component,
ceasing the ring activity as displayed in the CC recording (right). (d)
Schematic representation of the inuence of the molecular composition
of UBCs on their responses to stimulation. Left column: Uniform
Manifold Approximation and Projection (UMAP) with latent factor
loading (left) and major genes involved in synaptic transmission that
are differentially expressed along the gradient of the latent factor
(right). Note that the ON-UBCs and OFF-UBCs are positioned at the
top and bottom parts of the spectrum, respectively. Second to left column: This schematic summarizes the putative roles of the mGluR1
pathway (red) and mGluR2 pathway (blue) in the continuum of synaptic responses. Note the modifying impact of proteins such as TRPC3
and DGKβ/γ on the strength and duration of these responses. Third column: Together, the differential responses from small groups of UBCs
cover a multiscale set of temporal representations at the population
level, supporting learning over multiple timescales. Column on the
right: Normalized and replotted responses of the same cells on a logarithmic time axis, demonstrating Weber’s law behavior in that the mean
of the latency of the UBC responses correlates linearly with their variability. Panel a adapted from Van Dorp and De Zeeuw 2015; Panels b
and c modied from Borges-Merjane and Trussell (2015); Panel d
adapted from Guo etal. (2021b)
38 Role ofUnipolar Brush Cells intheVestibulocerebellum
https://t.me/medicina_free
249
38.6 Expansion Coding
intheVestibulocerebellum
The cerebellum is involved in learning processes that
require precise timing (De Zeeuw 2021). This also holds
for the vestibulocerebellum, which is involved in the tuning
of compensatory movements of eyes, head, and body during vestibular and/or visual stimulation (Schonewille etal.
2010; Winkelman etal. 2014; De Zeeuw and Ten Brinke
2015; Lisberger 2021). Since UBCs are most prominently
present in the vestibulocerebellum (Fig.38.4a–c), it is intuitive to elucidate their potential role in the context of these
movements. What is typical about these eye movement
reexes is that they compensate for direct sensory inputs
and that they can do so across a wide range of kinematic
parameters; the movements can be relatively fast (vestibulo-ocular reex) or slow (optokinetic reex or cervicoocular reex), they can last shortly or very long, and they
can occur at smaller or larger amplitudes, in any direction.
So even though the monodendritic UBCs in the vestibulocerebellum are well designed to preserve the signaling
identity of the mossy ber inputs that nd their origin in a
sensory organ or the proprioceptive system just one or a
few synapses upstream, in their output UBCs are likely to
contribute to the encoding and expansion of kinematic
parameters. Indeed, in the theoretical framework of distributed synergistic plasticity for cerebellar learning, it has
been proposed that UBCs serve to enhance the diversity of
temporal patterns in the granular layer, akin expansion coding in the temporal domain, so that the climbing bers that
induce plasticity in the molecular layer can optimize synaptic input by facilitating selection from a rich repertoire of
response patterns (Gao etal. 2012). The potential role of
UBCs in diversity enhancement of temporal signals is supported by the invitro nding that UBCs respond to sinusoidal modulations of their sensory input with a wide variety
of amplitudes and phase shifts (Zampini et al. 2016).
Moreover, exploiting these data in a model of the cerebellar
network indeed suggests that without UBCs Purkinje cells
struggle to optimize their output in response to any arbitrary sinusoidal input, whereas in the presence of UBCs
they are able to efciently acquire a proper output to any
phase input (Zampini etal. 2016).
38.7 Potential Role oftheTypical ON-UBC
To what extent do behavioral recordings following manipulation of ON-UBCs and/or electrophysiological recordings
of ON-UBCs in the vestibulocerebellum support their potential role in temporal expansion of kinematic parameters?
Recently, it was discovered that Moonwalker mice, which
suffer from a point mutation in the transient receptor potential channel Trpc3 (Becker etal. 2009; Becker 2014), show
an early-onset ablation of their ON-UBCs in the zebrinpositive or upbound microzones (Sekerkova etal. 2013; Wu
etal. 2019; De Zeeuw 2021). Given that TRPC3 is required
for mGluR1-dependent synaptic transmission (Hartmann
etal. 2008), these data align well with the preferred ablation
of ON-UBCs. Young adult Moonwalker mice show signicant gain decits and a persistent phase lead in their horizontal vestibulo-ocular reex across a broad range of frequencies
as well as in their horizontal optokinetic reex at lower frequencies and/or larger amplitudes (Koops et al. 2022)
(Fig.38.5a–e). In addition, Moonwalker mice show a signicant decit in phase reversal learning of their horizontal
vestibulo-ocular reex (Fig.38.5f, g). As ON-UBCs appear
prominently distributed in the main vertical axis zone of the
occulus (Schonewille et al. 2006a; Koops et al. 2022)
(Fig.38.4a, b), these data are in line with a potential role of
ON-UBCs in expansion coding during adaptation. It should
be noted though that Moonwalker mice also show a prominent late-onset, but progressive, degeneration of Purkinje
cells (Becker etal. 2009; Sekerkova etal. 2013; Wu et al.
