Progress In Neurobiology[JOURNAL]
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200 papers
Stress-induced heme metabolic disorder in peripheral B cells contributes to depressive-like behaviors in male mice.
Yin Y, Li B, Du L … +1 more , Wu S
Prog Neurobiol · 2025 Aug · PMID 40544657 · Publisher ↗
Major depressive disorder (MDD) is a common and burdensome psychiatric illness with high rates of recurrence. Most of the current therapeutic drugs for depression mainly achieve their antidepressant effect by tuning the...
Major depressive disorder (MDD) is a common and burdensome psychiatric illness with high rates of recurrence. Most of the current therapeutic drugs for depression mainly achieve their antidepressant effect by tuning the landscape of neurotransmitters in the central nervous system (CNS). However, almost half of patients with MDD cannot fully benefit from these available treatments. Consequently, it is urgent to find novel therapeutic targets for the treatment of MDD. Peripheral B lymphocytes have been reported as a major contributor to the occurrence of stress-induced depression. However, the pathological role and underlying regulatory mechanism of peripheral B cells in MDD have not been well established. Here, we show that peripheral B cells are significantly infiltrated into the CNS of male mice after exposure to chronic unpredictable mild stress (CUMS). Adoptive transfer of B cells from CUMS mice into B-cell-deficient male mice could significantly induce higher severity depressive symptoms than adoptive transfer of B cells from control mice. The lack of B cells protects male mice from CUMS-induced neuroinflammation and depressive-like behaviors. Interestingly, the pathological B cells in CUMS mice are characterized by increased heme biosynthesis, whereas its inhibition can ameliorate depressive-like behaviors in B-cell-deficient mice that received pathological B cells from CUMS mice. Our findings suggest a critical role of the heme biosynthesis in B cells for contributing to the pathogenesis of depression and indicate that these pathological B cells featuring high heme may be a promising immune target for the development of precision medicine approaches in MDD.
Differential susceptibility to repeated social stress induces synaptic plasticity impairment and cognitive deficit in the 5xFAD mouse model.
Yang EJ, Rahim MA, Masieri S … +1 more , Pasinetti GM
Prog Neurobiol · 2025 Aug · PMID 40543806 · Publisher ↗
Stress-related disorders including depression are common comorbidities in Alzheimer's Disease (AD). In AD, heightened stress reactivity may contribute to an increased risk of cognitive dysfunction. This study aimed to in...
Stress-related disorders including depression are common comorbidities in Alzheimer's Disease (AD). In AD, heightened stress reactivity may contribute to an increased risk of cognitive dysfunction. This study aimed to investigate the differential responses of wild-type (WT) and 5xFAD mice, a model of AD, to repeated social defeat stress (RSDS) and explore the molecular mechanisms associated with stress susceptibility. Both WT and 5xFAD mice exhibited susceptibility to initial exposure to RSDS, with a greater proportion of stress-susceptible (Sus) individuals observed in 5xFAD mice compared to WT mice. In presymptomatic 5xFAD mice repeatedly exposed to RSDS, cognitive impairment was evident through a lower discrimination index in the NOR test compared to controls. To investigate the effects of RSDS on peripheral immune responses, we performed CyTOF analysis, revealing a significant increase in CD8 + and CD4 + memory T cells exclusively in the peripheral blood of 5xFAD-Sus mice. To further explore the molecular mechanisms underlying RSDS in the brain, RNA sequencing revealed distinct patterns of differentially expressed genes associated with inflammatory pathways in stress-Sus mice. Specifically, 5xFAD-Sus mice exhibited dysregulation in immune-related pathways, while WT-Sus mice displayed alterations in pathways related to cell adhesion and cytoskeletal organization. In addition, when comparing 5xFAD-Sus to 5xFAD-resilience mice, significant disruptions in synaptic plasticity pathways were observed in 5xFAD-Sus mice, and these changes were accompanied by cognitive impairment. These findings suggest that increased stress susceptibility in 5xFAD is linked to distinct peripheral immune dysregulation, potentially contributing to synaptic plasticity impairments and cognitive dysfunction in the early stages of AD.
Beyond neurons: How does dopamine signaling impact astrocytic functions and pathophysiology?
