Biology subjects

Sandi, C.

Publications and source records attributed to Sandi, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Low testosterone promotes anxiety through astrocytic mitochondrial remodelling at the nucleus accumbens blood-brain barrier

Low testosterone is linked to anxiety in men, but its causal role and underlying brain mechanisms remain unknown. Here, using outbred male rats stratified by natural variation in anxiety-like behaviour, we establish its causal endocrine contribution and uncover an astrocytic mitochondrial mechanism at the nucleus accumbens (NAc) blood-brain barrier (BBB). High-anxiety rats showed a NAc-selective increase in BBB permeability, alongside reduced astrocytic endfoot coverage, disrupted endfoot mitochondrial organisation and mitochondria-endoplasmic reticulum contacts, and lower mitofusin 2 (Mfn2). Testosterone suppression increased anxiety in low-anxiety rats, whereas physiological testosterone restoration reduced anxiety, reconfigured astrocytic mitochondrial and BBB-related transcriptional programmes, increased astrocytic endfoot coverage and Mfn2, recovering BBB permeability, with related effects in aged low-testosterone rats. NAc androgen receptor (AR) knockdown blunted behavioural and neurovascular responses, whereas NAc astrocyte-specific Mfn2 overexpression reduced anxiety. Thus, testosterone-AR signalling engages an astrocytic mitochondrial programme at the NAc neurovascular interface linking low testosterone to anxiety vulnerability.

neuroscience↗

bioRxiv2024

A neurometabolic mechanism for effort-based decision-making in the dmPFC/dACC

Motivation levels vary across individuals, yet the underlying mechanisms driving these differences remain elusive. The dorsomedial prefrontal cortex/dorsal anterior cingulate cortex (dmPFC/dACC) and the anterior insula (aIns) play crucial roles in effort-based decision-making. Here, we investigate the influence of lactate, a key metabolite involved in energy metabolism and signaling, on decisions involving both physical and mental effort, as well as its effects on neural activation. Using proton magnetic resonance spectroscopy and functional MRI in 63 participants, we find that higher lactate levels in the dmPFC/dACC are associated with reduced motivation for physical effort, a relationship mediated by neural activity within this region. Additionally, plasma and dmPFC/dACC lactate levels correlate, suggesting a systemic influence on brain metabolism. Supported by path analysis, our results highlight lactates role as a modulator of dmPFC/dACC activity, hinting at a neurometabolic mechanism that integrates both peripheral and central metabolic states with brain function in effort-based decision-making.

neuroscience↗

bioRxiv2024

Predicting individual variations in mental effort-based decision-making using machine learning: Neurometabolic signature in the dorsomedial prefrontal cortex/dorsal anterior cingulate cortex

Motivation drives individuals to overcome costs to achieve desired outcomes, such as rewards or avoidance of punishment, with significant variability across individuals. The dorsomedial prefrontal cortex/dorsal anterior cingulate cortex (dmPFC/dACC) and anterior insula are key brain regions implicated in effort-based decision-making. Here, we utilized proton magnetic resonance spectroscopy (1H-MRS) at 7 Tesla on 69 healthy participants in these brain regions to uncover the neurometabolic factors that influence these differences. We designed and applied an effort-based decision-making task requiring mental and physical effort to probe motivated behavior, complemented by computational modeling to extract key behavioral parameters. Gradient boosting machine learning was applied to explore the predictive role of specific metabolites in motivated behavior. Our results reveal that a model established on dmPFC/dACC metabolites explains decisions to exert high mental effort and sensitivity to mental effort. In particular, glutamate, aspartate, and lactate in dmPFC/dACC, three metabolites linked through the tricarboxylic acid cycle and glycolysis, were identified as key discriminative metabolites in the dmPFC/dACC, predictive of mental effort choices, underpinning energy supply and cognitive processes. Anterior insula metabolites did not significantly relate to effort-related decisions. Notably, glutamine and lactate levels between the periphery (plasma) and the dmPFC/dACC were correlated, suggesting a metabolic link between peripheral and central biomarkers of effort. Our findings provide novel insights into the neurometabolic underpinnings of motivated behavior and propose novel biomarkers for mental effort-based decision-making. Importantly, our study highlights the relevance of multivariable approaches in elucidating complex cognitive functions.

