Temporal Pattern Of Stimulation Research Articles

Synaptic Plasticity in the Injured Brain Depends on the Temporal Pattern of Stimulation.

Neurostimulation protocols are increasingly used as therapeutic interventions, including for brain injury. In addition to the direct activation of neurons, these stimulation protocols are also likely to have downstream effects on those neurons' synaptic outputs. It is well known that alterations in the strength of synaptic connections (long-term potentiation, LTP; long-term depression, LTD) are sensitive to the frequency of stimulation used for induction; however, little is known about the contribution of the temporal pattern of stimulation to the downstream synaptic plasticity that may be induced by neurostimulation in the injured brain. We explored interactions of the temporal pattern and frequency of neurostimulation in the normal cerebral cortex and after mild traumatic brain injury (mTBI), to inform therapies to strengthen or weaken neural circuits in injured brains, as well as to better understand the role of these factors in normal brain plasticity. Whole-cell (WC) patch-clamp recordings of evoked postsynaptic potentials in individual neurons, as well as field potential (FP) recordings, were made from layer 2/3 of visual cortex in response to stimulation of layer 4, in acute slices from control (naive), sham operated, and mTBI rats. We compared synaptic plasticity induced by different stimulation protocols, each consisting of a specific frequency (1 Hz, 10 Hz, or 100 Hz), continuity (continuous or discontinuous), and temporal pattern (perfectly regular, slightly irregular, or highly irregular). At the individual neuron level, dramatic differences in plasticity outcome occurred when the highly irregular stimulation protocol was used at 1 Hz or 10 Hz, producing an overall LTD in controls and shams, but a robust overall LTP after mTBI. Consistent with the individual neuron results, the plasticity outcomes for simultaneous FP recordings were similar, indicative of our results generalizing to a larger scale synaptic network than can be sampled by individual WC recordings alone. In addition to the differences in plasticity outcome between control (naive or sham) and injured brains, the dynamics of the changes in synaptic responses that developed during stimulation were predictive of the final plasticity outcome. Our results demonstrate that the temporal pattern of stimulation plays a role in the polarity and magnitude of synaptic plasticity induced in the cerebral cortex while highlighting differences between normal and injured brain responses. Moreover, these results may be useful for optimization of neurostimulation therapies to treat mTBI and other brain disorders, in addition to providing new insights into downstream plasticity signaling mechanisms in the normal brain.

Irregular optogenetic stimulation waveforms can induce naturalistic patterns of hippocampal spectral activity

Objective. Therapeutic brain stimulation is conventionally delivered using constant-frequency stimulation pulses. Several recent clinical studies have explored how unconventional and irregular temporal stimulation patterns could enable better therapy. However, it is challenging to understand which irregular patterns are most effective for different therapeutic applications given the massively high-dimensional parameter space. Approach. Here we applied many irregular stimulation patterns in a single neural circuit to demonstrate how they can enable new dimensions of neural control compared to conventional stimulation, to guide future exploration of novel stimulation patterns in translational settings. We optogenetically excited the septohippocampal circuit with constant-frequency, nested pulse, sinusoidal, and randomized stimulation waveforms, systematically varying their amplitude and frequency parameters. Main results. We first found equal entrainment of hippocampal oscillations: all waveforms provided similar gamma-power increase, whereas no parameters increased theta-band power above baseline (despite the mechanistic role of the medial septum in driving hippocampal theta oscillations). We then compared each of the effects of each waveform on high-dimensional multi-band activity states using dimensionality reduction methods. Strikingly, we found that conventional stimulation drove predominantly ‘artificial’ (different from behavioral activity) effects, whereas all irregular waveforms induced activity patterns that more closely resembled behavioral activity. Significance. Our findings suggest that irregular stimulation patterns are not useful when the desired mechanism is to suppress or enhance a single frequency band. However, novel stimulation patterns may provide the greatest benefit for neural control applications where entraining a particular mixture of bands (e.g. if they are associated with different symptoms) or behaviorally-relevant activity is desired.

