Publications using the Synapse

Objective: An environmental context, which reliably predicts food availability, can increase the appetitive food drive within the same environment context. However, hunger is required for the development of such a context-induced feeding (CIF) response, suggesting the neural circuits sensitive to hunger link an internal energy state with a particular environment context. Since Agouti related peptide (AgRP) neurons are activated by energy deficit, we hypothesised that AgRP neurons are both necessary and sufficient to drive CIF. Methods: To examine the role of AgRP neurons in the CIF process, we used fibre photometry with GCaMP7f, chemogenetic activation of AgRP neurons, as well as optogenetic control of AgRP neurons to facilitate acute temporal control not permitted with chemogenetics. Results: A CIF response at test was only observed when mice were fasted during context training and AgRP population activity at test showed an attenuated inhibitory response to food, suggesting increased food-seeking and/or decreased satiety signalling drives the increased feeding response at test. Intriguingly, chemogenetic activation of AgRP neurons during context training did not increase CIF, suggesting precise temporal firing properties may be required. Indeed, termination of AgRP neuronal photostimulation during context training (ON-OFF in context), in the presence or absence of food, increased CIF. Moreover, photoinhibition of AgRP neurons during context training in fasted mice was sufficient to drive a subsequent CIF in the absence of food. Conclusions: Our results suggest that AgRP neurons regulate the acquisition of CIF when the acute inhibition of AgRP activity is temporally matched to context exposure. These results establish acute AgRP inhibition as a salient neural event underscoring the effect of hunger on associative learning.

Tyrosine hydroxylase (TH)-containing neurons of the dopamine (DA) cell group A13 are well positioned to impact known DA-related functions as their descending projections innervate target regions that regulate vigilance, sensory integration, and motor execution. Despite this connectivity, little is known regarding the functionality of A13-DA circuits. Using TH-specific loss-of-function methodology and techniques to monitor population activity in transgenic rats in vivo, we investigated the contribution of A13-DA neurons in reward and movement-related actions. Our work demonstrates a role for A13-DA neurons in grasping and handling of objects but not reward. A13-DA neurons responded strongly when animals grab and manipulate food items, whereas their inactivation or degeneration prevented animals from successfully doing so-a deficit partially attributed to a reduction in grip strength. By contrast, there was no relation between A13-DA activity and food-seeking behavior when animals were tested on a reward-based task that did not include a reaching/grasping response. Motivation for food was unaffected, as goal-directed behavior for food items was in general intact following A13 neuronal inactivation/degeneration. An anatomical investigation confirmed that A13-DA neurons project to the superior colliculus (SC) and also demonstrated a novel A13-DA projection to the reticular formation (RF). These results establish a functional role for A13-DA neurons in prehensile actions that are uncoupled from the motivational factors that contribute to the initiation of forelimb movements and help position A13-DA circuits into the functional framework regarding centrally located DA populations and their ability to coordinate movement.

The human auditory system extracts rich linguistic abstractions from speech signals. Traditional approaches to understanding this complex process have used linear feature-encoding models, with limited success. Artificial neural networks excel in speech recognition tasks and offer promising computational models of speech processing. We used speech representations in state-of-the-art deep neural network (DNN) models to investigate neural coding from the auditory nerve to the speech cortex. Representations in hierarchical layers of the DNN correlated well with the neural activity throughout the ascending auditory system. Unsupervised speech models performed at least as well as other purely supervised or fine-tuned models. Deeper DNN layers were better correlated with the neural activity in the higher-order auditory cortex, with computations aligned with phonemic and syllabic structures in speech. Accordingly, DNN models trained on either English or Mandarin predicted cortical responses in native speakers of each language. These results reveal convergence between DNN model representations and the biological auditory pathway, offering new approaches for modeling neural coding in the auditory cortex.

