Metabolic Fingerprinting of Different Sideritis Taxa Infusions and Their Neurogenic Activity.

Over the last years, Sideritis extracts were shown to improve memory. However, their potential to promote the generation of new neurons, starting with the neuronal differentiation of neural stem cells, remains unexplored. Therefore, the present study aimed to evaluate the neurogenic effects of different Sideritis infusions in neural stem and precursor cells and their impact on cell viability. Moreover, the metabolic fingerprints were recorded using LC-DAD, LC-HRESIMS, and GC-MS. The neurogenic potential of infusions of the eight Sideritis taxa tested was as potent as the classical neuronal inducer combination of retinoic acid and valproic acid. Further cytotoxicity assays revealed that the IC50 values of the extracts were between 163 and 322 µg/mL. Hierarchical cluster analyses of the metabolic fingerprints unveiled that the two Sideritis taxa with the lowest IC50 values were the most divergent in the analytical techniques used. As the analysis focused on polyphenols, it is reasonable to assume that these compounds are responsible for the effect on the cell viability of SH-SY5Y neuroblastoma cells. This study is the first report on the neurogenic potential of Sideritis taxa and might support the use of Sideritis herbal preparations in the context of neurodegenerative diseases.

Case-matched radiological and clinical outcome evaluation of interlaminar versus microsurgical decompression of lumbar spinal stenosis.

PURPOSE: Endoscopic spine surgery is a globally expanding technique advocated as less invasive for spinal stenosis treatment compared to the microsurgical approach. However, evidence on the efficiency of interlaminar full-endoscopic decompression (FED) vs. conventional microsurgical decompression (MSD) in patients with lumbar spinal stenosis is still scarce. We conducted a case-matched comparison for treatment success with consideration of clinical, laboratory, and radiologic predictors. METHODS: We included 88 consecutive patients (FED: 36/88, 40.9%; MSD: 52/88, 59.1%) presenting with lumbar central spinal stenosis. Surgery-related (operation time, complications, length of stay (LOS), American Society of Anesthesiologists physical status (ASA) score, C-reactive protein (CRP), white blood cell count, side of approach (unilateral/bilateral), patient-related outcome measures (PROMs) (Oswestry disability index (ODI), numeric rating scale of pain (NRS; leg-, back pain), EuroQol questionnaire (eQ-5D), core outcome measures index (COMI)), and radiological (dural sack cross-sectional area, Schizas score (SC), left and right lateral recess heights, and facet angles, respectively) parameters were extracted at different time points up to 1-year follow-up. The relationship of PROMs was analyzed using Spearman's rank correlation. Surgery-related outcome parameters were correlated with patient-centered and radiological outcomes utilizing a regression model to determine predictors for propensity score matching. RESULTS: Complication (most often residual sensorimotor deficits and restenosis due to hematoma) rates were higher in the FED (33.3%) than MSD (13.5%) group (p < 0.05), while all complications in the FED group were observed within the first 20 FED patients. Operation time was higher in the FED, whereas LOS was higher in the MSD group. Age, SC, CRP revealed significant associations with PROMs. We did not observe significant differences in the endoscopic vs. microsurgical group in PROMs. The correlation between ODI and COMI was significantly high, and both were inversely correlated with eQ-5D, whereas the correlations of these PROMs with NRS findings were less pronounced. CONCLUSIONS: Endoscopic treatment of lumbar spinal stenosis was similarly successful as the conventional microsurgical approach. Although FED was associated with higher complication rates in our single-center study experience, the distribution of complications indicated surgical learning curves to be the main factor of these findings. Future long-term prospective studies considering the surgical learning curve are warranted for reliable comparisons of these techniques.

Artificial intelligence-based analysis of associations between learning curve and clinical outcomes in endoscopic and microsurgical lumbar decompression surgery.

