Jeffrey Burgdorf
Northwestern University, Biomedical Engineering, Faculty Member
Although many neuronal membrane proteins undergo proteolytic cleavage, little is known about the biological significance of neuronal ectodomain shedding (ES). Here, we show that the neuronal sheddome is detectable in human cerebrospinal... more
Although many neuronal membrane proteins undergo proteolytic cleavage, little is known about the biological significance of neuronal ectodomain shedding (ES). Here, we show that the neuronal sheddome is detectable in human cerebrospinal fluid (hCSF) and is enriched in neurodevelopmental disorder (NDD) risk factors. Among shed synaptic proteins is the ectodomain of CNTNAP2 (CNTNAP2-ecto), a prominent NDD risk factor. CNTNAP2 undergoes activity-dependent ES via MMP9 (matrix metalloprotease 9), and CNTNAP2-ecto levels are reduced in the hCSF of individuals with autism spectrum disorder. Using mass spectrometry, we identified the plasma membrane Ca2+ ATPase (PMCA) extrusion pumps as novel CNTNAP2-ecto binding partners. CNTNAP2-ecto enhances the activity of PMCA2 and regulates neuronal network dynamics in a PMCA2-dependent manner. Our data underscore the promise of sheddome analysis in discovering neurobiological mechanisms, provide insight into the biology of ES and its relationship with the CSF, and reveal a mechanism of regulation of Ca2+ homeostasis and neuronal network synchrony by a shed ectodomain.
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Progetti e ricerche descritti alle pagine: da 112 a 114; da 117 a 11
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Abstract Exposure to stress is a risk factor for the development of several psychiatric disorders, including posttraumatic stress disorder and depression. The results of stress exposure can be conceptualized as a shift in the set point... more
Abstract Exposure to stress is a risk factor for the development of several psychiatric disorders, including posttraumatic stress disorder and depression. The results of stress exposure can be conceptualized as a shift in the set point from a positive emotional state to a negative emotional state. In adult rats, frequency-modulated 50-kHz ultrasonic vocalizations (USVs) have been shown to index positive emotional states whereas 22-kHz USVs reflect negative emotional states. A wide variety of stressors have been shown to reduce rates of hedonic 50-kHz USVs while simultaneously increasing rates of aversive 22-kHz USVs. Heterospecific rough-and-tumble play is hedonic in normal rats but aversive in stressed rats, indicating that stress shifts the set point for the induction of positive and negative emotional states. Importantly, a positive emotional state or antidepressant treatment can reverse stress effects on the emotional set point. At the physiological level, stress suppresses synaptic plasticity in the medial prefrontal cortex, a key structure for instigating the circuit for the hedonic 50-kHz USVs. These changes in plasticity could be reversed by antidepressant treatment or by a positive emotional state. At the biochemical level, hedonic rough-and-tumble play upregulates NMDA receptors as well as insulin-like growth factor-I signaling in the medial prefrontal cortex. Thus, stress shifts the threshold for the induction of a positive state and lowers the threshold for the negative emotional state, which is expressed as a suppression of synaptic plasticity in the medial prefrontal cortex positive emotional circuit. The facilitation of this form of plasticity via multiple independent mechanisms has therapeutic potential for the treatment of neuropsychiatric disorders associated with stress.
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Research Interests: Psychology, Developmental Psychology, Laughter, Medicine, Social Housing, and 15 moreReward, Dopamine, Classical Conditioning, Glutamate, Female, Animals, Male, Reinforcement, Social Environment, Instrumental Conditioning, Rats, Operant Conditioning, Genetic Variability, Psychology and Cognitive Sciences, and Medical and Health Sciences
Mammalian brains contain a variety of self-centered socio-emotional systems. An understanding of how they interact with more recent cognitive structures may be essential for understanding empathy. Preston & de Waal have neglected this... more
Mammalian brains contain a variety of self-centered socio-emotional systems. An understanding of how they interact with more recent cognitive structures may be essential for understanding empathy. Preston & de Waal have neglected this vast territory of proximal brain issues in their analysis.
