Non-nociceptive and nociceptive-like trigeminal Aß-afferent neurons of rats: Distinct electrophysiological properties, mechanical and chemical sensitivity.

The role of Aß-afferents in somatosensory function is often oversimplified as low threshold mechanoreceptors (LTMRs) with large omission of Aß-afferent involvement in nociception. Recently, we have characterized Aß-afferent neurons which have large diameter somas in the trigeminal ganglion (TG) and classified them into non-nociceptive and nociceptive-like TG afferent neurons based on their electrophysiological properties. Here, we extend our previous observations to further characterize electrophysiological properties of trigeminal Aß-afferent neurons and investigate their mechanical and chemical sensitivity by patch-clamp recordings from large-diameter TG neurons in ex vivo TG preparations of adult male and female rats. Based on cluster analysis of electrophysiological properties, trigeminal Aß-afferent neurons can be classified into five discrete types (type I, IIa, IIb, IIIa, and IIIb), which responded differentially to mechanical stimulation and sensory mediators including serotonin (5-HT), acetylcholine (ACh) and adenosine triphosphate (ATP). Notably, type I neuron action potential (AP) was small in amplitude, width was narrow in duration, and peak dV/dt repolarization was great with no deflection observed, whereas discretely graded differences were observed for type IIa, IIb, IIIa, and IIIb, as AP increased in amplitude, width broadened in duration, and peak dV/dt repolarization reduced with the emergence of increasing deflection. Type I, IIa, and IIb neurons were mostly mechanically sensitive, displaying robust and rapidly adapting mechanically activated current (IMA) in response to membrane displacement, while IIIa and IIIb, conversely, were almost all mechanically insensitive. Interestingly, mechanical insensitivity coincided with increased sensitivity to 5-HT and ACh. Together, type I, IIa and IIb display features of LTMR Aß-afferent neurons while type IIIa and type IIIb show properties of nociceptive Aß-afferent neurons.

Electrophysiological properties of maxillary trigeminal Aß-afferent neurons of rats.

Aß-afferents in maxillary or V2 trigeminal ganglion (TG) neurons are somatosensory neurons that may be involved in both non-nociceptive and nociceptive functions in orofacial regions. However, electrophysiological properties of these V2 trigeminal Aß-afferent neurons have not been well characterized so far. Here, we used rat ex vivo trigeminal nerve preparations and applied patch-clamp recordings to large-sized V2 TG neurons to characterize their electrophysiological properties. All the cells recorded had afferent conduction velocities in the range of Aß-afferent conduction speeds. However, these V2 trigeminal Aß-afferent neurons displayed different action potential (AP) properties. APs showed fast kinetics in some cells but slow kinetics with shoulders in repolarization phases in other cells. Based on the derivatives of voltages in AP repolarization with time (dV/dt), we classified V2 trigeminal Aß-afferent neurons into four types: type I, type II, type IIIa and type IIIb. Type I V2 trigeminal Aß-afferent neurons had the largest dV/dt of repolarization, the fastest AP conduction velocities, the shortest AP and afterhyperpolarization (AHP) durations, and the highest AP success rates. In contrast, type IIIb V2 trigeminal Aß-afferent neurons had the smallest dV/dt of AP repolarization, the slowest AP conduction velocities, the longest AP and AHP durations, and the lowest AP success rates. The type IIIb cells also had significantly lower voltage-activated K+ currents. For type II and type IIIa V2 trigeminal Aß-afferent neurons, AP parameters were in the range between those of type I and type IIIb V2 trigeminal Aß-afferent neurons. Our electrophysiological classification of V2 trigeminal Aß-afferent neurons may be useful in future to study their non-nociceptive and nociceptive functions in orofacial regions.

Background connectivity between frontal and sensory cortex depends on task state, independent of stimulus modality.