PURPOSE: A common spine surgery procedure involves decompression of the lumbar spine. The impact of the surgeon's learning curve on relevant clinical outcomes is currently not well examined in the literature. A variety of machine learning algorithms have been investigated in this study to determine how a surgeon's learning curve and other clinical parameters will influence prolonged lengths of stay (LOS), extended operating times (OT), and complications, as well as whether these clinical parameters can be reliably predicted. METHODS: A retrospective monocentric cohort study of patients with lumbar spinal stenosis treated with microsurgical (MSD) and full-endoscopic (FED) decompression was conducted. The study included 206 patients with lumbar spinal stenosis who underwent FED (63; 30.6%) and MSD (118; 57.3%). Prolonged LOS and OT were defined as those exceeding the 75th percentile of the cohort. Furthermore, complications were assessed as a dependent variable. Using unsupervised learning, clusters were identified in the data, which helped distinguish between the early learning curve (ELC) and the late learning curve (LLC). From 15 algorithms, the top five algorithms that best fit the data were selected for each prediction task. We calculated the accuracy of prediction (Acc) and the area under the curve (AUC). The most significant predictors were determined using a feature importance analysis. RESULTS: For the FED group, the median number of surgeries with case surgery type at the time of surgery was 72 in the ELC group and 274 in the LLC group. FED patients did not significantly differ in outcome variables (LOS, OT, complication rate) between the ELC and LLC group. The random forest model demonstrated the highest mean accuracy and AUC across all folds for each classification task. For OT, it achieved an accuracy of 76.08% and an AUC of 0.89. For LOS, the model reached an accuracy of 83.83% and an AUC of 0.91. Lastly, in predicting complications, the random forest model attained the highest accuracy of 89.90% and an AUC of 0.94. Feature importance analysis indicated that LOS, OT, and complications were more significantly affected by patient characteristics than the surgical technique (FED versus MSD) or the surgeon's learning curve. CONCLUSIONS: A median of 72 cases of FED surgeries led to comparable clinical outcomes in the early learning curve phase compared to experienced surgeons. These outcomes seem to be more significantly affected by patient characteristics than the learning curve or the surgical technique. Several study variables, including the learning curve, can be used to predict whether lumbar decompression surgery will result in an increased LOS, OT, or complications. To introduce the provided prediction tools into clinics, the algorithms need to be implemented into open-source software and externally validated through large-scale randomized controlled trials.

Clinical and radiomics feature-based outcome analysis in lumbar disc herniation surgery.

BACKGROUND: Low back pain is a widely prevalent symptom and the foremost cause of disability on a global scale. Although various degenerative imaging findings observed on magnetic resonance imaging (MRI) have been linked to low back pain and disc herniation, none of them can be considered pathognomonic for this condition, given the high prevalence of abnormal findings in asymptomatic individuals. Nevertheless, there is a lack of knowledge regarding whether radiomics features in MRI images combined with clinical features can be useful for prediction modeling of treatment success. The objective of this study was to explore the potential of radiomics feature analysis combined with clinical features and artificial intelligence-based techniques (machine learning/deep learning) in identifying MRI predictors for the prediction of outcomes after lumbar disc herniation surgery. METHODS: We included n = 172 patients who underwent discectomy due to disc herniation with preoperative T2-weighted MRI examinations. Extracted clinical features included sex, age, alcohol and nicotine consumption, insurance type, hospital length of stay (LOS), complications, operation time, ASA score, preoperative CRP, surgical technique (microsurgical versus full-endoscopic), and information regarding the experience of the performing surgeon (years of experience with the surgical technique and the number of surgeries performed at the time of surgery). The present study employed a semiautomatic region-growing volumetric segmentation algorithm to segment herniated discs. In addition, 3D-radiomics features, which characterize phenotypic differences based on intensity, shape, and texture, were extracted from the computed magnetic resonance imaging (MRI) images. Selected features identified by feature importance analyses were utilized for both machine learning and deep learning models (n = 17 models). RESULTS: The mean accuracy over all models for training and testing in the combined feature set was 93.31 ± 4.96 and 88.17 ± 2.58. The mean accuracy for training and testing in the clinical feature set was 91.28 ± 4.56 and 87.69 ± 3.62. CONCLUSIONS: Our results suggest a minimal but detectable improvement in predictive tasks when radiomics features are included. However, the extent of this advantage should be considered with caution, emphasizing the potential of exploring multimodal data inputs in future predictive modeling.

Neuron and Brain Maturation 2.0.

The mammalian central nervous system (CNS) is built up during embryogenesis by neural stem cells located in the periventricular germinal layers which undergo multiple division cycles [...].