The amygdala is a brain region primarily associated with emotional response. The use of genetic markers and single-cell transcriptomics can provide insights into behavior-associated cell state changes. Here we present a detailed cell-type taxonomy of the adult mouse amygdala during fear learning and memory consolidation. We perform single-cell RNA sequencing on naïve and fear-conditioned mice, identify 130 neuronal cell types and validate their spatial distributions. A subset of all neuronal types is transcriptionally responsive to fear learning and memory retrieval. The activated engram cells upregulate activity-response genes and coordinate the expression of genes associated with neurite outgrowth, synaptic signaling, plasticity and development. We identify known and previously undescribed candidate genes responsive to fear learning. Our molecular atlas may be used to generate hypotheses to unveil the neuron types and neural circuits regulating the emotional component of learning and memory.

In the classical model of the basal ganglia, direct pathway striatal projection neurons (dSPNs) send projections to the substantia nigra (SNr) and entopeduncular nucleus to regulate motor function. Recent studies have re-established that dSPNs also possess axon collaterals within the globus pallidus (GPe) (bridging collaterals), yet the significance of these collaterals for behavior is unknown. Here we use in vivo optical and chemogenetic tools combined with deep learning approaches in mice to dissect the roles of dSPN GPe collaterals in motor function. We find that dSPNs projecting to the SNr send synchronous motor-related information to the GPe via axon collaterals. Inhibition of native activity in dSPN GPe terminals impairs motor activity and function via regulation of Npas1 neurons. We propose a model by which dSPN GPe axon collaterals (striatopallidal Go pathway) act in concert with the canonical terminals in the SNr to support motor control by inhibiting Npas1 neurons.

Rapid-eye-movement (REM) sleep is accompanied by intense cortical activity, underlying its wake-like electroencephalogram (EEG). The neural activity inducing REM sleep is thought to originate from subcortical circuits in brainstem and hypothalamus. However, whether cortical neurons can also trigger REM sleep has remained unknown. Here, we show in mice that the medial prefrontal cortex (mPFC) strongly promotes REM sleep. Bidirectional optogenetic manipulations demonstrate that excitatory mPFC neurons promote REM sleep through their projections to the lateral hypothalamus (LH) and regulate phasic events, reflected in accelerated EEG theta oscillations and increased eye-movement density during REM sleep. Calcium imaging reveals that the majority of LH-projecting mPFC neurons are maximally activated during REM sleep and a subpopulation is recruited during phasic theta accelerations. Our results delineate a cortico-hypothalamic circuit for the top-down control of REM sleep and identify a critical role of the mPFC in regulating phasic events during REM sleep.

Intracortical microelectrode arrays (MEAs) can be used in a range of applications, from basic neuroscience research to providing an intimate interface with the brain as part of a brain-computer interface (BCI) system aimed at restoring function for people living with neurological disorders or injuries. Unfortunately, MEAs tend to fail prematurely, leading to a loss in functionality for many applications. An important contributing factor in MEA failure is oxidative stress resulting from chronically inflammatory-activated microglia and macrophages releasing reactive oxygen species (ROS) around the implant site. Antioxidants offer a means for mitigating oxidative stress and improving tissue health and MEA performance. Here, we investigate using the clinically available antioxidant dimethyl fumarate (DMF) to reduce the neuroinflammatory response and improve MEA performance in a rat MEA model. Daily treatment of DMF for 16 weeks resulted in a significant improvement in the recording capabilities of MEA devices during the sub-chronic (Weeks 5–11) phase (42% active electrode yield vs. 35% for control). However, these sub-chronic improvements were lost in the chronic implantation phase, as a more exacerbated neuroinflammatory response occurs in DMF-treated animals by 16 weeks post-implantation. Yet, neuroinflammation was indiscriminate between treatment and control groups during the sub-chronic phase. Although worse for chronic use, a temporary improvement (<12 weeks) in MEA performance is meaningful. Providing short-term improvement to MEA devices using DMF can allow for improved use for limited-duration studies. Further efforts should be taken to explore the mechanism behind a worsened neuroinflammatory response at the 16-week time point for DMF-treated animals and assess its usefulness for specific applications.