Favetta G, Bubacco L
Prog Neurobiol · 2025 Aug · PMID 40543805 · Publisher ↗
Astrocytes, the most abundant glial cells in the central nervous system (CNS), are critical regulators of brain homeostasis and play an active role in synaptic signaling and plasticity. While dopamine, a key catecholamin...
Astrocytes, the most abundant glial cells in the central nervous system (CNS), are critical regulators of brain homeostasis and play an active role in synaptic signaling and plasticity. While dopamine, a key catecholamine neurotransmitter, has been traditionally associated with neuronal functions, emerging evidence highlights its significant impact on astrocytic physiology. This review explores how astrocytes contribute to dopaminergic signaling and the implications of this interaction in both physiological and pathological contexts. Specifically, we examined astrocytic dopamine receptor expression, signaling mechanisms, and region-specific effects on neuroinflammation, synaptic regulation, and neurotrophic factor secretion. Notably, astrocytic dopamine receptor activation plays dual inflammatory roles, modulating both anti- and pro- inflammatory responses depending on the receptor subtype and pathological environment. Furthermore, dopamine-evoked gliotransmitter release and neurotrophin secretion highlight the role of astrocytes in astrocyte-to-neuron communication, which impacts synaptic plasticity and neuronal survival. Dysfunction of astrocytic dopaminergic signaling has been implicated in neurodegenerative diseases such as Parkinson's disease, where dopamine depletion drives reactive astrogliosis, altered glutamate homeostasis, and inflammatory responses. These findings underscore the complexity of astrocytic responses to dopamine and their potential as targets in conditions characterized by dysregulation of dopaminergic signaling. By highlighting recent advancements in understanding dopamine-astrocyte interactions, this review aims to provide insights into the broader roles of astrocytes in dopaminergic systems and their therapeutic potential in CNS disorders.
The low-density lipoprotein receptor-related protein-1 (LRP1) in Schwann cells controls mitochondria homeostasis in peripheral nerves.
Martellucci S, Heredia M, Wang Z … +12 more , Whisenant T, Strickland DK, Sanchez R, Arai T, Zhang M, Wang H, Gong Z, Asam K, Aouizerat BE, Pekkurnaz G, Ye Y, Campana WM
Prog Neurobiol · 2025 Aug · PMID 40541732 · Publisher ↗
Following peripheral nerve injury, Schwann cell (SC) survival is imperative for successful nerve regeneration. The low-density lipoprotein receptor-related protein-1 (LRP1) has been identified as a pro-survival SC plasma...
Following peripheral nerve injury, Schwann cell (SC) survival is imperative for successful nerve regeneration. The low-density lipoprotein receptor-related protein-1 (LRP1) has been identified as a pro-survival SC plasma membrane signaling receptor, however, the responsible mechanisms underlying SC homeostasis remain incompletely understood. Herein, we establish that LRP1 largely manages mitochondrial dynamics and bioenergetics in SCs by limiting mitochondria fission, maintaining healthy mitochondria membrane potentials, and reducing lactate production associated with peripheral sensitization. When SC LRP1 is suppressed, inner-mitochondria-linked pathways in peripheral nerve proteome are dramatically altered, and cristae integrity in unmyelinated C-fibers is compromised. SC LRP1 protected sensory neurons from mitochondrial dysfunction and modulated mitochondria-related biological pathways in the DRG transcriptome. Conditional deletion of LRP1 in SCs induces pain-related behaviors in mice without nerve injury. Results point to a significant role for LRP1 in SC mitochondrial homeostasis and advance our understanding of the sensory neuron response to alterations in SC bioenergetics.
Corrigendum to "Anatomo-functional organization of insular networks: From sensory integration to behavioral control" [Prog. Neurobiol. 247 (2025) 102748].
Simone L, Caruana F, Borra E … +5 more , Del Sorbo S, Jezzini A, Rozzi S, Luppino G, Gerbella M
Prog Neurobiol · 2025 Aug · PMID 40523831 · Publisher ↗
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Neuronal encoding of recognition memory for numerical quantities in macaque intraparietal and prefrontal cortices.
Machts T, Grüb J, Nieder A
Prog Neurobiol · 2025 Aug · PMID 40517805 · Publisher ↗
The parieto-frontal number network in primates is vital for extracting and memorizing numerical information. However, how neurons in these regions retain abstract numerical categories to recognize target numbers amidst o...
