Patterns Of Neuronal Activity Research Articles

Neuroimaging reveals functionally distinct neuronal networks associated with high-level alcohol consumption in two genetic rat models.

Human imaging data suggest that the motivational processes associated with alcohol reward are reflected in the patterns of neural activation after alcohol or alcohol-related cues. In animal models of alcohol drinking, however, the changes in brain activation during voluntary alcohol ingestion are poorly known. In order to improve the translational utility of animal models, we examined alcohol-induced functional brain activation in Alko Alcohol (AA) and Marchigian-Sardinian alcohol-preferring (msP) rats that drink voluntarily high levels of alcohol, but exhibit widely different neurochemical and behavioral traits cosegregated with alcohol preference. Brain imaging was performed using manganese-enhanced MRI (MEMRI), which is based on accumulation of Mn2+ ions in activated neurons, allowing the identification of functional neuronal networks recruited during specific behaviors in awake animals during a subsequent imaging session under anesthesia. MEMRI was performed following 4 weeks of voluntary alcohol drinking, using water drinking as the control. Despite similar levels of alcohol drinking, strikingly different alcohol-induced neuronal activity patterns were observed in AA and msP rats. Overall, functional activation in the AA rats was more widespread, involving large cortical areas and subcortical structures, such as the bed nucleus of the stria terminalis, preoptic area, hypothalamus, periaqueductal grey, and substantia nigra. In the msP rats, however, alcohol-related activation was largely confined to prefrontal cortical regions and insular cortex, and olfactory areas. Overlapping areas of activation found in both rat lines included the nucleus accumbens, prelimbic, orbital, and insular cortex. In conclusion, our data reveal strikingly different brain circuits associated with alcohol drinking in two genetically different rat lines and suggest innately different motivational and behavioral processes driving alcohol drinking. These findings have important implications for the use of these lines in translational alcohol research.

Micro Three-Dimensional Neuronal Cultures Generate Developing Cortex-Like Activity Patterns.

Studies aimed at neurological drug discovery have been carried out both in vitro and in vivo. In vitro cell culture models have showed potential as drug testing platforms characterized by high throughput, low cost, good reproducibility and ease of handling and observation. However, in vitro neuronal culture models are facing challenges in replicating in vivo-like activity patterns. This work reports an in vitro culture technique that is capable of producing micro three-dimensional (μ3D) cultures of only a few tens of neurons. The μ3D cultures generated by this method were uniform in size and density of neurons. These μ3D cultures had complex spontaneous synchronized neuronal activity patterns which were similar to those observed in the developing cortex and in much larger 3D cultures, but not in 2D cultures. Bursts could be reliably evoked by stimulation of single neurons. Synchronized bursts in μ3D cultures were abolished by inhibitors of glutamate receptors, while inhibitors of GABAA receptors had a more complex effect. This pharmacological profile is similar to bursts in neonatal cortex. Since large numbers of reproducible μ3D cultures can be created and observed in parallel, this model of the developing cortex may find applications in high-throughput drug discovery experiments.

Local Axonal Conduction Shapes the Spatiotemporal Properties of Neural Sequences

Sequential activation of neurons has been observed during various behavioral and cognitive processes, but the underlying circuit mechanisms remain poorly understood. Here, we investigate premotor sequences in HVC (proper name) of the adult zebra finch forebrain that are central to the performance of the temporally precise courtship song. We use high-density silicon probes to measure song-related population activity, and we compare these observations with predictions from a range of network models. Our results support a circuit architecture in which heterogeneous delays between sequentially active neurons shape the spatiotemporal patterns of HVC premotor neuron activity. We gauge the impact of several delay sources, and we find the primary contributor to be slow conduction through axonal collaterals within HVC, which typically adds between 1 and 7.5ms for each link within the sequence. Thus, local axonal "delay lines" can play an important role in determining the dynamical repertoire of neural circuits.

Perspective: Phase Amplitude Coupling-Based Phase-Dependent Neuromodulation in Parkinson's Disease.

