Biology subjects

Just, N.

Publications and source records attributed to Just, N..

5 recordsLinked to original sources

bioRxiv2026

Dissociation between hemodynamic and neurochemical responses during chemogenetic modulation of cortical circuits in rats

IntroductionChemogenetic tools such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) provide a powerful means to causally manipulate defined neuronal populations in vivo. While chemogenetic fMRI studies have consistently demonstrated robust hemodynamic responses following circuit perturbation, considerably less is known about the accompanying metabolic consequences. Functional magnetic resonance spectroscopy (fMRS) offers the potential to probe these neurochemical processes, yet the relationship between hemodynamic and metabolic responses remains poorly understood. Here, we combined chemogenetics, pharmacological fMRI (ph-fMRI), and proton magnetic resonance spectroscopy (1H-MRS/fMRS) at 7 T to investigate the temporal evolution of metabolic and hemodynamic responses in the rat motor cortex. MethodsFemale Fischer rats received viral injections in the motor cortex to express either a pan-neuronal hM3D(Gq) DREADD construct (hSyn-hM3Dq) or an interneuron-targeted construct (hDlx-hM3Dq). Ph-fMRI, fMRS, and 1H-MRS measurements were performed before, during, and following systemic administration of clozapine-N-oxide (CNO, 1 mg/kg). Functional MRS was acquired during the acute response phase (0-60 min post-injection), while conventional 1H-MRS measurements were obtained at a delayed time point (70 min post-injection). ResultsChemogenetic modulation produced robust and opposing hemodynamic responses. Pan-neuronal activation elicited focal positive BOLD responses (+3.5 {+/-} 1.5%), whereas interneuron-targeted activation generated significant negative BOLD responses (-3.3 {+/-} 0.8%). In contrast, acute fMRS measurements revealed no significant changes in Glx or GABA concentrations during the first hour following CNO administration, despite the presence of strong hemodynamic effects. However, delayed metabolic alterations were detected 70 min after CNO administration. Animals expressing the pan-neuronal construct exhibited significant increases in GABA (+14.4%) and total choline compounds (+57.8%), whereas interneuron-targeted animals displayed reductions in several metabolites, including Glx (-15.6%), total NAA (-16.9%), glucose (-25.9%), and total creatine (-25.4%). ConclusionChemogenetic perturbation of cortical circuits produced robust hemodynamic responses but more subtle and temporally complex metabolic effects. The absence of detectable acute changes in Glx and GABA despite strong BOLD responses, together with the emergence of delayed neurochemical alterations, highlights the challenges of interpreting metabolic signals in relation to circuit activity.

neuroscience↗

bioRxiv2022

1H-MRS characterization of metabolic changes induced by photoperiod in the sheep brain: a promising eye into in-vivo adult neurogenesis?

The hypothalamus is a central structure of the mammalian brain, which controls physiological, endocrine and metabolic brain homeostasis. Despite this essential role, little is known about the normal and altered neurochemical changes occurring within the hypothalamic structures. Here, the metabolism of the hypothalamus of ewes was investigated at 3T using proton magnetic resonance spectroscopy (1H-MRS). We used the sensitivity of these animals to photoperiod i.e. the ratio of day to night length, to investigate the hypothalamic metabolic changes and their relationship to hypothalamic adult neurogenesis. A longitudinal study involving 4 ewes per timepoint was conducted at 4 time points (P01, P02, P03 and P04) during long days (LD) and 4 time points during short days (SD). Significant metabolic changes were found between LD and SD at all time points in particular for glutamate (Glu), glutamine, myo-inositol and total N-acetyl-Aspartate (NAA). During SD, glutamate and glutamine concentrations were significantly smaller at P01 compared to all other time points while significant neurochemical changes occurred during the entire LD period. Neurochemical changes relative to P01 remained stable during LD and SD except for Glu and Gln which increased between P01 and P02 during SD. Relative metabolic changes were significantly higher on average for NAA and Glu and significantly smaller on average for total choline during SD compared to LD, respectively, paralleling the average changes in the numbers of neural stem cells and glial and oligodendrocyte progenitors found by immunohistochemistry. Despite important differences between MRS and immunohistochemistry in terms of spatial resolution, both techniques suggest complementary findings that should contribute to a better characterization of the hypothalamus during photoperiodism and adult neurogenesis. We conclude that 1H-MRS could be a promising non-invasive translational technique to investigate the existence of adult neurogenesis in-vivo in gyrencephalic brains.

