Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia, however no effective treatments are available. Here, based on magnetic resonance imaging studies of patients with white matter damage, we found that this damage is associated with disorganized cortical structure. In a mouse model, optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell (OPC) proliferation, remyelination in the corpus callosum, and recovery of cognitive ability after cerebral hypoperfusion. The therapeutic effect of such stimulation was restricted to the upper layers of the cortex, but also spanned a wide time window after ischemia. Mechanistically, enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic neurons. Additionally, skin stroking, an easier method to translate into clinical practice, activated the somatosensory cortex, thereby promoting OPC proliferation, remyelination and cognitive recovery following cerebral hypoperfusion. In summary, we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral hypoperfusion. It should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.

BACKGROUND: Key to the advancement of the field of bioelectronic medicine is the identification of novel pathways of neural regulation of immune function. Sensory neurons (termed nociceptors) recognize harmful stimuli and initiate a protective response by eliciting pain and defensive behavior. Nociceptors also interact with immune cells to regulate host defense and inflammatory responses. However, it is still unclear whether nociceptors participate in regulating primary IgG antibody responses to novel antigens.
METHODS: To understand the role of transient receptor potential vanilloid 1 (TRPV1)-expressing neurons in IgG responses, we generated TRPV1-Cre/Rosa-ChannelRhodopsin2 mice for precise optogenetic activation of TRPV1 + neurons and TRPV1-Cre/Lox-diphtheria toxin A mice for targeted ablation of TRPV1-expressing neurons. Antigen-specific antibody responses were longitudinally monitored for 28 days.
RESULTS: Here we show that TRPV1 expressing neurons are required to develop an antigen-specific immune response. We demonstrate that selective optogenetic stimulation of TRPV1+ nociceptors during immunization significantly enhances primary IgG antibody responses to novel antigens. Further, mice rendered deficient in TRPV1- expressing nociceptors fail to develop primary IgG antibody responses to keyhole limpet hemocyanin or haptenated antigen.
CONCLUSIONS: This functional and genetic evidence indicates a critical role for nociceptor TRPV1 in antigen-specific primary antibody responses to novel antigens. These results also support consideration of potential therapeutic manipulation of nociceptor pathways using bioelectronic devices to enhance immune responses to foreign antigens.

Background: It had been shown that selective cardiac vagal activation holds great potential for heart regeneration. Optogenetics has clinical translation potential as a novel means of modulating targeted neurons. This study aimed to investigate whether cardiac vagal activation via optogenetics could improve heart regenerative repair after myocardial infarction (MI) and to identify the underlying mechanism. Methods: We used an adeno-associated virus (AAV) as the vector to deliver ChR2, a light-sensitive protein, to the left nodose ganglion (LNG). To assess the effects of the cardiac vagus nerve on cardiomyocyte (CM) proliferation and myocardial regeneration in vivo, the light-emitting diode illumination (470 nm) was applied for optogenetic stimulation to perform the gain-of-function experiment and the vagotomy was used as a loss-of-function assay. Finally, sequencing data and molecular biology experiments were analyzed to determine the possible mechanisms by which the cardiac vagus nerve affects myocardial regenerative repair after MI. Results: Absence of cardiac surface vagus nerve after MI was more common in adult hearts with low proliferative capacity, causing a poor prognosis. Gain- and loss-of-function experiments further demonstrated that optogenetic stimulation of the cardiac vagus nerve positively regulated cardiomyocyte (CM) proliferation and myocardial regeneration in vivo. More importantly, optogenetic stimulation attenuated ventricular remodeling and improved cardiac function after MI. Further analysis of sequencing results and flow cytometry revealed that cardiac vagal stimulation activated the IL-10/STAT3 pathway and promoted the polarization of cardiac macrophages to the M2 type, resulting in beneficial cardiac regenerative repair after MI. Conclusions: Targeting the cardiac vagus nerve by optogenetic stimulation induced macrophage M2 polarization by activating the IL-10/STAT3 signaling pathway, which obviously optimized the regenerative microenvironment and then improved cardiac function after MI.

Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), using GABA provided by uptake via GABA transporter-1 (GAT1). Functions of GABA co-release are poorly understood. We asked whether co-released GABA autoinhibits dopamine release via axonal GABA type A receptors (GABAARs), complementing established inhibition by dopamine acting at axonal D2 autoreceptors. We show that dopamine axons express α3-GABAAR subunits in mouse striatum. Enhanced dopamine release evoked by single-pulse optical stimulation in striatal slices with GABAAR antagonism confirms that an endogenous GABA tone limits dopamine release. Strikingly, an additional inhibitory component is seen when multiple pulses are used to mimic phasic axonal activity, revealing the role of GABAAR-mediated autoinhibition of dopamine release. This autoregulation is lost in conditional GAT1-knockout mice lacking GABA co-release. Given the faster kinetics of ionotropic GABAARs than G-protein-coupled D2 autoreceptors, our data reveal a mechanism whereby co-released GABA acts as a first responder to dampen phasic-to-tonic dopamine signaling.

Low-voltage fast (LVF) seizure-onset is one of the two frequently observed temporal lobe seizure-onset patterns. Depth electroencephalogram profile analysis illustrated that the peak amplitude of LVF onset was deep temporal areas, e.g., hippocampus. However, the specific dynamic transition mechanisms between normal hippocampal rhythmic activity and LVF seizure-onset remain unclear. Recently, the optogenetic approach to gain control over epileptic hyper-excitability both in vitro and in vivo has become a novel noninvasive modulation strategy. Here, we combined biophysical modeling to study LVF dynamics following changes in crucial physiological parameters, and investigated the potential optogenetic intervention mechanism for both excitatory and inhibitory control. In an Ammon\'s horn 3 (CA3) biophysical model with light-sensitive protein channelrhodopsin 2 (ChR2), we found that the cooperative effects of excessive extracellular potassium concentration of parvalbumin-positive (PV+) inhibitory interneurons and synaptic links could induce abundant types of discharges of the hippocampus, and lead to transitions from gamma oscillations to LVF seizure-onset. Simulations of optogenetic stimulation revealed that the LVF seizure-onset and morbid fast spiking could not be eliminated by targeting PV+ neurons, whereas the epileptic network was more sensitive to the excitatory control of principal neurons with strong optogenetic currents. We illustrate that in the epileptic hippocampal network, the trajectories of the normal and the seizure state are in close vicinity and optogenetic perturbations therefore may result in transitions. The network model system developed in this study represents a scientific instrument to disclose the underlying principles of LVF, to characterize the effects of optogenetic neuromodulation, and to guide future treatment for specific types of seizures.

Fetal alcohol spectrum disorder (FASD) is the most common preventable form of developmental and neurobehavioral disability. Animal models have demonstrated that even low to moderate prenatal alcohol exposure (PAE) is sufficient to impair behavioral flexibility in multiple domains. Previously, utilizing a moderate limited access drinking in the dark paradigm, we have shown that PAE 1) impairs touchscreen pairwise visual reversal in male adult offspring 2) leads to small but significant decreases in orbitofrontal (OFC) firing rates 3) significantly increases dorsal striatum (dS) activity and 4) aberrantly sustains OFC-dS synchrony across early reversal. In the current study, we examined whether optogenetic stimulation of OFC-dS projection neurons would be sufficient to rescue the behavioral inflexibility induced by PAE in male C57BL/6J mice. Following discrimination learning, we targeted OFC-dS projections using a retrograde adeno-associated virus (AAV) delivered to the dS which expressed channel rhodopsin (ChR2). During the first four sessions of reversal learning, we delivered high frequency optogenetic stimulation to the OFC via optic fibers immediately following correct choice responses. Our results show that optogenetic stimulation significantly reduced the number of sessions, incorrect responses, and correction errors required to move past the early perseverative phase for both PAE and control mice. In addition, OFC-dS stimulation during early reversal learning reduced the increased sessions, correct and incorrect responding seen in PAE mice during the later learning phase of reversal but did not significantly alter later performance in control ChR2 mice. Taken together these results suggest that stimulation of OFC-dS projections can improve early reversal learning in PAE and control mice, and these improvements can persist even into later stages of the task days later. These studies provide an important foundation for future clinical approaches to improve executive control in those with FASD. This article is part of the Special Issue on \"PFC circuit function in psychiatric disease and relevant models\".

