Amygdala electrical stimulation for operant conditioning in rat navigation.

There have been several attempts to navigate the locomotion of animals by neuromodulation. The most common method is animal training with electrical brain stimulation for directional cues and rewards; the basic principle is to activate dopamine-mediated neural reward pathways such as the medial forebrain bundle (MFB) when the animal correctly follows the external commands. In this study, the amygdala, which is the brain region responsible for fear modulation, was targeted for punishment training. The brain regions of MFB, amygdala, and barrel cortex were electrically stimulated for reward, punishment, and directional cues, respectively. Electrical stimulation was applied to the amygdala of rats when they failed to follow directional commands. First, two different amygdala regions, i.e., basolateral amygdala (BLA) and central amygdala (CeA), were stimulated and compared in terms of behavior responses, success and correction rates for training, and gene expression for learning and memory. Then, the training was performed in three groups: group R (MFB stimulation for reward), group P (BLA stimulation for punishment), and group RP (both MFB and BLA stimulation for reward and punishment). In group P, after the training, RNA sequencing was conducted to detect gene expression and demonstrate the effect of punishment learning. Group P showed higher success rates than group R, and group RP exhibited the most effective locomotion control among the three groups. Gene expression results imply that BLA stimulation can be more effective as a punishment in the learning process than CeA stimulation. We developed a new method to navigate rat locomotion behaviors by applying amygdala stimulation.

Fabrication and validation of flexible neural electrodes based on polyimide tape and gold sheet.

This research was conducted to apply polyimide tape, which has the advantages of low price ans strong adhesive strength, to the neural electrode process. In addition, to maximize the low-cost characteristics, a fabrication process based on UV laser patterning rather than a photolithography process was introduced. The fabrication process started by attaching the gold sheet on the conductive double-sided tape without being torn or crushed. Then, the gold sheet and the double-sided tape were patterned together using UV laser. The patterned layer was transferred to the single-side polyimide tape. For insulation layer, electrode site opened single-sided polyimide tape was prepared. Polydimethylsiloxane was used as an adhesion layer, and alignment between electrode sites and opening sites was processed manually. The minimum line width achieved through the proposed fabrication process was approximately 100 µm, and the sheet resistance of the conductive layer was 0.635 Ω/sq. Measured cathodal charge storage capacity was 0.72 mC/cm2 and impedance at 1 kHz was 4.07 kΩ/cm2. Validation of fabricated electrode was confirmed by conducting 30 days accelerated soak test, flexibility test, adhesion test and ex vivo stimulation test. The novel flexible neural electrodes based on single-sided polyimide tape and UV laser patterned gold sheet was fabricated successfully. Conventional neural electrode fabrication processes based on polyimide substrate has a disadvantages such as long fabrication time, expensive costs, and probability of delamination between layers. However, the novel fabrication process which we introduced can overcome many shortcomings of existing processes, and offers great advantages such as simplicity of fabrication, inexpensiveness, flexibility and long-term reliability.

Ultrasound neuromodulation of cultured hippocampal neurons.

Ultrasound is becoming an emerging and promising method for neuromodulation due to its advantage of noninvasiveness and its high spatial resolution. However, the underlying principles of ultrasound neuromodulation have not yet been elucidated. We have herein developed a new in vitro setup to study the ultrasonic neuromodulation, and examined various parameters of ultrasound to verify the effective conditions to evoke the neural activity. Neurons were stimulated with 0.5 MHz center frequency ultrasound, and the action potentials were recorded from rat hippocampal neural cells cultured on microelectrode arrays. As the intensity of ultrasound increased, the neuronal activity also increased. There was a notable and significant increase in both the spike rate and the number of bursts at 50% duty cycle, 1 kHz pulse repetition frequency, and the acoustic intensities of 7.6 W/cm2 and 3.8 W/cm2 in terms of spatial-peak pulse-average intensity and spatial-peak temporal-average intensity, respectively. In addition, the impact of ultrasonic neuromodulation was assessed in the presence of a gamma-aminobutyric acid A (GABAA) receptor antagonist to exclude the effect of activated inhibitory neurons. Interestingly, it is noteworthy that the predominant neuromodulatory effects of ultrasound disappeared when the GABAA blocker was introduced, suggesting the potential of ultrasonic stimulation specifically targeting inhibitory neurons. The experimental setup proposed herein could serve as a useful tool for the clarification of the mechanisms underlying the electrophysiological effects of ultrasound.