2019) and that Pavlovian eyeblink conditioning, which is
mediated by a downbound microzone of lobule simplex (De
Zeeuw 2021), is signicantly affected (Wu et al. 2019).
Thus, if the late-onset Purkinje cell degeneration would at
some point also occur abundantly in the upbound microzones of the occulus, the UBC-associated phenotype
described above might be convoluted by Purkinje cell degeneration. However, since TRPC3 is only mildly expressed in
upbound microzones and since a Purkinje cell-specic knock
out of TRPC3 does not show any aberrations in its optokinetic or vestibulo-ocular reexes (Wu etal. 2019), it remains
to be seen to what extent this possibility forms a realistic
caveat.
The behavioral data highlighted above also raise the possibility that ON-UBCs in this region amplify not only vestibular, but also visual and/or oculomotor signals to optimize
compensatory eye movements. Unfortunately, probably no
or very few extracellular recordings of ON-UBCs in the occulus have been made during optokinetic or vestibular stimulation (Simpson etal. 2005; Hensbroek etal. 2015). This is
mainly due to the fact that the typical ON-UBCs are relatively silent during spontaneous activity compared to the
OFF-UBCs, which show the characteristic regular “motor
boat” sound in extracellular recordings (Ruigrok etal. 2011).
Moreover, the cell-bodies of ON-UBCs are also slightly
smaller, which further reduces the chance to pick them up.
Yet, from the responses of typical ON-UBCs invitro following sinusoidal stimulation, it is clear that these cells can
show prominent phase delays, in line with their late rebound
currents (Zampini etal. 2016).
250
https://t.me/medicina_free
a1 a2
R. N. Koops et al.
b1
c1
b2
c2
Fig. 38.4 Distribution of different types of UBCs in the mouse vestibulocerebellum. (a1) Fluorescence of ON-UBCs (in red) with the use of antibodies against metabotropic glutamate receptor 1α in coronal sections of
the occulus (FL) and paraocculus (PFL). (a2) Fluorescence of OFFUBCs (in gray) with the use of antibodies against calretinin in coronal
sections of the FL and PFL. (b1) Density map of ON-UBCs in the FL and
PFL. (b2) Density map of OFF-UBCs in the FL and PFL. (c1) Density map
of ON-UBCs in the vermis of the cerebellum (sagittal view), showing the
high, yet differential, distribution in the nodulus (lobule X) and uvula (lobule IX). (c2) Density map of OFF-UBCs in the vermis of the cerebellum.
Panels a and b are modied from Koops etal. (2022); panels c1 and c2 are
adapted from Martina and Sekerková (2016)
**
38 Role ofUnipolar Brush Cells intheVestibulocerebellum
https://t.me/medicina_free
251
a
cde
Drum moving
F
P
PC
GC
UBC
VN
MF
FL
b
CC D
Cam.
T
a
b
l
e
CF
Eye
OM
PN
PN
Slip
IO
CR
+
P
+
N
IR
T
m
u
r
D
**** ***** *** **
1
0.8
0.6
Gain
0.4
0.2
0
15
**** ****
0
-15
-30
-45
Phase angle (°)
-60
TRPC3
Control
-1
10
Mwk
10
Frequency (Hz) Frequency (Hz) Frequency (Hz)
Fig. 38.5 Eye movement studies in Moonwalker mice, which show a
preferred ablation of ON-UBCs. The Moonwalker mutation of Trpc3
Mwk
(TRPC3
) does affect both performance and adaptation of compensatory eye movements. (a) Circuitry of the occulus (FL) of the vestibulocerebellum controlling compensatory eye movements. Purkinje cells
(PCs) receive vestibular and visual input via the mossy ber (MF)—
parallel ber (PF) system (green) and climbing ber pathway (CF, blue)
from the inferior olive (IO). The unipolar brush cell (UBC; in red)
receives mossy ber signals and relays them to granule cells (GCs) that
give rise to the parallel bers. PCs inuence eye movements via the
vestibular nuclei (VN) neurons that innervate the oculomotor (OM)
neurons. (b) Schematic illustration of eye movement recording setup.