Sustained visual attention allows us to process and react to unpredictable, behaviorally relevant sensory input. Sustained attention engages communication between the higher-order visual thalamus and its connected cortical regions. However, it remains unclear whether there is a causal relationship between oscillatory circuit dynamics and attentional behavior in these thalamo-cortical circuits. By using rhythmic optogenetic stimulation in the ferret, we provide causal evidence that higher-order visual thalamus coordinates thalamo-cortical and cortico-cortical functional connectivity during sustained attention via spike-field phase locking. Increasing theta but not alpha power in the thalamus improved accuracy and reduced omission rates in a sustained attention task. Further, the enhancement of effective connectivity by stimulation was correlated with improved behavioral performance. Our work demonstrates a potential circuit-level causal mechanism for how the higher-order visual thalamus modulates cortical communication through rhythmic synchronization during sustained attention.

The ability to optogenetically perturb neural circuits opens an unprecedented window into mechanisms governing circuit function. We analyzed and theoretically modeled neuronal responses to visual and optogenetic inputs in mouse and monkey V1. In both species, optogenetic stimulation of excitatory neurons strongly modulated the activity of single neurons yet had weak or no effects on the distribution of firing rates across the population. Thus, the optogenetic inputs reshuffled firing rates across the network. Key statistics of mouse and monkey responses lay on a continuum, with mice/monkeys occupying the low-/high-rate regions, respectively. We show that neuronal reshuffling emerges generically in randomly connected excitatory/inhibitory networks, provided the coupling strength (combination of recurrent coupling and external input) is sufficient that powerful inhibitory feedback cancels the mean optogenetic input. A more realistic model, distinguishing tuned visual vs. untuned optogenetic input in a structured network, reduces the coupling strength needed to explain reshuffling.

UNASSIGNED: In patients with severe auditory impairment, partial hearing restoration can be achieved by sensory prostheses for the electrical stimulation of the central nervous system. However, these state-of-the-art approaches suffer from limited spectral resolution: electrical field spread depends on the impedance of the surrounding medium, impeding spatially focused electrical stimulation in neural tissue. To overcome these limitations, optogenetic activation could be applied in such prostheses to achieve enhanced resolution through precise and differential stimulation of nearby neuronal ensembles. Previous experiments have provided a first proof for behavioral detectability of optogenetic activation in the rodent auditory system, but little is known about the generation of complex and behaviorally relevant sensory patterns involving differential activation.
UNASSIGNED: In this study, we developed and behaviorally tested an optogenetic implant to excite two spatially separated points along the tonotopy of the murine inferior colliculus (ICc).
UNASSIGNED: Using a reward based operant Go/No-Go paradigm, we show that differential optogenetic activation of a sub-cortical sensory pathway is possible and efficient. We demonstrate how animals which were previously trained in a frequency discrimination paradigm (a) rapidly respond to either sound or optogenetic stimulation, (b) generally detect optogenetic stimulation of two different neuronal ensembles, and (c) discriminate between them.
UNASSIGNED: Our results demonstrate that optogenetic excitatory stimulation at different points of the ICc tonotopy elicits a stable response behavior over time periods of several months. With this study, we provide the first proof of principle for sub-cortical differential stimulation of sensory systems using complex artificial cues in freely moving animals.

Studying brain functions and activity during gamma oscillations can be a challenge because it requires careful planning to create the necessary conditions for a controlled experiment. Such an experiment consists of placing the brain into a gamma state and investigating cognitive processing with a careful design. Cortical oscillations in the gamma frequency range (30-80 Hz) play an essential role in a variety of cognitive processes, including visual processing and cognition. The present study aims to investigate the effects of a visual stimulus on the primary visual cortex under gamma oscillations. Specifically, we sought to explore the behavior of gamma oscillations triggered by optogenetic stimulation in the II and IV layers of the visual cortex, both with and without concurrent visual stimulation. Our results show that optogenetic stimulation increases the power of gamma oscillation in both layers of the visual cortex. However, the combined stimuli resulted in a reduction of gamma power in layer II and an increase and reinforcement in gamma power in layer IV. Modelling the results with the Wilson-Cowan model suggests changes in the input of the excitatory population due to the combined stimuli. In addition, our analysis of the data using the Lempel-Ziv complexity method supports our interpretations from the modeling. Thus, our results suggest that optogenetic stimulation enhances low gamma power in both layers of the visual cortex, while simultaneous visual stimulation has differing effects on the two layers, reducing gamma power in layer II and increasing it in layer IV.