The circadian rhythm pacemaker, the suprachiasmatic nucleus (SCN), mediates light entrainment via vasoactive intestinal peptide (VIP) neurons (SCNVIP). Yet, how these neurons uniquely respond and connect to intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing melanopsin (Opn4) has not been determined functionally in freely behaving animals. To address this, we first used monosynaptic tracing from SCNVIP neurons in mice and identified two SCNVIP subpopulations. Second, we recorded calcium changes in response to ambient light, at both bulk and single-cell levels, and found two unique activity patterns in response to high- and low-intensity blue light. The activity patterns of both subpopulations could be manipulated by application of an Opn4 antagonist. These results suggest that the two SCNVIP subpopulations connect to two types of Opn4-expressing ipRGCs, likely M1 and M2, but only one is responsive to red light. These findings have important implications for our basic understanding of non-image-forming circadian light processing.

Human language follows statistical regularities or linguistic laws. For instance, Zipf's law of brevity states that the more frequently a word is used, the shorter it tends to be. All human languages adhere to this word structure. However, it is unclear whether Zipf's law emerged de novo in humans or whether it also exists in the non-linguistic vocal systems of our primate ancestors. Using a vocal conditioning paradigm, we examined the capacity of marmoset monkeys to efficiently encode vocalizations. We observed that marmosets adopted vocal compression strategies at three levels: (i) increasing call rate, (ii) decreasing call duration and (iii) increasing the proportion of short calls. Our results demonstrate that marmosets, when able to freely choose what to vocalize, exhibit vocal statistical regularities consistent with Zipf's law of brevity that go beyond their context-specific natural vocal behaviour. This suggests that linguistic laws emerged in non-linguistic vocal systems in the primate lineage.

The N -acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) catalyzes the production of N -acylethanolamines (NAEs), a family of endogenous bioactive lipids, which are involved in various biological processes ranging from neuronal functions to energy homeostasis and feeding behaviors. Reward-dependent behaviors depend on dopamine (DA) transmission between the ventral tegmental area (VTA) and the nucleus accumbens (NAc), which conveys reward-values and scales reinforced behaviors. However, whether and how NAPE-PLD may contribute to the regulation of feeding and reward-dependent behaviors has not yet been investigated. This biological question is of paramount importance since NAEs are altered in obesity and metabolic disorders. Here, we show that transcriptomic meta-analysis highlights a potential role for NAPE-PLD within the VTA®NAc circuit. Using brain-specific invalidation approaches, we report that the integrity of NAPE-PLD is required for the proper homeostasis of NAEs within the midbrain VTA and it affects food-reward behaviors. Moreover, region-specific knock-down of NAPE-PLD in the VTA enhanced food-reward seeking and reinforced behaviors, which were associated with increased in vivo DA release dynamics in response to both food and non-food-related rewards together with heightened tropism towards food consumption. Furthermore, midbrain knock-down of NAPE-PLD, which increased energy expenditure and adapted nutrient partitioning, elicited a relative protection against high-fat diet-mediated body fat gain and obesity-associated metabolic features. In conclusion, these findings reveal a new key role of VTA NAPE-PLD in shaping DA-dependent events, feeding behaviors and energy homeostasis, thus providing new insights on the regulation of body metabolism.

