Jufang He

Low-frequency hippocampal–cortical activity drives brain-wide resting-state functional MRI connectivity

Significance The hippocampus with its dense reciprocal axonal projections to and from cortex is widely believed to mediate numerous cognitive functions. However, it is unknown whether and how specific hippocampal–cortical activity contributes to the brain-wide functional connectivity. Here, we use optogenetics and fMRI to examine how excitatory neural activity initiated in the dorsal dentate gyrus of the hippocampus propagates and modulates resting-state fMRI (rsfMRI) connectivity. We discover its robust propagation brain-wide at low frequency (1 Hz), which enhances interhemispheric rsfMRI connectivity and cortical and subcortical visual responses. Our findings highlight the important role of slow hippocampal–cortical oscillatory activity in driving brain-wide rsfMRI connectivity and mediating sensory processing. The hippocampus, including the dorsal dentate gyrus (dDG), and cortex engage in bidirectional communication. We propose that low-frequency activity in hippocampal–cortical pathways contributes to brain-wide resting-state connectivity to integrate sensory information. Using optogenetic stimulation and brain-wide fMRI and resting-state fMRI (rsfMRI), we determined the large-scale effects of spatiotemporal-specific downstream propagation of hippocampal activity. Low-frequency (1 Hz), but not high-frequency (40 Hz), stimulation of dDG excitatory neurons evoked robust cortical and subcortical brain-wide fMRI responses. More importantly, it enhanced interhemispheric rsfMRI connectivity in various cortices and hippocampus. Subsequent local field potential recordings revealed an increase in slow oscillations in dorsal hippocampus and visual cortex, interhemispheric visual cortical connectivity, and hippocampal–cortical connectivity. Meanwhile, pharmacological inactivation of dDG neurons decreased interhemispheric rsfMRI connectivity. Functionally, visually evoked fMRI responses in visual regions also increased during and after low-frequency dDG stimulation. Together, our results indicate that low-frequency activity robustly propagates in the dorsal hippocampal–cortical pathway, drives interhemispheric cortical rsfMRI connectivity, and mediates visual processing.

Encoding and Retrieval of Artificial Visuoauditory Memory Traces in the Auditory Cortex Requires the Entorhinal Cortex

Damage to the medial temporal lobe impairs the encoding of new memories and the retrieval of memories acquired immediately before the damage in human. In this study, we demonstrated that artificial visuoauditory memory traces can be established in the rat auditory cortex and that their encoding and retrieval depend on the entorhinal cortex of the medial temporal lobe in the rat. We trained rats to associate a visual stimulus with electrical stimulation of the auditory cortex using a classical conditioning protocol. After conditioning, we examined the associative memory traces electrophysiologically (i.e., visual stimulus-evoked responses of auditory cortical neurons) and behaviorally (i.e., visual stimulus-induced freezing and visual stimulus-guided reward retrieval). The establishment of a visuoauditory memory trace in the auditory cortex, which was detectable by electrophysiological recordings, was achieved over 20–30 conditioning trials and was blocked by unilateral, temporary inactivation of the entorhinal cortex. Retrieval of a previously established visuoauditory memory was also affected by unilateral entorhinal cortex inactivation. These findings suggest that the entorhinal cortex is necessary for the encoding and involved in the retrieval of artificial visuoauditory memory in the auditory cortex, at least during the early stages of memory consolidation.

Effect of stimulation on the input parameters of stochastic leaky integrate-and-fire neuronal model

The Ornstein-Uhlenbeck neuronal model is specified by two types of parameters. One type corresponds to the properties of the neuronal membrane, whereas the second type (local average rate of the membrane depolarization and its variability) corresponds to the input of the neuron. In this article, we estimate the parameters of the second type from an intracellular record during neuronal firing caused by stimulation (audio signal). We compare the obtained estimates with those from the spontaneous part of the record. As predicted from the model construction, the values of the input parameters are larger for the periods when neuron is stimulated than for the spontaneous ones. Finally, the firing regimen of the model is checked. It is confirmed that the neuron is in the suprathreshold regimen during the stimulation.