The Influence of Phosphene Synchrony in Driving Object Binding in a Simulation of Artificial Vision.

Electrical microstimulation techniques used in visual prostheses are designed to restore visual function following acquired blindness. Patterns of induced focal percepts, known as phosphenes, are achieved by applying localized electrical pulses to the visual pathway to bypass the impaired site in order to convey images from the external world. Here, we use a simulation of artificial vision to manipulate relationships between individual phosphenes to observe the effects on object binding and perception. We hypothesize that synchronous phosphene presentation will facilitate object perception as compared to asynchronous presentation. A model system that tracks gaze position of normal, sighted participants to present patterns of phosphenes on a computer screen was used to simulate prosthetic vision. Participants performed a reading task at varying font sizes (1.1-1.4 logMAR) and under varying levels of phosphene temporal noise while reading accuracy and speed were measured. Reading performance was significantly affected by temporal noise in phosphene presentation, with increasing desynchronization leading to lower reading scores. A drop in performance was also observed when the total latency between the gaze position and phosphene update was increased without adding temporal noise. Object perception (here, text perception) is enhanced with synchronously presented phosphenes as compared to asynchronously presented ones. These results are fundamental for developing an efficient temporal pattern of stimulation and for the creation of high-fidelity prosthetic vision.

Alteration in Cortical Activity and Perceived Sensation Following Modulated TENS.

Over the last decades, conventional transcutaneous electrical nerve stimulation (TENS) has been utilized as an efficient rehabilitation intervention for alleviation of chronic pain, including phantom limb pain (PLP). However, recently the literature has increasingly focused on alternative temporal stimulation patterns such as pulse width modulation (PWM). While the effect of non-modulated high frequency (NMHF) TENS on somatosensory (SI) cortex activity and sensory perception has been studied, the possible alteration following PWM TENS at the SI has not yet been explored. Therefore, we investigated the cortical modulation by PWM TENS for the first time and conducted a comparative analysis with the conventional TENS pattern. We recorded sensory evoked potentials (SEP) from 14 healthy subjects before, immediately, and 60 min after TENS interventions (PWM and NMHF). The results revealed suppression of SEP components, theta, and alpha band power simultaneously associated with the perceived intensity reduction when the single sensory pulses applied ipsilaterally to the TENS side. The reduction of N1 amplitude, theta, and alpha band activity occurred immediately after both patterns remained at least 60 min. However, the P2 wave was suppressed right after PWM TENS, while NMHF could not induce significant reduction immediately after the intervention phase. As such, since PLP relief has been shown to be correlated with inhibition at somatosensory cortex, we, therefore, believe that the result of this study provides further evidence that PWM TENS may also be potential therapeutic intervention for PLP reduction. Future studies on PLP patients with PWM TENS sessions is needed to validate our result.

Temporally optimized patterned stimulation (TOPS®) as a therapy to personalize deep brain stimulation treatment of Parkinson's disease.

Deep brain stimulation (DBS) is a well-established therapy for the motor symptoms of Parkinson’s disease (PD), but there remains an opportunity to improve symptom relief. The temporal pattern of stimulation is a new parameter to consider in DBS therapy, and we compared the effectiveness of Temporally Optimized Patterned Stimulation (TOPS) to standard DBS at reducing the motor symptoms of PD. Twenty-six subjects with DBS for PD received three different patterns of stimulation (two TOPS and standard) while on medication and using stimulation parameters optimized for standard DBS. Side effects and motor symptoms were assessed after 30 min of stimulation with each pattern. Subjects experienced similar types of side effects with TOPS and standard DBS, and TOPS were well-tolerated by a majority of the subjects. On average, the most effective TOPS was as effective as standard DBS at reducing the motor symptoms of PD. In some subjects a TOPS pattern was the most effective pattern. Finally, the TOPS pattern with low average frequency was found to be as effective or more effective in about half the subjects while substantially reducing estimated stimulation energy use. TOPS DBS may provide a new programing option to improve DBS therapy for PD by improving symptom reduction and/or increasing energy efficiency. Optimizing stimulation parameters specifically for TOPS DBS may demonstrate further clinical benefit of TOPS DBS in treating the motor symptoms of Parkinson’s disease.