The human brain has the ability to process identical information differently depending on the task. In order to perform a given task, the brain must select and react to the appropriate stimuli while ignoring other irrelevant stimuli. The dynamic nature of environmental stimuli and behavioral intentions requires an equally dynamic set of responses within the brain. Collectively, these responses act to set up and maintain states needed to perform a given task. However, the mechanisms that allow for setting up and maintaining a task state are not fully understood. Prior evidence suggests that one possible mechanism for maintaining a task state may be through altering 'background connectivity,' connectivity that exists independently of the trials of a task. Although previous studies have suggested that background connectivity contributes to a task state, these studies have typically not controlled for stimulus characteristics, or have focused primarily on relationships among areas involved with visual sensory processing. In the present study we examined background connectivity during tasks involving both visual and auditory stimuli. We examined the connectivity profiles of both visual and auditory sensory cortex that allow for selection of task-relevant stimuli, demonstrating the existence of a potentially universal pattern of background connectivity underlying attention to a stimulus. Participants were presented with simultaneous auditory and visual stimuli and were instructed to respond to only one, while ignoring the other. Using functional MRI, we observed task-based modulation of the background connectivity profile for both the auditory and visual cortex to certain brain regions. There was an increase in background connectivity between the task-relevant sensory cortex and control areas in the frontal cortex. This increase in synchrony when receiving the task-relevant stimulus as compared to the task irrelevant stimulus may be maintaining paths for passing information within the cortex. These task-based modulations of connectivity occur independently of stimuli and could be one way the brain sets up and maintains a task state.

Distinct effects of trial-driven and task Set-related control in primary visual cortex.

Task sets are task-specific configurations of cognitive processes that facilitate task-appropriate reactions to stimuli. While it is established that the trial-by-trial deployment of visual attention to expected stimuli influences neural responses in primary visual cortex (V1) in a retinotopically specific manner, it is not clear whether the mechanisms that help maintain a task set over many trials also operate with similar retinotopic specificity. Here, we address this question by using BOLD fMRI to characterize how portions of V1 that are specialized for different eccentricities respond during distinct components of an attention-demanding discrimination task: cue-driven preparation for a trial, trial-driven processing, task-initiation at the beginning of a block of trials, and task-maintenance throughout a block of trials. Tasks required either unimodal attention to an auditory or a visual stimulus or selective intermodal attention to the visual or auditory component of simultaneously presented visual and auditory stimuli. We found that while the retinotopic patterns of trial-driven and cue-driven activity depended on the attended stimulus, the retinotopic patterns of task-initiation and task-maintenance activity did not. Further, only the retinotopic patterns of trial-driven activity were found to depend on the presence of inter-modal distraction. Participants who performed well on the intermodal selective attention tasks showed strong task-specific modulations of both trial-driven and task-maintenance activity. Importantly, task-related modulations of trial-driven and task-maintenance activity were in opposite directions. Together, these results confirm that there are (at least) two different processes for top-down control of V1: One, working trial-by-trial, differently modulates activity across different eccentricity sectors - portions of V1 corresponding to different visual eccentricities. The second process works across longer epochs of task performance, and does not differ among eccentricity sectors. These results are discussed in the context of previous literature examining top-down control of visual cortical areas.

Early visual cortex reflects initiation and maintenance of task set.

The human brain is able to process information flexibly, depending on a person's task. The mechanisms underlying this ability to initiate and maintain a task set are not well understood, but they are important for understanding the flexibility of human behavior and developing therapies for disorders involving attention. Here we investigate the differential roles of early visual cortical areas in initiating and maintaining a task set. Using functional Magnetic Resonance Imaging (fMRI), we characterized three different components of task set-related, but trial-independent activity in retinotopically mapped areas of early visual cortex, while human participants performed attention demanding visual or auditory tasks. These trial-independent effects reflected: (1) maintenance of attention over a long duration, (2) orienting to a cue, and (3) initiation of a task set. Participants performed tasks that differed in the modality of stimulus to be attended (auditory or visual) and in whether there was a simultaneous distractor (auditory only, visual only, or simultaneous auditory and visual). We found that patterns of trial-independent activity in early visual areas (V1, V2, V3, hV4) depend on attended modality, but not on stimuli. Further, different early visual areas play distinct roles in the initiation of a task set. In addition, activity associated with maintaining a task set tracks with a participant's behavior. These results show that trial-independent activity in early visual cortex reflects initiation and maintenance of a person's task set.

Sodium-potassium ATPase emerges as a player in hippocampal phenotypes of Angelman syndrome mice.

Angelman syndrome is a neurodevelopmental disorder characterized by intellectual disabilities, ataxia, and unusually happy affect. The hippocampal pyramidal cells of Angelman syndrome model mice have altered intrinsic membrane properties, which Kaphzan et al. (Cell Rep 4: 405-412, 2013) demonstrate can be corrected by genetic reduction of the α1-subunit of the sodium-potassium ATPase. Intriguingly, this manipulation also restores hippocampal long-term potentiation and learning. In this Neuro Forum, we discuss translational implications of this work and remaining questions left in its wake.

Older adults, unlike younger adults, do not modulate alpha power to suppress irrelevant information.