neuroscience↗

bioRxiv2023

Adolescent stress induces behavioral deficits, ventral hippocampus redox dysregulation, and excitatory/inhibitory imbalance related to schizophrenia

Redox dysregulation has been proposed as a convergent point of childhood trauma and the emergence of psychiatric disorders, such as schizophrenia (SCZ). However, the impact of severe stressors during adolescence on the ventral hippocampus (vHip) redox states and their functional consequences, including behavioral and electrophysiological changes related to SCZ, are not entirely understood. After exposing adolescent animals to physical stress (postnatal day, PND31-40), we explored social and cognitive behaviors (PND47-49) and the activity of pyramidal glutamate neurons, the number of parvalbumin (PV) interneurons, and the transcriptomic signature of the vHip (PND51). We also evaluated the impact of stress on the redox system one and ten days after stress, while glutathione levels were measured in the vHip and serum following the behavioral test. Adolescent-stressed animals exhibited loss of sociability, cognitive impairment, and vHip excitatory/inhibitory (E/I) imbalance. Genome-wide transcriptional profiling unveiled the impact of stress on synaptic and redox system-related genes. Stress impacted mitochondrial respiratory function, leading to changes in reactive oxygen species levels in the vHip. Glutathione (GSH) and glutathione disulfide (GSSG) levels were elevated in the serum of stressed animals, while GSSG was also increased in the vHip and negatively correlated with sociability. Additionally, PV interneuron deficits in the vHip caused by adolescent stress were associated with oxidative stress. Our results highlight the negative impact of adolescent stress on vHip redox regulation and mitochondrial function, which are partially associated with E/I imbalance and behavioral abnormalities related to SCZ.

neuroscience↗

bioRxiv2023

Psychosocial experiences are associated with human brain mitochondrial biology

Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies heavily on energy transformation by mitochondria oxidative phosphorylation (OxPhos), and two main lines of evidence bi-directionally link mitochondria as both targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and possibly mood states alter multiple aspects of mitochondrial biology; and on the other hand, functional variations in mitochondrial OxPhos capacity alter social behavior, stress reactivity, and mood. However, knowledge on whether positive or negative psychosocial exposures and experiences are linked to mitochondrial biology in the human brain is currently unknown. By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we found that positive experiences (e.g. higher well-being) are linked to greater abundance of the mitochondrial OxPhos machinery, whereas negative experiences (e.g. higher negative mood) are linked to lower OxPhos protein content. Combined, psychosocial factors explained 18% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. To increase the sensitivity of our approach, we next interrogated mitochondrial psychobiological associations in specific neuronal and non-neuronal brain cells with single-nucleus RNA sequencing. These results revealed strong cell type specific associations, particularly between positive psychosocial experiences and molecular mitochondrial phenotypes in glial cells, whereas neurons tended to show opposite associations. Accordingly, in bulk transcriptomic analyses where all cells are pooled, these RNA-based associations were masked. Thus, our results highlight the likely underestimation of effect sizes in bulk brain tissues, and document novel cell type specific mitochondrial psychobiological associations in the human brain. Cell type specific mitochondrial recalibrations represent a potential psychobiological pathway linking positive and negative psychosocial experiences to human brain biology. Significance statementPsychosocial experiences predict health trajectories, but the underlying mechanism remains unclear. We found that positive psychosocial experiences are linked to greater abundance of the mitochondrial energy transformation machinery, whereas negative experiences are linked to lower abundance. Overall, we found that psychosocial experiences explain 18% of the variance in abundance of complex I proteins, the main entry point of the mitochondrial oxidative phosphorylation (OxPhos) system. At single-cell resolution using single nucleus transcriptomics, positive psychosocial experiences were particularly related to glial cell mitochondrial phenotypes. Opposite associations between glial cells and neurons were naturally masked in bulk transcriptomic analyses. Our results suggest that mitochondrial recalibrations in specific brain cell types may represent a potential psychobiological pathway linking psychosocial experiences to human brain health.

cell biology↗

bioRxiv2023

Blunted glucocorticoid responsiveness to stress causes behavioral and biological alterations that lead to posttraumatic stress disorder vulnerability

