Gravity and neuronal adaptation, in vitro and in vivo—from neuronal cells up to neuromuscular responses: a first model
Gravity and neuronal adaptation, in vitro and in vivo-from neuronal cells up to neuromuscular responses: a first model
Florian P. M. Kohn 0 1
Ramona Ritzmann 0 1
0 Institute of Sport and Sport Science, University of Freiburg , Freiburg , Germany
1 Department of Membrane Physiology (230b), Institute of Physiology (230), University of Hohenheim , Garbenstr. 30, 70599 Stuttgart , Germany
2 Florian P. M. Kohn
For decades it has been shown that acute changes in gravity have an effect on neuronal systems of human and animals on different levels, from the molecular level to the whole nervous system. The functional properties and gravity-dependent adaptations of these system levels have been investigated with no or barely any interconnection. This review summarizes the gravity-dependent adaptation processes in human and animal organisms from the in vitro cellular level with its biophysical properties to the in vivo motor responses and underlying sensorimotor functions of human subjects. Subsequently, a first model for short-term adaptation of neuronal transmission is presented and discussed for the first time, which integrates the responses of the different levels of organization to changes in gravity.
Microgravity; Hypergravity; Neuronal system; Adaptation; Sensorimotor function; Membrane properties; Electrophysiology
Introduction
Of the four fundamental interactions (strong interaction,
weak interaction, electromagnetic force, and gravity),
gravity is the weakest. Nevertheless, gravity is responsible for
the formation of stars and planets as the sun or earth
(Montmerle et al. 2006)
. During the development of life, many
properties on earth changed such as solar irradiation,
temperature, humidity, etc., but the gravity field remained
constant since the final stages of planet formation. Therefore,
since millions of years, earth life developed and adapted to
these persistent 1-g conditions.
This permanent gravity stimulus led to various
gravityperceiving systems in organisms that influence, i.e.,
movement and behavior or growth on earth. Gravity dependencies
have been described on the molecular, cellular, and complex
structural level of organisms: thereby, one of the most
intensively researched systems in humans and animals is the
nervous system (NS) that is—beside others—crucial for
movement control, sensory integration, and terrestrial locomotion
of earth species. The NS governs muscle contraction enabling
the body to counteract the gravitational force as a physical
impact and controlling typical body motion and locomotor
patterns as during the evolutionary shift from aqueous to
terrestrial life. The NS consists of interconnected neurons and
supporting glial cells. Neuronal communication is based
on electrochemical coupling, the modulation of intra- and
extracellular ions to modify the electrical properties of a cell
(intracellular signaling), and the controlled release of
transmitters (intercellular communication). On the complex level,
one of the most fundamental circuitries within the CNS is the
reflex arch
(Ritzmann et al. 2016)
. Spinal reflexes are simple
neuromuscular reactions in response to a stimulus providing
fast muscle contractions occurring with a delayed magnitude
proportional to the sensory input integrated into movement.
Allowing mobility of terrestrial life, sensory input from the
vestibular and visual systems and proprioception is processed
by the NS and by means of muscle innervation, appropriate
forces are generated to control simple posture or movement
(Margaria and Cavagna 1964; Layne et al. 2001; Ritzmann
et al. 2015; Bloomberg et al. 1999; Homick and Reschke
1977; Paloski et al. 1993)
. Life is based on these
sensorimotor competencies.
Decades of space research made gravity-induced
changes in the NS apparent, and since the first manned
space missions, the effect of microgravity on humans has
been investigated, as various effects on astronauts and
cosmonauts have been observed. With an emphasis on
weightlessness and our astronomical neighbors Mars and the
moon
(Margaria and Cavagna 1964; Spudis 1992)
, authors
found directly related health effects, among others a
persistent modulation in the sensory
(Paloski et al. 1993; Reschke
et al. 1986)
and motor system
(Blottner and Salanova 2015)
and the resulting structural loss of muscle
(Di Prampero
and Narici 2003)
and bone mass
(Loomer 2001)
. In
addition, there are modulations in the neuromuscular system
underlying those health-related changes that open up a lot
of questions on how gravity, and the absence of it,
influences the NS. These questions led to numerous experiments
to investigate the effect of varying gravity conditions on the
different levels of organization, from the molecular and
cellular level up to the whole NS and the interconnection with
movement control and mobility. The functional properties
of these levels were thoroughly investigated, however, with
barely any interconnection.