Depolarization and Hyperexcitability of Cortical Motor Neurons after Spinal Cord Injury Associates with Reduced HCN Channel Activity.

A spinal cord injury (SCI) damages the axonal projections of neurons residing in the neocortex. This axotomy changes cortical excitability and results in dysfunctional activity and output of infragranular cortical layers. Thus, addressing cortical pathophysiology after SCI will be instrumental in promoting recovery. However, the cellular and molecular mechanisms of cortical dysfunction after SCI are poorly resolved. In this study, we determined that the principal neurons of the primary motor cortex layer V (M1LV), those suffering from axotomy upon SCI, become hyperexcitable following injury. Therefore, we questioned the role of hyperpolarization cyclic nucleotide gated channels (HCN channels) in this context. Patch clamp experiments on axotomized M1LV neurons and acute pharmacological manipulation of HCN channels allowed us to resolve a dysfunctional mechanism controlling intrinsic neuronal excitability one week after SCI. Some axotomized M1LV neurons became excessively depolarized. In those cells, the HCN channels were less active and less relevant to control neuronal excitability because the membrane potential exceeded the window of HCN channel activation. Care should be taken when manipulating HCN channels pharmacologically after SCI. Even though the dysfunction of HCN channels partakes in the pathophysiology of axotomized M1LV neurons, their dysfunctional contribution varies remarkably between neurons and combines with other pathophysiological mechanisms.

Semi-Synthesis of Different Pyranoflavonoid Backbones and the Neurogenic Potential.

Flavonoids and chalcones are known for their manifold biological activities, of which many affect the central nervous system. Pyranochalcones were recently shown to have a great neurogenic potential, which is partly due to a specific structural motif-the pyran ring. Accordingly, we questioned if other flavonoid backbones with a pyran ring as structural moiety would also show neurogenic potential. Different semi-synthetic approaches starting with the prenylated chalcone xanthohumol, isolated from hops, led to pyranoflavanoids with different backbones. We identified the chalcone backbone as the most active backbone with pyran ring using a reporter gene assay based on the promoter activity of doublecortin, an early neuronal marker. Pyranochalcones therefore appear to be promising compounds for further development as a treatment strategy for neurodegenerative diseases.

Neuronal and Brain Maturation.

Can plasticity be considered as an extension of "immaturity" [...].

Spinal Cord Injury and Loss of Cortical Inhibition.

After spinal cord injury (SCI), the destruction of spinal parenchyma causes permanent deficits in motor functions, which correlates with the severity and location of the lesion. Despite being disconnected from their targets, most cortical motor neurons survive the acute phase of SCI, and these neurons can therefore be a resource for functional recovery, provided that they are properly reconnected and retuned to a physiological state. However, inappropriate re-integration of cortical neurons or aberrant activity of corticospinal networks may worsen the long-term outcomes of SCI. In this review, we revisit recent studies addressing the relation between cortical disinhibition and functional recovery after SCI. Evidence suggests that cortical disinhibition can be either beneficial or detrimental in a context-dependent manner. A careful examination of clinical data helps to resolve apparent paradoxes and explain the heterogeneity of treatment outcomes. Additionally, evidence gained from SCI animal models indicates probable mechanisms mediating cortical disinhibition. Understanding the mechanisms and dynamics of cortical disinhibition is a prerequisite to improve current interventions through targeted pharmacological and/or rehabilitative interventions following SCI.

One-Year Clinical Outcomes of Minimal-Invasive Dorsal Percutaneous Fixation of Thoracolumbar Spine Fractures.

