Publications using the Synapse

Dopaminergic signaling is essential for regulating movement, learning, and reward. Disruptions in this system are linked to neuropsychiatric disorders such as ADHD. ADGRL3, an adhesion G protein-coupled receptor highly expressed in the brain, is genetically associated with increased ADHD risk. ADGRL3 knockout in animals alters expression of dopaminergic markers and induces dopamine-related behavioral changes. However, its precise role in modulating dopamine signaling remains unclear. We investigated how ADGRL3 knockout affects striatal dopamine release in mice using ex vivo fast-scan cyclic voltammetry and in vivo fiber photometry with a dopamine sensor. Ex vivo measurements showed increased electrically-evoked dopamine release across the striatum. Conversely, in vivo recordings revealed reduced task-induced dopamine signals in the nucleus accumbens during an operant fixed interval task. This reduction was not due to impaired dopamine availability, as amphetamine-evoked release was unchanged. These findings suggest ADGRL3 modulates dopamine release in complex ways via different pre- and postsynaptic mechanisms.

The stress axis is always active, even in the absence of any threat. This manifests as hourly pulses of corticosteroid stress hormone secretion over the day. Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (CRH PVN ) control both the neuroendocrine stress axis as well as stress-associated behaviors. However, it is currently unclear how the resting activity of these neurons is coordinated with both spontaneous behavior and ultradian pulses of corticosteroid secretion. To investigate this, we performed fiber photometry recordings of CRH PVN neuron activity in Crh-Ires-Cre mice and a newly generated line of Crh-Ires-Cre rats. In both mice and rats, CRH PVN neurons displayed an ultradian rhythm of activity with reoccurring upstates of activity approximately once per hour over the 24-h day. Upstates in activity were coordinated with increases in animal activity/arousal. Chemogenetic activation of CRH PVN neurons was also sufficient to induce behavioral arousal. In rats, increases in CRH neural activity preceded some pulses of corticosteroid secretion but not others. Thus, while CRH PVN neurons display an ultradian rhythm of activity over the 24-h day that is coordinated with behavioral arousal, the relationship between CRH PVN activity and pulses of corticosteroid secretion is not one-to-one.

Brain-machine interfaces (BMIs) offer a viable option for restoring function in patients with motor disabilities post-stroke. Most BMI systems rely on signals from the motor cortex (M1), which is often compromised after stroke. The cerebellum, a subcortical structure involved in motor control, remains an underexplored source for neuroprosthetic control. Using chronic electrophysiological recordings in a rat stroke model, we show that cerebellar neural activity can effectively drive BMI control, performing comparably to M1-driven control. We observed this even in animals with motor impairments post-stroke. Simultaneous M1-cerebellum recordings during cerebellar BMI control revealed that cerebellar "direct" neurons driving the interface were influenced by both local cerebellar and distant M1 neurons. While cerebellar influence remained stable, M1's interaction with cerebellar direct neurons shifted from longer to shorter timescales after stroke. These findings highlight that cerebellar direct neural control is possible in the stroke brain and reveal changes in M1-cerebellar network dynamics post-stroke.

The basolateral amygdala (BLA) assigns valence to sensory stimuli, with a dedicated nociceptive ensemble encoding the negative valence of pain. However, the effects of chronic pain on the transcriptomic signatures and projection architecture of this BLA nociceptive ensemble are not well understood. Here, we show that optogenetic inhibition of the nociceptive BLA ensemble reduces affective-motivational behaviors in chronic neuropathic pain. Single-nucleus RNA sequencing revealed peripheral injury–induced changes in genetic pathways involved in axonal and presynaptic organization in nociceptive BLA neurons. Next, we identified a previously uncharacterized nociceptive hotspot in the nucleus accumbens shell that is innervated by BLA nociceptive neurons. Axonal calcium imaging of BLA projections to the accumbens and chemogenetic inhibition of this pathway revealed pain-related transmission from the amygdala to the medial nucleus accumbens, facilitating both acute and chronic pain affective-motivational behaviors. Together, this work defines a critical nociceptive amygdala-striatal circuit underlying pain unpleasantness across pain states.