With concurrent global epidemics of chronic pain and opioid use disorders, there is a critical need to identify, target and manipulate specific cell populations expressing the mu-opioid receptor (MOR). However, available tools and transgenic models for gaining long-term genetic access to MOR+ neural cell types and circuits involved in modulating pain, analgesia and addiction across species are limited. To address this, we developed a catalog of MOR promoter ( MORp ) based constructs packaged into adeno-associated viral vectors that drive transgene expression in MOR+ cells. MORp constructs designed from promoter regions upstream of the mouse Oprm1 gene ( mMORp ) were validated for transduction efficiency and selectivity in endogenous MOR+ neurons in the brain, spinal cord, and periphery of mice, with additional studies revealing robust expression in rats, shrews, and human induced pluripotent stem cell (iPSC)-derived nociceptors. The use of mMORp for in vivo fiber photometry, behavioral chemogenetics, and intersectional genetic strategies is also demonstrated. Lastly, a human designed MORp ( hMORp ) efficiently transduced macaque cortical OPRM1 + cells. Together, our MORp toolkit provides researchers cell type specific genetic access to target and functionally manipulate mu-opioidergic neurons across a range of vertebrate species and translational models for pain, addiction, and neuropsychiatric disorders.

The medial prefrontal cortex (mPFC) plays a key role in learning, mood and decision making, including in how individuals respond to threats 1–6 . mPFC undergoes a uniquely protracted development, with changes in synapse density, cortical thickness, long-range connectivity, and neuronal encoding properties continuing into early adulthood 7–21 . Models suggest that before adulthood, the slow-developing mPFC cannot adequately regulate activity in faster-developing subcortical centers 22,23 . They propose that during development, the enhanced influence of subcortical systems underlies distinctive behavioural strategies of juveniles and adolescents and that increasing mPFC control over subcortical structures eventually allows adult behaviours to emerge. Yet it has remained unclear how a progressive strengthening of top-down control can lead to nonlinear changes in behaviour as individuals mature 24,25 . To address this discrepancy, here we monitored and manipulated activity in the developing brain as animals responded to threats, establishing direct causal links between frontolimbic circuit activity and the behavioural strategies of juvenile, adolescent and adult mice. Rather than a linear strengthening of mPFC synaptic connectivity progressively regulating behaviour, we uncovered multiple developmental switches in the behavioural roles of mPFC circuits targeting the basolateral amygdala (BLA) and nucleus accumbens (NAc). We show these changes are accompanied by axonal pruning coinciding with functional strengthening of synaptic connectivity in the mPFC-BLA and mPFC-NAc pathways, which mature at different rates. Our results reveal how developing mPFC circuits pass through distinct architectures that may make them optimally adapted to the demands of age-specific challenges.

Rapid-eye-movement sleep (REMs) is characterized by activated electroencephalogram (EEG) and muscle atonia, accompanied by vivid dreams. REMs is homeostatically regulated, ensuring that any loss of REMs is compensated by a subsequent increase in its amount. However, the neural mechanisms underlying the homeostatic control of REMs are largely unknown. Here, we show that GABAergic neurons in the preoptic area of the hypothalamus projecting to the tuberomammillary nucleus (POA GAD2 →TMN neurons) are crucial for the homeostatic regulation of REMs. POA GAD2 →TMN neurons are most active during REMs, and inhibiting them specifically decreases REMs. REMs restriction leads to an increased number and amplitude of calcium transients in POA GAD2 →TMN neurons, reflecting the accumulation of REMs pressure. Inhibiting POA GAD2 →TMN neurons during REMs restriction blocked the subsequent rebound of REMs. Our findings reveal a hypothalamic circuit whose activity mirrors the buildup of homeostatic REMs pressure during restriction and that is required for the ensuing rebound in REMs.

Dopamine is broadly implicated in reinforcement learning, but how patterns of dopamine activity are generated is poorly resolved. Here, we demonstrate that two ion channels, Kv4.3 and BKCa1.1, regulate the pattern of dopamine neuron firing and dopamine release on different time scales to influence separate phases of reinforced behavior in mice. Inactivation of Kv4.3 in VTA dopamine neurons increases ex vivo pacemaker activity and excitability that is associated with increased in vivo firing rate and ramping dynamics before lever press in a learned instrumental paradigm. Loss of Kv4.3 enhances performance of the learned response and facilitates extinction. In contrast, loss of BKCa1.1 increases burst firing and phasic dopamine release that enhances learning of an instrumental response and enhances extinction burst lever pressing in early extinction that is associated with a greater change in activity between reinforced and unreinforced actions. These data demonstrate that disruption of intrinsic regulators of neuronal activity differentially affects dopamine dynamics during reinforcement and extinction learning.

