1 Introduction:
The prefrontal cortex (PFC), a critical brain region in the neural
circuitry of stress and emotion regulation, undergoes severe
pathological changes in psychiatric disorders(Carlen, 2017; Souza, Jesse
et al., 2016). The prelimbic cortex (PrL) and infralimbic cortex (IL)
are two major medial PFC (mPFC) areas in rodents thought to mediate the
control of depressive behaviors(Wellman, Bollinger et al., 2020).
Although the PrL and IL have similar projection patterns in certain
aspects, a growing body of research has revealed that they are
functionally distinguished in mediation of a variety of physiological
and behavior processes in rodents, including fear expression and
extinction(Sierra-Mercado, Padilla-Coreano et al., 2011),
cocaine-seeking(Shin, Templeton et al., 2018) and anxiety(Suzuki, Saitoh
et al., 2016). Fullana et al. demonstrated that the depressive-like
phenotype may be associated with IL hyperactivity, likely leading to an
excessive top-down inhibitory control of serotonergic activity through
IL-midbrain descending pathways(Fullana, Covelo et al., 2019). However,
the regional specificity of PrL and IL in the regulation of depressive
behaviors remains poorly understood.
Proinflammatory cytokines, including interleukin-6 (IL-6) and
interleukin-1beta (IL-1β), secreted by glial cells within the brain in
response to injury and infection, impair the 5-HT system through
activation of indoleamine-2,3-dioxygenase (IDO), the rate-limiting
enzyme catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn)
along the Kyn pathway(Garrison, Parrott et al., 2018). Consecutively,
intermediates of Kyn are metabolized into kynurenic acid (KA) with
neuroprotective effects mainly in astrocytes, while Kyn is metabolized
into 3-hydroxy-kynurenine (3-HK) and quinolinic acid in microglia
induces excitotoxic effects. Yet, it is unclear that the role of
IDO-related glial alterations in the regulation of mood disorders.
Kyn and several downstream metabolites have been proposed to be highly
correlated with depression(Deng, Zhou et al., 2021; Hestad, Alexander et
al., 2022). Further evidence speculated that the homeostasis imbalance
of downstream metabolites regulated by microglia and astrocytes might be
the prominent mechanism of depressive behaviors after IDO activation
induced by LPS(Tao, Yan et al., 2020). Intracerebroventricular injection
of streptozotocin (ICV-STZ) triggered progressive mood and cognitive
impairments by causing Aβ-Tau pathology, oxidative stress, insulin
resistance and immune-inflammatory responses in the cerebral cortex and
hippocampus of rats(Akhtar, Dhaliwal et al., 2021; Grieb, 2016). Souza
et al. reported that ICV-STZ can induce up-regulation of
pro-inflammatory cytokines and down-regulation of brain-derived
neurotrophic factor (BDNF) in the hippocampus of mice at the early stage
of the formation of a sporadic Alzheimer’s disease (sAD) model(Souza,
Filho et al., 2013; Souza, Jesse et al., 2017), and subcutaneous
administration of IDO inhibitor 1-MT improved depressive behaviors in
ICV-STZ mice(Souza, Jesse et al., 2017). However, its mechanism in the
central nervous system, especially in subdivided brain regions, has not
been studied.
Therefore, this study aimed to investigate whether there are differences
in the regulatory mechanisms caused by ICV-STZ activation of IDO in the
PrL and IL of rats. For this purpose, we evaluated the effects of
ICV-STZ on the Kyn pathway, microglia, astrocytes and synaptic
plasticity in the PrL and IL. In addition, 1-MT was directly injected
into the PrL and IL respectively, to study its antidepressant effect and
its influence on the above pathological mechanisms.
2 Method :