Pupillometry as a window to detect cognitive aging in the brain.

This study investigated whether there are aging-related differences in pupil dilation (pupillometry) while the cognitive load is manipulated using digit- and word-span tasks. A group of 17 younger and 15 cognitively healthy older adults performed digit- and word-span tasks. Each task comprised three levels of cognitive loads with 10 trials for each level. For each task, the recall accuracy and the slope of pupil dilation were calculated and analyzed. The raw signal of measured pupil size was low-pass filtered and interpolated to eliminate blinking artifacts and spike noises. Two-way ANOVA was used for statistical analyses. For the recall accuracy, the significant group differences emerged as the span increases in digit-span (5- vs. 7-digit) and word-span (4- vs. 5-word) tasks, while the group differences were not significant on 3-digit- and 3-word-span tasks with lower cognitive load. In digit-span tasks, there was no aging-related difference in the slope of pupil dilation. However, in word-span tasks, the slope of pupil dilation differed significantly between two groups as cognitive load increased, indicating that older adults presented a higher pupil dilation slope than younger adults especially under the conditions with higher cognitive load. The current study found significant aging effects in the pupil dilations under the more cognitive demanding span tasks when the types of span tasks varied (e.g., digit vs. word). The manipulations successfully elicited differential aging effects, given that the aging effects became most salient under word-span tasks with greater cognitive load especially under the maximum length. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-023-00315-6.

Implantable Neural Electrodes Fabrication Based on Perfluoroalkoxyalkane Film.

OBJECTIVE: In this paper, the fabrication of perfluoro-alkoxy alkane (PFA) film-based planar neural electrodes was proposed. METHODS: The fabrication of PFA-based electrodes started with cleaning of PFA film. The argon plasma pretreatment was performed on the PFA film surface and attached to a dummy silicon wafer. Metal layers were deposited and patterned using the standard Micro Electro Mechanical Systems (MEMS) process. Electrode-sites and pads were opened using reactive ion etching (RIE). Lastly, the electrode patterned PFA substrate film was thermally laminated with the other bare PFA film. Electrical-physical evaluation tests were conducted along with in vitro tests, ex vivo tests and soak tests to evaluate the electrode performance and biocompatibility. RESULTS: The electrical and physical performance of PFA-based electrodes had better performances compared to other biocompatible polymer-based electrodes. Also, the biocompatibility and longevity were verified by cytotoxicity test, elution test, and accelerated life test. CONCLUSION: The PFA film-based planar neural electrode fabrication was established and evaluated. The PFA based electrodes showed excellent benefits such as long-term reliability, low water absorption rate, and flexibility using the neural electrode. SIGNIFICANCE: For implantable neural electrodes, hermetic sealing is required for in vivo durability. PFA fulfilled a low water absorption rate with relatively low Young's modulus to increase the longevity and biocompatibility of the devices.

Liquid Crystal Polymer-Based Miniaturized Fully Implantable Deep Brain Stimulator.

A significant challenge in improving the deep brain stimulation (DBS) system is the miniaturization of the device, aiming to integrate both the stimulator and the electrode into a compact unit with a wireless charging capability to reduce invasiveness. We present a miniaturized, fully implantable, and battery-free DBS system designed for rats, using a liquid crystal polymer (LCP), a biocompatible and long-term reliable material. The system integrates the simulator circuit, the receiver coil, and a 20 mm long depth-type microelectrode array in a dome-shaped LCP package that is 13 mm in diameter and 5 mm in height. Wireless powering and control via an inductive link enable device miniaturization, allowing for full implantation and, thus, the free behavior of untethered animals. The eight-channel stimulation electrode array was microfabricated on an LCP substrate to form a multilayered system substrate, which was monolithically encapsulated by a domed LCP lid using a specialized spot-welding process. The device functionality was validated via an in vivo animal experiment using a neuropathic pain model in rats. This experiment demonstrated an increase in the mechanical withdrawal threshold of the rats with microelectrical stimulation delivered using the fully implanted device, highlighting the effectiveness of the system.

Effects of cochlear implantation on cognitive decline in older adults: A systematic review and meta-analysis.