Evaluating optimized temporal patterns of spinal cord stimulation (SCS)

BackgroundTemporal patterns of stimulation represent a novel dimension for improving the efficacy of spinal cord stimulation to treat chronic neuropathic pain. ObjectiveWe hypothesized that nonregular temporal patterns of stimulation designed using a computational model would be superior to conventional stimulation at constant frequencies or completely random patterns of stimulation. MethodsUsing a computational model of the dorsal horn network and an optimization algorithm based on biological evolution, we designed an optimized pattern of spinal cord stimulation with comparable efficacy and increased efficiency relative to constant frequency (CF) stimulation. We evaluated the effect of different temporal patterns on individual neurons recorded in the dorsal horn of urethane-anesthetized rats. ResultsThe optimized pattern and 50 Hz CF stimulation produced greater inhibition of spontaneously firing neurons recorded in vivo than random 50 Hz stimulation or a pattern designed intentionally with poor fitness. Spinal Cord Stimulation (SCS) led to significant changes in the firing patterns of recorded units, and stimulation patterns that generated significant inhibition also tended to reduce entropy and regularize the firing patterns of units, suggesting that patterns of dorsal horn neuron activity may be important for pain perception in addition to the firing rate. ConclusionsThese results demonstrate that the computational model can be used as a tool for optimizing stimulation parameters and suggest that optimized temporal patterns may increase the efficacy of spinal cord stimulation.

A defined human-specific platform for modeling neuronal network stimulation in vitro and in silico

BackgroundTranscription factor-based forward programming enables the efficient generation of forebrain excitatory and inhibitory neurons from human pluripotent stem cells (hPSCs). This provides an opportunity to study stimulation-response patterns in highly defined neuronal networks in a controlled and customizable in vitro environment. New methodCell populations composed of defined ratios of excitatory and inhibitory neurons were generated by forward programming genome-edited human hPSCs carrying the inducible transcription factors NGN2 and ASCL1/DLX2, respectively. These populations were cultured on multi-electrode arrays (MEAs), and population responses elicited by distinct spatial and temporal stimulation patterns were analyzed. In parallel, in silico network models fed with neuronal parameters obtained from the in vitro cultures were developed to explore potential mechanisms underlying experimental observations. ResultsNeuronal cultures developed network-level electrophysiological activities with pronounced synchronized network bursts (NBs), which responded to synaptic modulators. Interestingly, local electrical pulse stimulation at frequencies ≤ 0.2 Hz reliably elicited NBs, while frequencies of ≥ 1 Hz yielded no homogeneous responses, but only sporadic NBs. In contrast, multi-site stimulation at the same frequency could elicit NBs robustly. Data from computational models suggest that this phenomenon can be explained by exhaustion and presynaptic functional paralysis of targeted circuits by high-frequency local stimulation. Comparison with existing methodsCompared to hPSC-derived neurons generated solely by small molecule treatment, forward-programmed excitatory and inhibitory neurons enable the composition of highly confectionized networks. In silico simulation of induced biological network responses can be directly used to devise and validate mechanistic hypotheses underlying the recorded network dynamics. ConclusionsThe present study demonstrates the prospect of the iPSC technology for conducting personalized in vitro studies of human neuronal networks and their responses to electric stimuli. It also illustrates how the combined use of biological and in silico neuronal networks can support the development of mechanistic hypotheses underlying network responses to specific stimuli.

Temporal pattern and synergy influence activity of ERK signaling pathways during L-LTP induction.

