4 Discussion
Several studies on depression have compared PrL and IL based on
differences in cytoarchitecture, function and connectivity(Fullana,
Covelo et al., 2019; Garro-Martinez, Fullana et al., 2021; Liu, Ota et
al., 2015). In this study, we found that ICV-STZ activates IDO in both
PrL and IL, but its regulatory pathways of depressive behaviors in the
PrL and IL are different, with a remarkable attenuation of astrocytes in
the PrL and overactivation of microglia in the IL as shown in Figure 10.
The alteration of Trp levels in the PrL and IL was different, which
hinted at the regional specificity of Kyn pathways between two
subregions. Although the reason is unknown, a possible explanation is
that the up-regulation of Trp levels in the IL was a compensatory
increase induced by neuroinflammation. Furthermore, the increase of
pro-inflammatory cytokines was observed only in the IL but not PrL,
reflecting the neuroinflammatory region specificity in the ICV-STZ
induced depression.
There is substantial evidence of depression emerging from abnormalities
of astrocytes and microglia(Tao, Yan et al., 2020; Yang, Zhou et al.,
2020), and in the central nervous system, glia can respond positively to
neuroinflammation via regulating the kynurenine pathway balance(Dezsi,
Tuka et al., 2015; Garrison, Parrott et al., 2018). Although no
differences were observed in the structural distribution of glial cells
in the PrL and IL(Banqueri, Mendez et al., 2019; Gosselin, Gibney et
al., 2009), they appear to play different roles in the mediation of
depressive-like behaviors(Fullana, Covelo et al., 2019). The present
study illustrated that ICV-STZ induced depressive behavior was
paralleled by astrocytic defects in the PrL and microglia activation in
the IL. In the PrL, astrocytes were shown deficit and dysfunction
characterized by the decrease in astrocyte number, complexity of
branches and levels of GLT-1, GLAST and GFAP, with a concomitant
reduction in the neuroprotective metabolite KA. In the IL, microglia
activation was characterized by increased microglia numbers, Iba1
levels, pro-inflammatory cytokines and neurotoxicity metabolite 3-HK
with shortening of cellular processes and enlargement of the soma. The
level of KA in the IL was also reduced despite there were no astrocyte
deficits, which might be due to Kyn being more metabolized into 3-HK
induced by ICV-STZ. However, we did not observe activation of microglia
in the PrL and defect of astrocytes in the IL in ICV-STZ rats. All these
dysregulations were restored by regional selective inhibition of IDO,
suggesting that the antidepressant effects of 1-MT in the PrL might be
through normalizing astrocyte deficit and dysfunction, while the
antidepressant effects of 1-MT in the IL might be mediated, at least for
a part, by local anti-inflammatory processes.
Studies in human and animals indicated that the central inflammatory
response in depression may be associated with the reduction of total
volume, the shrinkage of dendrites and loss of spines within the
mPFC(Fan, Song et al., 2018; Meier, Drevets et al., 2016). Some studies
have shown that under chronic or acute stress, the dendritic branches of
neurons in the PrL(Moench & Wellman, 2017) and IL(Moench, Maroun et
al., 2016) can be seen retraction. In the present study, the dendritic
spine density and proportion of mushroom type in the PrL and IL were
significantly decreased, and this effect was reversed by local treatment
with 1-MT. The mushroom type was identified as the main type involved in
the regulation of synaptic plasticity because it is more stable and has
larger postsynaptic densities and contact areas than other types(Helm,
Dankovich et al., 2021). Both neuroplasticity and BDNF deficiency in the
PrL and IL suggested an additional mechanism implicated with IDO
activation in ICV-STZ rats and the effects of 1-MT on basal dendrites.
Noteworthy, enhanced thin type and filopodia type proportions
distributed on the dendrites of PrL were observed in ICV-STZ rats, while
in the IL, a larger proportion of stubby type was mainly detected.
Although ICV-STZ differentially altered structural plasticity in the PrL
and IL, these structural alterations were reversed by local treatment
with 1-MT, suggesting that 1-MT ameliorates depressive behaviors
involving the structural remodeling of dendritic spines.
The model of ICV-STZ was highly prevalent and has been used to resemble
sAD in decades(Kalafatakis & Zarros, 2014). Over time, ICV-STZ rats
showed typical pathological changes similar to sAD, such as the
deposition of Aβ and the hyperphosphorylation of Tau in the brain, and
started to develop learning and cognitive impairment on day 14(Song, Cui
et al., 2018). According to our study, although there were no such
pathological changes and learning and memory impairments on day 7,
depressive-like behaviors appeared. Evidence has reported that some
patients with sAD have depression in the early stage, and depression
might be a prodromal symptom of sAD(Burke, Cadet et al., 2018; Gatchel,
2021). Therefore, it is necessary to further study whether this animal
model can simulate the clinical processes of sAD. Although a clear
explanation of the mechanism of sAD formation is still lacking, the
ICV-STZ model might provide a valuable contribution to the field of sAD
model research. Additionally, our data show for the first time that the
regionally selective blockade of IDO by 1-MT within the mPFC, either PrL
or IL, protected rats from ICV-STZ induced depressive behaviors but
failed to produce an anxiolytic effect, suggesting that the anxiety-like
behaviors induced by ICV-STZ might not be due to the IDO activation in
the PrL and IL, which need further confirmation.