Background: Hearing loss has been reported as the most significant modifiable risk factor for dementia, but it is still unknown whether auditory rehabilitation can practically prevent cognitive decline. We aim to systematically analyze the longitudinal effects of auditory rehabilitation via cochlear implants (CIs). Methods: In this systematic review and meta-analysis, we searched relevant literature published from January 1, 2000 to April 30, 2022, using electronic databases, and selected studies in which CIs were performed mainly on older adults and follow-up assessments were conducted in both domains: speech perception and cognitive function. A random-effects meta-analysis was conducted for each domain and for each timepoint comparison (pre-CI vs. six months post-CI; six months post-CI vs. 12 months post-CI; pre-CI vs. 12 months post-CI), and heterogeneity was assessed using Cochran's Q test. Findings: Of the 1918 retrieved articles, 20 research papers (648 CI subjects) were included. The results demonstrated that speech perception was rapidly enhanced after CI, whereas cognitive function had different speeds of improvement for different subtypes: executive function steadily improved significantly up to 12 months post-CI (g = 0.281, p < 0.001; g = 0.115, p = 0.003; g = 0.260, p < 0.001 in the order of timepoint comparison); verbal memory was significantly enhanced at six months post-CI and was maintained until 12 months post-CI (g = 0.296, p = 0.002; g = 0.095, p = 0.427; g = 0.401, p < 0.001); non-verbal memory showed no considerable progress at six months post-CI, but significant improvement at 12 months post-CI (g = -0.053, p = 0.723; g = 0.112, p = 0.089; g = 0.214, p = 0.023). Interpretation: The outcomes demonstrate that auditory rehabilitation via CIs could have a long-term positive impact on cognitive abilities. Given that older adults' cognitive abilities are on the trajectory of progressive decline with age, these results highlight the need to increase the adoption of CIs among this population.

Cortical astrocytes modulate dominance behavior in male mice by regulating synaptic excitatory and inhibitory balance.

Social hierarchy is established as an outcome of individual social behaviors, such as dominance behavior during long-term interactions with others. Astrocytes are implicated in optimizing the balance between excitatory and inhibitory (E/I) neuronal activity, which may influence social behavior. However, the contribution of astrocytes in the prefrontal cortex to dominance behavior is unclear. Here we show that dorsomedial prefrontal cortical (dmPFC) astrocytes modulate E/I balance and dominance behavior in adult male mice using in vivo fiber photometry and two-photon microscopy. Optogenetic and chemogenetic activation or inhibition of dmPFC astrocytes show that astrocytes bidirectionally control male mouse dominance behavior, affecting social rank. Dominant and subordinate male mice present distinct prefrontal synaptic E/I balance, regulated by astrocyte activity. Mechanistically, we show that dmPFC astrocytes control cortical E/I balance by simultaneously enhancing presynaptic-excitatory and reducing postsynaptic-inhibitory transmission via astrocyte-derived glutamate and ATP release, respectively. Our findings show how dmPFC astrocyte-neuron communication can be involved in the establishment of social hierarchy in adult male mice.

Fast Reconfigurable Electrode Array Based on Titanium Oxide for Localized Stimulation of Cultured Neural Network.

Planar microelectrode arrays have become standard tools for in vitro neural-network analysis. However, these predefined micropatterned devices lack adaptability to target-specific cells within a cultured network. Herein, we fabricated a reconfigurable TiO2 electrode array with an anatase-brookite bicrystalline polymorphous mesoporous layer. Because of its selective absorption of ultraviolet (UV) light and corresponding photoconductivity, TiO2 electrode array was identified as a promising tool for high-resolution light-addressing. The TiO2 film was used as a semitransparent semiconductor with a high Roff/Ron ratio of 105 and a fast response time of 400 ms. In addition, the effect of UV radiation on the resistance of the TiO2 film over 30 d in an aqueous environment was analyzed, with the film exhibiting high stability. An arbitrary UV pattern was applied to a reconfigurable TiO2 electrode using a digital micromirror device (DMD), affording highly localized neural stimulation at the single-cell level. The reconfigurable TiO2 electrode with a patterned indium tin oxide (ITO) substrate enabled the independent connection of up to 60 points with external stimulators and signal recorders. We believe this technique would be helpful for electrophysiological research requiring the analysis of cell and neural-network features using a highly localized neural interface.