BACKGROUNDUnderstanding why only a subset of trauma-exposed individuals develop posttraumatic stress disorder (PTSD) is critical for advancing clinical strategies. A few behavioral (deficits in fear extinction) and biological (blunted glucocorticoid levels, small hippocampal size, and rapid-eye movement sleep (REMS) disturbances) traits have been identified as potential vulnerability factors. However, whether and to what extent these traits are interrelated and whether one of them could causally engender the others are not known. METHODSIn a genetically selected rat model of reduced corticosterone responsiveness to stress, we explored PTSD-related biobehavioral traits using ex vivo magnetic resonance imaging, cued fear conditioning, and polysomnographic recordings combined with in vivo photometric measurements. RESULTSWe showed that genetic selection for blunted glucocorticoid responsiveness leads to a correlated multitrait response, including impaired fear extinction, small hippocampal volume, and REMS disturbances, supporting their interrelatedness. Fear extinction deficits and concomitant disruptions in REMS could be normalized through postextinction corticosterone administration, causally implicating glucocorticoid deficiency in two core PTSD-related risk factors and manifestations. Furthermore, reduced REMS was accompanied by higher norepinephrine levels in the hippocampal dentate gyrus that were also reverted by postextinction corticosterone treatment. CONCLUSIONSOur results indicate a predominant role for glucocorticoid deficiency over the contribution of reduced hippocampal volume in engendering both REMS alterations and associated deficits in fear extinction consolidation, and causally implicate blunted glucocorticoids in sustaining neurophysiological disturbances leading to fear extinction deficits.

neuroscience↗

bioRxiv2022

Mitofusin-2 in nucleus accumbens D2-MSNs regulates social dominance and neuronal function

The nucleus accumbens (NAc) is a brain hub regulating motivated behaviors, including social competitiveness. Mitochondrial function in the NAc is critically implicated in the association between anxiety and social competitiveness, and the mitochondrial fusion protein mitofusin 2 (Mfn2) in NAc neurons has been shown to regulate anxiety-related behaviors. However, it remains unexplored whether accumbal Mfn2 levels also affect social behavior and whether Mfn2 actions in the emotional and social domain are driven by distinct cell types. Here, we found that subordinate-prone highly anxious rats show reduced accumbal Mfn2 levels and that Mfn2 overexpression promotes dominant behavior. In mice, selective Mfn2 downregulation in NAc dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) induced social subordination, accompanied by reduced mitochondrial function and decreased neuronal excitability. Instead, D1-MSN-targeted Mfn2 downregulation affected competitive ability only transiently mainly by increases in anxiety-like behaviors. Our results assign dissociable cell-type specific roles to Mfn2 in the NAc in modulating social dominance and anxiety.

neuroscience↗

bioRxiv2022

Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort

Emerging evidence is implicating mitochondrial function and metabolism in the nucleus accumbens in motivated performance. However, the brain is vulnerable to excessive oxidative insults resulting from neurometabolic processes and whether antioxidant levels in the nucleus accumbens contribute to motivated performance is not known. Here, we identify a critical role for glutathione (GSH), the most important endogenous antioxidant in the brain, in motivation. Using proton magnetic resonance spectroscopy (1H-MRS) at ultra-high field in both clinical and preclinical populations, we establish that higher accumbal GSH levels are highly predictive of better, and particularly steady performance over time in effort-related tasks. Causality was established in preclinical in vivo experiments that, first, showed that down-regulating GSH levels through micro-injections of the GSH synthesis inhibitor buthionine sulfoximine in the nucleus accumbens impaired effort-based reward-incentivized performance. In addition, systemic treatment with the GSH precursor N-acetyl-cysteine (NAC) increased accumbal GSH levels and led to improved performance, potentially mediated by a cell-type specific shift in glutamatergic inputs to accumbal medium spiny neurons. Our data indicate a close association between accumbal GSH levels and individuals capacity to exert reward-incentivized effort over time. They also suggest that improvement of accumbal antioxidant function may be a feasible approach to boost motivation.

neuroscience↗

bioRxiv2022

Involvement of prelimbic cortex neurons and related circuits in the acquisition of cooperative learning by pairs of rats

