Biology subjects

Sanchez-Leon, C. A.

Publications and source records attributed to Sanchez-Leon, C. A..

7 recordsLinked to original sources

bioRxiv2025

Cerebellar tDCS differentially modulates sensory inputs in somatosensory cortex and cerebellum.

Cerebellar transcranial direct current stimulation (Cb-tDCS) is a promising tool for non-invasive modulation of cerebellar function and is under investigation for treating cerebellum-related disorders. However, its local and remote effects on sensory processing remain poorly understood. We investigated the immediate and long-term effects of Cb-tDCS on sensory-evoked responses in the cerebellum and primary somatosensory cortex (S1) of awake mice. Sensory-evoked potentials (SEPs) were recorded in Crus I/II and S1 during and after short (15 s) or long (20 min) sessions of anodal or cathodal Cb-tDCS. In addition, vGLUT1 and GAD65-67 immunoreactivity were quantified, and spectral changes in local field potentials were assessed. Anodal and cathodal Cb-tDCS respectively induced an immediate increase and decrease in the trigeminal component in Crus I/II but no aftereffects were observed 20 min post-stimulation. In S1, Cb-tDCS resulted in polarity and intensity-dependent modulation of the N1 component during stimulation, which was opposite to the changes induced in Crus I/II, as well as a polarity-dependent modulation after stimulation. In addition, anodal Cb-tDCS was associated with reduced GAD65-67 immunoreactivity in S1, whereas vGLUT1 remained unchanged. While power spectrum analysis revealed no changes in Crus I/II, Cb-tDCS induced polarity-dependent post-stimulation changes in S1 spectral power, with higher values after cathodal stimulation. These findings show that Cb-tDCS differentially modulates sensory processing in cerebellar and cortical circuits. While cerebellar effects are mainly transient, stimulation induces longer-lasting changes in the remote cortical area investigated, S1. This underscores the need to consider both local and distant network effects when applying Cb-tDCS in translational and clinical settings.

neuroscience↗

bioRxiv2025

An in vivo model for transcranial direct current stimulation of the motor cortex in awake mice.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique mainly used in humans, in which weak direct currents are applied over the scalp to alter cortical excitability and induce neuroplasticity. Previous studies have demonstrated the value of tDCS for modulating sensory, motor, and cognitive functions, nevertheless, knowledge about how externally applied electric fields affect different components of neuronal networks is still incomplete, and in vivo animal models, which are required for a deeper understanding, are not fully developed. To evaluate the impact of tDCS on cortical excitability, many human experiments assess motor evoked potentials elicited by motor cortex (M1) stimulation. To develop a related in vivo animal model, we recorded electrical activity in M1 of alert mice during and after administration of tDCS over M1. M1 excitability was chronically recorded from layers 2-3, layer 5 and layer 6, evoked by stimulation of the ventral lateral nucleus of the thalamus (VAL). M1-tDCS was applied at 100 and 200 {micro}A for 5 s to test the acute effects on neuronal excitability, and for 15 min to induce after-effects. Acute M1-tDCS increased and decreased the amplitude of VAL-evoked potentials in a polarity-, layer- and intensity-dependent manner. For 15 minutes of anodal or cathodal tDCS, a similar polarity- and intensity-dependent modulation of VAL-evoked potential amplitudes during the 15 minutes of stimulation was observed. After tDCS was switched off, the highest intensity of anodal stimulation induced a significant excitability enhancement during at least two hours after stimulation, whereas the after-effects of cathodal tDCS were less pronounced. The current study demonstrates the feasibility of a mouse model of M1-tDCS to accomplish similar modulatory effects of tDCS on cortical excitability as observed in human experiments. A proper adjustment of tDCS parameters, as compared to application in humans, is however required to obtain these translational effects.

neuroscience↗

bioRxiv2025

Translatome profiling reveals opposing alterations in inhibitory and excitatory neurons of Fragile X mice and identifies EPAC2 as a therapeutic target.

Symptoms of Fragile X Syndrome (FXS), the leading monogenic cause of intellectual disability and autism, are thought to arise from an excitation/inhibition (E/I) imbalance. Here, we leverage cell type specific mRNA sequencing to profile molecular alterations of cortical excitatory and inhibitory neurons in Fmr1 knockout (KO) mice, integrating transcriptomic results with circuit and behavioral readouts to prioritize novel therapeutic targets. Differentially expressed genes (DEG) were largely upregulated in Camk2a expressing excitatory neurons but downregulated in Pvalb-expressing inhibitory neurons, and the underlying signaling pathways were often altered in opposite directions. Among the 184 DEGs that were concordantly dysregulated across both cell types, only Rapgef4 (Epac2) was also an FMRP target, an ASD risk gene and brain enriched. EPAC2 has been implicated in synaptic maturation and plasticity. Systemic administration of an EPAC2 antagonist restored cortical circuit function in Fmr1 KO mice and ameliorated sensory behavioral phenotypes. EPAC2 is a potential target for therapy in FXS.

neuroscience↗

bioRxiv2023

Somatodendritic orientation determines tDCS-induced neuromodulation of Purkinje cell activity in awake mice.