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Background The role of glutamatergic receptors in major depressive disorder continues to be of great interest for therapeutic development. Recent studies suggest that both negative and positive modulation of N-methyl-D-aspartate receptors... more
Background The role of glutamatergic receptors in major depressive disorder continues to be of great interest for therapeutic development. Recent studies suggest that both negative and positive modulation of N-methyl-D-aspartate receptors (NMDAR) can produce rapid antidepressant effects. Here we report that zelquistinel, a novel NMDAR allosteric modulator, exhibits high oral bioavailability and dose-proportional exposures in plasma and the central nervous system and produces rapid and sustained antidepressant-like effects in rodents by enhancing activity-dependent, long-term synaptic plasticity. Methods NMDAR-mediated functional activity was measured in cultured rat brain cortical neurons (calcium imaging), hNR2A or B subtype-expressing HEK cells, and synaptic plasticity in rat hippocampal and medial prefrontal cortex slices in vitro. Pharmacokinetics were evaluated in rats following oral administration. Antidepressant-like effects were assessed in the rat forced swim test and the c...
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Research Interests: Neuroscience, Psychology, Happiness, Neurobiology, Medicine, and 15 morePrefrontal Cortex, Emotions, Affect, Dopamine, Humans, Animals, Frontal Cortex, Amygdala, Positive Affect, Homeostasis, Limbic System, Positive Emotion, GABA receptor, Psychology and Cognitive Sciences, and Medical and Health Sciences
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Rat 22-kHz ultrasonic vocalizations (USVs) are exhibited in response to a wide variety of stimuli. Recently, we have shown that, depending on the internal state of the animal, a given stimulus can either trigger aversive 22-kHz USVs or... more
Rat 22-kHz ultrasonic vocalizations (USVs) are exhibited in response to a wide variety of stimuli. Recently, we have shown that, depending on the internal state of the animal, a given stimulus can either trigger aversive 22-kHz USVs or hedonic 50-kHz USVs. Notably, preexposure to reward/stress shifts this response of rats; we can selectively breed in a robust fashion for these differential responses. In addition, a change from hedonic 50-kHz to aversive 22-kHz USVs is typical during prolonged social interactions, which reflects a shift from initiation to approach, avoidance, and termination of behaviors; a similar pattern is seen with nonsocial stimuli. We now propose that 22-kHz USVs should not only be thought of as induced primarily by aversive stimuli but also by other stimuli as the transition from approach to avoidance for a wide variety of hedonic and aversive stimuli as well as a means to influence the refractory period for these motivated behaviors. A new model for motivated...
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In the past few years, several experimental studies have suggested that empathy occurs in the social lives of rodents. Thus, rodent behavioral models can now be developed to elucidate the mechanistic substrates of empathy at levels that... more
In the past few years, several experimental studies have suggested that empathy occurs in the social lives of rodents. Thus, rodent behavioral models can now be developed to elucidate the mechanistic substrates of empathy at levels that have heretofore been unavailable. For example, the finding that mice from certain inbred strains express behavioral and physiological responses to conspecific distress, while others do not, underscores that the genetic underpinnings of empathy are specifiable and that they could be harnessed to develop new therapies for human psychosocial impairments. However, the advent of rodent models of empathy is met at the outset with a number of theoretical and semantic problems that are similar to those previously confronted by studies of empathy in humans. The distinct underlying components of empathy must be differentiated from one another and from lay usage of the term. The primary goal of this paper is to review a set of seminal studies that are directly ...