Long-lasting long-term potentiation (L-LTP) is a cellular mechanism of learning and memory storage. Studies have demonstrated a requirement for extracellular signal-regulated kinase (ERK) activation in L-LTP produced by a diversity of temporal stimulation patterns. Multiple signaling pathways converge to activate ERK, with different pathways being required for different stimulation patterns. To answer whether and how different temporal patterns select different signaling pathways for ERK activation, we developed a computational model of five signaling pathways (including two novel pathways) leading to ERK activation during L-LTP induction. We show that calcium and cAMP work synergistically to activate ERK and that stimuli given with large intertrial intervals activate more ERK than shorter intervals. Furthermore, these pathways contribute to different dynamics of ERK activation. These results suggest that signaling pathways with different temporal sensitivities facilitate ERK activation to diversity of temporal patterns.

A quantitative description of macaque ganglion cell responses to natural scenes: the interplay of time and space.

Responses to natural scenes are the business of the retina. We find primate ganglion cell responses to such scenes consistent with those to simpler stimuli. A biophysical model confirmed this and predicted ganglion cell responses with close to retinal reliability. Primate ganglion cell responses to natural scenes were driven by temporal variations in colour and luminance over the receptive field centre caused by eye movements, and little influenced by interaction of centre and surround with structure in the scene. We discuss implications in the context of efficient coding of the visual environment. Much information in a higher spatiotemporal frequency band is concentrated in the magnocellular pathway. Responses of visual neurons to natural scenes provide a link between classical descriptions of receptive field structure and visual perception of the natural environment. A natural scene video with a movement pattern resembling that of primate eye movements was used to evoke responses from macaque ganglion cells. Cell responses were well described through known properties of cell receptive fields. Different analyses converge to show that responses primarily derive from the temporal pattern of stimulation derived from eye movements, rather than spatial receptive field structure beyond centre size and position. This was confirmed using a model that predicted ganglion cell responses close to retinal reliability, with only a small contribution of the surround relative to the centre. We also found that the spatiotemporal spectrum of the stimulus is modified in ganglion cell responses, and this can reduce redundancy in the retinal signal. This is more pronounced in the magnocellular pathway, which is much better suited to transmit the detailed structure of natural scenes than the parvocellular pathway. Whitening is less important for chromatic channels. Taken together, this shows how a complex interplay across space, time and spectral content sculpts ganglion cell responses.

T cells selectively filter oscillatory signals on the minutes timescale

T cells experience complex temporal patterns of stimulus via receptor-ligand-binding interactions with surrounding cells. From these temporal patterns, T cells are able to pick out antigenic signals while establishing self-tolerance. Although features such as duration of antigen binding have been examined, our understanding of how T cells interpret signals with different frequencies or temporal stimulation patterns is relatively unexplored. We engineered T cells to respond to light as a stimulus by building an optogenetically controlled chimeric antigen receptor (optoCAR). We discovered that T cells respond to minute-scale oscillations of activation signal by stimulating optoCAR T cells with tunable pulse trains of light. Systematically scanning signal oscillation period from 1 to 150 min revealed that expression of CD69, a T cell activation marker, reached a local minimum at a period of ∼25 min (corresponding to 5 to 15 min pulse widths). A combination of inhibitors and genetic knockouts suggest that this frequency filtering mechanism lies downstream of the Erk signaling branch of the T cell response network and may involve a negative feedback loop that diminishes Erk activity. The timescale of CD69 filtering corresponds with the duration of T cell encounters with self-peptide-presenting APCs observed via intravital imaging in mice, indicating a potential functional role for temporal filtering in vivo. This study illustrates that the T cell signaling machinery is tuned to temporally filter and interpret time-variant input signals in discriminatory ways.

Mechanism of Action in Burst Spinal Cord Stimulation: Review and Recent Advances.