Deep brain stimulation (DBS) is an effective surgical therapy for Parkinson’s disease (PD). However, limitations of the DBS systems have led to great interest in adaptive neuromodulation systems that can dynamically adjust stimulation parameters to meet concurrent therapeutic demand. Constant high-frequency motor cortex stimulation has not been remarkably efficacious, which has led to greater focus on modulation of subcortical targets. Understanding of the importance of timing in both cortical and subcortical stimulation has generated an interest in developing more refined, parsimonious stimulation techniques based on critical oscillatory activities of the brain. Concurrently, much effort has been put into identifying biomarkers of both parkinsonian and physiological patterns of neuronal activities to drive next generation of adaptive brain stimulation systems. One such biomarker is beta-gamma phase amplitude coupling (PAC) that is detected in the motor cortex. PAC is strongly correlated with parkinsonian specific motor signs and symptoms and respond to therapies in a dose-dependent manner. PAC may represent the overall state of the parkinsonian motor network and have less instantaneously dynamic fluctuation during movement. These findings raise the possibility of novel neuromodulation paradigms that are potentially less invasiveness than DBS. Successful application of PAC in neuromodulation may necessitate phase-dependent stimulation technique, which aims to deliver precisely timed stimulation pulses to a specific phase to predictably modulate to selectively modulate pathological network activities and behavior in real time. Overcoming current technical challenges can lead to deeper understanding of the parkinsonian pathophysiology and development of novel neuromodulatory therapies with potentially less side-effects and higher therapeutic efficacy.

Representation of what happened when

Neuroscience Episodic memory depends on the hippocampus and entorhinal cortex. Although the temporal coding properties of hippocampal neurons are well known, the temporal code in the entorhinal cortex, which provides important input to the hippocampus, is less understood. Bright et al. examined monkey entorhinal neuron responses in a 5-second period after presentation of an image. Entorhinal neurons were activated shortly after a visual stimulus and then decayed with a variety of rates, enabling reconstruction of when the image was presented. To determine whether the pattern of neuronal activation depended on the identity of the image presented, each image was shown twice during the experiment. These results suggest that entorhinal cortex context cells carry information about what happened in addition to when it happened. Proc. Natl. Acad. Sci. U.S.A. 117 , 20274 (2020).

Dorsal horn disinhibition and movement-induced behaviour in a rat model of inflammatory arthritis

Alterations beyond joint inflammation such as changes in dorsal horn (DH) excitability contribute to pain in inflammatory arthritis (IA). More complete understanding of specific underlying mechanisms will be important to define novel targets for the treatment of IA pain. Pre-clinical models are useful, but relevant pain assays are vital for successful clinical translation. For this purpose, a method is presented to assess movement-induced pain-related behaviour changes that was subsequently used to investigate DH disinhibition in IA. IA was induced by intra-articular injection of complete Freund's adjuvant (CFA) in male rats, and weight distribution was assessed before and after walking on a treadmill. To confirm increased activity in nociception-related pathways, fos expression was assessed in the superficial DH, including in nociceptive neurons, identified by neurokinin 1 (NK1) immunoreactivity, and interneurons. Inhibitory terminal density onto NK1+ neurons was assessed and lastly, a cohort of animals was treated for 3 days with gabapentin. At 4 weeks post-CFA, walking reduced weight distribution to the affected joint and increased DH fos expression, including in NK1+ neurons. Neuronal activity in inhibitory cells and inhibitory terminal density on NK1+ neurons were decreased in CFA-treated animals compared with controls. Treatment with gabapentin led to recovered behaviour and DH neuronal activity pattern in CFA-treated animals. We describe an assay to assess movement-induced pain-related behaviour changes in a rodent IA model. Furthermore, our results suggest that disinhibition may contribute to pain related to movement in IA.

Interindividual differences in memory system local field potential activity predict behavioral strategy on a dual-solution T-maze.

Individuals can use diverse behavioral strategies to navigate their environment including hippocampal-dependent place strategies reliant upon cognitive maps and striatal-dependent response strategies reliant upon egocentric body turns. The existence of multiple memory systems appears to facilitate successful navigation across a wide range of environmental and physiological conditions. The mechanisms by which these systems interact to ultimately generate a unitary behavioral response, however, remain unclear. We trained 20 male, Sprague-Dawley rats on a dual-solution T-maze while simultaneously recording local field potentials that were targeted to the dorsolateral striatum and dorsal hippocampus. Eight rats spontaneously exhibited a place strategy while the remaining 12 rats exhibited a response strategy. Interindividual differences in behavioral strategy were associated with distinct patterns of LFP activity between the dorsolateral striatum and dorsal hippocampus. Specifically, striatal-hippocampal theta activity was in-phase in response rats and out-of-phase in place rats and response rats exhibited elevated striatal-hippocampal coherence across a wide range of frequency bands. These contrasting striatal-hippocampal activity regimes were (a) present during both maze-learning and a 30 min premaze habituation period and (b) could be used to train support vector machines to reliably predict behavioral strategy. Distinct patterns of neuronal activity across multiple memory systems, therefore, appear to bias behavioral strategy selection and thereby contribute to interindividual differences in behavior.