Mice are head-xed at the center of a turntable for vestibular stimulation and surrounded by a randomly dotted pattern (Drum) for visual
stimulation. A CCD camera is used for infrared (IR) video-tracking of
the left eye. Inset upper right: example of video image showing the
position (white cross) of the pupil (P) in relation to the nasal (N) and
temporal (T) quadrant of the eye as well as to the center (black cross) of
the corneal reection (CR) of an illumination light that is stable in
space. (c) The optokinetic reex (OKR) in response to drum rotations
at lower frequencies is decreased in Moonwalker mice (red; N= 7)
compared to littermate controls (gray; N=7; with a C3H and C57Bl/6
background); note that this corresponds with higher amplitude stimulation as the peak velocity of the stimulus is constant. (d) The vestibuloocular reex in the presence of vision (VVOR) is close-to-optimal in
wildtype control mice (with near unit gain and no phase shift), but
strongly reduced in Moonwalker mice, which also show a typical
phase-lead. (e) Likewise, the vestibulo-ocular reex in the dark (VOR)
in Moonwalker mice is substantially reduced in gain and has a phaselead. (f1) In-phase mismatch stimulation of drum and table was used
Light onLight on Darkness
VOROKR
1
0.8
0.6
0.4
0.2
0
60
45
30
15
0
-1
10
-15
0
10
T
able movingTable moving
-1
10
0
VVOR
1
0.8
0.6
0.4
0.2
0
60
45
30
15
0
-15
10
across multiple days to train mice to decrease the gain and eventually
invert the direction of the eye movement (quantied as a reversal of the
phase). The phase of the VVOR eye movement response during training
is inverted in both Moonwalker and control mice, but Moonwalker mice
do not show the gain change and gradual adaptation toward the target
phase (180°—line) during the training that is evident in control mice.
Error bars indicate mean±SEM. (f2) Gain and phase of VOR trials in
the dark that serve to study the effect of the training (recorded in the
dark before, between and after sessions). Control mice adapt toward the
target phase of 180°, showing a gradually decreasing gain, which is
partly consolidated overnight. Because the mice start off with a high
VOR gain, the point at which the phase ips toward 180° is not yet
reached within 4 days of training. Moonwalker mice start off with a
reduced gain and hardly show any VOR adaptation during training, nor
overnight consolidation. Furthermore, the phase of the VOR shows an
initial phase lead of roughly 20° compared to the control mice, which
persists throughout all four training days. (g1) The gain and phase data
during the training plotted in polar form shows for the control mice
(gray) a clear adaptation trajectory toward the target conditions (blue
stars) for each training day. Moonwalker mice (red) do show a response
toward the target conditions, but the trajectory more noisy and does not
reach as far. (g2) The gain and phase data of the VOR plotted in polar
form shows for the control mice a clear gain-down VOR adaptation
trajectory toward the target conditions (blue stars). Moonwalker mice
(red) show a trajectory that is strongly shifted toward a phase lead. This
apparent trajectory is mostly shaped by the variability in gain between
individual mice, as VOR adaptation is almost absent. (g3) The average
eye velocity traces of the VOR are plotted before (left) and after (right)
training. Shaded areas indicate ± SEM. For details of recording
approaches and data, see also Wu etal. (2019) and Koops etal. (2022)
0
252
01
https://t.me/medicina_free
R. N. Koops et al.
f1 g1
VOR gain down - phase reversal training
Table 5°
Drum 5°
Table 5°
Drum 7.5°
Table 5°
Drum 10°
Table 5°
Drum 10°
0.6
0.4
0.2
Gain
0
180
120
g2
60
Phase angle (°)
f2
0.8
0.6
Gain
0.4
0.2
90
60
30
Phase angle (°)
0
Day 1
Day 2
1
Day 3
VOR
0
* * * *
0
Day 1
Day 2Day 3
Day 4
Day 4
g3
)s/°(yticolevralugnA
25 25
90°
123,4
240°
90°
12
240°
0.2
0.4
0.2
0.4
180°
180°
120°
150°
210°
240°
120°
150°
3,4
210°
240°
InitialVOR LearnedVOR
0
01
Ti me (s)
Table
0
-25-25
0.6
0.6
60°
0.8
300°
60°
0.8
300°
30°
0°
0°
33
1
°
30
0°
330°
1
T
able
Ti me (s)
Fig. 38.5 (continued)
38.8 Potential Role oftheTypical OFF-UBC
Tens of recordings have been made from presumptive OFFUBCs during the vestibulo-ocular reex around the vertical
axis in the occulus of both anesthetized and awake rabbits
(Simpson et al. 2005; Hensbroek et al. 2015). These cells
show a wide variety of sensitivities, including that for position, velocity and/or acceleration of eye and/or head, in different, sometimes even opposite, directions (Fig.38.6a, b). In
awake animals many, but not all, OFF-UBCs show relatively
long response delays of up to 500ms (Hensbroek etal. 2015).