The parieto-frontal number network in primates is vital for extracting and memorizing numerical information. However, how neurons in these regions retain abstract numerical categories to recognize target numbers amidst ongoing numerical input is unclear. To explore this, single neurons were recorded from the ventral intraparietal cortex (VIP) and lateral prefrontal cortex (PFC) of two male macaques trained to memorize and recognize target numerosities while viewing sequences of irrelevant numerosities. In the VIP, neuronal selectivity for both target and irrelevant numerosities declined rapidly, making it unable to distinguish relevant from irrelevant quantities. Conversely, PFC neurons maintained selective tuning for target numerosities over time but not for irrelevant ones, enabling the distinction between sought and irrelevant quantities. Match enhancement effects, where firing increased for repeated target numerosities, were observed only in the PFC. In contrast, match suppression effects, involving reduced firing for repeated target numerosities, occurred in both the VIP and PFC. These findings suggest the VIP primarily encodes displayed numerosities, while the PFC is specialized for processing, storing, and recognizing numerical quantities by enhancing familiar numerosities. This highlights the PFC's key role in recognition memory, contrasting with the transient coding observed in the VIP.
The social salience network hypothesis of autism: Disrupted network activity, oxytocin signaling, and implications for social symptoms.
Patwardhan A, Choe KY
Prog Neurobiol · 2025 Aug · PMID 40484364 · Publisher ↗
Autism Spectrum Disorder (ASD) is a complex condition characterized by its heterogeneity, with significant variability in symptoms across subtypes and associated comorbidities. Despite the urgent need to develop mechanis...
Autism Spectrum Disorder (ASD) is a complex condition characterized by its heterogeneity, with significant variability in symptoms across subtypes and associated comorbidities. Despite the urgent need to develop mechanism-based therapies for the core social symptoms of ASD, progress has been hindered by the heterogeneous etiology of this neurodevelopmental disorder and our still limited understanding of the neural mechanisms underlying social behavior. The evaluation of sociosensory cues and the modulation of motivation to engage socially are fundamental components of social interaction, thought to be coordinated by a network of interconnected brain regions called the social salience network (SSN). This network is strongly modulated by the neurohormone oxytocin (OXT) to facilitate appropriate social responses. It is increasingly recognized that disruptions within the SSN contribute to the atypical social perception and engagement observed in autistic individuals. This review will summarize evidence from current clinical and preclinical literature that provides compelling evidence for SSN disruptions as a possible mechanism that underlies the social symptoms of ASD. Furthermore, we discuss OXT-mediated correction of SSN disruptions at the regional and circuit levels that rescues social phenotypes in preclinical models of ASD-risk factors. These molecular, cellular, and circuit mechanisms within the SSN could serve as promising treatment targets which may propel the development of novel and effective options for alleviating the social difficulties of autistic individuals.
Changes in astrocyte function induced by stress-induced glucocorticoid exacerbate major depressive disorder.
Park B, Choi GE
Prog Neurobiol · 2025 Aug · PMID 40482767 · Publisher ↗
Major depressive disorder (MDD) is a prevalent psychiatric condition that affects millions of people worldwide and is a leading cause of disability. Chronic stress is a key factor in the development of MDD, leading to hy...
Major depressive disorder (MDD) is a prevalent psychiatric condition that affects millions of people worldwide and is a leading cause of disability. Chronic stress is a key factor in the development of MDD, leading to hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis and elevated glucocorticoid levels, which in turn affect brain function and structure. Astrocytes, crucial for maintaining central nervous system (CNS) homeostasis, play a significant role in the pathophysiology of MDD. Dysregulation of glucocorticoid signaling in astrocytes contributes to changes in astrocyte survival, reactivity, metabolism, neurotrophic support, gliotransmitter release, and neuroinflammation, exacerbating depressive symptoms. This review explains the necessity for exploring the effects of glucocorticoid on astrocytes and subsequent MDD progression. Firstly, we briefly explore the glucocorticoid signaling and the multifaceted function of astrocytes. Then, this study discusses the mechanisms by which chronic stress and glucocorticoid exposure induce astrocyte-mediated neurodegenerative changes, highlighting the importance of targeting glucocorticoid-related signaling of astrocytes in developing therapeutic interventions for MDD. Understanding these mechanisms could lead to the development of more effective treatments aimed at restoring astrocyte function and alleviating MDD.