Agonistic behaviors and neuronal activation in sexually naïve female Mongolian gerbils

Agonistic interaction is important for establishing social hierarchy and determining access to limited resources. Although there are substantial studies investigating the neural mechanisms of aggressive or defensive behavior in male rodents, little attention has been paid to the mechanisms underlying agonistic behaviors in females. In the present study, we depicted patterns of agonistic behaviors in sexually naïve female Mongolian gerbils (Meriones unguiculatus) and examined the neuronal activation in the brain by Fos-immunoreactive (Fos-ir) staining. We found that the winner-loser relationship was established rapidly. Winners displayed higher levels of aggression, environmental exploration, scent marking, and self-grooming, but less defensive behavior, in comparison to losers. Several patterns of Fos-ir expression emerged following agonistic interactions. Winners had the number of Fos-ir cells in the ventrolateral subnucleus of the ventromedial hypothalamus (VMHvl) and dorsal periaqueductal grey (PAGd) more than the controls but less than the losers. Losers also had more Fos-ir cells in the paraventricular nucleus of the hypothalamus (PVN), anterior medial (BSTam) and anteriolateral (BSTal) subnuclei of the bed nucleus of the stria terminalis (BST), and the ventral subnucleus of the lateral septum (LSv), as well as less Fos-ir cells in the dentate gyrus of the hippocampus (DG), compared to the controls. In addition, the number of Fos-ir cells showed similar increases in the principal nucleus (BSTpr) and interfascicular nucleus (BSTif) of the BST and amygdala (AMYG) in both the winners and losers, compared to the controls. Together, these data illustrate the patterns of altered neuronal activation in a behavior-, social status-, and brain region-specific manner, implicating potential roles of the brain neural circuit in mediating agonistic interactions in female Mongolian gerbils.

Brain-inspired replay for continual learning with artificial neural networks

Artificial neural networks suffer from catastrophic forgetting. Unlike humans, when these networks are trained on something new, they rapidly forget what was learned before. In the brain, a mechanism thought to be important for protecting memories is the reactivation of neuronal activity patterns representing those memories. In artificial neural networks, such memory replay can be implemented as ‘generative replay’, which can successfully – and surprisingly efficiently – prevent catastrophic forgetting on toy examples even in a class-incremental learning scenario. However, scaling up generative replay to complicated problems with many tasks or complex inputs is challenging. We propose a new, brain-inspired variant of replay in which internal or hidden representations are replayed that are generated by the network’s own, context-modulated feedback connections. Our method achieves state-of-the-art performance on challenging continual learning benchmarks (e.g., class-incremental learning on CIFAR-100) without storing data, and it provides a novel model for replay in the brain.

A comprehensive model-based framework for optimal design of biomimetic patterns of electrical stimulation for prosthetic sensation

Objective. Touch and proprioception are essential to motor function as shown by the movement deficits that result from the loss of these senses, e.g. due to neuropathy of sensory nerves. To achieve a high-performance brain-controlled prosthetic arm/hand thus requires the restoration of somatosensation, perhaps through intracortical microstimulation (ICMS) of somatosensory cortex (S1). The challenge is to generate patterns of neuronal activation that evoke interpretable percepts. We present a framework to design optimal spatiotemporal patterns of ICMS (STIM) that evoke naturalistic patterns of neuronal activity and demonstrate performance superior to four previous approaches. Approach. We recorded multiunit activity from S1 during a center-out reach task (from proprioceptive neurons in Brodmann’s area 2) and during application of skin indentations (from cutaneous neurons in Brodmann’s area 1). We implemented a computational model of a cortical hypercolumn and used a genetic algorithm to design STIM that evoked patterns of model neuron activity that mimicked their experimentally-measured counterparts. Finally, from the ICMS patterns, the evoked neuronal activity, and the stimulus parameters that gave rise to it, we trained a recurrent neural network (RNN) to learn the mapping function between the physical stimulus and the biomimetic stimulation pattern, i.e. the sensory encoder to be integrated into a neuroprosthetic device. Main results. We identified ICMS patterns that evoked simulated responses that closely approximated the measured responses for neurons within 50 µm of the electrode tip. The RNN-based sensory encoder generalized well to untrained limb movements or skin indentations. STIM designed using the model-based optimization approach outperformed STIM designed using existing linear and nonlinear mappings. Significance. The proposed framework produces an encoder that converts limb state or patterns of pressure exerted onto the prosthetic hand into STIM that evoke naturalistic patterns of neuronal activation.