This nding supports the possibility that UBCs can, among
other functions, transform vestibular input signals into
delayed signals that contribute to the control of slow motor
signals in the control of eye and head movements (Schonewille
etal. 2006b; Barmack and Yakhnitsa 2008; van Dorp and De
Zeeuw 2014; Hensbroek etal. 2015). Delayed and sustained
UBC responses to transient mossy ber signals are probably
relevant to the process of neural integration, which underlies
transformation of the head velocity signals relayed by the
vestibular afferents from the semicircular canals into the position signals that are required downstream in the oculomotor
pathway during the vestibulo-ocular reex (Arenz etal. 2008;
Robinson 1989). Indeed, considering the phase of the simple
spike activity of occular Purkinje cells with respect to that of
the vestibular mossy ber input during compensatory eye
movements and adaptation thereof (De Zeeuw etal. 1995;
Voges etal. 2017), robust phase changes, sometimes even virtually complete reversals, must take place in the relay from
the input to output stage of the vestibulocerebellum (De
Zeeuw 2021). Such phase reversals could well be produced
by the mGluR2-activated outward conductance in the typical
OFF-UBC (Zampini etal. 2016) and/or in any of the less typical OFF-UBCs (Guo etal. 2021b).
Time (s)
Spike frequency (Hz)
Spike frequency (Hz) Head position (°)
Position(°)Velocity (°/s)
Spike frequency (Hz)
https://t.me/medicina_free
38 Role ofUnipolar Brush Cells intheVestibulocerebellum
40
a
30
20
10
0
-10
150
100
50
0
-50
-100
-150
b
2
Ipsilateral
0
-2
-4
Contralateral
-6
253
Head
Eye
60
40
20
0
80
60
40
20
0
80
60
40
20
Fig. 38.6 Electrophysiological recordings of presumptive OFF-UBCs
in the occulus. (a) Kinematics of head position in degrees (top) and
head velocity in degrees per second (bottom) during sigmoidal rotation.
Peak velocity for either direction is indicated by dashed lines. (b) During
sigmoidal rotation (black) the eyes (blue) move in the opposite direction
and are able to hold the new position over time (top panel). Response
0
01
2
3
4
5
6
7
8
properties of three presumptive OFF-UBCs in the occulus of the awake
rabbit with relatively strong position (second panel from the top) and
velocity (two bottom panels) sensitivities during sigmoidal head rotation
in the light. Note that the responses of the two UBCs in the two bottom
panels show oppositely directed velocity proles, but a similarly directed
position prole. Adapted from Hensbroek etal. (2015)
254
https://t.me/medicina_free
R. N. Koops et al.
38.9 Preserving Identity ofInput
The input–output structure of the UBC with its single dendrite
and simple axon as well as the corresponding cell physiological properties of UBCs suggests that the sensory and/or motor
identity of the incoming mossy ber signal is well preserved.
The nding that Moonwalker mice show prominent decits of
the optokinetic reex at low frequencies when large amplitudes are required (Koops etal. 2022) (Fig.38.5c), raises the
possibility that visual mossy bers in the occulus of the vestibulocerebellum might target the typical ON-UBC.This conguration appears to be compatible with the distribution of
UBCs in the occulus. For example, the density of ON-UBCs
appears the highest in the main vertical axis zone of the occulus (Koops etal. 2022) (Fig.38.4a, b). Given that the ampli-
tude of optokinetic eye movements around the vertical axis is
signicantly larger than that around the horizontal axis (Stahl
etal. 2006; Renier etal. 2010) and given that increases in the
gain of compensatory eye movements generated by this zone
require an increment in simple spikes (Voges etal. 2017), the
kinematic requirements and thereby demand for ON-UBCs
might be highest in the vertical axis zone of the occulus.
Alternatively, one can also argue that Moonwalker mice show
robust phase leads of their vestibulo-ocular reex around the
vertical axis that are particularly signicant in the higher frequency range (Koops etal. 2022) (Fig.38.5e), raising the possibility that UBCs in the vertical axis zone of the occulus
might receive a preferred input from the secondary vestibular
afferents that receive input from the horizontal semicircular
canal. This possibility would be compatible with the nding
that OFF- UBCs are also prominently distributed in the vertical
axis zone (Fig.38.4a, b) and that they show a relatively strong
response to vestibular stimulation (Hensbroek et al. 2015)
(Fig. 38.6). The fact that UBCs receive input from a single
mossy ber may be benecial for the processing of vestibular
signals in the occulus, as it leaves the directional encoding of
eye and head movement in the reference frame formed by the
response axes of semicircular canals in the vestibular nucleus
intact. Thus, the sensory and/or motor identity of the UBC
input signals to the occulus might indeed be relatively well
preserved, while the patterning in the temporal domain could
be expanded so as to accommodate the specic kinetic requirements during the optokinetic and/or vestibulo-ocular reex.