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the evidence that frequency modulated (FM) 50 khz ultrasonic vocalizations (USVs) reflect a positive emotional state in rats is reviewed. positive emotional states in humans are measured by facial/vocal displays (e.g., Duchenne smiling... more
the evidence that frequency modulated (FM) 50 khz ultrasonic vocalizations (USVs) reflect a positive emotional state in rats is reviewed. positive emotional states in humans are measured by facial/vocal displays (e.g., Duchenne smiling and laughter), approach behavior and subjective self-reporting of feeling states. In laboratory animals, only facial–vocal displays, along with approach behavior, can be measured. FM 50 khz USVs are uniquely elevated by hedonic stimuli and suppressed by aversive stimuli. rates of FM 50 khz USVs are positively correlated to the rewarding value of the eliciting stimulus. playbacks of these vocalizations are also rewarding. the neural and pharmacological substrates of 50 khz USVs are consistent with those of human positive affective states. By experimentally eliciting FM 50 khz USVs, the novel molecular underpinning of positive affect can be elucidated and may be similar to those in humans. In humans, positive emotional states confer resilience to depres...
Since the realization that human emotional experiences and behavior evolved from mammalian ancestors and are evolutionary continuations of animal emotional behavior [...]
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Study Objectives The present studies examine the effects of NMDAR activation by NYX-2925 diurnal rhythmicity of both sleep and wake as well as emotion. Methods Twenty-four-hour sleep EEG recordings were obtained in sleep-deprived and... more
Study Objectives The present studies examine the effects of NMDAR activation by NYX-2925 diurnal rhythmicity of both sleep and wake as well as emotion. Methods Twenty-four-hour sleep EEG recordings were obtained in sleep-deprived and non-sleep-deprived rats. In addition, the day–night cycle of both activity and mood was measured using home cage ultrasonic-vocalization recordings. Results NYX-2925 significantly facilitated non-REM (NREM) sleep during the lights-on (sleep) period, and this effect persisted for 3 days following a single dose in sleep-deprived rats. Sleep-bout duration and REM latencies were increased without affecting total REM sleep, suggesting better sleep quality. In addition, delta power during wake was decreased, suggesting less drowsiness. NYX-2925 also rescued learning and memory deficits induced by sleep deprivation, measured using an NMDAR-dependent learning task. Additionally, NYX-2925 increased positive affect and decreased negative affect, primarily by faci...
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NYX-2925 is a novel N-methyl-D-aspartate (NMDA) receptor modulator that is currently being investigated in Phase 2 clinical studies for the treatment of painful diabetic peripheral neuropathy and fibromyalgia. Previous studies... more
NYX-2925 is a novel N-methyl-D-aspartate (NMDA) receptor modulator that is currently being investigated in Phase 2 clinical studies for the treatment of painful diabetic peripheral neuropathy and fibromyalgia. Previous studies demonstrated that NYX-2925 is a member of a novel class of NMDA receptor-specific modulators that affect synaptic plasticity processes associated with learning and memory. Studies here examined thermal and mechanical analgesic effects of NYX-2925 administration in rat peripheral chronic constriction nerve injury (CCI) and streptozotocin (STZ)-induced diabetic mechanical hypersensitivity. Additionally, NYX-2925 was examined in formalin-induced persistent pain and the tail flick model of acute nociception. Oral administration of NYX-2925 resulted in rapid and long-lasting analgesia in both of the neuropathic pain models and formalin-induced persistent pain, but was ineffective in the tail flick model. The analgesic effects of NYX-2925 were blocked by the systemi...
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Positive emotions have been shown to induce resilience to stress in humans, as well as increase cognitive abilities (learning, memory, and problem solving) and improve overall health. In rats, frequency modulated 50-kHz ultrasonic... more
Positive emotions have been shown to induce resilience to stress in humans, as well as increase cognitive abilities (learning, memory, and problem solving) and improve overall health. In rats, frequency modulated 50-kHz ultrasonic vocalizations (hedonic 50 kHz) reflect a positive affective state and are best elicited by rough-and-tumble play. A well-established rat chronic unpredictable stress paradigm was used to produce a robust and long-lasting decrease in positive affect, increase in negative affect, and learned helplessness in Sprague-Dawley rats. Rough-and-tumble play (3 min every 3 days) reversed stress-induced effects of chronic unpredictable stress in the Porsolt forced swim test, novelty-induced hypophagia, sucrose preference, and ultrasonic vocalization assays compared with a light touch control group. These data demonstrate that positive affect induces resilience to stress effects in rats, and that rough-and-tumble play can be used to explore the biological basis of resi...