Differentiating the Brain’s involvement in Executed and Imagined Stepping using fMRI

The purpose of this study was to extend the extant literature regarding brain areas that are activated during executed and imagined lower limb movement. Past research suggests that stepping, as a cyclical movement, should activate the motor control areas of the brain that integrates smooth movements with spinal cord nerves. The neuronal activity needed to imagine that same activity is likely to recruit additional sensory-motor areas that provide initiation and inhibition signals, making this task take on a neuronal activity pattern that is more similar to discrete movements. To assess this research question, 16 participants took part in the current study where they executed and imagined stepping, with movement at the hip, knee, and ankle joints, while viewing a computer-generated image of a human walking. A block design with a total of 10 blocks for rest and task for each condition was used. Rest blocks lasted 18 seconds, followed by an 18-second display of the visual stimulus. Results showed that in the executed condition, areas of the brain that are most prominently associated with sensory-motor activity were activated. In the imagined condition areas of the brain associated with movement control, inhibition of movement, and the integration of sensory input and motor output (parietal and occipital) were also activated. These findings contribute to the literature identifying brain areas that are activated in lower limb locomotion.

Object recognition is enabled by an experience-dependent appraisal of visual features in the brain’s value system

This paper addresses perceptual synthesis by comparing responses evoked by visual stimuli before and after they are recognized, depending on prior exposure. Using magnetoencephalography, we analyzed distributed patterns of neuronal activity – evoked by Mooney figures – before and after they were recognized as meaningful objects. Recognition induced changes were first seen at 100–120 ​ms, for both faces and tools. These early effects – in right inferior and middle occipital regions – were characterized by an increase in power in the absence of any changes in spatial patterns of activity. Within a later 210–230 ​ms window, a quite different type of recognition effect appeared. Regions of the brain’s value system (insula, entorhinal cortex and cingulate of the right hemisphere for faces and right orbitofrontal cortex for tools) evinced a reorganization of their neuronal activity without an overall power increase in the region. Finally, we found that during the perception of disambiguated face stimuli, a face-specific response in the right fusiform gyrus emerged at 240–290 ​ms, with a much greater latency than the well-known N170m component, and, crucially, followed the recognition effect in the value system regions. These results can clarify one of the most intriguing issues of perceptual synthesis, namely, how a limited set of high-level predictions, which is required to reduce the uncertainty when resolving the ill-posed inverse problem of perception, can be available before category-specific processing in visual cortex. We suggest that a subset of local spatial features serves as partial cues for a fast re-activation of object-specific appraisal by the value system. The ensuing top-down feedback from value system to visual cortex, in particular, the fusiform gyrus enables high levels of processing to form category-specific predictions. This descending influence of the value system was more prominent for faces than for tools, the fact that reflects different dependence of these categories on value-related information.

Altered spontaneous neuronal activity and functional connectivity pattern in primary angle-closure glaucoma: a resting-state fMRI study.