Transcranial direct-current stimulation (tDCS) of the cerebellum is a promising non-invasive neuromodulatory technique being proposed for the treatment of neurological and neuropsychiatric disorders. However, there is a lack of knowledge about how externally applied currents affect neuronal spiking activity in cerebellar circuits in vivo. We investigated how Cb-tDCS affects the firing rate of Purkinje cells (PC) and non-PC in the mouse cerebellar cortex to understand the underlying mechanisms behind the polarity-dependent modulation of neuronal activity induced by tDCS. Mice (n = 9) were prepared for the chronic recording of LFPs to assess the actual electric field gradient imposed by Cb-tDCS in our experimental design. Single-neuron extracellular recording of PCs in awake (n = 24) and anesthetized (n = 27) mice was combined with juxtacellular recordings and subsequent staining of PC with neurobiotin under anesthesia (n = 8) to correlate their neuronal orientation with their response to Cb-tDCS. Finally, a high-density Neuropixels recording system was used to demonstrate the relevance of neuronal orientation during the application of Cb-tDCS in awake mice (n = 6). In this study, we observe that Cb-tDCS induces a heterogeneous polarity-dependent modulation of the firing rate of Purkinje cells (PC) and non-PC in the mouse cerebellar cortex. We demonstrate that the apparently heterogeneous effects of tDCS on PC activity can be explained by taking into account the somatodendritic orientation relative to the electric field. Our findings highlight the need to consider neuronal orientation and morphology to improve tDCS computational models, enhance stimulation protocol reliability, and optimize effects in both basic and clinical applications.

neuroscience↗

bioRxiv2021

Altered cerebellar response to somatosensory stimuli in the Cntnap2 mouse model of autism

Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied cerebellar integration of sensory information in a mouse model of autism, knockout for the Cntnap2 gene. Cntnap2 is widely expressed in Purkinje cells and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in the Cntnap2 mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region upon electrical stimulation of the whisker pad in alert mice and found striking differences between WT and Cntnap2 KO mice. In addition, single-cell recordings identified alterations in both sensory-evoked and spontaneous firing patterns of Purkinje cells. These changes were accompanied by altered intrinsic properties and morphological features of these neurons. Together, these results indicate that the Cntnap2 mouse model could provide novel insight into the pathophysiological mechanisms of ASD core sensory deficits.

neuroscience↗

bioRxiv2020

Impact of chronic transcranial Random-Noise Stimulation (tRNS) on prefrontal cortex excitation-inhibition balance in juvenile mice.

Transcranial random noise stimulation (tRNS), a non-invasive neuromodulatory technique capable of altering cortical activity, has been proposed to improve the signal-to-noise ratio at the neuronal level and the sensitivity of the neurons following an inverted U-function. The aim of this study was to examine the effects of tRNS on vGLUT1 and GAD 65-67 and its safety in terms of pathological changes. For that, juvenile mice were randomly distributed in three different groups: "tRNS 1x" receiving tRNS at the density current used in humans (0.3 A/m2, 20 min), "tRNS 100x" receiving tRNS at two orders of magnitude higher (30.0 A/m2, 20 min) and "sham" (0.3 A/m2, 15 s). Nine tRNS sessions during five weeks were administered to the prefrontal cortex of alert animals. No detectable tissue macroscopic lesions were observed after tRNS sessions. Post-stimulation immunohistochemical analysis of GAD 65-67 and vGLUT1 immunoreactivity showed a reduced GAD 65-67 immunoreactivity levels in the region directly beneath the electrode for tRNS 1x group with no significant effects in the tRNS 100x nor sham group. The observed results points to an excitatory effect associated with a decrease in GABA levels in absence of major histopathological alterations providing a novel mechanistic explanation for tRNS effects.

neuroscience↗

bioRxiv2020

Immediate and long-term effects of transcranial direct-current stimulation in the mouse primary somatosensory cortex

Transcranial direct-current stimulation (tDCS) is a non-invasive brain stimulation technique consisting in the application of weak electric currents on the scalp. Although previous studies have demonstrated the clinical value of tDCS for modulating sensory, motor, and cognitive functions, there are still huge gaps in the knowledge of the underlying physiological mechanisms. To define the immediate impact as well as the after-effects of tDCS on sensory processing, we first performed electrophysiological recordings in primary somatosensory cortex (S1) of alert mice during and after administration of S1-tDCS, and followed up with immunohistochemical analysis of the stimulated brain regions. During the application of cathodal and anodal transcranial currents we observed polarity-specific bidirectional changes in the N1 component of the sensory-evoked potentials (SEPs) and associated gamma oscillations. Regarding the long-term effects observed after 20 min of tDCS, cathodal stimulation produced significant after-effects including a decreased SEP amplitude for up to 30 min, a power reduction in the 20-80 Hz range and a decrease in gamma event related synchronization (ERS). In contrast, no significant long-term changes in SEP amplitude or power analysis were observed after anodal stimulation except for a significant increase in gamma ERS after tDCS cessation. The polarity-specific differences of these long-term effects were corroborated by immunohistochemical analysis, which revealed an unbalance of GAD 65-67 immunoreactivity between the stimulated vs. non-stimulated S1 region only after cathodal tDCS. These results highlight the differences between immediate and long-term effects of tDCS, as well as the asymmetric long-term changes induced by anodal and cathodal stimulation. Significance StatementHere we provide a first glimpse at the immediate and long-term impact of tDCS on neural processing in alert animals. The obtained results highlight the complexity of tDCS-associated effects, which include both bidirectional as well as asymmetrical modulation depending on the polarity of the stimulation. This asymmetry suggests the implication of different mechanisms underlying the long-term effects induced by anodal and cathodal transcranial currents. Identifying and defining these effects and its associated mechanisms is crucial to help design effective protocols for clinical applications.

neuroscience↗