Introduction: Minimal-invasive instrumentation techniques have become a workhorse in spine surgery and require constant clinical evaluations. We sought to analyze patient-reported outcome measures (PROMs) and clinicopathological characteristics of thoracolumbar fracture stabilizations utilizing a minimal-invasive percutaneous dorsal screw-rod system. Methods: We included all patients with thoracolumbar spine fractures who underwent minimal-invasive percutaneous spine stabilization in our clinics since inception and who have at least 1 year of follow-up data. Clinical characteristics (length of hospital stay (LOS), operation time (OT), and complications), PROMs (preoperative (pre-op), 3-weeks postoperative (post-op), 1-year postoperative: eq5D, COMI, ODI, NRS back pain), and laboratory markers (leucocytes, c-reactive protein (CRP)) were analyzed, finding significant associations between these study variables and PROMs. Results: A total of 68 patients (m: 45.6%; f: 54.4%; mean age: 76.9 ± 13.9) were included. The most common fracture types according to the AO classification were A3 (40.3%) and A4 (40.3%), followed by B2 (7.46%) and B1 (5.97%). The Median American Society of Anesthesiologists (ASA) score was 3 (range: 1−4). Stabilized levels ranged from TH4 to L5 (mean number of targeted levels: 4.25 ± 1.4), with TH10-L2 (12/68) and TH11-L3 (11/68) being the most frequent site of surgery. Mean OT and LOS were 92.2 ± 28.2 min and 14.3 ± 6.9 days, respectively. We observed 9/68 complications (13.2%), mostly involving screw misalignments and loosening. CRP increased from 24.9 ± 33.3 pre-op to 34.8 ± 29.9 post-op (p < 0.001), whereas leucocyte counts remained stable. All PROMs showed a marked significant improvement for both 3-week and 1-year evaluations compared to the preoperative situation. Interestingly, we did not find an impact of OT, LOS, lab markers, complications, and other clinical characteristics on PROMs. Notably, a higher number of stabilized levels did not affect PROMs. Conclusions: Minimal-invasive stabilization of thoracolumbar fractures utilizing a dorsal percutaneous approach resulted in significant PROM outcome improvements, although we observed a complication rate of 13.2% for up to 1 year of follow-up. PROMs were not significantly associated with clinicopathological characteristics, technique-related variables, or the number of targeted levels.

Neuroregenerative Potential of Prenyl- and Pyranochalcones: A Structure-Activity Study.

Loss of neuronal tissue is a hallmark of age-related neurodegenerative diseases. Since adult neurogenesis has been confirmed in the human brain, great interest has arisen in substances stimulating the endogenous neuronal regeneration mechanism based on adult neural stem cells. Medicinal plants are a valuable source of neuroactive small molecules. In the structure-activity study presented here, the activities of prenyl- and pyranochalcones were compared to each other, using a differentiation assay based on the doublecortin promoter sequences. The latter revealed that the pyrano ring is a crucial structural element for the induction of neuronal differentiation of adult neural stem cells, while compounds with a prenyl group show significantly lower activities. Furthermore, a decrease of pro-differentiation activity was observed following structural modifications, such as substitutions on the pyrano ring and on the B-ring of the chalcone. We also initiated the elucidation of the structural characteristics of the newly discovered lead substance xanthohumol C, which correlated with the activation of the doublecortin promoter during neuronal differentiation.

Functional Integration of Neuronal Precursors in the Adult Murine Piriform Cortex.

The extent of functional maturation and integration of nonproliferative neuronal precursors, becoming neurons in the adult murine piriform cortex, is largely unexplored. We thus questioned whether precursors eventually become equivalent to neighboring principal neurons or whether they represent a novel functional network element. Adult brain neuronal precursors and immature neurons (complex cells) were labeled in transgenic mice (DCX-DsRed and DCX-CreERT2 /flox-EGFP), and their cell fate was characterized with patch clamp experiments and morphometric analysis of axon initial segments. Young (DCX+) complex cells in the piriform cortex of 2- to 4-month-old mice received sparse synaptic input and fired action potentials at low maximal frequency, resembling neonatal principal neurons. Following maturation, the synaptic input detected on older (DCX-) complex cells was larger, but predominantly GABAergic, despite evidence of glutamatergic synaptic contacts. Furthermore, the rheobase current of old complex cells was larger and the maximal firing frequency was lower than those measured in neighboring age-matched principal neurons. The striking differences between principal neurons and complex cells suggest that the latter are a novel type of neuron and new coding element in the adult brain rather than simple addition or replacement for preexisting network components.

Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition.

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HTT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.

PSA Depletion Induces the Differentiation of Immature Neurons in the Piriform Cortex of Adult Mice.