To explore the alterations of spontaneous neuronal activity and functional connectivity pattern using fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity (FC) in patients with primary angle-closure glaucoma (PACG) and fALFF relationship with the glaucoma clinical indices. Forty-two PACG patients and 21 normal controls were enrolled in this study. Resting-state functional magnetic resonance imaging was firstly analyzed by fALFF and brain regions with altered fALFF between groups were selected as seeds for the further FC analysis. The relationships between fALFF/FC values of abnormal regions and ophthalmological measures, including mean deviation of visual field (MDVF) and retinal nerve fiber layer (RNFL) thickness, were also analyzed. Compared with NC, PACG had significant lower fALFF values in the left cuneus, left middle temporal gyrus, right middle temporal gyrus, and right precentral gyrus, while higher fALFF values in the bilateral superior frontal gyrus (P < 0.05 after correction). Furthermore, PACG showed increased FC between left cuneus and bilateral superior frontal gyrus/bilateral posterior cingulate gyrus; between left middle temporal gyrus and bilateral superior frontal gyrus; and between right middle temporal gyrus and bilateral insular (P < 0.05 after correction). In addition, in the PACG group, the mean fALFF values of the left cuneus were positively correlated with MDVF (R = 0.419, P = 0.005) and RNFL thickness (R = 0.322, P = 0.038). Meanwhile, the mean fALFF values of bilateral superior frontal gyrus were negatively correlated with MDVF (R = - 0.454, P = 0.003) and RNFL thickness (R = - 0.556, P < 0.001). PACG exhibited abnormal spontaneous neural activity and connectivity in several brain regions mainly associated with visual and visual-related functions. In addition, the fALFF values of the left cuneus and bilateral superior frontal gyrus may be complementary biomarkers for assessing the disease severity.

Structural Correlates of CA2 and CA3 Pyramidal Cell Activity in Freely-Moving Mice.

Plasticity within hippocampal circuits is essential for memory functions. The hippocampal CA2/CA3 region is thought to be able to rapidly store incoming information by plastic modifications of synaptic weights within its recurrent network. High-frequency spike-bursts are believed to be essential for this process, by serving as triggers for synaptic plasticity. Given the diversity of CA2/CA3 pyramidal neurons, it is currently unknown whether and how burst activity, assessed in vivo during natural behavior, relates to principal cell heterogeneity. To explore this issue, we juxtacellularly recorded the activity of single CA2/CA3 neurons from freely-moving male mice, exploring a familiar environment. In line with previous work, we found that spatial and temporal activity patterns of pyramidal neurons correlated with their topographical position. Morphometric analysis revealed that neurons with a higher proportion of distal dendritic length displayed a higher tendency to fire spike-bursts. We propose that the dendritic architecture of pyramidal neurons might determine burst-firing by setting the relative amount of distal excitatory inputs from the entorhinal cortex.SIGNIFICANCE STATEMENT High-frequency spike-bursts are thought to serve fundamental computational roles within neural circuits. Within hippocampal circuits, spike-bursts are believed to serve as potent instructive signals, which increase the efficiency of information transfer and induce rapid modifications of synaptic efficacies. In the present study, by juxtacellularly recording and labeling single CA2/CA3 neurons in freely-moving mice, we explored whether and how burst propensity relates to pyramidal cell heterogeneity. We provide evidence that, within the CA2/CA3 region, neurons with higher proportion of distal dendritic length display a higher tendency to fire spike-bursts. Thus, the relative amount of entorhinal inputs, arriving onto the distal dendrites, might determine the burst propensity of individual CA2/CA3 neurons in vivo during natural behavior.

Non-invasive High Frequency Repetitive Transcranial Magnetic Stimulation (hfrTMS) Robustly Activates Molecular Pathways Implicated in Neuronal Growth and Synaptic Plasticity in Select Populations of Neurons.

Patterns of neuronal activity that induce synaptic plasticity and memory storage activate kinase cascades in neurons that are thought to be part of the mechanism for synaptic modification. One such cascade involves induction of phosphorylation of ribosomal protein S6 in neurons due to synaptic activation of AKT/mTOR and via a different pathway, activation of MAP kinase/ERK1/2. Here, we show that phosphorylation of ribosomal protein S6 can also be strongly activated by high frequency repetitive transcranial magnetic stimulation (hfrTMS). HfrTMS was delivered to lightly anesthetized rats using a stimulation protocol that is a standard for inducing LTP in the perforant path in vivo (trains of 8 pulses at 400 Hz repeated at intervals of 1/10 s). Stimulation produced stimulus-locked motor responses but did not elicit behavioral seizures either during or after stimulation. After as little as 10 min of hfrTMS, immunostaining using phospho-specific antibodies for the phosphorylated form of ribosomal protein S6 (rpS6) revealed robust induction of rpS6 phosphorylation in large numbers of neurons in the cortex, especially the piriform cortex, and also in thalamic relay nuclei. Quantification revealed that the extent of the increased immunostaining depended on the number of trains and stimulus intensity. Of note, immunostaining for the immediate early genes Arc and c-fos revealed strong induction of IEG expression in many of the same populations of neurons throughout the cortex, but not the thalamus. These results indicate that hfrTMS can robustly activate molecular pathways critical for plasticity, which may contribute to the beneficial effects of TMS on recovery following brain and spinal cord injury and symptom amelioration in human psychiatric disorders. These molecular processes may be a useful surrogate marker to allow optimization of TMS parameters for maximal therapeutic benefit.