The aim of this review is to give an overview of the
acute gravity-dependent adaptations of the NS of humans
and animals from the molecular level up to the
sensorimotor systems and to present and discuss a first model of
neuronal short-term adaptation that takes into account the
findings on the different levels of organization. This has been
done on the basis of in vitro and in vivo studies executed
in varying gravity environments. Consequences and
prospects for space missions and countermeasure applications
were integrated. Regarding the gravity-dependency on a
functional level of human organisms, beside direct motor
responses of single nerves, the monosynaptic reflex arc
(Crone et al. 1990; Zehr 2002)
have been selected for a
functional description with focuses on afferent and
efferent pathways. Even though many ongoing experiments are
focusing on the human brain (e.g., the NEUROMapping
program from NASA), the brain and its sub-compartments
have been excluded from the analysis as the interpretation
of the different studies is quite challenging and should be
addressed separately.
Methods
Literature search
We performed a computerized systematic literature search
in PubMed and Web of Knowledge from January 1950 up
to February 2016. Keywords were included in our final
Boolean search strategy as follows: ‘space’ OR ‘parabolic
flight’ OR ‘rocket’ OR ‘drop tower’ AND ‘neuro’ PR
‘neuron’ OR ‘ion channel’ OR “action potential” OR
‘sensorimotor’ OR ‘reflex’ OR ‘latency’ OR ‘neuromuscular’. The
search was limited to English and German languages, cells
and human species, and to full-text original articles, books,
and conference abstracts. We scanned each article’s
reference list in an effort to identify additional suitable studies
for inclusion in the database.
Selection criteria
To be eligible for inclusion, studies had to meet the
following criteria: experiments had to be executed in real
microgravity conditions in either space missions (MIR, ISS, or
Shuttle), parabolic flights, sounding rockets, or drop tower.
Studies were excluded if experiments were performed in
simulation studies (random positioning machine, clinostat,
bed rest, immobilization, water immersion, and partial
weight bearing) under the influence of gravitational
acceleration due to confounding side effects.
Inclusion criteria for cell biology were as follows: (1)
clear experiment design (2), related to (3) neuronal and (4)
neuromuscular effects, and (5) related molecular analyses.
Human life science studies had to meet the following
criteria: (1) controlled study design related to (2)
neuromuscular effects executed in (3) participants had to be
healthy with an age range of 18–70 years.
Coding of studies
Each study was coded for the following variables for cell
physiology: setting (parabolic flight, sounding rocket, space
flight) gravity conditions (hypo, normal, hyper), neuronal
properties (action potential, resting potential), ion channels
(open state, closed state, conductivity), biophysical
properties, membrane properties.
The following variables have been selected for human
life science studies: type of study (cross-sectional,
longitudinal), setting (parabolic flight, space flight), gravity
conditions (hypo, normal hyper), nerve (sensory, motor, sensory
motor interconnection).
Results
In vitro experiments
Due to the complexity of the experiments, most of the
experiments have been performed on short-term gravity
research platforms like the parabolic flight missions or drop
towers.
Goldermann and
Hanke (2001)
Kohn (2012)
A summarizing table of the used literature is given at the
end of the in vitro chapter (Table 1).
Membrane parameters
Subcellular parameters
Ion channel parameters
Up to now, all experiments investigating ion channel
parameters like open and closed state probability have been
performed with ion channels or pore forming peptides that
were reconstituted into artificial planar lipid bilayers.