neuroscience↗

bioRxiv2021

Evaluation of BOLD effects in the rat cortex

PurposeThis study aimed to characterize Blood oxygen level-dependent (BOLD) effects in 1H-MR spectra obtained during optogenetic activation of the rat forelimb cortex for the correction and estimation of accurate metabolite concentration changes. MethodsT2*-induced effects were characterized by linewidth changes and amplitude changes of water, NAA and tCr spectral peaks during the stimulation paradigm. Spectral linewidth-matching procedures were used to correct for the line-narrowing effect induced by BOLD. For an increased understanding of spectroscopic BOLD effects and the optimized way to correct them, a 1 Hz line-narrowing effect was also simulated on mouseproton MR spectrum 1H-fMRS data acquired using STEAM acquisitions at 9.4T in rats (n=8) upon optogenetic stimulation of the primary somatosensory cortex were used. Data were analyzed with MATLAB routines and LCModel. Uncorrected and corrected 1H-MR spectra of simulated and in-vivo data were quantified and compared. BOLD-corrected difference spectra were also calculated and analyzed. ResultsSignificant mean increases in water and NAA peak heights (+ 1.1% and +4.5%, respectively) were found accompanied by decreased linewidths (-0.5 Hz and -2.8%) upon optogenetic stimulation. These estimates were used for further definition of an accurate line-broadening factor (lb). Usage of an erroneous lb introduced false-positive errors in metabolite concentration change estimates thereby altering the specificity of findings. Using different water scalings within LCModel, the water and metabolite BOLD contributions were separated. ConclusionThe linewidth-matching procedure using a precise lb factor remains the most performant approach for the accurate quantification of small ({+/-}0.3 mol/g) metabolic changes in 1H-fMRS studies. A simple and preliminary compartmentation of BOLD effects was proposed, which will require validation.

biophysics↗

bioRxiv2020

The sheep brain: an interesting translational model for functional MRI studies?

Biomedical investigations in clinically relevant animal models is of crucial interest for faster and appropriate transfer to human. The ovine model has already demonstrated its potential compared to rodents and non-human primates (NHP) in various studies: sheep possess a gyrencephalic brain, captivity is not an issue and can undergo magnetic resonance imaging (MRI) in routine clinical scanners (1.5T, 3T) under identical conditions using similar techniques to humans. To date, the effects of anesthesia have been poorly explored and only few functional MRI (fMRI) studies were conducted in sheep. Here, Blood Oxygen Level dependent fMRI and perfusion MRI were conducted in lambs and adult ewes at 3 T. Robust but weak BOLD responses to visual stimulation were found in the lateral geniculate nucleus (LGN) up to 3% isoflurane anaesthesia. BOLD responses were weaker in adult sheep than in lambs while relative cerebral blood volumes (rCBV) and relative cerebral blood flows (rCBF) were significantly higher in lambs than in adult sheep for both gray and white matter in accordance with previous findings in the human. Assessment of functional responses in healthy individuals under adequate physiological conditions is essential for robust translational studies.

neuroscience↗

bioRxiv2020

Investigating peripubertal stress and exogenous corticosterone as endogenous stimulators of brain metabolism

Substantial research on the association between early-life stress and its long-lasting impact on lifetime mental health has been performed revealing that early-life environmental adversity strongly regulates brain function. Alterations of gene expression and behavior in the off-springs of paternally stressed rats were also revealed. However, the precise mechanisms underlying these changes remain poorly understood. Here, an improved characterization of these processes from investigations of the functional metabolism of animal models exposed to peripubertal stress (PS) is proposed. The ultimate goal of this study was to bring forward functional Magnetic Resonance Spectroscopy (fMRS) as a technique of interest for a better understanding of brain areas by endogenous stimulators such as stress. The present study evaluated, compared and classified effects of individual PS (iPS) and paternal PS (pPS) under corticosterone (CORT) challenge in the septal areas of adult rats. Acute stress was simulated by injection of CORT and metabolic concentration changes were analyzed as a function of time. Evaluation of Glucose and Lactate concentration changes allowed the classification of groups of rats using a Glc to Lac index. Moreover, metabolic responses of control rats (CC) and of pPS x iPS rats (SS) were similar while responses in pPS (SC) and iPS (CS) differed, revealing differential adaption of energetic metabolism and of glutamatergic neurotransmission. Findings have crucial interest for understanding the metabolic mechanisms underlying altered functional connectivity and neuronal plasticity in septal areas inducing increased aggressivity in early-life stressed rats.

biochemistry↗