Immature neurons are maintained in cortical regions of the adult mammalian brain. In rodents, many of these immature neurons can be identified in the piriform cortex based on their high expression of early neuronal markers, such as doublecortin (DCX) and the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). This molecule plays critical roles in different neurodevelopmental events. Taking advantage of a DCX-CreERT2/Flox-EGFP reporter mice, we investigated the impact of targeted PSA enzymatic depletion in the piriform cortex on the fate of immature neurons. We report here that the removal of PSA accelerated the final development of immature neurons. This was revealed by a higher frequency of NeuN expression, an increase in the number of cells carrying an axon initial segment (AIS), and an increase in the number of dendrites and dendritic spines on the immature neurons. Taken together, our results demonstrated the crucial role of the PSA moiety in the protracted development of immature neurons residing outside of the neurogenic niches. More studies will be required to understand the intrinsic and extrinsic factors affecting PSA-NCAM expression to understand how the brain regulates the incorporation of these immature neurons to the established neuronal circuits of the adult brain.

Involvement of Neuropeptide Galanin Receptors 2 and 3 in Learning, Memory and Anxiety in Aging Mice.

The neuropeptide galanin (GAL), which is expressed in limbic brain structures, has a strong impact on the regulation of mood and behavior. GAL exerts its effects via three G protein-coupled receptors (GAL1-3-R). Little is known about the effects of aging and loss of GAL-Rs on hippocampal-mediated processes connected to neurogenesis, such as learning, memory recall and anxiety, and cell proliferation and survival in the dorsal dentate gyrus (dDG) in mice. Our results demonstrate that loss of GAL3-R, but not GAL2-R, slowed learning and induced anxiety in older (12-14-month-old) mice. Lack of GAL2-R increased cell survival (BrdU incorporation) in the dDG of young mice. However, normal neurogenesis was observed in vitro using neural stem and precursor cells obtained from GAL2-R and GAL3-R knockouts upon GAL treatment. Interestingly, we found sub-strain differences between C57BL/6J and C57BL/6N mice, the latter showing faster learning, less anxiety and lower cell survival in the dDG. We conclude that GAL-R signaling is involved in cognitive functions and can modulate the survival of cells in the neurogenic niche, which might lead to new therapeutic applications. Furthermore, we observed that the mouse sub-strain had a profound impact on the behavioral parameters analyzed and should therefore be carefully considered in future studies.

Stroke Accelerates and Uncouples Intrinsic and Synaptic Excitability Maturation of Mouse Hippocampal DCX+ Adult-Born Granule Cells.

Stroke robustly stimulates adult neurogenesis in the hippocampal dentate gyrus. It is currently unknown whether this process induces beneficial or maladaptive effects, but morphological and behavioral studies have reported aberrant neurogenesis and impaired hippocampal-dependent memory following stroke. However, the intrinsic function and network incorporation of adult-born granule cells (ABGCs) after ischemia is unclear. Using patch-clamp electrophysiology, we evaluated doublecortin-positive (DCX+) ABGCs as well as DCX- dentate gyrus granule cells 2 weeks after a stroke or sham operation in DCX/DsRed transgenic mice of either sex. The developmental status, intrinsic excitability, and synaptic excitability of ABGCs were accelerated following stroke, while dendritic morphology was not aberrant. Regression analysis revealed uncoupled development of intrinsic and network excitability, resulting in young, intrinsically hyperexcitable ABGCs receiving disproportionately large glutamatergic inputs. This aberrant functional maturation in the subgroup of ABGCs in the hippocampus may contribute to defective hippocampal function and increased seizure susceptibility following stroke.SIGNIFICANCE STATEMENT Stroke increases hippocampal neurogenesis but the functional consequences of the postlesional response is mostly unclear. Our findings provide novel evidence of aberrant functional maturation of newly generated neurons following stroke. We demonstrate that stroke not only causes an accelerated maturation of the intrinsic and synaptic parameters of doublecortin-positive, new granule cells in the hippocampus, but that this accelerated development does not follow physiological dynamics due to uncoupled intrinsic and synaptic maturation. Hyperexcitable immature neurons may contribute to disrupted network integration following stroke.

Structural and Functional Maturation of Rat Primary Motor Cortex Layer V Neurons.