Somatosensory ECoG-based brain-machine interface with electrical stimulation on medial forebrain bundle.

Brain-machine interface (BMI) provides an alternative route for controlling an external device with one's intention. For individuals with motor-related disability, the BMI technologies can be used to replace or restore motor functions. Therefore, BMIs for movement restoration generally decode the neural activity from the motor-related brain regions. In this study, however, we designed a BMI system that uses sensory-related neural signals for BMI combined with electrical stimulation for reward. Four-channel electrocorticographic (ECoG) signals were recorded from the whisker-related somatosensory cortex of rats and converted to extract the BMI signals to control the one-dimensional movement of a dot on the screen. At the same time, we used operant conditioning with electrical stimulation on medial forebrain bundle (MFB), which provides a virtual reward to motivate the rat to move the dot towards the desired center region. The BMI task training was performed for 7 days with ECoG recording and MFB stimulation. Animals successfully learned to move the dot location to the desired position using S1BF neural activity. This study successfully demonstrated that it is feasible to utilize the neural signals from the whisker somatosensory cortex for BMI system. In addition, the MFB electrical stimulation is effective for rats to learn the behavioral task for BMI.

Hippocampal astrocytes modulate anxiety-like behavior.

Astrocytes can affect animal behavior by regulating tripartite synaptic transmission, yet their influence on affective behavior remains largely unclear. Here we showed that hippocampal astrocyte calcium activity reflects mouse affective state during virtual elevated plus maze test using two-photon calcium imaging in vivo. Furthermore, optogenetic hippocampal astrocyte activation elevating intracellular calcium induced anxiolytic behaviors in astrocyte-specific channelrhodopsin 2 (ChR2) transgenic mice (hGFAP-ChR2 mice). As underlying mechanisms, we found ATP released from the activated hippocampal astrocytes increased excitatory synaptic transmission in dentate gyrus (DG) granule cells, which exerted anxiolytic effects. Our data uncover a role of hippocampal astrocytes in modulating mice anxiety-like behaviors by regulating ATP-mediated synaptic homeostasis in hippocampal DG granule cells. Thus, manipulating hippocampal astrocytes activity can be a therapeutic strategy to treat anxiety.

Co-culture platform for neuron-astrocyte interaction using optogenetic modulation.

For decades, the role of glial cells has attracted attention in the neuroscience field. Particularly, although the astrocyte is the most abundant glial cell type, it was believed to function as a passive support cell. However, recent evidence suggests that astrocytes actively release various gliotransmitters and signaling entities that regulate the excitability of pre-and post-synaptic neurons in the brain. In this study, we optimized the ratio of astrocytes and neurons to investigate the interaction between astrocytes and neurons. To this end, postnatal day 0-1 rodent hippocampi were dissociated and cultured. The neuron-astrocyte ratio was monitored for up to 3 weeks after treating the cultures with 0, 1, and 5 µM of cytosine arabinoside (Ara-C) at DIV 2. Subsequently, from postnatal transgenic (TG) mouse expressing ChR2 on astrocytes, hippocampi were cultured on the microelectrode array (MEA) with the desired neuron-astrocyte ratio. The astrocyte was irradiated using a 473 nm blue laser for 30 s in a cycle of 10 Hz and electrophysiological recording was performed to verify the activities of neurons induced by the stimulated astrocytes. Astrocytes and neurons in both co-cultures increased at an identical ratio when treated with 1 µM Ara-C, whereas they decreased significantly when treated with 5 µM Ara-C. Particularly, the laser-stimulated astrocytes induced an increase in the frequency of neuronal activities and lasted after illumination. The proposed co-culture platform is expected to be used in experiments to investigate the network between astrocytes and neurons in vitro.

Development of a miniaturized, reconnectable, and implantable multichannel connector.