In the nodulus of the vestibulocerebellum, the same concept may hold. In this region, ON-UBCs probably receive
both primary afferents from the vestibular ganglion and secondary afferents from the vestibular nuclei, while OFFUBCs only receive secondary afferents (Balmer and Trussell
2019). Moreover, here too UBCs are differentially distrib-
uted, with the typical ON-UBCs and OFF-UBCs being more
prevalent in the ventral and dorsal parts of the nodulus,
respectively (Nunzi etal. 2002) (Fig.38.4c). Currently, it is
difcult to identify the precise function of UBCs in the nodulus, but by extrapolating the occulus studies highlighted
above, one might speculate that they also serve to broaden
the temporal window of sensory signals in the granular layer,
so as to improve the kinematics of eye, head, and body movements during for example balancing operations. Indeed, the
advantage of preserving, to some extent, the sensory encoding in the nodulus network might be that it allows for adequate actions upon specic inputs in the same reference
frames (MacNeilage and Glasauer 2018). By keeping the
primary afferents partly separated from the secondary afferents, one might be able to specically facilitate efcient integration downstream at the level of granule cells and Purkinje
cells, if and only if responses to incoming signals from the
otoliths or semicircular canals are required (Balmer and
Trussell 2019).
38.10 Relevance forDisease
Recently, Becker and colleagues found that a 40-year old
man, who presented with 2years of progressive imbalance
and ataxic gait, suffered from a p.Arg762His mutation in
Trpc3 that behaves similarly to the toxic gain-of-function
mutation of the pathogenic MoonWalker mouse (Fogel etal.
2015). The spinocerebellar ataxia (SCA) associated with this
mutation is now referred to as SCA41 (Smeets and Verbeek
2016). The question is to what extent neurodegeneration of
UBCs plays a relevant role in the observed ataxia. Functional
studies have shown that TRPC3 is a non-selective cation
channel that is expressed in the cerebellar cortex in both
UBCs and Purkinje cells (Hartmann et al. 2008; Becker
2014). Yet, it is expressed in a relatively specic fashion in
that it occurs predominantly in the UBCs and Purkinje cells
in the upbound and downbound microzones, respectively
(Wu etal. 2019; De Zeeuw 2021). Given the well-known
role of Purkinje cells in ataxia (De Zeeuw etal. 2011) and
given the association of progressive Purkinje cell degeneration with the downbound microzones (Cerminara etal. 2015;
De Zeeuw 2021; De Zeeuw etal. 2021; White etal. 2021),
the ataxia observed in the patient with SCA41 may be well
explained by degeneration of Purkinje cells. However, since
the Trpc3 mutation in young adult MoonWalker mice results
in early-onset degeneration of their UBCs in upbound microzones (Sekerkova etal. 2013; De Zeeuw 2021) as well as in
aberrant compensatory eye movements (Koops etal. 2022)
(Fig. 38.5), it will be interesting to nd to what extent
younger patients with a p.Arg762His mutation in Trpc3 also
show decits in performance and/or adaptation of their compensatory eye movements. Such study might reveal the
potential clinical relevance of UBCs for early-onset motor
problems. The nding that a global genetic loss of TRPC3,
38 Role ofUnipolar Brush Cells intheVestibulocerebellum
https://t.me/medicina_free
255
which affects in the cerebellar cortex not only Purkinje cells
but also UBCs, results in ataxia (Hartmann et al. 2008),
whereas a Purkinje cell specic loss of TRPC3 does not (Wu
et al. 2019), raises the possibility that a combined loss of
Purkinje cells in predominantly downbound microzones and
UBCs in predominantly upbound microzones might be particularly detrimental. The fact that disruption of the TRPC3
signaling pathway is a rather common pathological mechanism underlying various forms of genetic cerebellar ataxia,
including not only SCA41, but also SCA1, SCA14 and
SCA15 (Shakkottai and Fogel 2013), underscores the relevance of studying the role of not only Purkinje cells but also
that of UBCs in health and disease.
38.11 Conclusions
The data reviewed above for the vestibulocerebellum support
the hypothesis that UBCs in mammals may serve to expand the
temporal coding of mossy ber signals in the granular layer,
while preserving their sensory and/or motor identity, so as to
enrich output parameters of specic kinematics in the Purkinje
cell layer. Before this theory can be considered as established,
the experiments highlighted above need to be conrmed with
more and better cell-specic manipulations and recordings as
well as a more extensive exploration of the visual-vestibularoculomotor parameter space. Moreover, common principles of
UBC function in the cerebellar network can be inferred by
comparing the UBC operation in the vestibulocerebellum to
cerebellar circuits with other functions across species and in
different experimental paradigms. For example, delays inserted
by UBCs in the cerebellum-like electrosensory lobe of mormyrid sh may be instrumental in transforming motor commands into sensory predictions (Kennedy etal. 2014; Dempsey
etal. 2019). Such transformation is critical for effective implementation of sensory cancellation during self-generated motor
actions, which is considered to be one of the fundamental concepts in the ontogeny of cerebellar function. If the ingredients
of identity preservation and temporal expansion hold under all
these conditions, we can start to promote input preservation—
output expansion as a general principle for UBCs.
