Journal of Neuroscience Research

doi: 10.1002/jnr.25106pmid: N/A

doi: 10.1002/jnr.24886pmid: N/A

Garg, Pranjal; Sengupta, Sumedha

doi: 10.1002/jnr.25097pmid: 35711136

Marfia, Giovanni; Navone, Stefania Elena; Guarnaccia, Laura; Campanella, Rolando; Locatelli, Marco; Miozzo, Monica; Perelli, Pietro; Della Morte, Giulio; Catamo, Leonardo; Tondo, Pietro; Campanella, Carmelo; Lucertini, Marco; Ciniglio Appiani, Giuseppe; Landolfi, Angelo; Garzia, Emanuele

doi: 10.1002/jnr.25066

Schmaußer, Maximilian; Hoffmann, Sven; Raab, Markus; Laborde, Sylvain

doi: 10.1002/jnr.25062pmid: 35582757

Noninvasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation and transcranial direct current stimulation are widely used to test the involvement of specific cortical regions in various domains such as cognition and emotion. Despite the capability of stimulation techniques to test causal directions, this approach has been only sparsely used to examine the cortical regulation of autonomic nervous system (ANS) functions such as heart rate (HR) and heart rate variability (HRV) and to test current models in this regard. In this preregistered (PROSPERO) systematic review and meta‐analysis, we aimed to investigate, based on meta‐regression, whether NIBS represents an effective method for modulating HR and HRV measures, and to evaluate whether the ANS is modulated by cortical mechanisms affected by NIBS. Here we have adhered to the PRISMA guidelines. In a series of four meta‐analyses, a total of 131 effect sizes from 35 sham‐controlled trials were analyzed using robust variance estimation random‐effects meta‐regression technique. NIBS was found to effectively modulate HR and HRV with small to medium effect sizes. Moderator analyses yielded significant differences in effects between stimulation of distinct cortical areas. Our results show that NIBS is a promising tool to investigate the cortical regulation of ANS, which may add to the existing brain imaging and animal study literature. Future research is needed to identify further factors modulating the size of effects. As many of the studies reviewed were found to be at high risk of bias, we recommend that methods to reduce potential risk of bias be used in the design and conduct of future studies.

Bales, Katie L.; Chacko, Alicia S.; Nickerson, John M.; Boatright, Jeffrey H.; Pardue, Machelle T.

doi: 10.1002/jnr.25063pmid: 35582827

Exercise is an effective neuroprotective intervention that preserves retinal function and structure in several animal models of retinal degeneration. However, the retinal cell types governing exercise‐induced neuroprotection remain elusive. Previously, we found exercise‐induced retinal neuroprotection was associated with increased levels of retinal brain‐derived neurotrophic factor (BDNF) and required intact signal transduction with its high‐affinity receptor, tropomyosin kinase B (TrkB). Brain studies have shown astrocytes express BDNF and TrkB and that decreased BDNF–TrkB signaling in astrocytes contributes to neurodegeneration. Additionally, exercise has been shown to alter astrocyte morphology. Using a light‐induced retinal degeneration (LIRD) model, we investigated how exercise influences retinal astrocytes in adult male BALB/c mice. Treadmill exercise in dim control and LIRD groups had increased astrocyte density, GFAP labeling, branching, dendritic endpoints, and arborization. Meanwhile, inactive LIRD animals had significant reductions in all measured parameters. Additionally, exercised groups had increased astrocytic BDNF expression that was visualized using proximity ligase assay. Isolated retinal astrocytes from exercised LIRD groups had significantly increased expression of a specific isoform of TrkB associated with cell survival, TrkB.FL. Conversely, inactive LIRD isolated retinal astrocytes had significantly increased expression of TrkB.T1, which has been implicated in neuronal cell death. Our data indicate exercise not only alters retinal astrocyte morphology but also promotes specific BDNF–TrkB signaling associated with cell survival and protection during retinal degeneration. These findings provide novel insights into the effects of treadmill exercise on retinal astrocyte morphology and cellular expression, highlighting retinal astrocytes as a potential cell type involved in BDNF–TrkB signaling.

Ramasamy, Ramalakshmi; Hardy, Cara C.; Crocker, Stephen J.; Smith, Phillip P.

doi: 10.1002/jnr.25065pmid: 35596557

Multiple sclerosis (MS) is a chronic, progressively debilitating demyelinating disease of the central nervous system (CNS). Nearly 80% of MS patients experience lower urinary tract dysfunction early in their diagnosis. This significantly affects the quality of life, and in latter stages of disease is a leading cause of hospitalization. Previously, animal models have shown that inflammatory demyelination in the CNS causes profound bladder dysfunction, but the confounding influence of systemic inflammation limits the potential interpretation of the contribution of CNS demyelination to bladder dysfunction. Since the micturition circuit has myelinated neuronal connections in the cortex, brainstem, and spinal cord, we examined alterations in bladder function in the cuprizone model characterized by demyelinating lesions in the cortex and corpus callosum that are independent of T‐cell–mediated autoimmunity. Herein, we report that a 4‐week dietary cuprizone treatment in C57Bl/6J mice induced alterations in voiding behavior with increased micturition frequency and reduced volume voided, similar to human MS bladder dysfunction. Subsequently, recovery from cuprizone treatment restored normal bladder function. Demyelination and remyelination were confirmed by Luxol Fast Blue staining of the corpus callosum. Additionally, we also determined that an 8‐week cuprizone treatment, resulting in chronic demyelination lacking spontaneous remyelination potential, is associated with an exacerbated voiding phenotype. Interestingly, while cuprizone‐induced CNS demyelination severely affected conscious (cortical) urinary behavior, the brainstem and spinal cord reflex remained unchanged, as confirmed by urethane‐anesthetized cystometry. This is the first study to show that cortical demyelination independent of inflammation can negatively impact urinary function.