Social behaviors such as cooperation are crucial for mammals. A deeper knowledge of the neuronal mechanisms underlying cooperation can be beneficial for people suffering from pathologies with impaired social behavior. Our aim was to study the brain activity when two animals synchronize their behavior to obtain a mutual reinforcement. In a previous work, we showed that the activity of the prelimbic cortex (PrL) was enhanced during cooperation in rats, especially in the ones leading most cooperative trials (leader rats). In this study, we investigated the specific cell type/s in the PrL contributing to cooperative behaviors. To this end, we collected rats brains at key moments of the learning process to analyze the levels of c-FOS expression in the main cellular groups of the PrL (glutamatergic cells containing D1 and D2 receptors and interneurons). Leader rats showed increased c-FOS activity in cells expressing D1 receptors during cooperation. In addition, we analyzed the levels of anxiety, dominance, and locomotor behavior, finding that leader rats are in general less anxious and less dominant than followers. We also recorded local field potentials (LFPs) from the PrL, the nucleus accumbens septi (NAc), and the basolateral amygdala (BLA). Spectral analysis showed that delta activity in PrL and NAc increased when rats cooperated, while BLA activity in delta and theta bands decreased considerably during cooperation. The PrL and NAc also increased their connectivity in the high theta band during cooperation. Thus, the present work identifies the specific PrL cell types engaged in this behavior, as well as its connectivity with subcortical brain regions (BLA, NAc) during cooperation. Significance StatementBrain mechanisms underlying cooperative behaviors remain unknown. The present study identified specific neuronal types from the PrL cortex engaged in the acquisition of a cooperative task, as well as their connectivity with subcortical projection sites, such as the NAc and the BLA during cooperation. Rats leading the cooperation trials (designated leaders) presented an increased activation of D1-containing neurons in the PrL during cooperation. The PrL and NAc electrical activity increased when rats were cooperating, while the BLA activity increased before cooperation. The PrL and NAc showed increased functional connectivity at the moment of cooperation on the platform, whereas during the individual phase the highest connectivity was found before the animals climbed individually onto the platform.

neuroscience↗

bioRxiv2021

Creatine transporter deficient rat show motor dysfunction linked with cerebellar alterations and muscle creatine deficiency without muscle atrophy

Creatine (Cr) is a nitrogenous organic acid and plays roles as fast phosphate energy buffer to replenish ATP, osmolyte, antioxidant, neuromodulator, and as a compound with anabolic and ergogenic properties in muscle. Cr is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Loss-of-function mutations in the genes encoding for the enzymes or the transporter cause Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain Cr deficiency, intellectual disability with severe speech delay, behavioral troubles, epilepsy and motor dysfunction. Among CCDS, the X-linked Cr transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different animal models of CTD show reduced brain Cr levels, cognitive deficiencies and together they cover other traits similar to those of patients. However, motor function was poorly explored in CTD models and some controversies in the phenotype exist in comparison with CTD patients. Our recently described Slc6a8Y389C knock-in (KI) rat model of CTD showed mild impaired motor function, morphological alterations in cerebellum, reduced muscular mass, Cr deficiency and increased guanidinoacetate content in muscle, although no consistent signs of muscle atrophy. Our results indicate that such motor dysfunction co-occurred with both nervous and muscle dysfunction, suggesting that muscle strength and performance as well as neuronal connectivity might be affected by this Cr deficiency in muscle and brain.

pathology↗

bioRxiv2021

Mouse brain-wide mitochondrial connectivity anchored in gene, brain and behavior

The brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not been systematically studied on a brain-wide scale. Here we examined the association between multiple features of mitochondrial respiratory chain capacity and stress-related behaviors in mice with diverse behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain enzyme activities and mitochondrial DNA (mtDNA) content were deployed on 571 samples across 17 brain areas, defining specific patterns of mito-behavior associations. By applying multi-slice network analysis to our brain-wide mitochondrial dataset, we identified three large-scale networks of brain areas with shared mitochondrial signatures. A major network composed of cortico-striatal areas exhibited the strongest mitochondria-behavior correlations, accounting for up to 50% of animal-to-animal behavioral differences, suggesting that this mito-based network is functionally significant. The mito-based brain networks also overlapped with regional gene expression and structural connectivity and quantitatively diverged in their molecular mitochondrial phenotype signatures. Therefore, this work provides convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct, behaviorally-relevant mitochondrial phenotypes exist across the mouse brain.

