Search Results (101)

A wide range of strategies have been developed to modulate dysfunctional brain activities. This narrative review provides a comparative analysis of biophysical, genetic, and biological neuromodulation approaches with an emphasis on their known or unknown molecular targets and translational potential. The review incorporates data from both preclinical and clinical studies covering deep brain stimulation, transcranial electrical and magnetic stimulation, focused ultrasound, chemogenetics, optogenetics, magnetogenetics, and toxin-based neuromodulation. Each method was assessed based on specificity, safety, reversibility, and mechanistic clarity. Biophysical methods are widely used in clinical practice but often rely on empirical outcomes due to undefined molecular targets. Genetic tools offer cell-type precision in experimental systems but face translational barriers related to delivery and safety. Biological agents, such as botulinum neurotoxins, provide long-lasting yet reversible inhibition via well-characterized molecular pathways. However, they require stereotaxic injections and remain invasive. To overcome individual limitations and improve targeting, delivery, and efficacy, there is a growing interest in the synthesis of multiple approaches. This review highlights a critical gap in the mechanistic understanding of commonly used methods. Addressing this gap by identifying molecular targets may help to improve therapeutic precision. This concise review could be valuable for researchers looking to enter the evolving field of the neuromodulation of brain function. Full article

Astrocyte activation and gender differences play critical roles in the prognosis following stroke. Recent studies have shown that optogenetic technology can promote brain repair after stroke by activating astrocytes in male rats. However, it remains unclear whether gender differences influence the efficacy of optogenetic activation of astrocytes in regulating post-stroke brain repair and its underlying mechanisms. In this study, we activated astrocytes in the ipsilateral cortex of adult glial fibrillary acidic protein-channelrhodopsin 2-enhanced yellow fluorescent protein (GFAP-ChR2-EYFP) transgenic Sprague Dawley rats using optogenetic stimulation at 24, 36, 48, and 60 h after inducing photothrombosis stroke. Neurobehavioral tests, cresyl violet staining, RT-qPCR, Western blot, and immunofluorescence analysis were performed on both female and male rats. Our results showed that male rats exhibited significant improvements in behavioral scores and reduction in infarct size after optogenetic activation of astrocytes at three days post-stroke (p < 0.05), whereas no significant changes were observed in female rats. Additionally, in female rats, the expression of basic fibroblast growth factor (bFGF) increased after ischemic stroke and astrocytic optogenetic stimulation (p < 0.05), leading to enhanced endothelial cell proliferation compared to male rats (p < 0.05). In vitro experiments further demonstrated that the astrocyte activation was inhibited in the presence of bFGF (p < 0.05). These findings suggest that the increase in bFGF levels in females following stroke may inhibit the optogenetic activation of astrocytes, thereby attenuating the therapeutic effect of astrocyte activation on post-stroke brain repair. This study provides important insights into the gender-specific roles of astrocytes in the acute phase of ischemic stroke. Full article

Advances in microfluidics, optogenetics and electronics have enabled the study of dynamically controlled inputs on cellular fate. Here, we applied a microfluidic system to deliver periodic inputs of growth factors to pheochromocytoma cells and measured the extent of premature differentiation as a function of input frequency. Epidermal growth factor-triggered differentiation peaked at two cycles/hour, while nerve growth factor-triggered differentiation peaked at one cycle/hour. To interpret the results, we analyzed a published model that attributed pheochromocytoma cell differentiation to the linear combination of activated enzymes extracellular signal-regulated kinase (ERK), cAMP response element binding protein (CREB), protein kinase B (AKT) and c-Jun N-terminal kinase (JNK) at specific times after step input stimulation. Transfer functions for enzyme activation were derived from the published time-domain activation kinetics and these transfer functions were combined in a parallel architecture as a predictor of neurite outgrowth, as a function of input frequency. Qualitative agreement was observed between the model and the experiments. Full article

Neuroplasticity, the ability of the nervous system to adapt structurally and functionally in response to environmental interactions and injuries, is a cornerstone of recovery in the central (CNS) and peripheral nervous systems (PNS). This review explores the mechanisms underlying neuroplasticity, focusing on the dynamic roles of cellular and molecular processes in recovery from nervous system injuries. Key cellular players, including Schwann cells, oligodendrocytes, and neural stem cells, are highlighted for their contributions to nerve repair, myelination, and regeneration. Advances in therapeutic interventions, such as electrical stimulation, bioluminescent optogenetics, and innovative nerve grafting techniques, are discussed alongside their potential to enhance recovery and functional outcomes. The molecular underpinnings of plasticity, involving synaptic remodeling, homeostatic mechanisms, and activity-dependent regulation of gene expression, are elucidated to illustrate their role in learning, memory, and injury repair. Integrating emerging technologies and therapeutic approaches with a foundational understanding of neuroplasticity offers a pathway toward more effective strategies for restoring nervous system functionality after injury. Full article