Glutamine transport via amino acid transporter NTT4 (SLC6A17) maintains presynaptic glutamate supply at excitatory synapses in the CNS.
Nicoli AL, Al Abed AS, Hulme SR … +9 more , Das A, Gauthier-Coles G, Bröer A, Balkrishna S, Burgio G, Dehorter N, Rae CD, Bröer S, Billups B
Prog Neurobiol · 2025 Jul · PMID 40436200 · Publisher ↗
The glutamate-glutamine cycle is thought to be the principle metabolic pathway that recycles glutamate at synapses. In this cycle, synaptically released glutamate is sequestered by astrocytes and forms glutamine, before...
The glutamate-glutamine cycle is thought to be the principle metabolic pathway that recycles glutamate at synapses. In this cycle, synaptically released glutamate is sequestered by astrocytes and forms glutamine, before being returned to the presynaptic terminal for conversion back into glutamate to replenish the neurotransmitter pool. While many aspects of this cycle are established, a key component remains unknown: the nature of the transporter responsible for the presynaptic uptake of glutamine. We hypothesise that neurotransmitter transporter 4 (NTT4/SLC6A17) plays this role. Accordingly, we generated NTT4 knockout mice to assess its contribution to presynaptic glutamine transport and synaptic glutamate supply. Using biochemical tracing of C metabolites in awake mice, we observe a reduction of neuronal glutamate supply when NTT4 is absent. In addition, direct electrical recording of hippocampal mossy fibre boutons reveals a presynaptic glutamine transport current that is eliminated when NTT4 is removed or inhibited. The role of NTT4 in neurotransmission was demonstrated by electrophysiological recordings in hippocampal slices, which reveal that NTT4 is required to maintain vesicular glutamate content and to sustain adequate levels of glutamate supply during periods of high-frequency neuronal activity. Finally, behavioural studies in mice demonstrate a deficit in trace fear conditioning, and alterations in anxiety behaviour and social preference. These results demonstrate that NTT4 is a presynaptic glutamine transporter, which is a central component of the glutamate-glutamine cycle. NTT4 and hence the glutamate-glutamine cycle maintain neuronal glutamate supply for excitatory neurotransmission during high-frequency synaptic activity, and are important regulators of memory retention and normal behaviour.
Switching state to engage and sustain attention: Dynamic synchronization of the frontoparietal network.
Ross G, Huang WA, Reiling J … +6 more , Zhang M, Park J, Radtke-Schuller S, Hopfinger J, Zuberer A, Frohlich F
Prog Neurobiol · 2025 Jul · PMID 40389123 · Publisher ↗
Sustained attention (SA) is essential for maintaining focus over time, with disruptions linked to various neurological and psychiatric disorders. The oscillatory dynamics and functional connectivity in the dorsal frontop...
Sustained attention (SA) is essential for maintaining focus over time, with disruptions linked to various neurological and psychiatric disorders. The oscillatory dynamics and functional connectivity in the dorsal frontoparietal network (dFPN) are crucial in SA. However, the neuronal mechanisms that control the level of SA, especially in response to heightened attentional demands, remain poorly understood. To examine the role of rhythmic synchronization in the dFPN in SA, we recorded local field potential and single unit activity in ferrets that performed the 5-Choice Serial Reaction Time Task (5-CSRTT) under both low and high attentional load. Under high attentional load, dFPN exhibited a pronounced state shift that corresponded with behavioral changes in the animal. Prior to the onset of the target stimulus, animals transitioned from a stationary state, characterized by frontal theta oscillations and dFPN theta connectivity, to an active exploration state associated with sensory processing. This shift was indexed by a suppression of inhibitory alpha oscillations and an increase in excitatory theta and gamma oscillations in parietal cortex. We further show that dFPN theta connectivity predicts performance fluctuations under high attentional load. Together, these results suggest that behavioral strategies for maintaining SA are tightly linked to neuronal state dynamics in the dFPN. Importantly, these findings identify rhythmic synchronization within the FPN as a potential neural target for novel therapeutic strategies for disrupted attention.
Awake reactivation of cortical memory traces predicts subsequent memory retrieval.