neuroscience↗

bioRxiv2021

Acute stress affects peripersonal space representation

Peripersonal space (PPS) is the region of space surrounding the body. It has a dedicated multisensory-motor representation, whose purpose is to predict and plan interactions with the environment, and which can vary depending on environmental circumstances. Here, we investigated the effect on the PPS representation of an experimentally induced stress response. We assessed PPS representation in healthy humans, before and after a stressful manipulation, by quantifying visuotactile interactions as a function of the distance from the body, while monitoring salivary cortisol concentration. Participants, who showed a cortisol stress response, presented enhanced visuotactile integration for stimuli close to the body and reduced for far stimuli. Conversely, individuals, with a less pronounced cortisol response, showed a reduced difference in visuotactile integration between the near and the far space. In our interpretation, physiological stress resulted in a freezing-like response, where multisensory-motor resources are allocated only to the area immediately surrounding the body.

neuroscience↗

bioRxiv2020

Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency

Neuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the mitochondrial pyruvate carrier, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation in these excitatory neurons, mice were normal at rest. Paradoxically, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behaviour of control mice remained unchanged. We show that neurons with a deficient MPC are intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduces M-type potassium channel activity. Provision of ketone bodies restores energy status, calcium homeostasis and M-channel activity and attenuates seizures in animals fed a ketogenic diet. Our results provide an explanation for the paradoxical seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit. One Sentence SummaryDecreased OXPHOS and Ca2+-mediated neuronal hyperexcitability lead to seizure in a mouse model of mitochondrial pyruvate import deficiency.

neuroscience↗

bioRxiv2020

Clostridium perfringenosum sp. nov., a closely related species toClostridium perfringens and its virulence factors, isolated from a humansoft tissue infection

Two Gram-positive, anaerobic bacteria, designated 27733 and 27737, were isolated from a soft tissue infection from a human patient. They were preliminarily identified as Clostridium perfringens through a series of phenotypic tests, including Gram-staining, determination of lipase and hemolytic activities, MALDI-ToF profiling, and a commercial biochemical identification system. In line with these results, genomes obtained for both isolates were ~3.56 Mbp in size, showed a DNA G+C content of ~28.4%, and contained C. perfringens ribosomal markers (i.e. 16S rRNA gene identity >99.0% to C. perfringens ATCC13124T). A closer examination of these sequences; however, revealed low average Nucleotide Identity (~87%) and digital DNA-DNA Hybridization (~35%) values between isolates 27733/27737 and C. perfringens ATCC13124T, as well as substantial differences in gene content to multiple C. perfringens strains, indicating that they represent a novel species within the genus Clostridium. Congruently, Bayesian dating analyses placed the divergence of this new species and C. perfringens from its common ancestor hundreds of thousands of years ago. Isolates 27733/27737 are not genomically identical (34-197 SNPs apart) and carry genes for C. perfringens-like toxins (<94% nucleotide sequence identity), including plc (alpha toxin), pfoA (perfringolysin O, theta-toxin), nagHIJKL (hyalorudinase, mu-toxin), nanHIJ (exo-alpha sialidase), and cloSI (alpha-clostripain). They do not have known antibiotic resistance genes but were catalogued as resistant to clindamycin through phenotypic tests. On the basis of the presented evidence, and due to its resemblance and potential confusion with C. perfringens, we herein propose the species C. perfringenosum sp. nov. and strain 27733 as its type strain.

microbiology↗

bioRxiv2020

Deletion of Crtc1 leads to hippocampal neuroenergetic impairments associated with depressive-like behavior

Mood disorders (MD) are a major burden on society as their biology remains poorly understood, challenging both diagnosis and therapy. Among many observed biological dysfunctions, homeostatic dysregulation, such as metabolic syndrome (MeS), shows considerable comorbidity with MD. Recently, CREB-regulated transcription coactivator 1 (CRTC1), a regulator of brain metabolism, was proposed as a promising factor to understand this relationship. Searching for imaging biomarkers and associating them with pathophysiological mechanisms using preclinical models, can provide significant insight into these complex psychiatric diseases and help the development of personalized healthcare. Here, we used neuroimaging technologies to show that deletion of Crtc1 in mice leads to an imaging fingerprint of hippocampal metabolic impairment related to depressive-like behavior. By identifying the underlying molecular/physiological origin, we could assign an energy-boosting mood-stabilizing treatment, ebselen, which rescued behavior and neuroimaging markers. Finally, our results point towards the GABAergic system as a potential therapeutic target for behavioral dysfunctions related to metabolic disorders. This study provides new insights on Crtc1s and MeSs relationship to MD and establishes depression-related markers with clinical potential.

