Introduction
The striatum is the central part of the basal ganglia that integrates
and processes information from the cortex, the hippocampus, the
substantia nigra, and the thalamus (Lanciego et al. , 2012; Haber,
2016). While functions of the ventral striatum are associated with the
reward system, reinforcement, and emotions, the dorsal striatum
(neostriatum) composed of the caudate nucleus and the putamen mainly
participates in motor control and operational learning (Lanciegoet al. , 2012; Haber, 2016). Communication of the striatum with
other brain regions is mediated by spiny projection neurons (SPNs),
GABAergic striatofugal cells, which are traditionally divided into the
two populations (Kreitzer, 2009). In the dorsal striatum, activation of
SPNs induces direct (striatonigral) pathway of the basal ganglia that
stimulates the motor cortex and promotes initiation of movements (Bateupet al. , 2010; Wall et al. , 2013). Cells of the second
population initiate indirect (striatopallidal) pathway suppressing the
activity of the motor cortex and locomotion (Bateup et al. , 2010;
Wall et al. , 2013).
Proper activity of the striatal SPNs, in turn, is maintained by dopamine
provided by neurons of the substantia nigra pars compacta (SNc) (Gantzet al. , 2018). According to the classical concept, bursts of
nigrostriatal dopamine differentially stimulate SPNs of direct pathway
and inhibit SPNs of indirect one facilitating activation of the direct
circuits and suppressing indirect ones (Kreitzer, 2009; Lanciegoet al. , 2012). Low dopamine signaling, in opposite, results in
predominance of indirect pathway (Duty & Jenner, 2011). Thus, dopamine
coordinates the work of stimulating and suppressing circuits and
provides optimal level of striatal activation necessary for maintaining
locomotor activity according to the currents needs. Plenty of data
indicate that physical activity is promoted by enhanced metabolism of
dopamine and its massive release in synapses between dopaminergic
neurons of SNc and striatal SPNs (Korchounov et al. , 2010;
Gepshtein et al. , 2014). At the same time insufficient dopamine
signaling in the dorsal striatum can be associated with motor disorders,
including akinesia, bradykinesia, tremor, changed muscle tone, and
postural abnormalities (inability to maintain equilibrium under dynamic
or static conditions), observed in patients with Parkinson’s disease and
in corresponding animal models (Duty & Jenner, 2011; Palakurthi &
Burugupally, 2019).
It is well-known that microgravity, the main negative factor of
spaceflights, strongly impairs locomotor function provoking such
disorders as impaired gait, postural instability, and changes in muscle
tone (Reschke et al. , 1998; Lacquaniti et al. , 2017; Tayset al. , 2021). Similar alterations were observed in ground-based
conditions with volunteers which experienced antiorthostatic hypokinesia
(head-down bed rest) (Parry & Puthucheary, 2015) and in experimental
animals exposed to hindlimb unloading (HU) (Canu et al. , 2007).
The hindlimb unloading (HU) model is a widely used approach to simulate
microgravity in ground-based animal studies. It effectively reproduces
such negative effects of spaceflights as removal of the support loading
from the hindlimbs, cerebrospinal fluid shift, and degeneration in bones
and muscles (Morey-Holton & Globus, 2002; Globus & Morey-Holton,
2016).
Furthermore, investigation of experimental animals revealed that real
microgravity significantly affects dopaminergic system of the brain
(Popova et al. , 2015, 2020; Tsybko et al. , 2015). Thus,
30-day spaceflight induced a considerable reduction in mRNA of proteins
responsible for dopamine synthesis (tyrosine hydroxylase, TH),
degradation (catechol-O-methyltransferase, monoamine oxidases), and
postsynaptic effects (dopamine receptors) in the nigrostriatal system
(Popova et al. , 2015). In addition, studies revealed reduced
nigrostriatal expression of neurotrophins GDNF (glial cell-line derived
nervous factor) and CDNF (cerebral dopamine neurotrophic factor) which
are necessary for optimal functioning of dopaminergic neurons (Tsybkoet al. , 2015). However, available data concern only long-term
effect of microgravity, while the main processes of adaptation are
expected to occur during a shorter period of exposure. In addition,
these data are associated mainly with analysis of mRNA which does not
always fully correlate with protein amount and activity (Popova et
al. , 2020). Thus, further investigations are needed to disclose
detailed mechanisms of altered dopaminergic regulation in the brain
under pathological and extremal conditions associated with restricted
motility, loss of sensorimotor stimuli, and muscle disuse.
Ground-based animal studies could provide more information about
detailed mechanisms of dysregulation in the dopaminergic system of the
brain. However, the studies showed that in rodents the effect of 30-day
HU on the dopaminergic system considerably differed from those of actual
spaceflight (Kulikova et al. , 2017). Expression of some crucial
markers affected by the real microgravity (TH, GDNF, CDNF) showed no
changes in response to HU, while others, such as dopamine receptors D1
(D1R), demonstrated the opposite alterations. These data confirmed that
HU model could not be considered as universal approach to study the
physiological effects of microgravity (Kulikova et al. , 2017).
Nevertheless, it is still can be perspective to investigate various
alterations induced by ground-based pathological conditions such as
inactivity, bed rest, and immobilization (Globus & Morey-Holton, 2016).
Social isolation (SI) is another factor that can produce a number of
negative physiological outcomes including chronic stress, motor decline,
and cognitive disorders (Arzate-Mejía et al. , 2020; Vitale &
Smith, 2022). For example, it was shown that in elderly people,
loneliness was associated with more rapid rate of motor decline
manifesting as decrease in muscle strength, walking speed, and physical
performance (Buchman et al. , 2010; Philip et al. , 2020).
Animal models of SI also revealed dysregulation of dopamine signaling,
however, main changes were observed in the ventral striatum (Benderskyet al. , 2021; Zhang et al. , 2021; McWain et al. ,
2022), while alterations the nigrostriatal dopaminergic system still
remain unclear.
On the other hand, SI is the important factor that should be mentioned
both in spaceflight and ground-based experiments. Experimental data
indicated that isolation contributed to negative effects of
gravitational unloading including violations in the musculoskeletal
apparatus and locomotor activity (Morey-Holton et al. , 2000;
Tsvirkun et al. , 2012; Tahimic et al. , 2019). Thus,
studying combined effects of SI and HU on the brain systems responsible
for locomotor control is also of considerable interest.
The aim of the present work was to analyze the effect of short-term
(3-day) HU and SI on the dopaminergic regulation of the dorsal striatum
in mice. Obtained results showed that HU negatively affected dopamine
biosynthesis and dopamine-mediated signaling in the nigrostriatal system
indicating a decrease in dopaminergic neurotransmission. Contribution of
SI into effects of HU was also revealed.