ObjectiveThis is a comprehensive, structured review synthesizing and summarizing the current experimental data and knowledge about the mechanisms of action (MOA) underlying spinal cord stimulation with the burst waveform (as defined by De Ridder) in chronic pain treatment.MethodsMultiple database queries and article back-searches were conducted to identify the relevant literature and experimental findings for results integration and interpretation. Data from recent peer-reviewed conference presentations were also included for completeness and to ensure that the most up-to-date scientific information was incorporated. Both human and animal data were targeted in the search to provide a translational approach in understanding the clinical relevance of the basic science findings.Results/ConclusionsBurst spinal cord stimulation likely provides pain relief via multiple mechanisms at the level of both the spinal cord and the brain. The specific waveforms and temporal patterns of stimulation both play a role in the responses observed. Differential modulation of neurons in the dorsal horn and dorsal column nuclei are the spinal underpinnings of paresthesia-free analgesia. The burst stimulation pattern also produces different patterns of activation within the brain when compared with tonic stimulation. The latter may have implications for not only the somatic components of chronic pain but also the lateral and affective pathway dimensions as well.

Behavior Responses to Chemical and Optogenetic Stimuli in Drosophila Larvae.

An animal’s ability to navigate an olfactory environment is critically dependent on the activities of its first-order olfactory receptor neurons (ORNs). While considerable research has focused on ORN responses to odorants, the mechanisms by which olfactory information is encoded in the activities of ORNs and translated into navigational behavior remain poorly understood. We sought to determine the contributions of most Drosophila melanogaster larval ORNs to navigational behavior. Using odorants to activate ORNs and a larval tracking assay to measure the corresponding behavioral response, we observed that larval ORN activators cluster into four groups based on the behavior responses elicited from larvae. This is significant because it provides new insights into the functional relationship between ORN activity and behavioral response. Subsequent optogenetic analyses of a subset of ORNs revealed previously undescribed properties of larval ORNs. Furthermore, our results indicated that different temporal patterns of ORN activation elicit different behavioral outputs: some ORNs respond to stimulus increments while others respond to stimulus decrements. These results suggest that the ability of ORNs to encode temporal patterns of stimulation increases the coding capacity of the olfactory circuit. Moreover, the ability of ORNs to sense stimulus increments and decrements facilitates instantaneous evaluations of concentration changes in the environment. Together, these ORN properties enable larvae to efficiently navigate a complex olfactory environment. Ultimately, knowledge of how ORN activity patterns and their weighted contributions influence odor coding may eventually reveal how peripheral information is organized and transmitted to subsequent layers of a neural circuit.

Reduced auditory cortical adaptation in autism spectrum disorder.

Adaptation is a fundamental property of cortical neurons and has been suggested to be altered in individuals with autism spectrum disorder (ASD). We used fMRI to measure adaptation induced by repeated audio-visual stimulation in early sensory cortical areas in individuals with ASD and neurotypical (NT) controls. The initial transient responses were equivalent between groups in both visual and auditory cortices and when stimulation occurred with fixed-interval and randomized-interval timing. However, in auditory but not visual cortex, the post-transient sustained response was greater in individuals with ASD than NT controls in the fixed-interval timing condition, reflecting reduced adaptation. Further, individual differences in the sustained response in auditory cortex correlated with ASD symptom severity. These findings are consistent with hypotheses that ASD is associated with increased neural responsiveness but that responsiveness differences only manifest after repeated stimulation, are specific to the temporal pattern of stimulation, and are confined to specific cortical regions.

Less Might Be More: Conduction Failure as a Factor Possibly Limiting the Efficacy of Higher Frequencies in rTMS Protocols.