It was shown that a porin channel from Escherichia coli
has a clear gravity dependence
(Goldermann and Hanke
2001)
. Under microgravity conditions, the mean open state
is significantly decreased; at increased gravity conditions,
the mean open state is increased. This effect is also fully
reversible. The conductance of this porin channel was not
affected significantly.
A second model system used is alamethicin, a
poreforming peptide from Trichoderma viride. Similar to the E.
coli porins, the activity of alamethicin is increased towards
higher gravity (>1 g) and is decreased towards
microgravity
(Klinke et al. 2000; Wiedemann et al. 2003)
.
Biological cell membranes are complex structures and are
mainly composed of lipids and proteins
(Pollard and
Earnshaw 2008)
. In neurons, the functional changes to modify
the membrane potential are usually attributed to the
integrated membrane proteins, the ion channels and ion pumps.
Nevertheless, it is well established that parameters of the
lipid matrix are directly modifying the function of proteins
(Lee 2004)
. For the sensorimotor system, i.e., it has been
shown that the closed state probability of nicotinic
acetylcholine receptor channels increased towards an amplified
membrane viscosity
(Zanello et al. 1996)
.
As single neuronal cells do not have a specific
gravity-sensing structure, a logical experiment is to monitor
membrane properties under conditions of variable
gravity. Experiments with an adapted 96-well plate reader have
been performed and it was shown that membrane viscosity
clearly shows a gravity dependence. Under microgravity
conditions, membrane viscosity is significantly decreased
(the membrane is getting more fluid), under conditions of
1.8 g, the viscosity is significantly increased (the fluidity is
decreased). Membrane viscosity of artificial asolectin
vesicles and of human SH-SY5Y cells have been investigated
and both samples show a similar gravity dependence, but
in a different distinctness
(Sieber et al. 2014)
. It is assumed
that the cytoskeleton or lipid composition might explain the
difference in the gravity-dependent changes of membrane
viscosity, but this has to be verified in future experiments.
This finding potentially has a huge impact on cellular
experiments, as this effect might be a basic mechanism of
how single cells detect changes in gravity, without having
dedicated sensory structures.
Cellular parameters
The electrophysiological properties of various cell types
have been investigated with different methods.
It was shown that the resting potential of human
neuronal cells is slightly depolarized by 3 mV under
microgravity and slightly hyperpolarized under hypergravity
conditions
(Kohn 2012)
.
A similar depolarization under microgravity was
observed in SF-21 cells
(Wiedemann et al. 2011)
.
Electrophysiological experiments with oocytes from Xenopus
laevis also show a significant decrease in transmembrane
current at a holding potential of −100 mV during microgravity
and show a trend of increased transmembrane currents at
hypergravity
(Schaffhauser et al. 2011)
.
The changes in electrophysiological properties are very
fast and reversible, they change within milliseconds as soon
as the gravity is changed and return to normal when gravity
returns to 1 g.
Action potentials
Two parameters of action potentials (AP) were analyzed. In
spontaneous spiking leech neurons, it was shown that the
rate of action potentials is increased under microgravity
(Meissner and Hanke 2005)
.
To monitor the propagation velocity of action potentials,
intact earthworms, isolated earthworm, and rat axons have
been used. All three systems show a similar, with
varying degree of significance, decrease in AP velocity under
microgravity and an increase in AP velocity at
hypergravity. Similar to the cellular and subcellular level, the changes
are very fast and reversible.
Summary 1: in vitro experiments
In vivo experiments
Based on the knowledge that molecular and cellular
properties in neurons are modulated by gravity, complex life
science studies were conducted to describe gravity-induced
neuroplasticity in humans using micro- and hypergravity
research platforms in parabolic flight campaigns or during
long-term space missions with a duration of 10 days up to
1.5 years in human subjects. Stimulation techniques such
as peripheral nerve stimulation (PNS) have been applied
in order to gather a deeper understanding of
microgravity-induced deconditioning in motor control
(Crone et al.