neuroscience↗

bioRxiv2020

Programming effects of peripubertal stress on spatial learning

Exposure to adversity during early life can have profound influences on brain function and behavior later in life. The peripubertal period is emerging as an important time-window of susceptibility to stress, with substantial evidence documenting long-term consequences in the emotional and social domains. However, little is known about how stress during this period impacts subsequent cognitive functioning. Here, we assessed potential long-term effects of peripubertal stress on spatial learning and memory using the water maze task. In addition, we interrogated whether individual differences in stress-induced behavioral and endocrine changes are related to the degree of adaptation of the corticosterone response to repeated stressor exposure during the peripubertal period. We found that, when tested at adulthood, peripubertally stressed animals displayed a slower learning rate. Strikingly, the level of spatial orientation in the water maze completed on the last training day was predicted by the degree of adaptation of the recovery -and not the peak-of the corticosterone response to stressor exposure (i.e., plasma levels at 60 min post-stressor) across the peripubertal stress period. In addition, peripubertal stress led to changes in emotional and glucocorticoid reactivity to novelty exposure, as well as in the expression levels of the plasticity molecule PSA-NCAM in the hippocampus. Importantly, by assessing the same endpoints in another peripubertally stressed cohort tested during adolescence, we show that the observed effects at adulthood are the result of a delayed programming manifested at adulthood and not protracted effects of stress. Altogether, our results support the view that the degree of stress-induced adaptation of the hypothalamus-pituitary-adrenal axis responsiveness at the important transitional period of puberty relates to the long-term programming of cognition, behavior and endocrine reactivity.

neuroscience↗

bioRxiv2020

A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

Creatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in the Slc6a8 gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficiency and autistic features. Slc6a8xY389C KI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation.

pathology↗

bioRxiv2020

Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala

Increasing evidence suggests that crosstalk between -synuclein pathology formation and mitochondrial dysfunctions plays a central role in the pathogenesis of Parkinsons disease and related synucleinopathies. While mitochondrial dysfunction is a well-studied phenomenon in the substantia nigra, which is selectively vulnerable in Parkinsons disease and some models thereof, less information is available in other brain regions that are also affected by synuclein pathology. Therefore, we sought to test the hypothesis that early -synuclein pathology causes mitochondrial dysfunction, and that this effect might be exacerbated in conditions of increased vulnerability of affected brain regions, such as the amygdala. We combined a model of intracerebral -synuclein pathology seeding with chronic glucocorticoid treatment modelling non-motor symptoms of Parkinsons disease and affecting amygdala physiology. We measured mitochondrial respiration, ROS generation and protein abundance as well as -synuclein pathology in male mice. Chronic corticosterone administration induced mitochondrial hyperactivity in the amygdala. Although injection of -synuclein preformed fibrils into the striatum resulted in pronounced -synuclein pathology in both striatum and amygdala, mitochondrial respiration in these brain regions was altered in neither chronic corticosterone nor control conditions. Our results suggest that early stage -synuclein pathology does not influence mitochondrial respiration in the striatum and amygdala, even in corticosterone-induced respirational hyperactivity. We discuss our findings in light of relevant literature, warn of a potential publication bias and encourage scientist to report their negative results in the frame of this model. Significance statementWe provide evidence that early stage synucleinopathy by itself or in combination with exogenous corticosterone induced amygdala hyperactivity did not compromise mitochondrial respiration in the striatum and amygdala in one of the most commonly used models of synucleinopathies. These results may explain, why this model in the hands of many research groups does not elicit pronounced Parkinsons disease like symptoms in the absence of mitochondrial dysfunction in brain regions strongly affected by synuclein pathology and involved in non-motor (amygdala) and motor (striatum) symptoms. Our findings call for rigorous investigation of the short- and long-term effects of -synuclein pathology on mitochondrial function/dysfunction in this model, in particular in brain regions strongly affected by neurodegeneration such as the substantia nigra pars compacta.

neuroscience↗