Duan W, Lu P, Xu Z … +6 more , Wang J, Lu Y, Wang M, Paller KA, Axmacher N, Wang L
Prog Neurobiol · 2025 Jul · PMID 40381829 · Publisher ↗
Brief periods of rest after learning facilitate consolidation of new memories. Memory reactivation and hippocampal-cortical dialogue have been proposed as candidate mechanisms supporting consolidation. However, the study...
Brief periods of rest after learning facilitate consolidation of new memories. Memory reactivation and hippocampal-cortical dialogue have been proposed as candidate mechanisms supporting consolidation. However, the study of these mechanisms has mostly concerned sleep-based consolidation. Whether and how awake reactivation can selectively consolidate cortical memory traces to guide subsequent behavior requires more human electrophysiological evidence. This study addressed these issues by utilizing intracranial electroencephalography (iEEG) recordings from 11 patients with drug-resistant epilepsy, who learned a set of object-location associations. Using representational similarity analysis, we found that, among the multiple cortical memory traces of object-location associations for the same object generated through several rounds of learning, the association corresponding to memory traces with stronger cortical activation during wakeful rest was more likely to be retrieved later. Awake reactivation of cortical memory trace was accompanied by increased hippocampal ripple rates and enhanced theta-band hippocampal-cortical communication, with hippocampal interactions with cortical regions within the default mode network preceding cortical reactivation. Together, these results suggest that awake reactivation of cortical memory trace during post-learning rest supports memory consolidation, predicting subsequent recall.
Neural dynamics encoding risky choices during deliberation reveal separate choice subspaces.
Peters LM, Roadarmel A, Overton JA … +4 more , Stickle MP, Kong Z, Saez I, Moxon KA
Prog Neurobiol · 2025 Jul · PMID 40345520 · Publisher ↗
Human decision-making involves the coordinated activity of multiple brain areas, acting in concert, to enable humans to make choices. Most decisions are carried out under conditions of uncertainty, where the desired outc...
Human decision-making involves the coordinated activity of multiple brain areas, acting in concert, to enable humans to make choices. Most decisions are carried out under conditions of uncertainty, where the desired outcome may not be achieved if the wrong decision is made. In these cases, humans deliberate before making a choice. The neural dynamics underlying deliberation are unknown and intracranial recordings in clinical settings present a unique opportunity to record high temporal resolution electrophysiological data from many (hundreds) brain locations during behavior. Combined with dynamic systems modeling, these allow identification of latent brain states that describe the neural dynamics during decision-making, providing insight into these neural dynamics and computations. Results show that the neural dynamics underlying risky decisions, but not decisions without risk, converge to separate subspaces depending on the subject's preferred choice and that the degree of overlap between these subspaces declines as choice approaches, suggesting a network level representation of evidence accumulation. These results bridge the gap between regression analyses and data driven models of latent states and suggest that during risky decisions, deliberation and evidence accumulation toward a final decision are represented by the same neural dynamics, providing novel insights into the neural computations underlying human choice.
Bidirectional control of generalized absence epilepsy networks via real-time direct depolarization of thalamocortical neurons.
Morais TP, Taylor HL, Nagy O … +4 more , Mátyás F, David F, Crunelli V, Lőrincz ML
Prog Neurobiol · 2025 Sep · PMID 40339636 · Publisher ↗
Absence seizures (ASs), characterized by bilateral spike-and-wave discharges (SWDs), are a hallmark of idiopathic generalized epilepsies. We investigated the role of thalamocortical (TC) neurons in the generation and ter...
Absence seizures (ASs), characterized by bilateral spike-and-wave discharges (SWDs), are a hallmark of idiopathic generalized epilepsies. We investigated the role of thalamocortical (TC) neurons in the generation and termination of ASs using optogenetic techniques in freely behaving GAERS rats, a well-established AS model. We demonstrate that direct depolarization of ChR2-transfected TC neurons in the ventrobasal thalamic nuclei during quiet wakefulness (QW) reliably elicits ethosuximide-sensitive ASs that have similar duration and frequency to those of spontaneous ASs, while showing little and no effect during active wakefulness (AW) and slow wave sleep (SWS), respectively. Light-stimulation of TC neurons fails to elicit ASs during AW, QW and SWS in non-epileptic control (NEC) rats, whereas it could evoke short ASs in Wistar rats, prevalently during QW. Notably, brief light stimulation effectively halted ongoing spontaneous ASs in GAERS rats (i.e. both SWDs and immobility), immediately altering thalamic multi-unit activity from rhythmic to irregular firing, irrespective of the SWD phase at which it was delivered. These findings support the view that the excitability of cortico-thalamic-cortical network is highly behavioural state-dependent, with increased susceptibility to the induction of ASs during QW, thus questioning the necessity of low-threshold burst firing of TC neurons in the generation of these seizures. Moreover, they highlight the dual control of ASs by TC neurons, underscoring their potential as therapeutic targets for AS modulation.