A Brain-Machine-Muscle Interface for Restoring Hindlimb Locomotion after Complete Spinal Transection in Rats

A brain-machine interface (BMI) is a neuroprosthetic device that can restore motor function of individuals with paralysis. Although the feasibility of BMI control of upper-limb neuroprostheses has been demonstrated, a BMI for the restoration of lower-limb motor functions has not yet been developed. The objective of this study was to determine if gait-related information can be captured from neural activity recorded from the primary motor cortex of rats, and if this neural information can be used to stimulate paralysed hindlimb muscles after complete spinal cord transection. Neural activity was recorded from the hindlimb area of the primary motor cortex of six female Sprague Dawley rats during treadmill locomotion before and after mid-thoracic transection. Before spinal transection there was a strong association between neural activity and the step cycle. This association decreased after spinal transection. However, the locomotive state (standing vs. walking) could still be successfully decoded from neural recordings made after spinal transection. A novel BMI device was developed that processed this neural information in real-time and used it to control electrical stimulation of paralysed hindlimb muscles. This system was able to elicit hindlimb muscle contractions that mimicked forelimb stepping. We propose this lower-limb BMI as a future neuroprosthesis for human paraplegics.

Multiplexed Optogenetic Stimulation of Neurons with Spectrum-Selective Upconversion Nanoparticles

Optical modulation of nervous system becomes increasingly popular as the wide adoption of optogenetics. For these applications, upconversion materials hold great promise as novel photonic elements. This study describes an upconversion based strategy for combinatorial neural stimulation both in vitro and in vivo by using spectrum-selective upconversion nanoparticles (UCNPs). NaYF4 based UCNPs are used to absorb near-infrared (NIR) energy and to emit visible light for stimulating neurons expressing different channelrhodopsin (ChR) proteins. The emission spectrum of the UCNPs is selectively tuned by different doping strategy (Tm3+ or Er3+ ) to match the responsive wavelength of ChR2 or C1V1. When the UCNPs are packaged into a glass microoptrode, and placed close to or in direct contact with neurons expressing ChR2 or C1V1, the cells can be reliably activated by NIR illumination at single cell level as well as network level, which is characterized by patch-clamping and multielectrode-array recording in culture primary neurons. Furthermore, the UCNP-based optrode is implanted into the brain of live rodents to achieve all-optical remote activation of brain tissues in mammalian animals. It is believed that this proof-of-concept study opens up completely new applications of upconversion materials for regulating physiological functions, especially in neuroscience research.

5-HT2 receptors mediate functional modulation of GABAa receptors and inhibitory synaptic transmissions in human iPS-derived neurons

Neural progenitors differentiated from induced pluripotent stem cells (iPS) hold potentials for treating neurological diseases. Serotonin has potent effects on neuronal functions through multiple receptors, underlying a variety of neural disorders. Glutamate and GABA receptors have been proven functional in neurons differentiated from iPS, however, little is known about 5-HT receptor-mediated modulation in such neuronal networks. In the present study, human iPS were differentiated into cells possessing featured physiological properties of cortical neurons. Whole-cell patch-clamp recording was used to examine the involvement of 5-HT2 receptors in functional modulation of GABAergic synaptic transmission. We found that serotonin and DOI (a selective agonist of 5-HT2A/C receptor) reversibly reduced GABA-activated currents, and this 5-HT2A/C receptor mediated inhibition required G protein, PLC, PKC, and Ca2+ signaling. Serotonin increased the frequency of miniature inhibitory postsynaptic currents (mIPSCs), which could be mimicked by α-methylserotonin, a 5-HT2 receptor agonist. In contrast, DOI reduced both frequency and amplitude of mIPSCs. These findings suggested that in iPS-derived human neurons serotonin postsynaptically reduced GABAa receptor function through 5-HT2A/C receptors, but presynaptically other 5-HT2 receptors counteracted the action of 5-HT2A/C receptors. Functional expression of serotonin receptors in human iPS-derived neurons provides a pre-requisite for their normal behaviors after grafting.

Stimulus-specific adaptation at the synapse level in vitro.

Stimulus-specific adaptation (SSA) is observed in many brain regions in humans and animals. SSA of cortical neurons has been proposed to accumulate through relays in ascending pathways. Here, we examined SSA at the synapse level using whole-cell patch-clamp recordings of primary cultured cortical neurons of the rat. First, we found that cultured neurons had high firing capability with 100-Hz current injection. However, neuron firing started to adapt to repeated electrically activated synaptic inputs at 10 Hz. Next, to activate different dendritic inputs, electrical stimulations were spatially separated. Cultured neurons showed similar SSA properties in the oddball stimulation paradigm compared to those reported in vivo. Single neurons responded preferentially to a deviant stimulus over repeated, standard stimuli considering both synapse-driven spikes and excitatory postsynaptic currents (EPSCs). Compared with two closely placed stimulating electrodes that activated highly overlapping dendritic fields, two separately placed electrodes that activated less overlapping dendritic fields elicited greater SSA. Finally, we used glutamate puffing to directly activate postsynaptic glutamate receptors. Neurons showed SSA to two separately placed puffs repeated at 10 Hz. Compared with EPSCs, GABAa receptor-mediated inhibitory postsynaptic currents showed weaker SSA. Heterogeneity of the synaptic inputs was critical for producing SSA, with glutamate receptor desensitization participating in the process. Our findings suggest that postsynaptic fatigue contributes largely to SSA at low frequencies.