Acknowledgements Financial support was provided by the
Netherlands Organization for Scientic Research (NWO-ALW
824.02.001; CIDZ and CC), the Netherlands Organization for Scientic
Research (NWO Women in STEM 19224; CC), the Dutch Organization
for Medical Sciences (ZonMW 91120067; CIDZ and BW), Medical
Neuro-Delta (MD 01092019-31082023; CIDZ), INTENSE LSH-NWO
(TTW/00798883; CIDZ), ERC-adv (GA-294775 CIDZ) and ERC-POC
(nrs. 737619 and 768914; CIDZ); Stichting Vrienden van het
Herseninstituut (240-840407; CIDZ and RK), European Research
Council Starter Grant (ERC-Stg #680235; MS) en China Scholarship
Council (#201306230130; BWu) as well as the Dutch NWO Gravitation
Program (DBI2; CIDZ).
References
Allen Institute for Brain Science (2004) Allen Mouse Brain Atlas
Eomes. mouse.brain- map.org. Allen Institute for Brain Science
(2011)
Altman J, Bayer SA (1977) Time of origin and distribution of a new cell
type in the rat cerebellar cortex. Exp Brain Res 29:265–274. https://
doi.org/10.1007/BF00237046
Alvarez MI, Lacruz C, Toledano-Diaz A, Monleon E, Monzon M,
Badiola JJ, Toledano A (2008) Calretinin-immunopositive cells and
bers in the cerebellar cortex of normal sheep. Cerebellum 7:417–
429. https://doi.org/10.1007/s12311- 008- 0044- x
Arenz A, Silver RA, Schaefer AT, Margrie TW (2008) The contribu-
tion of single synapses to sensory representation invivo. Science
321:977–980. https://doi.org/10.1126/science.1158391
Balmer TS, Trussell LO (2019) Selective targeting of unipolar brush cell
subtypes by cerebellar mossy bers. elife:8. https://doi.org/10.7554/
eLife.44964
Balmer TS, Borges-Merjane C, Trussell LO (2021) Incomplete removal
of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse. elife:10. https://doi.org/10.7554/
eLife.63819
Barmack NH, Yakhnitsa V (2008) Functions of interneurons in mouse
cerebellum. J Neurosci 28:1140–1152. https://doi.org/10.1523/
JNEUROSCI.3942- 07.2008
Becker EB (2014) The moonwalker mouse: new insights into TRPC3
function, cerebellar development, and ataxia. Cerebellum 13:628–
636. https://doi.org/10.1007/s12311- 014- 0564- 5
Becker EB, Oliver PL, Glitsch MD, Banks GT, Achilli F, Hardy A,
Nolan PM, Fisher EM, Davies KE (2009) A point mutation in
TRPC3 causes abnormal Purkinje cell development and cerebellar
ataxia in moonwalker mice. Proc Natl Acad Sci U S A 106:6706–
6711. https://doi.org/10.1073/pnas.0810599106
Berthie B, Axelrad H (1994) Granular layer collaterals of the unipolar
brush cell axon display rosette-like excrescences. A Golgi study in
the rat cerebellar cortex. Neurosci Lett 167:161–165. https://doi.
org/10.1016/0304- 3940(94)91052- 9
Billups D, Liu YB, Birnstiel S, Slater NT (2002) NMDA receptor-
mediated currents in rat cerebellar granule and unipolar brush
cells. J Neurophysiol 87:1948–1959. https://doi.org/10.1152/
jn.00599.2001
Birnstiel S, Slater NT, McCrimmon DR, Mugnaini E, Hartell NA (2009)
Voltage-dependent calcium signaling in rat cerebellar unipolar
brush cells. Neuroscience 162:702–712. https://doi.org/10.1016/j.
neuroscience.2009.01.051
Borges-Merjane C, Trussell LO (2015) ON and OFF unipolar brush
cells transform multisensory inputs to the auditory system. Neuron
85:1029–1042. https://doi.org/10.1016/j.neuron.2015.02.009
Braak E, Braak H (1993) The new monodendritic neuronal type within
the adult human cerebellar granule cell layer shows calretininimmunoreactivity. Neurosci Lett 154:199–202. https://doi.
org/10.1016/0304- 3940(93)90206- z
Cerminara NL, Lang EJ, Sillitoe RV, Apps R (2015) Redening the
cerebellar cortex as an assembly of non-uniform Purkinje cell
microcircuits. Nat Rev Neurosci 16:79–93. https://doi.org/10.1038/
nrn3886
Chan-Palay V, Palay SL (1971) The synapse en marron between
golgi II neurons and mossy bers in the rat’s cerebellar cortex. Z
Anat Entwicklungsgesch 133:274–287. https://doi.org/10.1007/
BF00519303
Chung SH, Marzban H, Watanabe M, Hawkes R (2009a) Phospholipase
Cbeta4 expression identies a novel subset of unipolar brush cells
in the adult mouse cerebellum. Cerebellum 8:267–276. https://doi.