The mycotoxin deoxynivalenol activates GABAergic neurons in the reward system and inhibits feeding and maternal behaviours

Deoxynivalenol (DON) or vomitoxin, is a trichothecene mycotoxin produced mainly by Fusarium graminearum and culmorum. Mycotoxins or secondary metabolic products of mold fungi are micro-pollutants, which may affect human and animal health. The neuronal and behavioural actions of DON were analysed in the present study. To address, which neurons can be affected by DON, the neuronal activation pattern following intraperitoneal injection of DON (1 mg/kg) was investigated in adult male rats and the results were confirmed in mice, too. DON-induced neuronal activation was assessed by c-Fos immunohistochemistry. DON injection resulted in profound c-Fos activation in only the elements of the reward system, such as the accumbens nucleus, the medial prefrontal cortex, and the ventral tegmental area. Further double labelling studies suggested that GABAergic neurons were activated by DON treatment. To study the behavioural relevance of this activation, we examined the effect of DON on feed intake as an example of reward-driven behaviours. Following DON injection, feed consumption was markedly reduced but returned to normal the following day suggesting an inhibitory action of DON on feed intake without forming taste-aversion. To further test how general the effect of DON on goal-directed behaviours is, its actions on maternal behaviour was also examined. Pup retrieval latencies were markedly increased by DON administration, and DON-treated mother rats spent less time with nursing suggesting reduced maternal motivation. In a supplementary control experiment, DON did not induce conditioned place preference arguing against its addictive or aversive actions. The results imply that acute uptake of the mycotoxin DON can influence the reward circuit of the brain and exert inhibitory actions on goal-directed, reward-driven behaviours. In addition, the results also suggest that DON exposure of mothers may have specific implications.

Stress-Related Neuronal Clusters in Sublenticular Extended Amygdala of Basal Forebrain Show Individual Differences of Positions.

To understand functional neuronal circuits for emotion in the basal forebrain, patterns of neuronal activation were examined in mice by immunohistochemistry of immediate-early gene products (Zif268/Egr1 and c-Fos). In all mice examined, clusters of 30–50 neurons expressing Zif268 were found on both sides in the area between the extended amygdala (EA) and globus pallidus (GP), generally designated as sublenticular extended amygdala (SLEA). The clusters consisted of 79.9 ± 3.0% of GABAergic neurons in GAD65-mCherry mice. The expression of the cholinergic marker choline acetyltransferase and the GP markers parvalbumin, proenkephalin, and FoxP2 indicated that these neurons were different from known types of neurons in the EA and GP; therefore, we named them the sublenticular extended amygdalar Zif268/Egr1-expressing neuronal cluster (SLEA-zNC). Sublenticular extended amygdalar Zif268/Egr1-expressing neuronal clusters participated in stress processing because increasing numbers of cells were observed in SLEA-zNCs after exposure to restraint stress (RS), the induction of which was suppressed by diazepam treatment. Mapping SLEA-zNCs showed that their positions and arrangement varied individually; SLEA-zNCs were distributed asymmetrically and tended to be situated mainly in the middle region between the anterior commissure (AC) and posterior end of the GP. However, the total cell number in SLEA-zNCs was compatible between the right and left hemispheres after activation by RS. Therefore, SLEA-zNCs were distributed asymmetrically but were not lateralized. Because time courses of activation differed between the Zif268 and c-Fos, the sequential dual treatment of RSs enabled us to differentiate SLEA-zNCs activated by the first and second RS. The results supported that the same SLEA-zNCs responded to both the first and second RS, and this also applied for all SLEA-zNCs. Thus, we concluded that the cluster positions were invariable under RS in each mouse but were distributed differently between individual mice. We name these newly identified neuronal clusters as stress-related neuronal clusters, SLEA-zNCs, which are considered to be novel functional units of “islands of activation.” Moreover, SLEA-zNCs were situated at different positions in all mice examined, showing individual differences in their positions.