Sleep disorders increase the risk of cardiovascular diseases. However, the underlying mechanisms remain unclear. This study aims to examine the critical role of oxytocin neurons in the paraventricular nucleus (PVN^OXT) in regulating the cardiovascular system and to elucidate potential mechanisms through which sleep disturbance may contribute to cardiovascular diseases. In this study, using an automated sleep deprivation system, mice were given chronic sleep deprivation (cSD) for 7 days, 6 h per day. cSD induced blood transcriptomic alterations accompanied by lower heart rate, higher blood pressure, and elevated cardiac autophagy/apoptosis. Instant optogenetic activation of oxytocin neurons in the paraventricular nucleus (PVN^OXT) provoked heart rate suppression in normal mice, whereas in cSD mice, activation precipitated intermittent cardiac arrest. On the contrary, inhibition of PVN^OXT showed no influence on the cardiovascular system of normal mice, but it attenuated cSD-induced rise in blood pressure. Long-term low-frequency stimulation (LTF) of PVN^OXT decreased neuronal excitability and oxytocin release, effectively reversing cSD-mediated cardiovascular responses. Mechanistically, cSD triggered the upregulation of blood-derived 3-mercaptopyruvate sulfurtransferase (mPST), and a suppression of PVN^OXT postsynaptic activity to a certain extent. The quick and long-term decrease of oxytocin by LTF could lead to feedback inhibition in mPST expression and thus reverse cSD-mediated cardiovascular responses. Altogether, modulation of PVN^OXT could mediate cSD-induced cardiovascular abnormalities without affecting normal mice. Our research provided potential targets and key mechanisms for cardiovascular diseases associated with sleep disorders. Full article

Anxiety is a physiological, emotional response that anticipates distal threats. When kept under control, anxiety is a beneficial response, helping animals to maintain heightened attention in environments with potential dangers. However, an overestimation of potential threats can lead to an excessive expression of anxiety that, in humans, may evolve into anxiety disorders. Pharmacological treatments show variable efficacy among patients, highlighting the need for more efforts to better understand the pathogenesis of anxiety disorders. Mounting evidence suggests that astrocytes, a type of glial cells, are active partners of neurons in brain circuits and in the regulation of behaviors under both physiological and pathological conditions. In this review, I summarize the current literature on the role of astrocytes from different brain regions in modulating anxious states, with the goal of exploring novel cerebral mechanisms to identify potential innovative therapeutic targets for the treatment of anxiety disorders. Full article

Optical techniques to study neuronal activity have greatly advanced the field of neuroscience over recent decades. Multichannel silicon-based recording probes combined with optical fibers allow for simultaneous recording and manipulation of neuronal activity that underpins cognitive processes and behavior. The recent development of neural probes incorporating organic light-emitting diodes (OLEDs) and photodiode-based organic photodetectors (OPDs) offer additional advantages of biocompatibility, ultra-small footprint, multifunctionality, and low cost. These developments are ushering in a new generation of devices that are ideal for the interrogation of neuronal activity in vitro and in vivo. In this review, we discuss recent progress in OLED- and OPD-based neural probes, their applications in the optical control of neuronal function, and current challenges and prospects for the future. Full article

Three-dimensional neuronal organoids, spheroids, and tissue mimics are increasingly used to model cognitive processes in vitro. These 3D constructs are also used to model the effects of neurological and psychiatric disorders and to perform computational tasks. The brain’s complex network of neurons is activated via feedforward sensory pathways. Therefore, an interface to 3D constructs that models sensory pathway-like inputs is desirable. In this work, an optical interface for 3D neuronal constructs was developed. Dendrites and axons extended by cortical neurons within the 3D constructs were guided into microchannel-confined bundles. These neurite bundles were then optogenetically stimulated, and evoked responses were evaluated by calcium imaging. Optical stimulation was designed to deliver distinct input patterns to the network in the 3D construct, mimicking sensory pathway inputs to cortical areas in the intact brain. Responses of the network to the stimulation possessed features of neuronal population code, including separability by input pattern and mixed selectivity of individual neurons. This work represents the first demonstration of a pathway-like activation of networks in 3D constructs. Another innovation of this work is the development of an all-optical interface to 3D neuronal constructs, which does not require the use of expensive microelectrode arrays. This interface may enable the use of 3D neuronal constructs for investigations into cortical information processing. It may also enable studies into the effects of neurodegenerative or psychiatric disorders on cortical computation. Full article