MDMA is a promising adjunct to psychotherapy and has well-known abuse liability, although less than other amphetamine analogs. While the reinforcing dopamine (DA)-releasing properties of MDMA are on par with methamphetamine (METH), MDMA is a far more potent serotonin (5-HT) releaser, via the 5-HT transporter (SERT). MDMA-mediated 5-HT release in a major reward center, the nucleus accumbens (NAc), drives prosocial behaviors via 5-HT1BR activation. We hypothesized that this prosocial mechanism contributes to the reduced reinforcing properties of MDMA compared to METH and used a platform of assays to predict the balance of prosocial and abuse-linked effects of (R)-MDMA, a novel entactogen in clinical development. NAc DA release, measured by GRAB-DA photometry in vivo, increased in proportion to MDMA (7.5 and 15 mg/kg, i.p.) and METH (2 mg/kg i.p.)-conditioned place preference (CPP). Using conditional knockouts (cKOs) for DAT and SERT, microdialysis, and photometry, we found that MDMA-released 5-HT limited MDMA-released DA through actions in the NAc, rather than at ventral tegmental area DAergic cell bodies. SERT cKO reduced the MDMA dose required for CPP three-fold. This enhanced MDMA-CPP and increased DA release were replicated by intra-NAc infusion of either a 5-HT reuptake inhibitor (escitalopram) to prevent MDMA interaction with SERT, or a 5-HT2CR antagonist (SB242084), but not by the 5-HT1BR antagonist NAS-181. These data support separate mechanisms for the low abuse potential versus prosocial effect of MDMA. Using this platform of assays, (R)-MDMA is predicted to have prosocial effects and low abuse potential.

Dopamine (DA)-producing neurons of the ventral tegmental area (VTA) regulate consummatory behavior in a state-dependent manner (e.g. when hungry or thirsty). The mechanisms by which and extent to which DA neurons are regulated by these interoceptive signals are poorly understood. Here, we identify transient receptor potential canonical type 6 (TRPC6) channels as selective mediators of neuropeptide receptor-induced calcium signaling in VTA-DA neurons. These channels regulate DA neuron activity and consummatory behavior in a state-dependent manner. We find that TRPC6 channels regulate distinct aspects of neuropeptide-induced calcium signals in DA neurons but make little contribution to calcium dynamics associated with metabotropic neurotransmitter receptor signaling. We further show that TRPC6 channels regulate scalable reward valuation and consummatory behavior in hungry but not thirsty mice. These findings demonstrate that neuropeptide-and neurotransmitter-activated G-protein coupled receptors (GPCRs) regulate cellular calcium dynamics through distinct mechanisms, and that TRPC6 channels are important determinants of how animals respond to different homeostatic demands.

Nicotine addiction remains a major cause of disease and premature death worldwide. Nicotine modulates neural pathways that underlie both rewarding and aversive behavioral effects, but persistent activation of brain reward circuitry drives nicotine consumption despite the negative consequences. When nicotine users attempt to quit, additional neural mechanisms are recruited to generate an aversive withdrawal state, which contributes to the remarkably high relapse rate among nicotine users. The interpeduncular nucleus (IPN) and its presynaptic inputs from the medial habenula are key mediators of aversive nicotine withdrawal symptoms, but the downstream neural targets mediating these effects are unknown. The aversive effects of acute exposure to high doses of nicotine require inhibitory IPN GABAergic projections to the laterodorsal tegmentum (LDTg), a key driver of reward-related dopamine signaling. Here we show that optogenetic inhibition of these IPN→LDTg projections reduces behavioral and physiological effects of nicotine withdrawal in male and female mice. Using fiber photometry, we found that nicotine withdrawal reduced reward-related signaling with decreases in both LDTg neuronal activity and nucleus accumbens dopamine release. These studies demonstrate a direct link between aversive and appetitive neural pathways that is active during nicotine withdrawal, providing novel targets for treating nicotine addiction.

Intracortical microelectrodes are used for recording activity from individual neurons, providing both a valuable neuroscience tool and an enabling medical technology for individuals with motor disabilities. Standard neural probes carrying the microelectrodes are rigid silicon-based structures that can penetrate the brain parenchyma to interface with the targeted neurons. Unfortunately, within weeks after implantation, neural recording quality from microelectrodes degrades, owing largely to a neuroinflammatory response. Key contributors to the neuroinflammatory response include mechanical mismatch at the device-tissue interface and oxidative stress. We developed a mechanically-adaptive, resveratrol-eluting (MARE) neural probe to mitigate both mechanical mismatch and oxidative stress and thereby promote improved neural recording quality and longevity. In this work, we demonstrate that compared to rigid silicon controls, highly-flexible MARE probes exhibit improved recording performance, more stable impedance, and a healing tissue response. With further optimization, MARE probes can serve as long-term, robust neural probes for brain-machine interface applications.

