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Prefrontal cortex astroglia modulate anhedonia-like behavior.

ABSTRACT: Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent chronic stress models. Here, we examine the consequences of PFC GFAP+ cell depletion and cell activity enhancement on depressive-like behaviors in rodents. Using viral expression of diphtheria toxin receptor in PFC GFAP+ cells, which allows experimental depletion of these cells following diphtheria toxin administration, we demonstrated that PFC GFAP+ cell depletion induced anhedonia-like behavior within 2 days and lasting up to 8 days, but no anxiety-like deficits. Conversely, activating PFC GFAP+ cell activity for 3 weeks using designer receptor exclusively activated by designer drugs (DREADDs) reversed chronic restraint stress-induced anhedonia-like deficits, but not anxiety-like deficits. Our results highlight a critical role of cortical astroglia in the development of anhedonia and further support the idea of targeting astroglia for the treatment of depression.

SUBMITTER: Codeluppi SA

PROVIDER: S-EPMC10914619 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Prefrontal cortex astroglia modulate anhedonia-like behavior.

Codeluppi S A SA Xu M M Bansal Y Y Lepack A E AE Duric V V Chow M M Muir J J Bagot R C RC Licznerski P P Wilber S L SL Sanacora G G Sibille E E Duman R S RS Pittenger C C Banasr M M

Molecular psychiatry 20230911 11

Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent chronic stress models. Here, we examine the consequences of PFC GFAP+ cell depletion and cell activity enhancement on depressive-like behaviors in rodents. Using viral expression of diphtheria toxin receptor in PFC GFAP+ cells, which allows experimental depletion of these cells following diphtheria toxin administration, we demon ...[more]

PMID: 37696873

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Project description:BackgroundMajor depressive disorder (MDD) is associated with deficits in cognitive function, thought to be related to underlying decreased hedonic experiences. Further research is needed to fully elucidate the role of functional brain activity in this relationship. In this study, we investigated the neurofunctional correlate of the interplay between cognitive function and hedonic experiences in medication-free MDD using functional near-infrared spectroscopy (fNIRS).MethodsWe examine differences of brain activation corresponding to the verbal fluency test (VFT) between MDD patients and healthy controls (HCs). Fifty-six MDD patients and 35 HCs underwent fMRI scanning while performing the VFT. In exploratory analyses, cognitive performance, as assessed by the Cambridge Neuropsychological Test Automated Battery (CANTAB), four dimensions of hedonic processing (desire, motivation, effort, and consummatory pleasure) measured by the Dimensional Anhedonia Rating Scale (DARS), and relative changes in oxygenated hemoglobin concentration during the VFT were compared across groups.ResultsPatients with MDD demonstrated impairments in sustained attention and working memory, accompanied by lower total and subscale scores on the DARS. Compared to healthy controls, MDD patients exhibited reduced activation in the prefrontal cortex (PFC) during the VFT task (t = 2.32 to 4.77, p < 0.001 to 0.02, FDR corrected). DARS motivation, desire, and total scores as well as sustained attention, were positively correlated with activation in the dorsolateral PFC and Broca's area (p < 0.05, FDR corrected).ConclusionsThese findings indicate that changes in prefrontal lobe oxygenated hemoglobin levels, a region implicated in hedonic motivation and cognitive function, may serve as potential biomarkers for interventions targeting individuals with MDD. Our results corroborate the clinical consensus that the prefrontal cortex is a primary target for non-invasive neuromodulatory treatments for depression.

Project description:Cocaine affects both cerebral blood vessels and neuronal activity in brain. Cocaine can also disrupt astrocytes, which modulate neurovascular coupling-a process that regulates cerebral hemodynamics in response to neuronal activation. However, separating neuronal and astrocytic effects from cocaine's direct vasoactive effects has been challenging, partially due to limitations of neuroimaging techniques able to differentiate vascular from neuronal and glial effects at high temporal and spatial resolutions. Here, we used a newly-developed multi-channel fluorescence and optical coherence Doppler microscope (fl-ODM) that allows for simultaneous measurements of neuronal and astrocytic activities (reflected by the intracellular calcium changes in neurons Ca2+N and astrocytes Ca2+A, respectively) alongside their vascular interactions in vivo to address this challenge. Using green and red genetically-encoded Ca2+ indicators differentially expressed in astrocytes and neurons, fl-ODM enabled concomitant imaging of large-scale astrocytic and neuronal Ca2+ fluorescence and 3D cerebral blood flow velocity (CBFv) in vascular networks in the mouse cortex. We assessed cocaine's effects in the prefrontal cortex (PFC) and found that the CBFv changes triggered by cocaine were temporally correlated with astrocytic Ca2+A activity. Chemogenetic inhibition of astrocytes during the baseline state resulted in blood vessel dilation and CBFv increases but did not affect neuronal activity, suggesting modulation of spontaneous blood vessel's vascular tone by astrocytes. Chemogenetic inhibition of astrocytes during a cocaine challenge prevented its vasoconstricting effects alongside the CBFv decreases, but it also attenuated the neuronal Ca2+N increases triggered by cocaine. These results document a role of astrocytes both in regulating vascular tone and consequently blood flow, at baseline and for modulating the vasoconstricting and neuronal activation responses to cocaine in the PFC. Strategies to inhibit astrocytic activity could offer promise for ameliorating vascular and neuronal toxicity from cocaine misuse.

Dataset Information

Prefrontal cortex astroglia modulate anhedonia-like behavior.

Publications

Prefrontal cortex astroglia modulate anhedonia-like behavior.

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