1990; Zehr 2002)
. In those methodological approaches
neurons, axons or cell bodies are depolarized and muscle
membrane potentials serve for the interpretation of output
signals. The nerve tibialis posterior and muscle soleus have
been used in terms of a model to describe overall
adaptation to micro-, hypo-, or hypergravity in most experiments.
Changes in characteristics of neuromuscular responses,
displayed as H-reflexes have been described according to their
attributes related to timing and shaping (Ritzmann et al.
2016): stimulation threshold, amplitude neuromuscular
latency, and inter peak interval. A summarizing table of the
used literature is given at the end of this chapter (Table 2).
Threshold
Changes in threshold levels to depolarize an axon or
nervous cell body describes the responsiveness of a nerve to the
input stimulus. Threshold data exist for short-term
microand hypergravity. Higher stimulation currents were
necessary for PNS to depolarize axons of efferent and
afferent neurons in gravity conditions equal to the moon and
Mars corresponding to 0.16 and 0.38 g, respectively. In
hypergravity, smaller stimulation currents were necessary
to depolarize the axons
(Ritzmann et al. 2016)
. Thus, in
microgravity the threshold is increased; in hypergravity the
threshold is decreased.
Amplitude
The amplitude describes the output signal after peripheral
nerve stimulation. Gravity dependency has been reported
in cross-sectional study designs with neuroplastic changes
for amplitudes of H-reflexes and stretch reflexes
(Ritzmann
et al. 2015; Sato et al. 2001; Miyoshi et al. 2003; Nomura
et al. 2001; Ohira et al. 2002; Kramer et al. 2013)
.
Independently of stimulation methodology, the peak-to-peak
amplitudes and integrals increased when acutely exposed to
hypergravity in parabolic flight maneuvers
(Ritzmann et al.
2015; Miyoshi et al. 2003)
.
For reduced-gravity conditions, study results are
equivocal: lunar and Martian gravity studies revealed a
gradual decrease in peak-to-peak amplitudes of Hmax with
decreasing gravitation
(Ritzmann et al. 2016)
. However,
microgravity caused either an increase in H-reflex
amplitude
(Sato et al. 2001; Miyoshi et al. 2003; Nomura et al.
2001; Ohira et al. 2002)
or revealed no changes
(Ritzmann et al. 2015; Kramer et al. 2013)
. An ISS experiment
executed by Watt (2003) in weightlessness documented
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a decline of H-reflexes in space. These adaptations
persisted during 5 months of weightlessness upon returning
to earth and recovered the days after.
Threshold adaptations most probably caused the
inhomogeneous findings observable in H-reflex
amplitudes due to differences in methodology
(Ritzmann et al.
2016)
. As M-wave and H-reflex amplitudes depend on the
stimulation threshold, the increase in H-reflex amplitudes
should be interpreted on the basis of threshold declines
in microgravity when H-reflexes are recorded with a
constant stimulation intensity
(Sato et al. 2001; Miyoshi
et al. 2003; Nomura et al. 2001; Ohira et al. 2002)
. While
H/M recruitment curves are independent of the
stimulation threshold
(Ritzmann et al. 2015; Kramer et al. 2013)
,
gravity-induced changes in H-reflexes elicited
submaximally with a constant stimulation threshold result rather
from threshold shifts than gravity changes
(Sato et al.
2001; Miyoshi et al. 2003; Nomura et al. 2001; Ohira
et al. 2002)
.
Neuromuscular latency
Neuromuscular latency describes the axonal and/or
nerve conduction velocity until a muscle response is
observable in the electromyogram. Various experiments
investigated the latency of the H-reflex and M-wave
in the Soleus muscle in settings of short-
(Ohira et al.
2002; Ritzmann et al. 2016)
and long-term (Ruegg
et al. 2003) varying gravity with equivocal findings:
with gradually decreasing gravity from hyper- to earth
to Martian to lunar gravity, Ritzmann et al.
demonstrated in eight subjects an increase in latencies of
H-reflexes while M-wave latencies likewise showed a
strong tendency to increase towards microgravity
(Ritzmann et al. 2016)
. In contrast, exposure to micro- or
hypergravity showed no short-term effects in H-reflex
and M-wave latencies in experiments executed by Ohira
et al.