Brain circuits in reward-associated behaviors are potent drivers of feeding behavior but also recently emerged as regulator of metabolism. Short or chronic exposures to caloric food alter brain structures and are associated with increased astrocytes reactivity and pro-inflammatory responses in both mice and humans. However, the role of striatal astrocytes in regulating adaptive and maladaptive behavioral and metabolic responses to energy-dense food remains elusive. In this study we reveal that chemogenetic manipulation of the astrocytes in striatal structures can exert a direct effect on peripheral metabolism in male mice, and that manipulation of astrocytes in the dorsal striatum can alter peripheral metabolism and is sufficient to restore cognitive deficit induced by chronic high fat high sucrose (HFHS) diet exposure in obese mice. Altogether, this work reveals a yet unappreciated role for striatal astrocytes as a direct operator of flexible behavior and metabolic control.

Experiencing a single severe stressor is sufficient to drive sexually dimorphic psychiatric disease development. The ventral subiculum (vSUB) emerges as a site where stress may induce sexually dimorphic adaptations due to its sex-specific organization and pivotal role in stress integration. Using a 1 h acute restraint stress model in mice, we uncover that stress causes a net decrease in vSUB activity in females driven by adrenergic receptor signaling. By contrast, males exhibit a net increase in vSUB activity that is driven by corticosterone signaling. We further identified sexually dimorphic changes in vSUB output to the anterior bed nucleus of the stria terminalis and in anxiety-like behaviors in response to stress. These findings reveal striking changes in psychiatric disease-relevant brain regions and behavior following stress with sex-, cell-type, and synapse-specificity that contribute to our understanding of sexually dimorphic adaptations that may shape stress-related psychiatric disease risk.

The activity of neurotransmitter-based cell types in the cuneiform and pedunculopontine nuclei during locomotion, non-locomotor behaviors, and following sensory stimulation is not fully understood. Using fiber photometry in mice, we found cell-type specific responses to sensory stimuli. Glutamatergic and GABAergic cells responded to sound, visual looming, and air puffs, except for pedunculopontine GABAergic cells, which did not respond to visual looming. Cholinergic cells responded to air puffs. Air puffs triggered high-speed locomotion, whereas visual looming and sound stimuli evoked low-speed locomotion. During air puff–evoked locomotion, cuneiform glutamatergic neuron activity was higher than in trials without locomotion. In contrast, during locomotion evoked by visual looming or sound, activity in pedunculopontine glutamatergic neurons was higher than when no locomotion occurred. In the open-field arena, mice exhibited spontaneous low-speed locomotion during which activity increased in pedunculopontine glutamatergic cells. Activity also increased in a cell type-specific manner during grooming or rearing. Our study shows cell type-specific activity in the cuneiform or pedunculopontine nuclei during locomotion, non-locomotor behaviors, and following sensory stimulation. Sensory responsiveness likely has relevance in Parkinson’s disease, where sensory circuits are increasingly targeted to improve walking.

The neurotransmitter histamine is involved in control of food intake, yet its dynamics during individual feeding episodes remain unexplored. Therefore, we used the novel genetically‐encoded histamine sensor, HisLightG, combined with fiber photometry to measure histamine release in two hypothalamic regions critical for the food‐suppressive effects of histamine, the paraventricular nucleus of the hypothalamus (PVH), and the ventromedial hypothalamus (VMH). Male mice were tested under different conditions to assess whether hunger, time of day, or the caloric content of the solution they were given affected histamine fluctuations. We found that histamine levels changed rapidly in response to eating. These histamine fluctuations were influenced by experimental conditions, with slightly smaller responses when the test solution was sucralose (both regions) or during the light cycle (PVH only). Notable regional differences were identified, such that in the PVH histamine rebounded to above baseline levels, whereas in the VMH histamine remained lower than baseline for at least 10 s after licking ceased. In a separate cohort of male and female mice, enhancing histamine tone via administration of a histamine precursor (L‐histidine) reduced the number of licks across multiple sucrose concentrations. Together, these findings indicate that histaminergic activity is modulated rapidly during ingestive episodes, and that understanding these release patterns will give insight into histamine's role in appetite suppression. image