This study examines the neural mechanisms through which younger and older adults ignore irrelevant information, a process that is necessary to effectively encode new memories. Some age-related memory deficits have been linked to a diminished ability to dynamically gate sensory input, resulting in problems inhibiting the processing of distracting stimuli. Whereas oscillatory power in the alpha band (8-12 Hz) over visual cortical areas is thought to dynamically gate sensory input in younger adults, it is not known whether older adults use the same mechanism to gate out sensory input. Here we identified a task in which both older and younger adults could suppress the processing of irrelevant sensory stimuli, allowing us to use electroencephalography (EEG) to explore the neural activity associated with suppression of visual processing. As expected, we found that the younger adults' suppression of visual processing was correlated with robust modulation of alpha oscillatory power. However, older adults did not modulate alpha power to suppress processing of visual information. These results demonstrate that suppression of alpha power is not necessary to inhibit the processing of distracting stimuli in older adults, suggesting the existence of alternative strategies for suppressing irrelevant, potentially distracting information.

Subcortical short-term plasticity elicited by deep brain stimulation.

OBJECTIVE: To investigate local short-term neuroplasticity elicited by subthalamic, thalamic, and pallidal deep brain stimulation (DBS) for movement disorders. METHODS: During DBS surgery, we delivered pairs of stimulus pulses with both circular and directional leads across 90 interstimulus intervals in 17 participants and recorded local field potentials from unused contacts on the implanted electrode array. We removed the stimulus artifact, validated the neural origin of the underlying signals, and examined short-term plasticity as a function of interstimulus interval and DBS target, using linear mixed effects models. RESULTS: DBS evokes short latency local field potentials that are readily detected with both circular and directional leads at all stimulation targets (0.31 ± 0.10 msec peak latency, mean ± SD). Peak amplitude, area, and latency are modified strongly by interstimulus interval (P < 0.001) and display absolute and relative refractory periods (0.56 ± 0.08 and 2.94 ± 1.05 msec, respectively). We also identified later oscillatory activity in the subthalamic-pallidal circuit (4.50 ± 1.11 msec peak latency) that displays paired pulse facilitation (present in 5/8 subthalamic, 4/5 pallidal, and 0/6 thalamic trajectories, P = 0.018, Fisher's exact test), and correlates with resting beta frequency power (P < 0.001), therapeutic DBS frequencies, and stimulation sites chosen later for therapy in the ambulatory setting (P = 0.031). INTERPRETATION: Paired DBS pulses synchronize local circuit electrophysiology and elicit short-term neuroplasticity in the subthalamic-pallidal circuit. Collectively, these responses likely represent the earliest detectable interaction between the DBS pulse and local neuronal tissue in humans. Evoked subcortical field potentials could serve as a predictive biomarker to guide the implementation of next-generation directional and adaptive stimulation devices.

Parvalbumin interneurons provide spillover to newborn and mature dentate granule cells.

Parvalbumin-expressing interneurons (PVs) in the dentate gyrus provide activity-dependent regulation of adult neurogenesis as well as maintain inhibitory control of mature neurons. In mature neurons, PVs evoke GABAA postsynaptic currents (GPSCs) with fast rise and decay phases that allow precise control of spike timing, yet synaptic currents with fast kinetics do not appear in adult-born neurons until several weeks after cell birth. Here we used mouse hippocampal slices to address how PVs signal to newborn neurons prior to the appearance of fast GPSCs. Whereas PV-evoked currents in mature neurons exhibit hallmark fast rise and decay phases, newborn neurons display slow GPSCs with characteristics of spillover signaling. We also unmasked slow spillover currents in mature neurons in the absence of fast GPSCs. Our results suggest that PVs mediate slow spillover signaling in addition to conventional fast synaptic signaling, and that spillover transmission mediates activity-dependent regulation of early events in adult neurogenesis.

Subcortical Intermittent Theta-Burst Stimulation (iTBS) Increases Theta-Power in Dorsolateral Prefrontal Cortex (DLPFC).