Introduction: rTMS has been proven effective in the treatment of neuropsychiatric conditions, with class A (definite efficacy) evidence for treatment of depression and pain (Lefaucheur et al., 2014). The efficacy in stimulation protocols is, however, quite heterogeneous. Saturation of neuronal firing by HFrTMS without allowing time for recovery may lead to neuronal response failures (NRFs) that compromise the efficacy of stimulation with higher frequencies.Objectives: To examine the efficacy of different rTMS temporal stimulation patterns focusing on a possible upper stimulation limit related to response failures. Protocol patterns were derived from published clinical studies on therapeutic rTMS for depression and pain. They were compared with conduction failures in cell cultures.Methodology: From 57 papers using protocols rated class A for depression and pain (Lefaucheur et al., 2014) we extracted Inter-train interval (ITI), average frequency, total duration and total number of pulses and plotted them against the percent improvement on the outcome scale. Specifically, we compared 10 Hz trains with ITIs of 8 s (protocol A) and 26 s (protocol B) in vitro on cultured cortical neurons.Results: In the in vitro experiments, protocol A with 8-s ITIs resulted in more frequent response failures, while practically no response failures occurred with protocol B (26-s intervals). The HFrTMS protocol analysis exhibited no significant effect of ITIs on protocol efficiency.Discussion: In the neuronal culture, longer ITIs appeared to allow the neuronal response to recover. In the available human dataset on both depression and chronic pain, data concerning shorter ITIs is does not allow a significant conclusion.Significance: NRF may interfere with the efficacy of rTMS stimulation protocols when the average stimulation frequency is too high, proposing ITIs as a variable in rTMS protocol efficacy. Clinical trials are necessary to examine effect of shorter ITIs on the clinical outcome in a controlled setting.

Compressive Temporal Summation in Human Visual Cortex.

Combining sensory inputs over space and time is fundamental to vision. Population receptive field models have been successful in characterizing spatial encoding throughout the human visual pathways. A parallel question, how visual areas in the human brain process information distributed over time, has received less attention. One challenge is that the most widely used neuroimaging method, fMRI, has coarse temporal resolution compared with the time-scale of neural dynamics. Here, via carefully controlled temporally modulated stimuli, we show that information about temporal processing can be readily derived from fMRI signal amplitudes in male and female subjects. We find that all visual areas exhibit subadditive summation, whereby responses to longer stimuli are less than the linear prediction from briefer stimuli. We also find fMRI evidence that the neural response to two stimuli is reduced for brief interstimulus intervals (indicating adaptation). These effects are more pronounced in visual areas anterior to V1-V3. Finally, we develop a general model that shows how these effects can be captured with two simple operations: temporal summation followed by a compressive nonlinearity. This model operates for arbitrary temporal stimulation patterns and provides a simple and interpretable set of computations that can be used to characterize neural response properties across the visual hierarchy. Importantly, compressive temporal summation directly parallels earlier findings of compressive spatial summation in visual cortex describing responses to stimuli distributed across space. This indicates that, for space and time, cortex uses a similar processing strategy to achieve higher-level and increasingly invariant representations of the visual world.SIGNIFICANCE STATEMENT Combining sensory inputs over time is fundamental to seeing. Two important temporal phenomena are summation, the accumulation of sensory inputs over time, and adaptation, a response reduction for repeated or sustained stimuli. We investigated these phenomena in the human visual system using fMRI. We built predictive models that operate on arbitrary temporal patterns of stimulation using two simple computations: temporal summation followed by a compressive nonlinearity. Our new temporal compressive summation model captures (1) subadditive temporal summation, and (2) adaptation. We show that the model accounts for systematic differences in these phenomena across visual areas. Finally, we show that for space and time, the visual system uses a similar strategy to achieve increasingly invariant representations of the visual world.

An improved genetic algorithm for designing optimal temporal patterns of neural stimulation

Objective. Electrical neuromodulation therapies typically apply constant frequency stimulation, but non-regular temporal patterns of stimulation may be more effective and more efficient. However, the design space for temporal patterns is exceedingly large, and model-based optimization is required for pattern design. We designed and implemented a modified genetic algorithm (GA) intended for design optimal temporal patterns of electrical neuromodulation. Approach. We tested and modified standard GA methods for application to designing temporal patterns of neural stimulation. We evaluated each modification individually and all modifications collectively by comparing performance to the standard GA across three test functions and two biophysically-based models of neural stimulation. Main results. The proposed modifications of the GA significantly improved performance across the test functions and performed best when all were used collectively. The standard GA found patterns that outperformed fixed-frequency, clinically-standard patterns in biophysically-based models of neural stimulation, but the modified GA, in many fewer iterations, consistently converged to higher-scoring, non-regular patterns of stimulation. Significance. The proposed improvements to standard GA methodology reduced the number of iterations required for convergence and identified superior solutions.