(Ohira et al. 2002)
. The authors did not state the
sample size.
Inter‑peak‑interval (IPI)
The IPI between the negative and positive maxima of
the biphasic amplitude describes the conduction
velocity along the muscle fibers via the motor endplates at the
neuromuscular junction where the nerve interconnects
with the muscle. Short-term experiments executed in
parabolic flights revealed that IPIs significantly increase
for the biphasic m. Soleus Mmax and Hmax with decreasing
gravitation from hyper- to earth to Martian to lunar
gravity conditions
(Ritzmann et al. 2016)
.
Summary 2: in vivo experiments
A first model of neuronal short‑term adaptation to microgravity
The proposed model aims to integrate the results from
the cellular level up to the neuromuscular interface. To
exclude possible adaptation processes, it only contains
data from short-term experiments.
Molecular level
On the molecular level, gravity has an effect on both
the membrane and integrated functional membrane
proteins including ion channels. Under microgravity
conditions, the membrane viscosity is decreased (the fluidity is
increased). This changed membrane viscosity decreases
the open-state probability of ion channels (Fig. 1). At
hypergravity, these effects are inversed: membrane
viscosity increases and the open-state probability increases.
Non-space related biophysical experiments clearly show
that ion channel properties are dependent on membrane
parameters such as lateral pressure. For alamethicin, it is
known that the open state of the pore clearly depends on
the lateral pressure of the membrane
(Hanke and Schluhe
1993)
, with increased pressure, the activity increases.
For other ion channels it was also shown that ion channel
parameters are affected by changes in lateral membrane
pressure, e.g., the closed-state probability of nicotinic
acetylcholine receptor channels increases towards increased
membrane viscosity
(Zanello et al. 1996)
.
Resting potential
The resting potential of single cells is depolarized several
millivolts under microgravity and hyperpolarized under
hypergravity. With a slightly increased resting potential,
Fig. 2 The extended model of the cellular gravity dependence of a
single neuronal cell. Due to the changed membrane viscosity and the
changed open-state probability, the cell depolarizes several mV. This
leads to a decreased potential difference between the resting
potential and the AP threshold, therefore action potentials can be triggered
more easily
the threshold to trigger an action potential (AP) can be
reached more easily (Fig. 2). In spontaneously spiking
neurons, this gravity-dependent effect was found. The
rate of APs is increased in microgravity.
Propagation of action potentials
In isolated single axons as well as in living animals and in
human test subjects, the effect of microgravity can clearly
be seen, the propagation speed of APs decreases under
microgravity and increases under hypergravity.
In humans, the properties of neuromuscular reflexes
are affected by microgravity. The latencies are increased,
which can be interpreted as a decreased conduction speed.
The peak-to-peak amplitude of the H-reflex is decreased
under reduced gravity (with heterogenous data at real
microgravity) and a higher stimulus has to be given to get
the same Hmax as in 1 g. The stimulation and recording
method cannot be compared directly to single cell
patchclamp experiments, but the effect might be explained by a
decreased propagation velocity along the axon in
microgravity compared to 1-g conditions: less action potentials
per time stimulate muscle contraction and therefore Hmax is
decreased. This interpretation is supported by the decrease
in IPI under microgravity, which indicates a decreased
signal speed at the neuromuscular junction. All these findings
are also reversed under hypergravity.
The previously described effects can be summarized as a
gravity-dependent decrease in neuronal conduction velocity
(or as an increase in electrical and chemical time constants)
under reduced gravity with an increase under hypergravity.