Head-fixed behavioral experiments in rodents permit unparalleled experimental control, precise measurement of behavior, and concurrent modulation and measurement of neural activity. Here, we present OHRBETS (Open-Source Head-fixed Rodent Behavioral Experimental Training System; pronounced ‘Orbitz’), a low-cost, open-source platform of hardware and software to flexibly pursue the neural basis of a variety of motivated behaviors. Head-fixed mice tested with OHRBETS displayed operant conditioning for caloric reward that replicates core behavioral phenotypes observed during freely moving conditions. OHRBETS also permits optogenetic intracranial self-stimulation under positive or negative operant conditioning procedures and real-time place preference behavior, like that observed in freely moving assays. In a multi-spout brief-access consumption task, mice displayed licking as a function of concentration of sucrose, quinine, and sodium chloride, with licking modulated by homeostatic or circadian influences. Finally, to highlight the functionality of OHRBETS, we measured mesolimbic dopamine signals during the multi-spout brief-access task that display strong correlations with relative solution value and magnitude of consumption. All designs, programs, and instructions are provided freely online. This customizable platform enables replicable operant and consummatory behaviors and can be incorporated with methods to perturb and record neural dynamics in vivo.

Social interaction among conspecifics is essential for maintaining adaptive, cooperative, and social behaviors, along with survival among mammals. The 5-hydroxytryptamine (5-HT) neuronal system is an important neurotransmitter system for regulating social behaviors; however, the circadian role of 5-HT in social interaction behaviors is unclear. To investigate whether the circadian nuclear receptor REV-ERBα, a transcriptional repressor of the rate-limiting enzyme tryptophan hydroxylase 2 (Tph2) gene in 5-HT biosynthesis, may affect social interaction behaviors, we generated a conditional knockout (cKO) mouse by targeting Rev-Erbα in dorsal raphe (DR) 5-HT neurons (5-HT DR -specific REV-ERBα cKO) using the CRISPR/Cas9 gene editing system and assayed social behaviors, including social preference and social recognition, with a three-chamber social interaction test at two circadian time (CT) points, i.e., at dawn (CT00) and dusk (CT12). The genetic ablation of Rev-Erbα in DR 5-HTergic neurons caused impaired social interaction behaviors, particularly social preference but not social recognition, with no difference between the two CT points. This deficit of social preference induced by Rev-Erbα in 5-HT DR -specific mice is functionally associated with real-time elevated neuron activity and 5-HT levels at dusk, as determined by fiber-photometry imaging sensors. Moreover, optogenetic inhibition of DR to nucleus accumbens (NAc) 5-HTergic circuit restored the impairment of social preference in 5-HT DR -specific REV-ERBα cKO mice. These results suggest the significance of the circadian regulation of 5-HT levels by REV-ERBα in regulating social interaction behaviors.

Deformable semi-solid liquid metal particles (LMP) have emerged as a promising substitute for rigid conductive fillers due to their excellent electrical properties and stable conductance under strain. However, achieving a compact and robust coating of LMP on fibers remains a persistent challenge, mainly due to the incompatibility of conventional coating techniques with LMP. Additionally, the limited durability and absence of initial electrical conductivity of LMP restrict their widespread application. In this study, we propose a solution process that robustly and compactly assembles mechanically durable and initially conductive LMP on fibers. Specifically, we present a shearing-based deposition of polymer-attached LMP followed by additional coating with CNT-attached LMP to create bi-layer LMP composite with exceptional durability, electrical conductivity, stretchability, and biocompatibility on various fibers. The versatility and reliability of this manufacturing strategy for 1D electronics are demonstrated through the development of sewn electrical circuits, smart clothes, stretchable biointerfaced fiber, and multifunctional fiber probes.

