Astrocytes play several critical roles in the normal functioning of the mammalian brain, including ion homeostasis, synapse formation, and synaptic plasticity. Following injury and infection or in the setting of neurodegeneration, astrocytes become hypertrophic and reactive, a process termed astrogliosis. Although acute reactive gliosis is beneficial in limiting further tissue damage, chronic gliosis becomes detrimental for neuronal recovery and regeneration. Several extracellular factors have been identified that generate reactive astrocytes; however, very little is known about the cell-autonomous transcriptional mechanisms that regulate the maintenance of astrocytes in the normal non-reactive state. Here, we show that conditional deletion of the stimulus-dependent transcription factor, serum response factor (SRF) in astrocytes ( Srf GFAPCKO) results in astrogliosis marked by hypertrophic morphology and increased expression of GFAP, vimentin, and nestin. These reactive astrocytes were not restricted to an...

Functional magnetic resonance imaging (fMRI) neurofeedback (NF) is a promising tool to study the relationship between behavior and brain activity. It enables people to self-regulate their brain signal. Here, we applied fMRI NF to train healthy participants to increase activity in their supplementary motor area (SMA) during a motor imagery (MI) task of complex body movements while they received a continuous visual feedback signal. This signal represented the activity of participants’ localized SMA regions in the NF group and a prerecorded signal in the control group (sham feedback). In the NF group only, results showed a gradual increase in SMA-related activity across runs. This upregulation was largely restricted to the SMA, while other regions of the motor network showed no, or only marginal NF effects. In addition, we found behavioral changes, i.e., shorter reaction times in a Go/No-go task after the NF training only. These results suggest that NF can assist participants to develop greater control over a...

Olfaction guides navigation and decision-making in organisms from multiple animal phyla. Understanding how animals use olfactory cues to guide navigation is a complicated problem for two main reasons. First, the sensory cues used to guide animals to the source of an odor consist of volatile molecules, which form plumes. These plumes are governed by turbulent air currents, resulting in an intermittent and spatiotemporally varying olfactory signal. A second problem is that the technologies for chemical quantification are cumbersome and cannot be used to detect what the freely moving animal senses in real time. Understanding how the olfactory system guides this behavior requires knowing the sensory cues and the accompanying brain signals during navigation. Here, we present a method for real-time monitoring of olfactory information using low-cost, lightweight sensors that robustly detect common solvent molecules, like alcohols, and can be easily mounted on the heads of freely behaving mice engaged in odor-guid...

The failure of adult CNS neurons to survive and regenerate their axons after injury or in neurodegenerative disease remains a major target for basic and clinical neuroscience. Recent data demonstrated in the adult mouse that exogenous expression of Sry-related high-mobility-box 11 (Sox11) promotes optic nerve regeneration after optic nerve injury but exacerbates the death of a subset of retinal ganglion cells (RGCs), α-RGCs. During development, Sox11 is required for RGC differentiation from retinal progenitor cells (RPCs), and we found that mutation of a single residue to prevent SUMOylation at lysine 91 (K91) increased Sox11 nuclear localization and RGC differentiation in vitro . Here, we explored whether this Sox11 manipulation similarly has stronger effects on RGC survival and optic nerve regeneration. In vitro , we found that non-SUMOylatable Sox11K91A leads to RGC death and suppresses axon outgrowth in primary neurons. We furthermore found that Sox11K91A more strongly promotes axon regeneration but al...

There has been a long-standing debate regarding the role of peripheral afferents in mediating rapid-onset anorexia among other responses elicited by peripheral inflammatory insults. Thus, the current study assessed the sufficiency of peripheral afferents expressing toll-like receptor 4 (TLR4) to the initiation of the anorexia caused by peripheral bacterial lipopolysaccharide (LPS). We generated a Tlr4 null (Tlr4LoxTB) mouse in which Tlr4 expression is globally disrupted by a loxP-flanked transcription blocking (TB) cassette. This novel mouse model allowed us to restore the endogenous TLR4 expression in specific cell types. Using Zp3-Cre and Nav1.8-Cre mice, we produced mice that express TLR4 in all cells (Tlr4LoxTB X Zp3-Cre) and in peripheral afferents (Tlr4LoxTB X Nav1.8-Cre), respectively. We validated the Tlr4LoxTB mice, which were phenotypically identical to previously reported global TLR4 knock-out mice. Contrary to our expectations, the administration of LPS did not cause rapid-onset anorexia in mic...