INTRODUCTION: Cognitive symptoms from Parkinson's disease cause severe disability and significantly limit quality of life. Little is known about mechanisms of cognitive impairment in PD, although aberrant oscillatory activity in basal ganglia-thalamo-prefrontal cortical circuits likely plays an important role. While continuous high-frequency deep brain stimulation (DBS) improves motor symptoms, it is generally ineffective for cognitive symptoms. Although we lack robust treatment options for these symptoms, recent studies with transcranial magnetic stimulation (TMS), applying intermittent theta-burst stimulation (iTBS) to dorsolateral prefrontal cortex (DLPFC), suggest beneficial effects for certain aspects of cognition, such as memory or inhibitory control. While TMS is non-invasive, its results are transient and require repeated application. Subcortical DBS targets have strong reciprocal connections with prefrontal cortex, such that iTBS through the permanently implanted lead might represent a more durable solution. Here we demonstrate safety and feasibility for delivering iTBS from the DBS electrode and explore changes in DLPFC electrophysiology. METHODS: We enrolled seven participants with medically refractory Parkinson's disease who underwent DBS surgery targeting either the subthalamic nucleus (STN) or globus pallidus interna (GPi). We temporarily placed an electrocorticography strip over DLPFC through the DBS burr hole. After placement of the DBS electrode into either GPi (n = 3) or STN (n = 4), awake subjects rested quietly during iTBS (three 50-Hz pulses delivered at 5 Hz for 2 s, followed by 8 s of rest). We contrasted power spectra in DLPFC local field potentials during iTBS versus at rest, as well as between iTBS and conventional high-frequency stimulation (HFS). RESULTS: Dominant frequencies in DLPFC at rest varied among subjects and along the subdural strip electrode, though they were generally localized in theta (3-8 Hz) and/or beta (10-30 Hz) ranges. Both iTBS and HFS were well-tolerated and imperceptible. iTBS increased theta-frequency activity more than HFS. Further, GPi stimulation resulted in significantly greater theta-power versus STN stimulation in our sample. CONCLUSION: Acute subcortical iTBS from the DBS electrode was safe and well-tolerated. This novel stimulation pattern delivered from the GPi may increase theta-frequency power in ipsilateral DLPFC. Future studies will confirm these changes in DLPFC activity during iTBS and evaluate whether they are associated with improvements in cognitive or behavioral symptoms from PD.

Adult-born neurons modify excitatory synaptic transmission to existing neurons.

Adult-born neurons are continually produced in the dentate gyrus but it is unclear whether synaptic integration of new neurons affects the pre-existing circuit. Here we investigated how manipulating neurogenesis in adult mice alters excitatory synaptic transmission to mature dentate neurons. Enhancing neurogenesis by conditional deletion of the pro-apoptotic gene Bax in stem cells reduced excitatory postsynaptic currents (EPSCs) and spine density in mature neurons, whereas genetic ablation of neurogenesis increased EPSCs in mature neurons. Unexpectedly, we found that Bax deletion in developing and mature dentate neurons increased EPSCs and prevented neurogenesis-induced synaptic suppression. Together these results show that neurogenesis modifies synaptic transmission to mature neurons in a manner consistent with a redistribution of pre-existing synapses to newly integrating neurons and that a non-apoptotic function of the Bax signaling pathway contributes to ongoing synaptic refinement within the dentate circuit.

Neurogenesis, the creation of new brain cells called neurons, occurs primarily before birth. However, a region of the brain called the dentate gyrus, which is involved in memory, continues to produce new neurons throughout life. Recent studies suggest that adding neurons to the dentate gyrus helps the brain to distinguish between similar sights, sounds and smells. This in turn makes it easier to encode similar experiences as distinct memories. The brain's outer layer, called the cortex, processes information from our senses and sends it, along with information about our location in space, to the dentate gyrus. By combining this sensory and spatial information, the dentate gyrus is able to generate a unique memory of an experience. But how does neurogenesis affect this process? As the dentate gyrus accumulates more neurons, the number of neurons in the cortex remains unchanged. Do some cortical neurons transfer their connections ­ called synapses ­ to the new neurons? Or does the brain generate additional synapses to accommodate the newborn cells? Adlaf et al. set out to answer this question by genetically modifying mice to alter the number of new neurons that could form in the dentate gyrus. Increasing the number of newborn neurons reduced the number of synapses between the cortex and the mature neurons in the dentate gyrus. Conversely, killing off newborn neurons had the opposite effect, increasing the strength of the synaptic connections to older cells. This suggests that new synapses are not formed to accommodate new neurons, but rather that there is a redistribution of synapses between old and new neurons in the dentate gyrus. Further work is required to determine how this redistribution of synapses contributes to how the dentate gyrus works. Does redistributing synapses disrupt existing memories? And how do these findings relate to the effects of exercise ­ does this natural way of increasing neurogenesis increase the overall number of synapses in the system, potentially creating enough connections for both new and old neurons?