At first glance, it might look like an inconsistency that
at the same time the rate of action potentials is increased
in microgravity but the propagation velocity of APs is
decreased. In 1977,
Matsumoto and Tasaki (1977)
found a
mathematical equation to calculate the speed of conduction
in unmyelinated nerve fibers, which can be used to estimate
the speed also in myelinated fibers. With this equation, the
apparent inconsistency can be resolved:
vaxon ≈
d
8 · ρC2 · R∗
,
where the vaxon is the conduction velocity, C is the
membrane capacity, d is the diameter of the nerve, R* is the
resistance of the membrane, ρ is the axoplasmic resistance.
According to the proposed model, the resting potential is
increased due to a reduced open-state probability of the ion
channels, therefore the resistance of the membrane (R*) is
increased. If membrane capacity (C), diameter of the axon
(d) and axoplasmic resistance (ρ) are treated as constant in
varying gravity, the increased resistance of the membrane
leads to a decreased conduction velocity (vaxon).
With this proposed model (Fig. 3), the short-term
reaction of the sensorimotor system can be explained without
any inconsistencies from the single neuronal cell up to
the neuromuscular level. But of course, it opens up a lot
of questions and open points, which will be discussed
subsequently.
Discussion
The aim of this review was to sum up and interconnect
relevant publications about the adaptation of neuronal
processes from the molecular to the (sub-) cellular level up to
the complex neuromuscular system. Many separate in vitro
and in vivo experiments on the different levels of the NS
have been performed, each with a discrete result. Until
now, no effort has been made to integrate these findings to
either a working model, and/or to illustrate possible
unresolved discrepancies, aiming for a better understanding of
neuronal adaptation to variable gravity conditions and for a
“roadmap” for future experiments. It is also an appeal for a
more interdisciplinary approach to new experiments and to
unite results of previously acquired data serving as a better
comprehension of the gravity-induced challenges on
organisms during prolonged manned space missions and to face
them.
The presented short-term model interconnects results
of separately working life science disciplines and these
interconnections are based on assumptions, which have to
be verified in future experiments. They are discussed as
follows:
On the cellular level, it is not clear if membrane viscosity
and the open-state probability of ion channels are the only
gravity-sensitive parameters. For instance, the
cytoskeleton of different cells is also affected by changes in gravity
Fig. 3 The final model from subcellular to multicellular level. Due
to the changed membrane viscosity and the changed open-state
probability, the cell depolarizes and the threshold to generate action
potentials is reached more easily, but the AP velocity of the axons
and therefore it is an additional sensor for g-load
(Li et al.
2008)
, but the possible effect of a changed cytoskeleton on
membrane fluidity has not been investigated in detail, yet.
Until now, a model system (based on artificial membrane
vesicles) and neuronal cells have been investigated
separately and the authors showed a gravity-induced difference,
which might be due to the absence of a cytoskeleton in the
artificial vesicles
(Sieber et al. 2014)
. It might also be
possible that the lipid composition plays a role. The artificial
vesicles were made of asolectin but the lipid composition
of real cell membranes is more heterogeneous, depending
on the cell type.
Two models for ion channels have been used to show
the clear gravity dependence of the open-state
probability of ion channels
(Goldermann and Hanke 2001; Klinke
et al. 2000)
, but there is no single channel data for real
(neuronal) ion channels. Although the whole cell
recordings from several research groups indicate that there is
a gravity dependence of ion channels
(Goldermann and
Hanke 2001; Klinke et al. 2000; Schaffhauser et al. 2011;
Richard et al. 2012)
, it is still unclear from the literature
if all ion channel families, e.g., the relevant ion
channel families for AP generation, react similar to changes
in gravity. For the proposed model, this is assumed, but
it still has to be investigated much more systematically.
This has to be done with single-channel
electrophysiology. Despite the challenge of doing this in microgravity,
outside the ground-based laboratory, there are several
promising approaches already indicating ion channel
sensitivity to gravity
(Wiedemann et al. 2011;
Schaffhauser et al. 2011; Richard et al. 2012)
. In addition, the
and the transmission speed at synapses in the motoric end plate are
decreased, which seems to have a bigger impact than the reduced AP
threshold
open-state probability is not the only relevant parameter.
