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