Temporal impact of sepsis on Alzheimer's disease pathology and neuroinflammation.
Vo Q, Nacionales DC, McFarland KN … +8 more , Gorski C, Barrios EL, Park G, Moldawer LL, Casadesus G, Nagpal R, Efron PA, Chakrabarty P
Prog Neurobiol · 2025 Jul · PMID 40324581 · Full text
Epidemiological evidence has revealed an associative link between sepsis survivorship and increased risk of dementia, particularly Alzheimer's disease (AD). Paradoxically, population studies show females are less suscept...
Epidemiological evidence has revealed an associative link between sepsis survivorship and increased risk of dementia, particularly Alzheimer's disease (AD). Paradoxically, population studies show females are less susceptible to sepsis but more vulnerable to post-sepsis dementia. Here, we examined the temporal impacts of sepsis in the context of AD by using an AD-amyloidosis model (TgCRND8) and their wild-type littermates and assessing outcomes at 7 days and 3 months post-sepsis in male and female mice. Following 7-days recovery, the microglia and astrocytes in AD-model mice were largely refractile to the systemic immune stimuli. Notably, the female AD-model mice accumulated higher hippocampal amyloid-beta (Aβ) burden and upregulated AD-type transcriptomic signature at this time. On the other hand, male AD-model mice showed no Aβ changes. At this time, the wild-type post-septic males, but not females, displayed robust astrocytosis, with nominal microgliosis. By 3 months post-sepsis, microgliosis was specifically elevated in wild-type females, indicating a prolonged central immune response. At this time, both male and female AD-model mice showed exacerbated Aβ and anxiety indices. Gene network analysis revealed a stronger immune response in females, while the male response was linked to estrogen receptor (ESR) signaling, with ERα protein upregulated in the brains of post-septic AD-model males. Together, our data highlights a sex-dimorphic temporal response in post-sepsis neuroinflammation, with ESR signaling playing a key role in males, while Aβ burden is affected similarly in both males and females.
EphB2 receptor tyrosine kinase-mediated excitatory synaptic functions are negatively modulated by MDGA2.
Kim H, Jeon Y, Kim S … +6 more , Guo Y, Kim D, Jang G, Brasch J, Um JW, Ko J
Prog Neurobiol · 2025 Jul · PMID 40316130 · Full text
MDGA2 is an excitatory synapse-specific suppressor that uses distinct extracellular mechanisms to negatively regulate various postsynaptic properties. Here, we identify EphB2, an excitatory synapse-specific receptor tyro...
MDGA2 is an excitatory synapse-specific suppressor that uses distinct extracellular mechanisms to negatively regulate various postsynaptic properties. Here, we identify EphB2, an excitatory synapse-specific receptor tyrosine kinase, as a new binding partner for MDGA2. The first three immunoglobulin domains of MDGA2 undergo cis-binding to the ligand-binding domain of EphB2, enabling MDGA2 to compete with Ephrin-B1 for binding to EphB2. Moreover, EphB2 forms complexes with MDGA2 and GluN2B-containing NMDA receptors (NMDARs) in mouse brains. MDGA2 deletion promotes formation of the EphB2/Ephrin-B1 complex but does not alter the surface expression levels and Ephrin-stimulated activation of EphB2 receptors and downstream GluN2B-containing NMDARs in cultured neurons. AlphaFold-based molecular replacement experiments reveal that MDGA2 must bind EphB2 to suppress spontaneous synaptic transmission and NMDAR-mediated, but not AMPAR-mediated, postsynaptic responses at excitatory synapses in cultured neurons. These results collectively suggest that MDGA2 is a versatile factor that suppresses distinct excitatory postsynaptic properties via different transsynaptic pathways.
Glycine-gated extrasynaptic NMDARs activated during glutamate spillover drive burst firing in nigral dopamine neurons.