Neuromodulation stands as a cutting-edge approach in the fields of neuroscience and therapeutic intervention typically involving the regulation of neural activity through physical and chemical stimuli. The purpose of this review is to provide an overview and evaluation of different neuromodulation techniques, anticipating a clearer understanding of the future developmental trajectories and the challenges faced within the domain of neuromodulation that can be achieved. This review categorizes neuromodulation techniques into genetic neuromodulation methods (including optogenetics, chemogenetics, sonogenetics, and magnetogenetics) and non-genetic neuromodulation methods (including deep brain stimulation, transcranial magnetic stimulation, transcranial direct current stimulation, transcranial ultrasound stimulation, photobiomodulation therapy, infrared neuromodulation, electromagnetic stimulation, sensory stimulation therapy, and multi-physical-factor stimulation techniques). By systematically evaluating the principles, mechanisms, advantages, limitations, and efficacy in modulating neuronal activity and the potential applications in interventions of neurological disorders of these neuromodulation techniques, a comprehensive picture is gradually emerging regarding the advantages and challenges of neuromodulation techniques, their developmental trajectory, and their potential clinical applications. This review highlights significant advancements in applying these techniques to treat neurological and psychiatric disorders. Genetic methods, such as sonogenetics and magnetogenetics, have demonstrated high specificity and temporal precision in targeting neuronal populations, while non-genetic methods, such as transcranial magnetic stimulation and photobiomodulation therapy, offer noninvasive and versatile clinical intervention options. The transformative potential of these neuromodulation techniques in neuroscience research and clinical practice is underscored, emphasizing the need for integration and innovation in technologies, the optimization of delivery methods, the improvement of mediums, and the evaluation of toxicity to fully harness their therapeutic potential. Full article

Optogenetics is a combination of optical and genetic technologies used to activate or, conversely, inhibit specific cells in living tissues. The possibilities of using optogenetics approaches for the treatment of epilepsy, Parkinson’s and Alzheimer’s disease (AD) are being actively researched. In recent years, it has become clear that one of the most important players in the development of AD is astrocytes. Astrocytes affect amyloid clearance, participate in the development of neuroinflammation, and regulate the functioning of neural networks. We used an adeno-associated virus carrying the glial fibrillary acidic protein (GFAP) promoter driving the optogenetic channelrhodopsin-2 (ChR2) gene to transduce astrocytes in primary mouse hippocampal cultures. We recorded the bioelectrical activity of neural networks from day 14 to day 21 of cultivation using multielectrode arrays. A single optogenetic stimulation of astrocytes at 14 day of cultivation (DIV14) did not cause significant changes in neural network bioelectrical activity. Chronic optogenetic stimulation from DIV14 to DIV21 exerts a stimulatory effect on the bioelectrical activity of primary hippocampal cultures (the proportion of spikes included in network bursts significantly increased since DIV19). Moreover, chronic optogenetic stimulation over seven days partially preserved the activity and functional architecture of neuronal network in amyloidosis modeling. These results suggest that the selective optogenetic activation of astrocytes may represent a promising novel therapeutic strategy for combating AD. Full article

When exposed to X-rays, scintillators emit visible luminescence. X-ray-mediated optogenetics employs scintillators for remotely activating light-sensitive proteins in biological tissue through X-ray irradiation. This approach offers advantages over traditional optogenetics, allowing for deeper tissue penetration and wireless control. Here, we assessed the short-term safety and efficacy of candidate scintillator materials for neuronal control. Our analyses revealed that lead-free halide scintillators, such as Cs₃Cu₂I₅, exhibited significant cytotoxicity within 24 h and induced neuroinflammatory effects when injected into the mouse brain. In contrast, cerium-doped gadolinium aluminum gallium garnet (Ce:GAGG) nanoparticles showed no detectable cytotoxicity within the same period, and injection into the mouse brain did not lead to observable neuroinflammation over four weeks. Electrophysiological recordings in the cerebral cortex of awake mice showed that X-ray-induced radioluminescence from Ce:GAGG nanoparticles reliably activated 45% of the neuronal population surrounding the implanted particles, a significantly higher activation rate than europium-doped GAGG (Eu:GAGG) microparticles, which activated only 10% of neurons. Furthermore, we established the cell-type specificity of this technique by using Ce:GAGG nanoparticles to selectively stimulate midbrain dopamine neurons. This technique was applied to freely behaving mice, allowing for wireless modulation of place preference behavior mediated by midbrain dopamine neurons. These findings highlight the unique suitability of Ce:GAGG nanoparticles for X-ray-mediated optogenetics. The deep tissue penetration, short-term safety, wireless neuronal control, and cell-type specificity of this system offer exciting possibilities for diverse neuroscience applications and therapeutic interventions. Full article