0005 Cataplexy Triggered by Social Cues: A Role for Oxytocin in the Amygdala

Abstract Introduction People with narcolepsy type 1 report that cataplexy is triggered most often by positive social experiences such as laughing with friends, yet the mechanisms through which social interaction promotes cataplexy are unknown. We hypothesize a subpopulation of central amygdala neurons that are sensitive to the prosocial neuropeptide, oxytocin (CeAOTR), respond to positive valence and trigger cataplexy. Methods We have used in vivo calcium imaging, chemogenetic and optogenetic approaches to characterize the activity pattern of these neurons and to manipulate their activity state. Results Cre-dependent anterograde tracing of the CeAOTR neurons of the central amygdala indicate a moderate to dense projection to the REM sleep-regulatory region of the ventral lateral periaqueductal gray (vlPAG). Additionally, Channel Rhodopsin Assisted Circuit Mapping (CRACM) experiments show that CeAOTR neurons inhibit vlPAG neurons that innervate the REM atonia-promoting region, the sublaterodorsal nucleus. Targeted photostimulation (15Hz (10ms) for 20sec every hour) of the CeAOTR fibers in the vlPAG doubled the amount of cataplexy. Preliminary in vivo calcium imaging indicates that the CeAOTR are active just prior to the onset of cataplexy. Chemogenetic and optogenetic activation of CeAOTR neurons increased cataplexy. Conclusion We conclude that the CeAOTR subpopulation is sufficient to promote cataplexy. Our future directions include determining the necessity of these oxytocin sensitive neurons in cataplexy under different conditions of positive valence. Support R01 NS106032 and WakeUp Narcolepsy.

The effects of direct brain stimulation in humans depend on frequency, amplitude, and white-matter proximity

BackgroundResearchers have used direct electrical brain stimulation to treat a range of neurological and psychiatric disorders. However, for brain stimulation to be maximally effective, clinicians and researchers should optimize stimulation parameters according to desired outcomes. ObjectiveThe goal of our large-scale study was to comprehensively evaluate the effects of stimulation at different parameters and locations on neuronal activity across the human brain. MethodsTo examine how different kinds of stimulation affect human brain activity, we compared the changes in neuronal activity that resulted from stimulation at a range of frequencies, amplitudes, and locations with direct human brain recordings. We recorded human brain activity directly with electrodes that were implanted in widespread regions across 106 neurosurgical epilepsy patients while systematically stimulating across a range of parameters and locations. ResultsOverall, stimulation most often had an inhibitory effect on neuronal activity, consistent with earlier work. When stimulation excited neuronal activity, it most often occurred from high-frequency stimulation. These effects were modulated by the location of the stimulating electrode, with stimulation sites near white matter more likely to cause excitation and sites near gray matter more likely to inhibit neuronal activity. ConclusionBy characterizing how different stimulation parameters produced specific neuronal activity patterns on a large scale, our results provide an electrophysiological framework that clinicians and researchers may consider when designing stimulation protocols to cause precisely targeted changes in human brain activity.

Extinction of cue-evoked food-seeking recruits a GABAergic interneuron ensemble in the dorsal medial prefrontal cortex of mice.

Animals must quickly adapt food-seeking strategies to locate nutrient sources in dynamically changing environments. Learned associations between food and environmental cues that predict its availability promote food-seeking behaviors. However, when such cues cease to predict food availability, animals undergo "extinction" learning, resulting in the inhibition of food-seeking responses. Repeatedly activated sets of neurons, or "neuronal ensembles," in the dorsal medial prefrontal cortex (dmPFC) are recruited following appetitive conditioning and undergo physiological adaptations thought to encode cue-reward associations. However, little is known about how the recruitment and intrinsic excitability of such dmPFC ensembles are modulated by extinction learning. Here, we used in vivo 2-Photon imaging in male Fos-GFP mice that express green fluorescent protein (GFP) in recently behaviorally activated neurons to determine the recruitment of activated pyramidal and GABAergic interneuron dmPFC ensembles during extinction. During extinction, we revealed a persistent activation of a subset of interneurons which emerged from a wider population of interneurons activated during the initial extinction session. This activation pattern was not observed in pyramidal cells, and extinction learning did not modulate the excitability properties of activated pyramidal cells. Moreover, extinction learning reduced the likelihood of reactivation of pyramidal cells activated during the initial extinction session. Our findings illuminate novel neuronal activation patterns in the dmPFC underlying extinction of food-seeking, and in particular, highlight an important role for interneuron ensembles in this inhibitory form of learning.