Ringlet S, Motta Z, Vandries L … +5 more , Seutin V, Jehasse K, Caldinelli L, Pollegioni L, Engel D
Prog Neurobiol · 2025 Jun · PMID 40294743 · Publisher ↗
Burst firing in substantia nigra pars compacta dopamine neurons is a critical biomarker temporally associated to movement initiation. This phasic change is generated by the tonic activation of NMDARs but the respective r...
Burst firing in substantia nigra pars compacta dopamine neurons is a critical biomarker temporally associated to movement initiation. This phasic change is generated by the tonic activation of NMDARs but the respective role of synaptic versus extrasynaptic NMDARs in the ignition of a burst and what is their level of activation remains unknown. Using ex vivo electrophysiological recordings from adolescent rats, we demonstrate that extrasynaptic NMDARs are the primary driver of burst firing. This pool of receptors is recruited during intense synaptic activity via spillover of glutamate and require the binding of NMDAR co-agonist glycine for full activation. Basal synaptic transmission activating only synaptic NMDARs with the support of D-serine is insufficient to generate a burst. Notably, both synaptic and extrasynaptic NMDARs share the same subunit composition but are regulated by distinct co-agonists. Location of NMDARs and regionalization of co-agonists but not NMDAR subunit composition underly burst generation and may serve as a guideline in understanding the physiological role of dopamine in signaling movement.
Whole-brain effective connectivity of the sensorimotor system using 7 T fMRI with electrical microstimulation in non-human primates.
Han MJ, Oh Y, Ann Y … +5 more , Kang S, Baeg E, Hong SJ, Sohn H, Kim SG
Prog Neurobiol · 2025 Jul · PMID 40280291 · Publisher ↗
The sensorimotor system is a crucial interface between the brain and the environment, and it is endowed with multiple computational mechanisms that enable efficient behaviors. For example, predictive processing via an ef...
The sensorimotor system is a crucial interface between the brain and the environment, and it is endowed with multiple computational mechanisms that enable efficient behaviors. For example, predictive processing via an efference copy of a motor command has been proposed as one of the key computations used to compensate for the sensory consequence of movement. However, the neural pathways underlying this process remain unclear, particularly regarding whether the M1-to-S1 pathway plays a dominant role in predictive processing and how its influence compares to that of other pathways. In this study, we present a causally inferable input-output map of the sensorimotor effective connectivity that we made by combining ultrahigh-field functional MRI, electrical microstimulation of the S1/M1 cortex, and dynamic causal modeling for the whole sensorimotor network in anesthetized primates. We investigated how motor signals from M1 are transmitted to S1 at the circuit level, either via direct cortico-cortical projections or indirectly via subcortical structures such as the thalamus. Across different stimulation conditions, we observed a robust asymmetric connectivity from M1 to S1 that was also the most prominent output from M1. In the thalamus, we identified distinct activations: M1 stimulation showed connections to the anterior part of ventral thalamic nuclei, whereas S1 was linked to the more posterior regions of the ventral thalamic nuclei. These findings suggest that the cortico-cortical projection from M1 to S1, rather than the cortico-thalamic loop, plays a dominant role in transmitting movement-related information. Together, our detailed dissection of the sensorimotor circuitry underscores the importance of M1-to-S1 connectivity in sensorimotor coordination.
Slumber under pressure: REM sleep and stress response.
Schaefke B, Li J, Zhao B … +2 more , Wang L, Tseng YT
Prog Neurobiol · 2025 Jun · PMID 40273975 · Publisher ↗
Sleep, a state of reduced responsiveness and distinct brain activity, is crucial across the animal kingdom. This review explores the potential adaptive functions of REM sleep in adapting to stress, emphasizing its role i...
Sleep, a state of reduced responsiveness and distinct brain activity, is crucial across the animal kingdom. This review explores the potential adaptive functions of REM sleep in adapting to stress, emphasizing its role in memory consolidation, emotional regulation, and threat processing. We further explore the underlying neural mechanisms linking stress responses to REM sleep. By synthesizing current findings, we propose that REM sleep allows animals to "rehearse" or simulate responses to danger in a secure, offline state, while also maintaining emotional balance. Environmental factors, such as predation risk and social dynamics, further influence REM sleep. This modulation may enhance survival by optimizing stress responses while fulfilling physiological needs in animals. Insights into REM sleep's role in animals may shed light on human sleep in the context of modern stressors and sleep disruptions. This review also explores the complex interplay between stress, immunity, sleep disruptions-particularly involving REM sleep-and their evolutionary underpinnings.