Background The purpose of this study was to evaluate if kilohertz frequency alternating current (KHFAC) stimulation of peripheral nerve could serve as a treatment for lumbar radiculopathy. Prior work shows that KHFAC stimulation can treat sciatica resulting from chronic sciatic nerve constriction. Here, we evaluate if KHFAC stimulation is also beneficial in a more physiologic model of low back pain which mimics nucleus pulposus (NP) impingement of a lumbar dorsal root ganglion (DRG). Methods To mimic a lumbar radiculopathy, autologous tail NP was harvested and placed upon the right L5 nerve root and DRG. During the same surgery, a cuff electrode was implanted around the sciatic nerve with wires routed to a headcap for delivery of KHFAC stimulation. Male Lewis rats (3 mo., n = 18) were separated into 3 groups: NP injury + KHFAC stimulation ( n = 7), NP injury + sham cuff ( n = 6), and sham injury + sham cuff ( n = 5). Prior to surgery and for 2 weeks following surgery, animal tactile sensitivity, gait, and static weight bearing were evaluated. Results KHFAC stimulation of the sciatic nerve decreased behavioral evidence of pain and disability. Without KHFAC stimulation, injured animals had heightened tactile sensitivity compared to baseline ( p < 0.05), with tactile allodynia reversed during KHFAC stimulation ( p < 0.01). Midfoot flexion during locomotion was decreased after injury but improved with KHFAC stimulation ( p < 0.05). Animals also placed more weight on their injured limb when KHFAC stimulation was applied ( p < 0.05). Electrophysiology measurements at end point showed decreased, but not blocked, compound nerve action potentials with KHFAC stimulation ( p < 0.05). Conclusions KHFAC stimulation decreases hypersensitivity but does not cause additional gait compensations. This supports the idea that KHFAC stimulation applied to a peripheral nerve may be able to treat chronic pain resulting from sciatic nerve root inflammation.

Degeneration of dopamine neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinson’s disease (PD). In idiopathic cases, high levels of mitochondrial DNA (mtDNA) mutations associated with mitochondrial dysfunction are a central feature of these vulnerable neurons. Here we present a mouse model expressing the K320E-variant of the mitochondrial helicase Twinkle in dopamine neurons, leading to accelerated mtDNA ageing. K320E-Twinkle DaN mice showed normal motor function at 20 months of age, although already ∼70% of nigral dopamine neurons had perished. The remaining neuron population still preserved ∼75% of axon terminals in the dorsal striatum, which enabled normal dopamine release. Transcriptome analysis and viral tracing confirmed compensatory axonal sprouting of surviving nigral dopamine neurons. We conclude that a small population of substantia nigra neurons can adapt to mtDNA mutations and maintain motor control in mice, holding chances for new treatment strategies in PD patients.

The rate model of basal ganglia function predicts that muscle activity in dystonia is due to disinhibition of thalamus resulting from decreased inhibitory input from pallidum. We seek to test this hypothesis in children with dyskinetic cerebral palsy undergoing evaluation for deep brain stimulation (DBS) to analyze movement-related activity in different brain regions. The results revealed prominent beta-band frequency peaks in the globus pallidus interna (GPi), ventral oralis anterior/posterior (VoaVop) subnuclei of the thalamus, and subthalamic nucleus (STN) during movement but not at rest. Connectivity analysis indicated stronger coupling between STN-VoaVop and STN-GPi compared to GPi-STN. These findings contradict the hypothesis of decreased thalamic inhibition in dystonia, suggesting that abnormal patterns of inhibition and disinhibition, rather than reduced GPi activity, contribute to the disorder. Additionally, the study implies that correcting abnormalities in GPi function may explain the effectiveness of DBS targeting the STN and GPi in treating dystonia.