Distinct basolateral amygdala (BLA) cell populations influence emotions in manners thought important for anxiety and anxiety disorders. The BLA contains numerous cell types which can broadcast information into structures that may elicit changes in emotional states and behaviors. BLA excitatory neurons can be divided into two main classes, one of which expresses Ppp1r1b (encoding protein phosphatase 1 regulatory inhibitor subunit 1B) which is downstream of the genes encoding the D1 and D2 dopamine receptors (Drd1 and Drd2 respectively). The role of Drd1+ or Drd2+ BLA neurons in learned and unlearned emotional responses is unknown. Here, we identified that the Drd1+ and Drd2+ BLA neuron populations form two parallel pathways for communication with the ventral striatum. These neurons arise from the basal nucleus of the BLA, innervate the entire space of the ventral striatum, and are capable of exciting ventral striatum neurons. Further, through two separate behavioral assays, we found that the Drd1+ and Drd2+ parallel pathways distinctly influence both learned and unlearned emotional states when they are activated or suppressed and do so depending upon where they synapse in the ventral striatum - with unique contributions of Drd1+ and Drd2+ circuitry on negative emotional states. Overall, these results contribute to a model whereby parallel, genetically-distinct BLA to ventral striatum circuits inform emotional states in a projection-specific manner.

Food sensory perception has emerged as a potent regulator of specialized feeding circuits; yet, the consequences on feeding behaviour and the underlying neuronal basis remain poorly understood. Here, we reveal a sensory pathway that co-ordinately integrates food odours to control forthcoming nutrient intake in male mice. Unbiased whole-brain mapping of food odour-induced brain activity revealed a potent activation of the medial septum (MS), where food odours selectively activate MS glutamatergic neurons (MS VGLUT2 ). Activity dynamics of MS VGLUT2 neurons uncovered a biphasic modulation of their neuronal activity with a transient activation after detection of food odours and a long-lasting inhibition following food ingestion, independent of the caloric value and identity of the food. MS VGLUT2 neurons receive direct projections from the olfactory bulb (OB) and acute optogenetic stimulation of OB→MS projections selectively before food ingestion decreased feeding in lean mice. However, acute OB→MS optogenetic stimulation in diet-induced obese mice failed to reduce feeding, suggesting the involvement of this pathway in calorie-rich diet-induced hyperphagia and obesity development. Altogether, our study uncovered a sensory circuit by which the organism integrates olfactory food cues to prime satiety at the outset of a meal.

A crucial aspect of auditory perception is the ability to use sound cues to predict future events and to time actions accordingly. For example, the sound of an approaching vehicle signals when it is safe to cross the street; distinct smartphone notification sounds reflect a call that needs to be answered within a few seconds, or a text that can be read later. Other animals similarly use sounds to plan, time and execute behaviors such as hunting, evading predation and tending to offspring. However, the neural mechanisms that underlie sound-guided prediction of upcoming salient event timing are not well understood. To address this gap, we employed an appetitive sound-triggered reward time prediction behavior in head-fixed mice. We find that mice trained on this task reliably estimate the time from a sound cue to upcoming reward on the scale of a few seconds, as demonstrated by learning-dependent well-timed increases in predictive licking for reward. Moreover, mice showed a dramatic impairment in their ability to use sound to predict delayed reward when the auditory cortex was inactivated, demonstrating its causal involvement. To identify the neurophysiological signatures of auditory cortical reward-timing prediction, we recorded local field potentials during learning and performance of this behavior and found that the magnitude of auditory cortical responses to the sound prospectively encoded the duration of the anticipated sound-reward time interval. Next, we explored how and where these sound-triggered time interval prediction signals propagate from the auditory cortex to time and initiate consequent action. We targeted the monosynaptic projections from the auditory cortex to the posterior striatum and found that chemogenetic inactivation of these projections impaired animals’ ability to predict sound-triggered delayed reward. Simultaneous neural recordings in the auditory cortex and posterior striatum during task performance revealed coordination of neural activity across these regions during the sound cue predicting the time interval to reward. Collectively, our findings identify an auditory cortical-striatal circuit supporting sound-triggered timing-prediction behaviors.