Electronic bypass of spinal lesions: activation of lower motor neurons directly driven by cortical neural signals

BackgroundLower motor neurons in the spinal cord lose supraspinal inputs after complete spinal cord injury, leading to a loss of volitional control below the injury site. Extensive locomotor training with spinal cord stimulation can restore locomotion function after spinal cord injury in humans and animals. However, this locomotion is non-voluntary, meaning that subjects cannot control stimulation via their natural “intent”. A recent study demonstrated an advanced system that triggers a stimulator using forelimb stepping electromyographic patterns to restore quadrupedal walking in rats with spinal cord transection. However, this indirect source of “intent” may mean that other non-stepping forelimb activities may false-trigger the spinal stimulator and thus produce unwanted hindlimb movements.MethodsWe hypothesized that there are distinguishable neural activities in the primary motor cortex during treadmill walking, even after low-thoracic spinal transection in adult guinea pigs. We developed an electronic spinal bridge, called “Motolink”, which detects these neural patterns and triggers a “spinal” stimulator for hindlimb movement. This hardware can be head-mounted or carried in a backpack. Neural data were processed in real-time and transmitted to a computer for analysis by an embedded processor. Off-line neural spike analysis was conducted to calculate and preset the spike threshold for “Motolink” hardware.ResultsWe identified correlated activities of primary motor cortex neurons during treadmill walking of guinea pigs with spinal cord transection. These neural activities were used to predict the kinematic states of the animals. The appropriate selection of spike threshold value enabled the “Motolink” system to detect the neural “intent” of walking, which triggered electrical stimulation of the spinal cord and induced stepping-like hindlimb movements.ConclusionWe present a direct cortical “intent”-driven electronic spinal bridge to restore hindlimb locomotion after complete spinal cord injury.

Cortically Controlled Electrical Stimulation for Locomotion of the Spinal Cord Injured

Brain Machine Interface (BMI) is a neuroprosthetic approach for the restoration of motor functions of paralyzed people. While BMI has demonstrated the feasibility of upper-limb neuroprosthesis, it has not yet been evaluated for the restoration of lower-limb motor functions for the disables. In this article we address the following questions 1) whether different step gait related activities can be captured in parallel from rat’s primary motor cortex during walking, and 2) whether this neural information can be used for locomotion or not. We found two categories of cortical neurons: one with their firing rate highly tuned and the other with less or untuned with the step gait cycles. The activities of highly tuned neurons show strong relationship of their firing rates with step gait cycles. Finally, we developed a neuroprosthetic device that stimulates the below of transacted spinal cord from this cortical recording. We propose BMI as a solution for lowerlimb neuroprosthesis.

Brain responses to facial attractiveness induced by facial proportions: evidence from an fMRI study

Brain responses to facial attractiveness induced by facial proportions are investigated by using functional magnetic resonance imaging (fMRI), in 41 young adults (22 males and 19 females). The subjects underwent fMRI while they were presented with computer-generated, yet realistic face images, which had varying facial proportions, but the same neutral facial expression, baldhead and skin tone, as stimuli. Statistical parametric mapping with parametric modulation was used to explore the brain regions with the response modulated by facial attractiveness ratings (ARs). The results showed significant linear effects of the ARs in the caudate nucleus and the orbitofrontal cortex for all of the subjects, and a non-linear response profile in the right amygdala for only the male subjects. Furthermore, canonical correlation analysis was used to learn the most relevant facial ratios that were best correlated with facial attractiveness. A regression model on the fMRI-derived facial ratio components demonstrated a strong linear relationship between the visually assessed mean ARs and the predictive ARs. Overall, this study provided, for the first time, direct neurophysiologic evidence of the effects of facial ratios on facial attractiveness and suggested that there are notable gender differences in perceiving facial attractiveness as induced by facial proportions.