Biology subjects

Bielefeld, P.

Publications and source records attributed to Bielefeld, P..

5 recordsLinked to original sources

bioRxiv2023

Cannabinoid type 2 receptor inhibition enhances the antidepressant and proneurogenic effects of physical exercise after chronic stress

Chronic stress is a major risk factor of neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects upon cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophin levels, we hypothesized that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, and an overall reduction in neuroinflammation. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasizes the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalize on lifestyle interventions complemented with endocannabinoid pharmacomodulation.

neuroscience↗

bioRxiv2023

Traumatic brain injury modifies adult hippocampal neural stem cell fate to promote neurogenesis at the cost of astrogliogenesis.

Moderate Traumatic brain injury (TBI) can result in long-lasting changes in brain function. Although frequently spared from the acute primary injury, the hippocampus becomes affected during a secondary phase that takes place hours, or even days, after TBI, contributing to cognitive deficits. The hippocampus is one of the few brain areas in the adult brain harboring native neural stem cells (NSCs) that continue to generate new neurons (neurogenesis), and to a lesser extent new astrocytes (astrogliogenesis). While deregulation of hippocampal NSCs and neurogenesis have been observed after TBI, very little is known about how TBI may affect hippocampal astrogliogenesis. Here, we aimed to assess how TBI affects hippocampal NSCs and their subsequent commitment to the neuronal or astroglial lineages. Using a controlled cortical impact model of TBI, single cell RNA sequencing and spatial transcriptomics, we observed a cell population-specific increase in NSC-derived neuronal cells and a decrease in NSC-derived astrocytic cells. These cellular changes were associated with cell-population specific changes in gene expression and dysplasia within the dentate gyrus. Overall, our findings support the conclusion that TBI modifies adult hippocampal NSC fate to promote neurogenesis at the cost of astrogliogenesis, and highlights specific cell populations as possible targets to counteract the changes induced by TBI in the hippocampus.

neuroscience↗

bioRxiv2022

Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation

The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune-modulation and a delivery system capable of crossing the blood-brain-barrier. The recent identification and characterization of a small population of regulatory T cells (Tregs) resident in the brain presents one such potential therapeutic target. Here we identified brain IL2 levels as a limiting factor for brain-resident Tregs. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially-direct delivery to inflammatory sites. Mice with brain-specific IL2 delivery were protected from traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL2 gene-delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.

immunology↗

bioRxiv2020

The piRNA pathway sustains adult neurogenesis by repressing protein synthesis

Adult Neural progenitor cells (aNPCs) ensure lifelong neurogenesis in the mammalian hippocampus. Proper regulation of aNPC fate entails important implications for brain plasticity and healthy aging. Piwi proteins and the small noncoding RNAs interacting with them (piRNAs) are best known in gonads as repressors of transposons. Here, we show that Piwil2 (Mili) and piRNAs are abundant in aNPCs of the postnatal mouse hippocampus and demonstrate that this pathway is essential for proper neurogenesis. Particularly, depleting the piRNA pathway in aNPCs impaired neurogenesis, increased senescence and accordingly the generation of reactive glia. Moreover, this manipulation primarily elevated 5S ribosomal RNA, SINEB1 and mRNAs encoding ribosomal proteins and regulators of translation, resulting in higher polysome density and protein synthesis upon differentiation. Our results provide evidence of an essential role for the piRNA pathway in maintaining homeostasis to sustain neural stem cell fate, underpinning its possible involvement in brain plasticity and successful aging.

neuroscience↗

bioRxiv2019

Early life stress decreases the proliferation and numbers of adult hypothalamic neural stem cells.

Early life stress (ELS) is a potent environmental factor that can confer enduring effects on brain structure and function. Exposure to stress during early life has been linked to a wide range of physiopathological consequences later in life. In particular, ELS has been shown to have lasting effects on neurogenesis in the adult brain, suggesting that ELS is a significant regulator of adult neural stem cell function. Here, we investigated the effect of ELS on the numbers and proliferation of neural stem cells in the hypothalamus of adult mice. We show that ELS has long term negative effects on hypothalamic neural stem cell numbers and on their proliferation. Specifically, ELS reduced the total numbers of PCNA+ cells present in hypothalamic areas surrounding the 3rd ventricle; the numbers of PCNA+/Sox2+/Nestin-GFP+ cells present in the medial eminence at the base of the 3rd ventricle; and the number of {beta}-tanycytes around the ventral 3rd ventricle, without affecting the numbers of -tanycytes in more dorsal areas. These results suggest that a reduction of proliferation and tanycyte numbers contributes to the effects of ELS on the hypothalamus and its consequent physiological alterations.

neuroscience↗