Photopharmacology is a unique approach that through a combination of photochemistry methods and advanced life science techniques allows the study and control of specific biological processes, ranging from intracellular pathways to brain circuits. Recently, a first photochromic channel blocker of anion-selective GABAA receptors, the azobenzene-nitrazepam-based photochromic compound (Azo-NZ1), has been described. In the present study, using patch-clamp technique in heterologous system and in mice brain slices, site-directed mutagenesis and molecular modeling we provide evidence of the interaction of Azo-NZ1 with glycine receptors (GlyRs) and determine the molecular basis of this interaction. Glycinergic synaptic neurotransmission determines an important inhibitory drive in the vertebrate nervous system and plays a crucial role in the control of neuronal circuits in the spinal cord and brain stem. GlyRs are involved in locomotion, pain sensation, breathing, and auditory function, as well as in the development...

For decades, a role for the Ca2+-binding protein calmodulin (CaM) in Ca2+-dependent presynaptic modulation of synaptic transmission has been recognized. Here, we investigated the influence of CaM on evoked and spontaneous neurotransmission at rod bipolar (RB) cell→AII amacrine cell synapses in the mouse retina. Our work was motivated by the observations that expression of CaM in RB axon terminals is extremely high and that [Ca2+] in RB terminals normally rises sufficiently to saturate endogenous buffers, making tonic CaM activation likely. Taking advantage of a model in which RBs can be stimulated by expressed channelrhodopsin-2 (ChR2) to avoid dialysis of the presynaptic terminal, we found that inhibition of CaM dramatically decreased evoked release by inhibition of presynaptic Ca channels while at the same time potentiating both Ca2+-dependent and Ca2+-independent spontaneous release. Remarkably, inhibition of myosin light chain kinase (MLCK), but not other CaM-dependent targets, mimicked the effects of ...

Expertise enables humans to achieve outstanding performance on domain-specific tasks, and programming is no exception. Many studies have shown that expert programmers exhibit remarkable differences from novices in behavioral performance, knowledge structure, and selective attention. However, the underlying differences in the brain of programmers are still unclear. We here address this issue by associating the cortical representation of source code with individual programming expertise using a data-driven decoding approach. This approach enabled us to identify seven brain regions, widely distributed in the frontal, parietal, and temporal cortices, that have a tight relationship with programming expertise. In these brain regions, functional categories of source code could be decoded from brain activity and the decoding accuracies were significantly correlated with individual behavioral performances on a source-code categorization task. Our results suggest that programming expertise is built on fine-tuned cor...

Early-life stress (ELS) is associated with a higher risk of psychopathologies in adulthood, such as depression, which may be related to persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to evaluate the effects of ELS on the functioning of the HPA axis in clinical and experimental situations. Clinically, patients with current depressive episodes, with and without ELS, and healthy controls, composed the sample. Subjects took a capsule containing placebo, fludrocortisone, prednisolone, dexamethasone or spironolactone followed by an assessment of plasma cortisol the morning after. Experimentally, male Wistar rats were submitted to ELS protocol based on variable, unpredictable stressors from postnatal day (PND)1 to PND21. On PND65 animals were behaviorally evaluated through the forced-swimming test (FST). At PND68, pharmacological challenges started, using mifepristone, dexamethasone, spironolactone, or fludrocortisone, and corticosterone levels were determined 3 h after inje...

Speech signals have a unique shape of long-term modulation spectrum that is distinct from environmental noise, music, and non-speech vocalizations. Does the human auditory system adapt to the speech long-term modulation spectrum and efficiently extract critical information from speech signals? To answer this question, we tested whether neural responses to speech signals can be captured by specific modulation spectra of non-speech acoustic stimuli. We generated amplitude modulated (AM) noise with the speech modulation spectrum and 1/f modulation spectra of different exponents to imitate temporal dynamics of different natural sounds. We presented these AM stimuli and a 10-min piece of natural speech to 19 human participants undergoing electroencephalography (EEG) recording. We derived temporal response functions (TRFs) to the AM stimuli of different spectrum shapes and found distinct neural dynamics for each type of TRFs. We then used the TRFs of AM stimuli to predict neural responses to the speech signals, ...