Lethal Interactions of neuronal networks in epilepsy mediated by both synaptic and volume transmission indicate approaches to prevention.
Faingold CL
Prog Neurobiol · 2025 Jun · PMID 40258456 · Full text
Neuronal network interactions are important in normal brain physiology and also in brain disorders. Many mesoscopic networks, including the auditory and respiratory network, mediate a single brain function. Macroscopic n...
Neuronal network interactions are important in normal brain physiology and also in brain disorders. Many mesoscopic networks, including the auditory and respiratory network, mediate a single brain function. Macroscopic networks, including the locomotor network, central autonomic network (CAN), and many seizure networks involve interactions among multiple mesoscopic networks. Network interactions are mediated by neuroactive substances, acting via synaptic transmission, which mediate rapid interactions between networks. Slower, but vitally important network interactions, are mediated by volume transmission. Changes in the interactions between networks, mediated by neuroactive substances, can significantly alter network function and interactions. The acoustic startle response involves interactions between auditory and locomotor networks, and also includes brainstem reticular formation (BRF) nuclei, which participate in many different networks. In the fear-potentiated startle paradigm this network interacts positively with the amygdala, induced by conditioning. Seizure networks can interact negatively with the respiratory network, which becomes lethal in sudden unexpected death in epilepsy (SUDEP), a tragic emergent property of the seizure network. SUDEP models that exhibit audiogenic seizures (AGSz) involve interactions between the auditory and locomotor networks with BRF nuclei. In the DBA/1 mouse SUDEP model the AGSz network interacts negatively with the respiratory network, resulting in postictal apnea. The apnea is lethal unless the CAN is able to initiate autoresuscitation. These network interactions involve synaptic transmission, mediated by GABA and glutamate and volume transmission mediated by adenosine, CO and serotonin. Altering these interaction mechanisms may prevent SUDEP. These epilepsy network interactions illustrate the complex mechanisms that can occur among neuronal networks.
Modulation of premotor cortex excitability mitigates the behavioral and electrophysiological abnormalities in a Parkinson's disease mouse model.
Choi IS, Kim J, Choi JH … +3 more , Kim EM, Choi JW, Rah JC
Prog Neurobiol · 2025 Jun · PMID 40258455 · Publisher ↗
The subthalamic nucleus (STN) plays a crucial role in suppressing prepotent response tendency. The prefrontal regions innervating the STN exhibit increased activity during the stop-signal responses, and the optogenetic a...
The subthalamic nucleus (STN) plays a crucial role in suppressing prepotent response tendency. The prefrontal regions innervating the STN exhibit increased activity during the stop-signal responses, and the optogenetic activation of these neurons suppresses ongoing behavior. High-frequency electrical stimulation of the STN effectively treats the motor symptoms of Parkinson's disease (PD), yet its underlying circuit mechanisms remain unclear. Here, we investigated the involvement of STN-projecting premotor (M2) neurons in PD mouse models and the impact of deep brain stimulation targeting the STN (DBS-STN). We found that the M2 neurons exhibited enhanced burst firing and synchronous oscillations in the PD mouse model. Remarkably, high-frequency stimulation of STN-projecting M2 neurons, simulating antidromic activation during DBS-STN relieved motor symptoms and hyperexcitability. These changes were attributed to reduced firing frequency vs. current relationship through normalized hyperpolarization-activated inward current (Ih). The M2 neurons in the PD model mouse displayed increased Ih, which was reversed by high-frequency stimulation. Additionally, the infusion of ZD7288, an HCN channel blocker, into the M2 replicated the effects of high-frequency stimulation. In conclusion, our study reveals excessive excitability and suppressive motor control through M2-STN synapses in a PD mouse model. Antidromic excitation of M2 neurons during DBS-STN alleviates this suppression, thereby improving motor impairment. These findings provide insights into the circuit-level dynamics underlying deep brain stimulation's therapeutic effects in PD, suggesting that M2-STN synapses could serve as potential targets for future therapeutic strategies.
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