Commentary: 2016 Epilepsia Basic Science Prize.

Commentary: 2016 Epilepsia Basic Science Prize.

Failure to suppress low-frequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation.

Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established treatment for the motor symptoms of Parkinson's disease (PD). However, the mechanisms of action of DBS are unknown. Random temporal patterns of DBS are less effective than regular DBS, but the neuronal basis for this dependence on temporal pattern of stimulation is unclear. Using a rat model of PD, we quantified the changes in behavior and single-unit activity in globus pallidus externa and substantia nigra pars reticulata during high-frequency STN DBS with different degrees of irregularity. Although all stimulus trains had the same average rate, 130-Hz regular DBS more effectively reversed motor symptoms, including circling and akinesia, than 130-Hz irregular DBS. A mixture of excitatory and inhibitory neuronal responses was present during all stimulation patterns, and mean firing rate did not change during DBS. Low-frequency (7-10 Hz) oscillations of single-unit firing times present in hemiparkinsonian rats were suppressed by regular DBS, and neuronal firing patterns were entrained to 130 Hz. Irregular patterns of DBS less effectively suppressed 7- to 10-Hz oscillations and did not regularize firing patterns. Random DBS resulted in a larger proportion of neuron pairs with increased coherence at 7-10 Hz compared with regular 130-Hz DBS, which suggested that long pauses (interpulse interval >50 ms) during random DBS facilitated abnormal low-frequency oscillations in the basal ganglia. These results suggest that the efficacy of high-frequency DBS stems from its ability to regularize patterns of neuronal firing and thereby suppress abnormal oscillatory neural activity within the basal ganglia.

Control of βAR- and N-methyl-D-aspartate (NMDA) Receptor-Dependent cAMP Dynamics in Hippocampal Neurons.

Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs), facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP) at the Schaffer collateral CA1 synapse require stimulation of both βARs and N-methyl-D-aspartate receptors (NMDARs). To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA), and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory.

Prelimbic Stimulation Ameliorates Depressive-Like Behaviors and Increases Regional BDNF Expression in a Novel Drug-Resistant Animal Model of Depression.

Approximately one third of all major depression patients fail to respond to conventional pharmacological antidepressants, and brain stimulation methods pose a promising alternative for this population. Recently, based on repeated multifactorial selective inbreeding of rats for depressive-like behaviors, we introduced a novel animal model for MDD. Rats from this Depressive Rat Line (DRL) exhibit inherent depressive-like behaviors, which are correlated with lower levels of brain-derived neurotrophic factor (BDNF) in specific brain regions. In addition, DRL rats do not respond to antidepressant medication but respond to electroconvulsive treatment, and they can thus be utilized to test the effectiveness of brain stimulation on hereditary, medication-resistant depressive-like behaviors. To test the effect of sub-convulsive electrical stimulation (SCES) of the prelimbic cortex, using TMS-like temporal pattern of stimulation, on depressive-like behaviors and regional BDNF levels in DRL rats. SCES sessions were administered daily for 10 days through chronically implanted electrodes. Temporal stimulation parameters were similar to those used in TMS for major depression in human patients. Depressive-like behaviors were assayed after treatment, followed by brain extraction and regional BDNF measurements. SCES normalized both the depressive-like behaviors and the reduced BDNF levels observed in DRL rats. Correlation analyses suggest that changes in specific behaviors are mediated, at least in part, by BDNF expression in reward-related brain regions. Brain stimulation is effective in a drug-resistant, inherited animal model for depression. BDNF alterations in specific regions may mediate different antidepressant effects.