In regards to the completeness of nerve condition
characteristics, e.g., the conductivity of the ion channels has to
be investigated, as there are publications that indicate a
dependence on gravity
(Schaffhauser et al. 2011; Richard
et al. 2012)
.
A detailed analysis of these parameters in the future
would significantly help understanding the gravity
dependence of cellular electrophysiology and ultimately the
multicellular communication as in the neuromuscular system
transferred to complex sensorimotor function. Based on
the existing literature database, it is evident that
molecular and cellular changes in response to gravity mentioned
above affect the sensorimotor system in regard to human
movement.
Immediate adaptations are reported in short-term
experiments as well as in long-term investigations executed on the
ISS or pre-post space flight, respectively. Analysis of motor
and sensory responses regarding their timing and
shaping
(Ritzmann et al. 2015, 2016; Sato et al. 2001; Miyoshi
et al. 2003; Nomura et al. 2001; Ohira et al. 2002; Kramer
et al. 2013; Davey et al. 2004)
demonstrate that NS
function for muscle activation is changed and these changes
most probably rely on molecular dysfunction: when axons
conduct AP more slowly, consequently the motor response
and muscle contraction are delayed
(Ritzmann et al. 2016)
.
Regarding human space flight, this is known to be a
limitation for a safe return to earth as well as stopovers on other
planets: for practical issues such as movement precision
and control required for fall prevention or force generation,
the cellular changes impact space mission safety
(Blottner
and Salanova 2015)
. Likewise, smaller neuromuscular
responses as demonstrated by changes in reflex and motor
response amplitude are associated with a reduction of
muscle force
(Aagaard 2003)
.
Based on gravity-induced changes in frequency
originated on the subcellular level, this is also of considerable
relevance: a reduced muscle response concomitant with a
slowed down reaction negatively impacts motor control in
daily relevant activities, such as in gait, posture control, or
fine motor tasks
(Layne et al. 2001; Bloomberg et al. 1999;
Paloski et al. 1993; Mulavara et al. 2010)
.
This is exactly where security debates and
countermeasure development move into focus: as reported in many
space experiments, astronauts suffer from motor
dysfunction associated with neuromuscular degradations and a
performance decline after their return to earth
(Blottner and
Salanova 2015; Mulavara et al. 2010; Hargens et al. 2012;
Clark and Bacal 2008)
.
Thereby, in cohorts of astronauts and cosmonauts with
stays in space for 10–241 days, a sustaining increase of
amplitudes
(Reschke et al. 1986; Kozlovskaya et al. 1981;
Grigoriev and Yegorov 1990; Baker et al. 1976)
,
neuromuscular latency
(Davey et al. 2004; Ruegg et al. 2003)
,
and IPIs
(Ruegg et al. 2003)
concomitant with decreased
PNS thresholds
(Kozlovskaya et al. 1981; Grigoriev and
Yegorov 1990)
for H-reflexes, stretch and vibration reflexes
after returning to earth could be demonstrated. Importantly,
adaptations persisted beyond weightlessness for up to 2
weeks of earth life after space. As astronauts suffer from
sensorimotor impairments associated with
gravity-dependent changes in the nervous system, which limit the
duration of space-stays (Edgerton et al. 2001), this concern is a
major issue for the space agencies. Achievements of critical
task under variable gravitation conditions depend on
sensorimotor function
(Edgerton et al. 2001)
. They are crucial
for a safe space flight and return to earth.
However, there are limitations to the model that need
to be considered: in vitro studies revealed contradictory
results concerning the amplitude and latency of reflexes.
Due to different methodologies, the outcomes are hardly
comparable and a conclusive statement integrated into our
working model is still speculative. Furthermore, the model
does not take into account possible changes in nerve
geometry, as there are electrophysiological properties as
axoplasmic resistance and other electrical parameters. However, up
to now, there are no experiments that have been performed
focusing on this point, although it might be possible to
investigate this with single cells, nerve fibers, or tissue
samples of animals and humans.