Objective. Connectors for implantable neural prosthetic systems provide several advantages such as simplification of surgery, safe replacement of implanted devices, and modular design of the implant systems. With the rapid advancement of technologies for neural implants, miniaturized multichannel implantable connectors are also required. In this study, we propose a reconnectable and area-efficient multichannel implantable connector.Approach. A female-to-female adapter was fabricated using the thermal-press bonding of micropatterned liquid crystal polymer films. A bump inside the adapter enabled a reliable electrical connection by increasing the contact pressure between the contact pads of the adapter and the inserted cable. After connection, the adapter is enclosed in a metal case sealed with silicone elastomer packing. With different sizes of the packings, leakage current tests were performed under accelerated conditions to determine the optimal design for long-term reliability. Repeated connection tests were performed to verify the durability and reconnectability of the fabricated connector. The connector was implanted in rats, and the leakage currents were monitored to evaluate the stability of the connectorin vivo. Main results. The fabricated four- and eight-channel implantable connectors, assembled with the metal cases, had a diameter and length of 6 and 17 mm, respectively. Further, the contact resistances of the four- and eight-channel connectors were 53.2 and 75.2 mΩ, respectively. The electrical contact remained stable during repeated connection tests (50 times). The fabricated connectors with packings having 125%, 137%, and 150% volume ratios to the internal space of the metal case failed after 14, 88, and 14 d, respectively, in a 75 °C saline environment. In animal tests with rats, the connector maintained low leakage current levels for up to 92 d.Significance. An implantable and reconnectable multichannel connector was developed and evaluated. The feasibility of the proposed connector was evaluated in terms of electrical and mechanical characteristics as well as sealing performance. The proposed connector is expected to have potential applications in implantable neural prosthetic systems.

Optrode Array for Simultaneous Optogenetic Modulation and Electrical Neural Recording.

During the last decade, optogenetics has become an essential tool for the investigation of neural signaling due to its unique capability of selective neural modulation or monitoring. As specific types of neuronal cells can be genetically modified to express opsin proteins, optogenetics enables optical stimulation or inhibition of the selected neurons. There have been several technological advances in the optical system for optogenetics. Recently, it was proposed to combine the optical waveguide for light delivery with electrophysiological recording to simultaneously monitor the neural responses to optogenetic stimulation or inhibition. In this study, an implantable optrode array (2x2 optical fibers) was developed with embedded multichannel electrodes. A light-emitting diode (LED) was employed as a light source, and a microfabricated microlens array was integrated to provide sufficient light power at the tip of the optical fibers. The optrode array system comprises the disposable part and the reusable part. The disposable part has optical fibers and electrodes, while the reusable part has the LED and electronic circuitry for light control and neural signal processing. The novel design of the implantable optrode array system is introduced in the accompanying video in addition to the procedure of the optrode implantation surgery, optogenetic light stimulation, and the electrophysiological neural recording. The results of in vivo experiments successfully showed time-locked neural spikes evoked by the light stimuli from hippocampal excitatory neurons of mice.

Silicon optrode array with monolithically integrated SU-8 waveguide and single LED light source.

Objective. This paper presents a conventional light emitting diode (LED) and polymer waveguide coupled silicon optrode array.Approach. Unique lens design at the waveguide inlet enables a high light coupling efficiency with a single LED light source, and provides small power consumption compatible with a wireless optogenetic neuromodulation system. To increase the light intensity at the waveguide tip, a lensed waveguide is fabricated with epoxy-based photoresist SU-8, which has a plano-convex lens shape at the waveguide inlet to focus the light in the horizontal direction. In addition, a cylindrical lens is assembled in front of the waveguide inlet to focus the source light in the vertical direction.Main results. The glass cylindrical lens and SU-8 plano-convex lens increased the light coupling efficiency by 6.7 dB and 6.6 dB, respectively. The fabricated 1 × 4 array of optrodes is assembled with a single LED with 465 nm wavelength, which produces a light intensity of approximately 2.7 mW mm-2at the SU-8 waveguide outlet when 50 mA input current is applied to the LED. Each optrode has four recording electrodes at the SU-8 waveguide outlet. The average impedance of the iridium oxide (IrOx) electroplated recording electrodes is 43.6 kΩ.Significance.In-vivoexperiment at the hippocampus region CA1 and CA2 demonstrated the capability of optical stimulation and neural signal recording through the LED and SU-8 waveguide coupled silicon optrode array.

Aging-Related Dissociation of Spatial and Temporal N400 in Sentence-Level Semantic Processing: Evidence From Source Analyses.

