Astrocyte reactivation in medial prefrontal cortex contributes to obesity-promoted depressive-like behaviors

Abstract

Background Little is known about how the obesogenic environment influences emotional states associated with glial responses and neuronal function. Here, we investigated glial reactivation and neuronal electrophysiological properties in emotion-related brain regions of high-fat diet (HFD) and ob/ob mice under chronic stress. Methods The glial reactivation and neuronal activities in emotion-related brain regions were analyzed among normal diet mice (ND), HFD mice, wild-type mice, and ob/ob mice. To further activate or inhibit astrocytes in medial prefrontal cortex (mPFC), we injected astrocytes specific Gq-AAV or Gi-AAV into mPFC and ongoing treated mice with CNO. Results The results showed that obesogenic factors per se had no significant effect on neuronal activities in emotion-related brain regions, or on behavioral performance. However, exposure to a chronic stressor profoundly reduced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and spontaneous excitatory postsynaptic currents (sEPSCs) in the mPFC; depressive-like behaviors were seen, accompanied by significant upregulation of astrocyte reactivation. We identified resilient and susceptible mice among chronic social defeat stress-exposed HFD mice. As expected, astrocyte reactivity was upregulated, while neuronal activity was depressed, in the mPFC of susceptible compared to resilient mice. Furthermore, activating astrocytes resulted in similar levels of neuronal activity and depressive-like behaviors between resilient and susceptible mice. Additionally, inhibiting astrocyte reactivation in the mPFC of HFD mice upregulated neuronal activities and inhibited depressive-like behaviors. Conclusions These observations indicate that obesogenic factors increase the risk of depression, and improve our understanding of the pathological relationship between obesity and depression. Graphical Abstract

Astrocytic Regulation of Endocannabinoid-Dependent Synaptic Plasticity in the Dorsolateral Striatum

“…In addition, the capacity to activate or deactivate astrocytes via G-protein-coupled receptors have also been questioned [ 45 , 46 ]. However, while the activation of both astrocytic Gi- and Gq-coupled receptors may increase intracellular [Ca 2+ ] i in astrocytes, the downstream signaling pathways, including phospholipase C and protein kinase A, still appear to be sufficient to produce specific and functional outputs [ 65 , 66 , 67 , 68 ].…”

Astrocytes mGluR3 deficiency and inhibition restores depressive-like behaviors in CSDS mice

“…The selection of mice (Supplementary Fig. S1A, S1B), devoid of innate extreme motor and social behaviors, was conducted utilizing speci c criteria 21 , including a social interaction (SI) test score ranging from 0.2 to 2, time spent in the center (TIC) during the open eld test (OFT) exceeding 20 seconds, time spent in the open arms (TIO) of the elevated plus maze (EPM) exceeding 20 seconds, immobility time (IT) during the tail suspension test (TST) exceeding 20 seconds, and IT during the forced swim test (FST) exceeding 20 seconds. Subsequently, CSDS was administered to the selected cohort (27 control mice and 30 experimental mice).…”

Obesity-Induced Brain Neuroinflammatory and Mitochondrial Changes

“…Subjects with obesity have high circulating proinflammatory adipocytokines that trigger chronic inflammation. Systemic low-grade chronic inflammation has been reported to cause neuroinflammation and changes in different brain structures, such as the cerebellum, amygdala, cerebral cortex, and hypothalamus [ 57 , 73 , 74 , 75 ]. Obesity-induced inflammation has been related to changes in the integrity of blood–brain barrier permeability, inducing leukocyte extravasation, along with the potential entry of pathogens and toxins into the central nervous system, which, in turn, stimulate more inflammatory responses in a vicious cycle [ 57 ].…”