Furthermore, the model only takes into account the
changes of the electrophysiological component of
neuromuscular latency. Of course, the sensorimotor reflex
system has more components than that. Surely the
electrochemical coupling in the neuronal synapses and
the motoric end plate must be taken into account, as the
findings on the IPIs indicate that this chemical
component is also affected by gravity
(Ritzmann et al. 2016)
.
Experiments have to be designed that focus on receptor–
ligand interactions under varying gravity conditions to
clarify the possible gravity dependence of this process, as
it might have a huge impact on neuronal and
neuromuscular communication.
Besides neuroplasticity of the gravity-induced cell
physiology, modulations in neural excitation could also
be causal for the in vivo experimental outcomes. While
cell physiology involves molecular adaptation based on
electrochemical changes of the neural cell body or axon
(Goldermann and Hanke 2001; Sieber et al. 2014; Kohn
2012)
, in contrast the excitability of reflexes and motor
responses rely on a non-persisting phenomenon caused
by spontaneous and task- or environment-specific
inhibition or facilitation of neuronal pathways
(Crone et al.
1990; Zehr 2002; Aagaard 2003)
.
Although an interlink of the observed gravity effects
on the above-mentioned subcellular structures and the
resulting nerve’s level of depolarization with the
timing of reflexes and motor responses is apparent: the less
fluid the membrane and the less open the ion channels
are, the slower the action potentials will be transmitted
via the axon. Hence, the period of the reflex latency, the
duration, and the inter-peak-intervals as they occurred
in reduced gravitation below normal gravity are longer.
Consequently, the overall decrease in timing in micro-,
lunar, and Martian gravity compared to earth and
hypergravity most probably relies on gravity-induced cellular
changes in neurons. Nevertheless, for
gravity-dependent threshold changes and adaptations in amplitude, the
underlying origins are less clear. Besides gravitational
cell physiology as illustrated in the model, modulated
excitations such as pre- and postsynaptic inhibition or
facilitation should be taken into account
(Ritzmann et al.
2015; Zehr 2002; Kohn 2012)
. Modulated proprioceptive
sensory feedback and related central changes in motor
commands descending from brain structures may have
caused an inhibition of spinal reflexes in microgravity
and a facilitation in hypergravity
(Ritzmann et al. 2015;
Davey et al. 2004)
. Vestibular, visual, and somatosensory
input is altered in varying gravity
(Layne et al. 2001;
Homick and Reschke 1977; Paloski et al. 1993;
Bloomberg et al. 1997)
reflected by a highly reduced
vestibulesomatosensory feedback concomitant with a
predominance in vision for microgravity conditions
(Layne et al.
2001; Paloski et al. 1993; Bloomberg et al. 1997)
. This
may also have a large impact on motor commands and
the inhibition or facilitation of Ia afferent pathways. For a
more conclusive statement to clarify the origin of timing
and shaping of reflex adaptations, further experiments are
mandatory.
The prospect of a sustainable overview and proper
understanding of the gravity-dependency of the NS
requires a number of new investigations. A lack of
knowledge can be reduced by interdisciplinarity,
including the gravitational influence on the cytoskeleton and
conductivity of the ion channels of nervous cells as well
as experiments in the motoric end plate. Moreover, novel
approaches including the brain and peripheral circuitries
using electrophysiology with an emphasis on long-term
adaptations have the potential to further clarify if
excitability changes are gravity-dependent and influence motor
control.
In contrast to in vivo data, there is basically no data
for cellular long-term adaptation processes as the
technical and biological requirements for cellular long-term
experiments in microgravity are challenging.
Nevertheless, this topic should be addressed in the future to be
able to extend the short-term adaptation model with the
long-term adaptation mechanisms.
Acknowledgements The research was supported by the German
Aerospace Center (DLR), the European Space Agency (ESA), and
Novespace.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
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