org/10.1007/s12311- 009- 0092- x
256
https://t.me/medicina_free
R. N. Koops et al.
Chung SH, Sillitoe RV, Croci L, Badaloni A, Consalez G, Hawkes R
(2009b) Purkinje cell phenotype restricts the distribution of unipolar
brush cells. Neuroscience 164:1496–1508. https://doi.org/10.1016/j.
neuroscience.2009.09.080
Cozzi MG, Rosa P, Greco A, Hille A, Huttner WB, Zanini A, De
Camilli P (1989) Immunohistochemical localization of secreto-
granin II in the rat cerebellum. Neuroscience 28:423–441. https://
doi.org/10.1016/0306- 4522(89)90190- 5.
D’Angelo E, De Zeeuw CI (2009) Timing and plasticity in the cerebel-
lum: focus on the granular layer. Trends Neurosci 32:30–40. https://
doi.org/10.1016/j.tins.2008.09.007
van Dorp S, De Zeeuw CI (2015) Forward signaling by unipolar brush
cells in the mouse cerebellum. Cerebellum 14:528–533. https://doi.
org/10.1007/s12311- 015- 0693- 5
De Zeeuw CI (2021) Bidirectional learning in upbound and downbound
microzones of the cerebellum. Nat Rev Neurosci 22:92–110. https://
doi.org/10.1038/s41583- 020- 00392- x
De Zeeuw CI, Ten Brinke MM (2015) Motor learning and the cer-
ebellum. Cold Spring Harb Perspect Biol 7:a021683. https://doi.
org/10.1101/cshperspect.a021683
De Zeeuw CI, Wylie DR, Stahl JS, Simpson JI (1995) Phase relations
of Purkinje cells in the rabbit occulus during compensatory eye
movements. J Neurophysiol 74:2051–2064. https://doi.org/10.1152/
jn.1995.74.5.2051
De Zeeuw CI, Hoebeek FE, Bosman LWJ, Schonewille M, Witter L,
Koekkoek SK (2011) Spatiotemporal ring patterns in the cer-
ebellum. Nat Rev Neurosci 12:327–344. https://doi.org/10.1038/
nrn3011
De Zeeuw CI, Lisberger SG, Raymond JL (2021) Diversity and dyna-
mism in the cerebellum. Nat Neurosci 24:160–167. https://doi.
org/10.1038/s41593- 020- 00754- 9
Dempsey C, Abbott LF, Sawtell NB (2019) Generalization of learned
responses in the mormyrid electrosensory lobe. elife:8. https://doi.
org/10.7554/eLife.44032
Diana MA, Otsu Y, Maton G, Collin T, Chat M, Dieudonne S
(2007) T-type and L-type Ca2+ conductances dene and encode
the bimodal ring pattern of vestibulocerebellar unipolar
brush cells. J Neurosci 27:3823–3838. https://doi.org/10.1523/
JNEUROSCI.4719- 06.2007
Dino MR, Willard FH, Mugnaini E (1999) Distribution of unipolar
brush cells and other calretinin immunoreactive components in the
mammalian cerebellar cortex. J Neurocytol 28:99–123. https://doi.
org/10.1023/a:1007072105919
Dino MR, Schuerger RJ, Liu Y, Slater NT, Mugnaini E (2000) Unipolar
brush cell: a potential feedforward excitatory interneuron of the
cerebellum. Neuroscience 98:625–636. https://doi.org/10.1016/
s0306- 4522(00)00123- 8
Dugue GP, Dumoulin A, Triller A, Dieudonne S (2005) Target-
dependent use of co-released inhibitory transmitters at central
synapses. J Neurosci 25:6490–6498. https://doi.org/10.1523/
JNEUROSCI.1500- 05.2005
Euler T, Haverkamp S, Schubert T, Baden T (2014) Retinal bipo-
lar cells: elementary building blocks of vision. Nat Rev Neurosci
15:507–519. https://doi.org/10.1038/nrn3783
Floris A, Dino M, Jacobowitz DM, Mugnaini E (1994) The unipolar
brush cells of the rat cerebellar cortex and cochlear nucleus are
calretinin-positive: a study by light and electron microscopic immu-
nocytochemistry. Anat Embryol (Berl) 189:495–520. https://doi.