Rodent neocortical neurons undergo prominent postnatal development and maturation. The process is associated with structural and functional maturation of the axon initial segment (AIS), the site of action potential initiation. In this regard, cell size and optimal AIS length are interconnected. In sensory cortices, developmental onset of sensory input and consequent changes in network activity cause phasic AIS plasticity that can also control functional output. In non-sensory cortices, network input driving phasic events should be less prominent. We, therefore, explored the relationship between postnatal functional maturation and AIS maturation in principal neurons of the primary motor cortex layer V (M1LV), a non-sensory area of the rat brain. We hypothesized that a rather continuous process of AIS maturation and elongation would reflect cell growth, accompanied by progressive refinement of functional output properties. We found that, in the first two postnatal weeks, cell growth prompted substantial decline of neuronal input resistance, such that older neurons needed larger input current to reach rheobase and fire action potentials. In the same period, we observed the most prominent AIS elongation and significant maturation of functional output properties. Alternating phases of AIS plasticity did not occur, and changes in functional output properties were largely justified by AIS elongation. From the third postnatal week up to five months of age, cell growth, AIS elongation, and functional output maturation were marginal. Thus, AIS maturation in M1LV is a continuous process that attunes the functional output of pyramidal neurons and associates with early postnatal development to counterbalance increasing electrical leakage due to cell growth.

Aging restricts the ability of mesenchymal stem cells to promote the generation of oligodendrocytes during remyelination.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.

Early functional connectivity deficits and progressive microstructural alterations in the TgF344-AD rat model of Alzheimer's Disease: A longitudinal MRI study.

The development and characterization of new improved animal models is pivotal in Alzheimer's Disease (AD) research, since valid models enable the identification of early pathological processes, which are often not accessible in patients, as well as subsequent target discovery and evaluation. The TgF344-AD rat model of AD, bearing mutant human amyloid precursor protein (APPswe) and Presenilin 1 (PSEN1ΔE9) genes, has been described to manifest the full spectrum of AD pathology similar to human AD, i.e. progressive cerebral amyloidosis, tauopathy, neuronal loss and age-dependent cognitive decline. Here, AD-related pathology in female TgF344-AD rats was examined longitudinally between 6 and 18 months by means of complementary translational MRI techniques: resting state functional MRI (rsfMRI) to evaluate functional connectivity (FC) and diffusion tensor imaging (DTI) to assess the microstructural integrity. Additionally, an evaluation of macroscopic changes (3D anatomical MRI) and an image-guided validation of ex vivo pathology were performed. We identified slightly decreased FC at 6 months followed by severe and widespread hypoconnectivity at 10 months of age as the earliest detectable pathological MRI hallmark. This initial effect was followed by age-dependent progressive microstructural deficits in parallel with age-dependent ex vivo AD pathology, without signs of macroscopic alterations such as hippocampal atrophy. This longitudinal MRI study in the TgF344-AD rat model of AD revealed early rsfMRI and DTI abnormalities as seen in human AD patients. The characterization of AD pathology in this rat model using non-invasive MRI techniques further highlights the translational value of this model, as well as its use for potential treatment evaluation.

Cellular Plasticity in the Adult Murine Piriform Cortex: Continuous Maturation of Dormant Precursors Into Excitatory Neurons.

Neurogenesis in the healthy adult murine brain is based on proliferation and integration of stem/progenitor cells and is thought to be restricted to 2 neurogenic niches: the subventricular zone and the dentate gyrus. Intriguingly, cells expressing the immature neuronal marker doublecortin (DCX) and the polysialylated-neural cell adhesion molecule reside in layer II of the piriform cortex. Apparently, these cells progressively disappear along the course of ageing, while their fate and function remain unclear. Using DCX-CreERT2/Flox-EGFP transgenic mice, we demonstrate that these immature neurons located in the murine piriform cortex do not vanish in the course of aging, but progressively resume their maturation into glutamatergic (TBR1+, CaMKII+) neurons. We provide evidence for a putative functional integration of these newly differentiated neurons as indicated by the increase in perisomatic puncta expressing synaptic markers, the development of complex apical dendrites decorated with numerous spines and the appearance of an axonal initial segment. Since immature neurons found in layer II of the piriform cortex are generated prenatally and devoid of proliferative capacity in the postnatal cortex, the gradual maturation and integration of these cells outside of the canonical neurogenic niches implies that they represent a valuable, but nonrenewable reservoir for cortical plasticity.