The dorsal raphe nucleus (DRN) has gained attention owing to its involvement in various physiological functions, such as sleep–awake, feeding, and emotion, with its analgesic role being particularly significant. It is described as the “pain inhibitory nucleus” in the brain. The DRN has diverse projections from hypothalamus, midbrain, and pons. In turn, the DRN is a major source of projections to diverse cortex, limbic forebrain thalamus, and the midbrain and contains highly heterogeneous neuronal subtypes. The activation of DRN neurons in mice prevents the establishment of neuropathic, chronic pain symptoms. Chemogenetic or optogenetic inhibition neurons in the DRN are sufficient to establish pain phenotypes, including long-lasting tactile allodynia, that scale with the extent of stimulation, thereby promoting nociplastic pain. Recent progress has been made in identifying the neural circuits and cellular mechanisms in the DRN that are responsible for sensory modulation. However, there is still a lack of comprehensive review addressing the specific neuron types in the DRN involved in pain modulation. This review summarizes the function of specific cell types within DRN in the pain regulation, and aims to improve understanding of the mechanisms underlying pain regulation in the DRN, ultimately offering insights for further exploration. Full article

The intracerebral spread of tau is a critical mechanism associated with functional decline in Alzheimer’s disease (AD) and other tauopathies. Recently, a hypothesis has emerged suggesting that tau propagation is linked to functional neuronal connections, specifically driven by neuronal hyperactivity. However, experimental validation of this hypothesis remains limited. In this study, we investigated how tau propagation from the entorhinal cortex to the hippocampus, the neuronal circuit most susceptible to tau pathology in AD, is affected by the selective stimulation of neuronal activity along this circuit. Using a mouse model of seed-induced propagation combined with optogenetics, we found that the chronic stimulation of this neuronal connection over a 4-week period resulted in a significant increase in insoluble tau accumulation in both the entorhinal cortex and hippocampus. Importantly, the ratio of tau accumulation in the hippocampus relative to that in the entorhinal cortex, serving as an indicator of transcellular spreading, was significantly higher in mice subjected to chronic stimulation. These results support the notion that abnormal neuronal activity promotes tau propagation, thereby implicating it in the progression of tauopathy. Full article

The brain–computer interface (BCI) is one of the most powerful tools in neuroscience and generally includes a recording system, a processor system, and a stimulation system. Optogenetics has the advantages of bidirectional regulation, high spatiotemporal resolution, and cell-specific regulation, which expands the application scenarios of BCIs. In recent years, optogenetic BCIs have become widely used in the lab with the development of materials and software. The systems were designed to be more integrated, lightweight, biocompatible, and power efficient, as were the wireless transmission and chip-level embedded BCIs. The software is also constantly improving, with better real-time performance and accuracy and lower power consumption. On the other hand, as a cutting-edge technology spanning multidisciplinary fields including molecular biology, neuroscience, material engineering, and information processing, optogenetic BCIs have great application potential in neural decoding, enhancing brain function, and treating neural diseases. Here, we review the development and application of optogenetic BCIs. In the future, combined with other functional imaging techniques such as near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI), optogenetic BCIs can modulate the function of specific circuits, facilitate neurological rehabilitation, assist perception, establish a brain-to-brain interface, and be applied in wider application scenarios. Full article

Heterosynaptic plasticity, along with Hebbian homosynaptic plasticity, is an important mechanism ensuring the stable operation of learning neuronal networks. However, whether heterosynaptic plasticity occurs in the whole brain in vivo, and what role(s) in brain function in vivo it could play, remains unclear. Here, we used an optogenetics approach to apply a model of intracellular tetanization, which was established and employed to study heterosynaptic plasticity in brain slices, to study the plasticity of response properties of neurons in the mouse visual cortex in vivo. We show that optogenetically evoked high-frequency bursts of action potentials (optogenetic tetanization) in the principal neurons of the visual cortex induce long-term changes in the responses to visual stimuli. Optogenetic tetanization had distinct effects on responses to different stimuli, as follows: responses to optimal and orthogonal orientations decreased, responses to null direction did not change, and responses to oblique orientations increased. As a result, direction selectivity of the neurons decreased and orientation tuning became broader. Since optogenetic tetanization was a postsynaptic protocol, applied in the absence of sensory stimulation, and, thus, without association of presynaptic activity with bursts of action potentials, the observed changes were mediated by mechanisms of heterosynaptic plasticity. We conclude that heterosynaptic plasticity can be induced in vivo and propose that it may play important homeostatic roles in operation of neural networks by helping to prevent runaway dynamics of responses to visual stimuli and to keep the tuning of neuronal responses within the range optimized for the encoding of multiple features in population activity. Full article