org/10.1007/BF00186824
Fogel BL, Hanson SM, Becker EBE (2015) Do mutations in the murine
ataxia gene TRPC3 cause cerebellar ataxia in humans? Mov Disord
30:284–286
Fortin M, Marchand R, Parent A (1998) Calcium-binding proteins
in primate cerebellum. Neurosci Res 30:155–168. https://doi.
org/10.1016/s0168- 0102(97)00124- 7
Gao Z, van Beugen BJ, De Zeeuw CI (2012) Distributed synergistic
plasticity and cerebellar learning. Nat Rev Neurosci 13:619–635.
https://doi.org/10.1038/nrn3312
Guo C, Rudolph S, Neuwirth ME, Regehr WG (2021a) Purkinje cell
outputs selectively inhibit a subset of unipolar brush cells in the
input layer of the cerebellar cortex. elife:10. https://doi.org/10.7554/
eLife.68802
Guo C, Huson V, Macosko EZ, Regehr WG (2021b) Graded hetero-
geneity of metabotropic signaling underlies a continuum of cellintrinsic temporal responses in unipolar brush cells. Nat Commun
12:5491. https://doi.org/10.1038/s41467- 021- 22893- 8
Harris J, Moreno S, Shaw G, Mugnaini E (1993) Unusual neurolament
composition in cerebellar unipolar brush neurons. J Neurocytol
22:1039–1059. https://doi.org/10.1007/BF01235748
Hartmann J, Dragicevic E, Adelsberger H, Henning HA, Sumser M,
Abramowitz J, Blum R, Dietrich A, Freichel M, Flockerzi V etal
(2008) TRPC3 channels are required for synaptic transmission and
motor coordination. Neuron 59:392–398
Hensbroek RA, Ruigrok TJ, van Beugen BJ, Maruta J, Simpson JI
(2015) Visuo-vestibular information processing by unipolar brush
cells in the rabbit occulus. Cerebellum 14:578–583. https://doi.
org/10.1007/s12311- 015- 0710- 8
Hevner RF, Hodge RD, Daza RA, Englund C (2006) Transcription fac-
tors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Neurosci Res 55:223–233.
https://doi.org/10.1016/j.neures.2006.03.004
Hockeld S (1987) A Mab to a unique cerebellar neuron generated by
immunosuppression and rapid immunization. Science 237:67–70.
https://doi.org/10.1126/science.3603010
Jaarsma D, Wenthold RJ, Mugnaini E (1995) Glutamate receptor subunits
at mossy ber-unipolar brush cell synapses: light and electron microscopic immunocytochemical study in cerebellar cortex of rat and cat.
J Comp Neurol 357:145–160. https://doi.org/10.1002/cne.903570113
Jaarsma D, Dino MR, Cozzari C, Mugnaini E (1996) Cerebellar choline
acetyltransferase positive mossy bres and their granule and unipolar brush cell targets: a model for central cholinergic nicotinic neurotransmission. J Neurocytol 25:829–842. https://doi.org/10.1007/
BF02284845
Jaarsma D, Diño MR, Ohishi H, Shigemoto R, Mugnaini E (1998)
Metabotropic glutamate receptors are associated with non- synaptic
appendages of unipolar brush cells in rat cerebellar cortex and
cochlear nuclear complex. J Neurocytol 27:303–327. https://doi.org
/10.1023/a:1006982023657
Jaarsma D, Blot FGC, Wu B, Venkatesan S, Voogd J, Meijer D, Ruigrok
TJH, Gao Z, Schonewille M, De Zeeuw CI (2018) The basal interstitial nucleus (BIN) of the cerebellum provides diffuse ascending
inhibitory input to the occular granule cell layer. J Comp Neurol
526:2231–2256. https://doi.org/10.1002/cne.24479
Kalinichenko SG, Pushchin II (2008) Calcium-binding proteins in
the cerebellar cortex of the bottlenose dolphin and harbour porpoise. J Chem Neuroanat 35:364–370. https://doi.org/10.1016/j.
jchemneu.2008.03.003
Kennedy A, Wayne G, Kaifosh P, Alvina K, Abbott LF, Sawtell NB
(2014) A temporal basis for predicting the sensory consequences
of motor commands in an electric sh. Nat Neurosci 17:416–422.
https://doi.org/10.1038/nn.3650
Kim JA, Sekerkova G, Mugnaini E, Martina M (2012)
Electrophysiological, morphological, and topological properties of
two histochemically distinct subpopulations of cerebellar unipolar
brush cells. Cerebellum 11:1012–1025. https://doi.org/10.1007/
s12311- 012- 0380- 8
Kinney GA, Overstreet LS, Slater NT (1997) Prolonged physiological
entrapment of glutamate in the synaptic cleft of cerebellar unipolar
brush cells. J Neurophysiol 78:1320–1333. https://doi.org/10.1152/
jn.1997.78.3.1320
Соседние файлы в папке Библиотека им академика М.И. Перельмана