Affective and consumption circuits in the brain are intertwined, with changes in each domain often affecting the other. Therapeutic interventions that reduce consumption, thereby facilitating weight loss, have tended to increase anxiety and depression. Obesity is a major risk factor for poor health; thus, it is important to understand the circuits and signals that regulate consummatory and affective behavior. Neurons expressing Urocortin-1 (Ucn) in the Edinger-Westphal (EW) nucleus have been hypothesized to play an important role in regulating both consummatory and affective behavioral domains and responses to stress. We generated UcnCre mice to allow measurement of Ucn neuron calcium activity and to directly activate these neurons during consummatory behaviors and repeated restraint stress. Our findings provide evidence for Ucn neuron regulation of consummatory behaviors and some affective behaviors.

Animals continuously adapt their behavior to balance survival and fulfilling essential needs. This balancing act involves prioritization of safety over the pursuit of other needs. However, the specific deep brain circuits that regulate safety-seeking behaviors in conjunction with motor circuits remain poorly understood. Here, we identify a class of glutamatergic neurons in the mouse lateral hypothalamic area (LHA) that target the midbrain locomotor-promoting pedunculopontine nucleus (PPN). Following activation, this LHA-PPN pathway orchestrates context-dependent locomotion, prioritizing safety-directed movement over other essential needs such as foraging or social contact. Remarkably, the neuronal activity of this circuit correlates directly with safety-seeking behavior. The circuit may respond to both intrinsic and extrinsic cues, having a pivotal role in ensuring survival. Our findings uncover a circuit motif within the lateral hypothalamus that, when recruited, prioritizes critical needs through the recruitment of an appropriate motor action.

The posterior medial (POm) thalamus is heavily interconnected with sensory and motor circuitry and is likely involved in behavioral modulation and sensorimotor integration. POm provides axonal projections to the dorsal striatum, a hotspot of sensorimotor processing, yet the role of POm-striatal projections has remained undetermined. Using optogenetics with mouse brain slice electrophysiology, we found that POm provides robust synaptic input to direct and indirect pathway striatal spiny projection neurons (D1- and D2-SPNs, respectively) and parvalbumin-expressing fast spiking interneurons (PVs). During the performance of a whisker-based tactile discrimination task in head-restrained mice, POm-striatal projections displayed learning-related activation correlating with anticipatory, but not reward-related, pupil dilation. Inhibition of POm-striatal axons across learning caused slower reaction times and an increase in the number of training sessions for expert performance. Our data indicate that POm-striatal inputs provide a behaviorally relevant arousal-related signal, which may prime striatal circuitry for efficient integration of subsequent choice-related inputs.

Understanding how threats drive fear memory formation is crucial to understanding how organisms adapt to environments and treat threat-related disorders such as PTSD. While traditional Pavlovian conditioning studies have provided valuable insights, the exclusive reliance on electric shock as a threat stimulus has limited our understanding of diverse threats. To address this, we developed a conditioning paradigm using a looming visual stimulus as an unconditioned stimulus (US) in mice and identified a distinct neural circuit for visual threat conditioning. Parabrachial CGRP neurons were necessary for both conditioning and memory retrieval. Upstream neurons in the posterior insular cortex (pIC) responded to looming stimuli, and their projections to the parabrachial nucleus (PBN) induced aversive states and drove conditioning. However, this pIC-to-PBN pathway was not required for foot-shock conditioning. These findings reveal how non-nociceptive visual stimuli can drive aversive states and fear memory formation, expanding our understanding of aversive US processing beyond traditional models.

Phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, is a common cause of intellectual disability. However, the mechanisms by which elevated Phe levels cause cognitive impairment remain unclear. Here, we show that submillimolar Phe perturbs synaptic plasticity through the hyperactivation of GluN2B-containing NMDARs. Pah Enu2 PKU model mice exhibited submillimolar and supramillimolar concentrations of Phe in the cerebrospinal fluid (CSF) and serum, respectively. l-Phe produced concentration-dependent bidirectional effects on NMDA-induced currents, without affecting synaptic NMDA receptors (NMDARs) in hippocampal CA1 neurons. l-Phe-induced hyperactivation of extrasynaptic GluN2B resulted in activity-dependent downregulation of AMPA receptors during burst or sustained synaptic activity. Administration of l-Phe in mice decreased neural activity and impaired memory, which were blocked by pretreatment with GluN2B inhibitors. Furthermore, pharmacological and virus-mediated suppression of GluN2B reversed the impaired learning in Pah Enu2 mice. Collectively, these results suggest the concentration of Phe in the CSF of patients with PKU perturbs extrasynaptic NMDARs and synaptic plasticity and that suppression of GluN2B may have the potential to improve cognitive function in patients with PKU.