Age-related differences in sentence-level lexical-semantic processes have been extensively studied, based on the N400 component of event-related potential (ERP). However, there is still a lack of understanding in this regard at the brain-region level. This study explores aging effects on sentence-level semantic processing by comparing the characteristics of the N400 ERP component and brain engagement patterns within individual N400 time windows for two age groups (16 younger adults aged 24.38 ± 3.88 years and 15 older adults aged 67.00 ± 5.04 years) during sentence processing with different plausibility conditions. Our results demonstrated that the N400 effect according to the plausibility condition occurred in different temporal windows in the two age groups, with a delay in the older group. Moreover, it was identified that there was a distinct difference between the groups in terms of the source location of the condition-dependent N400 effect even though no significant difference was derived in its magnitude itself at the sensor-level. Interestingly, the source analysis results indicated that the two groups involved different functional networks to resolve the same semantic violations: the younger group activated the regions corresponding to the typical lexical-semantic network more, whereas the older group recruited the regions belonging to the multiple-demand network more. The findings of this study could be used as a basis for understanding the aging brain in a linguistic context.

Fabrication of Planar Microelectrode Array Using Laser-Patterned ITO and SU-8.

For several decades, microelectrode array (MEA) has been a powerful tool for in vitro neural electrophysiology because it provides a unique approach for monitoring the activity of a number of neurons over time. Due to the various applications of MEAs with different types of cells and tissues, there is an increasing need to customize the electrode designs. However, the fabrication of conventional MEAs requires several microfabrication procedures of deposition, etching, and photolithography. In this study, we proposed a simple fabrication method with a laser-patterned indium tin oxide (ITO) conductor and SU-8 photoresist insulation. Unlike in a conventional metal patterning process, only the outlines of ITO conductors are ablated by laser without removing background ITO. Insulation is achieved simply via SU-8 photolithography. The electrode sites are electroplated with iridium oxide (IrOX) to improve the electrochemical properties. The fabricated MEAs are electrochemically characterized and the stability of insulation is also confirmed by impedance monitoring for three weeks. Dissociated neurons of rat hippocampi are cultured on MEAs to verify the biocompatibility and the capacity for extracellular neural recording. The electrochemical and electrophysiological results with the fabricated MEAs are similar to those from conventional SiNX-insulated MEAs. Therefore, the proposed MEA with laser-patterned ITO and SU-8 is cost-effective and equivalently feasible compared with the conventional MEAs fabricated using thin-film microfabrication techniques.

Implantable Optrode Array for Optogenetic Modulation and Electrical Neural Recording.

During the last decade, optogenetics has become an essential tool for neuroscience research due to its unrivaled feature of cell-type-specific neuromodulation. There have been several technological advances in light delivery devices. Among them, the combination of optogenetics and electrophysiology provides an opportunity for facilitating optogenetic approaches. In this study, a novel design of an optrode array was proposed for realizing optical modulation and electrophysiological recording. A 4 × 4 optrode array and five-channel recording electrodes were assembled as a disposable part, while a reusable part comprised an LED (light-emitting diode) source and a power line. After the characterization of the intensity of the light delivered at the fiber tips, in vivo animal experiment was performed with transgenic mice expressing channelrhodopsin, showing the effectiveness of optical activation and neural recording.

Ethanol induces persistent potentiation of 5-HT3 receptor-stimulated GABA release at synapses on rat hippocampal CA1 neurons.

Several studies have shown that ethanol (EtOH) can enhance the activity of GABAergic synapses via presynaptic mechanisms, including in hippocampal CA1 neurons. The serotonin type 3 receptor (5-HT3-R) has been implicated in the neural actions of ethanol (EtOH) and in modulation of GABA release from presynaptic terminals. In the present study, we investigated EtOH modulation of GABA release induced by 5-HT3-R activation using the mechanically isolated neuron/bouton preparation from the rat CA1 hippocampal subregion. EtOH application before and during exposure to the selective 5-HT3 receptor agonist, m-chlorophenylbiguanide (mCPBG) potentiated the mCPBG-induced increases in the peak frequency and charge transfer of spontaneous GABAergic inhibitory postsynaptic currents. Interestingly, the potentiation was maintained even after EtOH was removed from the preparation. A protein kinase A inhibitor reduced the magnitude of EtOH potentiation. Fluorescent Ca2+ imaging showed that Ca2+ transients in the presynaptic terminals increased during EtOH exposure. These findings indicate that EtOH produces long-lasting potentiation of 5-HT3-induced GABA release by modulating calcium levels, via a process involving cAMP-mediated signaling in presynaptic terminals.