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N-methyl-D-aspartate receptors (NMDAR) are one member of a family of ionotropic glutamate receptors that play a pivotal role in synaptic plasticity processes associated with learning and have become attractive therapeutic targets for... more
N-methyl-D-aspartate receptors (NMDAR) are one member of a family of ionotropic glutamate receptors that play a pivotal role in synaptic plasticity processes associated with learning and have become attractive therapeutic targets for diseases such as depression, anxiety, schizophrenia, and neuropathic pain. NYX-2925 ((2S, 3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide) is one member of a spiro--lactam-based chemical platform that mimics some of the dipyrrolidine structural features of rapastinel (formerly GLYX-13: threonine-proline-proline-threonine) and is distinct from known NMDAR agonists or antagonists such as D-cycloserine, ketamine, MK-801, kynurenic acid or ifenprodil. The in vitro and in vivo pharmacological properties of NYX-2925 were examined. NYX-2925 has a low potential for "off-target" activity as it did not exhibit any significant affinity for a large panel of neuroactive receptors, including hERG receptors. NYX-2925 increase...
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Posttraumatic stress disorder is an anxiety disorder characterized by deficits in the extinction of aversive memories. Insulin-like growth factor 1 (IGF1) is the only growth factor that has shown anxiolytic and antidepressant properties... more
Posttraumatic stress disorder is an anxiety disorder characterized by deficits in the extinction of aversive memories. Insulin-like growth factor 1 (IGF1) is the only growth factor that has shown anxiolytic and antidepressant properties in human clinical trials. In animal studies, insulin-like growth factor binding protein 2 (IGFBP2) shows both IGF1-dependent and IGF1-independent pharmacological effects, and IGFBP2 expression is upregulated by rough-and-tumble play that induces resilience to stress. IGFBP2 was evaluated in Porsolt, contextual fear conditioning, and chronic unpredictable stress models of posttraumatic stress disorder. The dependence of IGFBP2 effects on IGF1- and AMPA-receptor activation was tested using selective receptor antagonists. Dendritic spine morphology was measured in the dentate gyrus and the medial prefrontal cortex 24 hours after in vivo dosing. IGFBP2 was 100 times more potent than IGF1 in the Porsolt test. Unlike IGF1, effects of IGFBP2 were not blocke...
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The authors provide initial documentation that juvenile rats emit short, high-frequency ultrasonic vocalizations (high USVs, approximately 55 kHz) during rough-and-tumble play. In an observational study, they further observe that these... more
The authors provide initial documentation that juvenile rats emit short, high-frequency ultrasonic vocalizations (high USVs, approximately 55 kHz) during rough-and-tumble play. In an observational study, they further observe that these vocalizations both correlate with and predict appetitive components of the play behavioral repertoire. Additional experiments characterized eliciting conditions for high USVs. Without prior play exposure, rats separated by a screen vocalized less than playing rats, but after only 1 play session, separated rats vocalized more than playing rats. This findings suggested that high USVs were linked to a motivational state rather than specific play behaviors or general activity. Furthermore, individual rats vocalized more in a chamber associated with play than in a habituated control chamber. Finally, congruent and incongruent motivational manipulations modulated vocalization expression. Although play deprivation enhanced high USVs, an arousing but aversive stimulus (bright light) reduced them. Taken together, these findings suggest that high USVs may index an appetitive motivation to play in juvenile rats.
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The evidence that frequency modulated (FM) 50 kHz ultrasonic vocalizations (USVs) reflect a positive emotional state in rats is reviewed. Positive emotional states in humans are measured by facial/vocal displays (e.g., Duchenne smiling... more
The evidence that frequency modulated (FM) 50 kHz ultrasonic vocalizations (USVs) reflect a positive emotional state in rats is reviewed. Positive emotional states in humans are measured by facial/vocal displays (e.g., Duchenne smiling and laughter), approach behavior and subjective self-reporting of feeling states. In laboratory animals, only facial-vocal displays, along with approach behavior, can be measured. FM 50 kHz USVs