Pothion, Hugo; Lihrmann, Isabelle; Duclos, Celia; Riou, Gaëtan; Cartier, Dorthe; Boukhzar, Loubna; Lefranc, Benjamin; Leprince, Jérôme; Guérout, Nicolas; Marie, Jean‐Paul; Anouar, Youssef

doi: 10.1002/jnr.25098pmid: 35730417

Peripheral nerve injury (PNI) is frequent and many patients suffer lifelong disabilities in severe cases. Although the peripheral nervous system is able to regenerate, its potential is limited. In this study, we tested in a nerve regeneration model in rat the potential beneficial effect of a short mimetic peptide, named PSELT, which derives from SELENOT, an essential thioredoxin‐like selenoprotein endowed with neuroprotective and antioxidant activities. For this purpose, the right facial nerve of female Long–Evans rats was axotomized then bridged with a free femoral vein interposition graft. PSELT (1 μM) was injected into the vein immediately and 48 h after the injury, and the effects observed were compared to those found after an end‐to‐end suture used as a gold standard treatment. Whisking behavior, electrophysiological potential, and histological analyses were performed 3 months after injury to determine the effects of these treatments. These analyses revealed that PSELT‐treated animals exhibit a better motor recovery in terms of protraction amplitude and velocity of vibrissae compared to control and end‐sutured nerve animal groups. Moreover, administration of PSELT following injury enhanced muscle innervation, axonal elongation, and myelination of newly formed nerve fibers. Altogether, these results indicate that a PSELT‐based treatment is sufficient to enhance facial nerve myelination and regeneration and could represent a new therapeutic tool to treat PNI.

Winter, Andrew; McMurray, Katherine M. J.; Ahlbrand, Rebecca; Allgire, Emily; Shukla, Sachi; Jones, James; Sah, Renu

doi: 10.1002/jnr.25059pmid: 35553084

An important role of pH homeostasis has been suggested in the physiology of panic disorder, with acidosis as an interoceptive trigger leading to fear and panic. Identification of novel mechanisms that can translate acidosis into fear will promote a better understanding of panic physiology. The current study explores a role of the subfornical organ (SFO), a blood–brain barrier compromised brain area, in translating acidosis to fear‐relevant behaviors. We performed SFO‐targeted acidification in male, wild‐type mice and mice lacking microglial acid‐sensing G protein–coupled receptor—T‐cell death‐associated gene 8 (TDAG8). Localized SFO acidification evoked significant freezing and reduced exploration that was dependent on the presence of acid‐sensor TDAG8. Acidosis promoted the activation of SFO microglia and neurons that were absent in TDAG8‐deficient mice. The assessment of regional neuronal activation in wild‐type and TDAG8‐deficient mice following SFO acidification revealed significant acidosis and genotype‐dependent alterations in the hypothalamus, amygdala, prefrontal cortex, and periaqueductal gray nuclei. Furthermore, mapping of interregional co‐activation patterns revealed that SFO acidosis promoted positive hypothalamic‐cortex associations and desynchronized SFO‐cortex and amygdala‐cortex associations, suggesting an interplay of homeostatic and fear regulatory areas. Importantly, these alterations were not evident in TDAG8‐deficient mice. Overall, our data support a regulatory role of subfornical organ microglial acid sensing in acidosis‐evoked fear, highlighting a centralized role of blood–brain barrier compromised nodes in interoceptive sensing and behavioral regulation. Identification of pathways by which humoral information can modulate fear behavior is relevant to panic disorder, where aberrant interoceptive signaling has been reported.

Montarolo, Francesca; Martire, Serena; Chiara, Francesco; Allegra, Sarah; De Francia, Silvia; Hoxha, Eriola; Tempia, Filippo; Capobianco, Marco Alfonso; Bertolotto, Antonio

doi: 10.1002/jnr.25067pmid: 35593070

The transcription factor NURR1 is essential to the generation and maintenance of midbrain dopaminergic (mDA) neurons and its deregulation is involved in the development of dopamine (DA)‐associated brain disorders, such as Parkinson's disease (PD). The old male NURR1 heterozygous knockout (NURR1‐KO) mouse has been proposed as a model of PD due to its altered motor performance that was, however, not confirmed in a subsequent study. Based on these controversial results, we explored the effects of the NURR1 deficiency on locomotor activity, motor coordination, brain and plasma DA levels, blood pressure and heart rate of old mice, also focusing on the potential effect of sex. As a probable consequence of the role of NURR1 in DA pathway, we observed that the old NURR1‐KO mouse is characterized by motor impairment, and increased brain DA level and heart rate, independently from sex. However, we also observed an alteration in spontaneous locomotor activity that only affects males. In conclusion, NURR1 deficiency triggers sex‐ and age‐specific alterations of behavioral responses, of DA levels and cardiovascular abnormalities. Further studies in simplified systems will be necessary to dissect the mechanism underlying these observations.