Progress In Neurobiology[JOURNAL]
Sun
200 papers
Translated retained intron 11 sequence confers pathological properties to Tau in Alzheimer's disease.
Tan YY, Leow CY, Choo CT … +2 more , Tan J, Ong CT
Prog Neurobiol · 2026 Feb · PMID 41422990 · Publisher ↗
A novel Tau11i isoform was previously found to be enriched in Alzheimer's disease (AD) brains. Further characterization showed that the 19-amino acid peptide encoded by retained intron 11 facilitates the formation of hig...
A novel Tau11i isoform was previously found to be enriched in Alzheimer's disease (AD) brains. Further characterization showed that the 19-amino acid peptide encoded by retained intron 11 facilitates the formation of high-molecular-weight heterodimers and phase-separated liquid droplets, as well as enhances heparin-induced β-sheet aggregation and cellular seeding of Tau11i. Compared to full-length Tau441 isoform, expression of Tau11i in human neurons caused significant transcriptional changes that recapitulated single-cell molecular signatures of neurofibrillary tangle (NFT)-free excitatory AD neurons in the prefrontal cortex. Additionally, Tau11i-expressing neurons showed dysregulated levels of specific ribosomal proteins and p21. Unlike Tau441, Tau11i interacts with Pinin and Poly(A)-binding protein Cytoplasmic 1 (PABPC1) in cells lacking AD pathology, mimicking the sequestration of RNA-binding proteins (RBP) by pathological Tau in AD brains. Notably, PABPC1 colocalizes with Tau11i in AD temporal lobes and is enriched at the 3' untranslated regions of genes upregulated in Tau11i-expressing neurons. These findings suggest that Tau11i contribute to AD pathology by inducing neuronal senescence, pathological aggregation of RBPs, and transcriptional dysregulation that resembles the molecular signatures of NFT-free AD neurons.
Extracellular vesicle dysfunction contributes to synaptic and cognitive deficits in a mouse model of Angelman syndrome.
Penna E, Su W, Reece T … +5 more , Braga M, Shigemitsu H, Ta K, Baudry M, Bi X
Prog Neurobiol · 2026 Feb · PMID 41407260 · Publisher ↗
Angelman syndrome (AS) is a devastating neurodevelopmental disorder caused by deficiency of the maternally inherited UBE3A. It is characterized by severe cognitive impairment, motor dysfunction, seizures, and development...
Angelman syndrome (AS) is a devastating neurodevelopmental disorder caused by deficiency of the maternally inherited UBE3A. It is characterized by severe cognitive impairment, motor dysfunction, seizures, and developmental delays. Several mouse models of AS reproduce these debilitating features, including impaired memory function and synaptic plasticity, reduced dendritic spine density, and lysosomal alterations. Emerging research highlights the critical role of extracellular vesicles (EVs) in brain development and function, with growing evidence linking EV dysregulation to various neurological disorders. In this study, we first compared key features of EVs between wild-type (WT) and AS mice. EV secretion from forebrain synaptosomes was impaired in AS mice as compared to WT. Importantly, Ube3a was detected in EVs released from WT forebrain synaptosomes, suggesting a role for Ube3a in neuronal communication. We then identified TRPML1, a lysosomal ion channel, as a regulator of EV release and uptake, unveiling a novel molecular mechanism underlying EV dynamics. Furthermore, treatment with WT neuron-derived EVs significantly improved dendritic and spine morphology of cultured hippocampal neurons prepared from AS mice. Remarkably, systemic administration of WT brain-derived EVs restored hippocampal neuronal morphology and improved learning and memory in AS mice. These findings not only enhance our understanding of AS pathophysiology but also support EVs as a promising strategy for treating this currently incurable disorder.
NLRP3-mediated neuroinflammation in the ventrolateral orbital cortex contributes to the formation of morphine-induced addiction memory by upregulating GRIN3B.
Liu Y, Chen H, Guo Y … +14 more , Zhu L, Meng W, Jia W, Li C, Zhou D, Tu W, Zhang T, Yi S, Yao Z, Liu B, Wang C, Zhang R, Zhao B, Wei L
Prog Neurobiol · 2026 Feb · PMID 41401853 · Publisher ↗
Addiction is a prevalent adverse effect of opioid analgesics. Morphine, a frequently employed opioid analgesic in clinical practice, has been demonstrated to possess rewarding properties that contribute to the establishm...
Addiction is a prevalent adverse effect of opioid analgesics. Morphine, a frequently employed opioid analgesic in clinical practice, has been demonstrated to possess rewarding properties that contribute to the establishment of addiction memory. Morphine administration elicits the NOD-like receptor protein 3 (NLRP3)-mediated neuroinflammatory response. Neuroinflammation can modulate the expression of GRIN/NMDAR (glutamate ionotropic receptor NMDA type), a key determinant of synaptic plasticity and memory formation. For this reason, we performed morphine conditioned place preference test to observe the effects of behavioral training, inhibition of NLRP3, and Grin3b knockout on the formation of addiction memory. Repeated morphine administration caused NLRP3-relative neuroinflammation, increased GRIN3B protein expression, and contributed to the formation of addiction memory in a task-dependent manner. Inhibiting NLRP3 attenuated neuroinflammation, decreased astrocyte activation and GRIN3B levels, and inhibited the formation of morphine-induced addiction memory by altering synaptic structure. Knocking out Grin3b impeded the formation of addiction memory but did not alleviate neuroinflammation or glial cells activation. Our findings indicate that NLRP3-mediated neuroinflammation modulates synaptic plasticity and contributes to the formation of morphine-induced addiction memory through GRIN3B.
Ferroptosis in ischemic stroke: From a glia-neuron crosstalk perspective.
Zhang C, Cheng J, Yan X … +8 more , Zheng Y, Lan X, Zhao Y, Liu Y, Wu Y, Cheng F, Li C, Wang X
Prog Neurobiol · 2026 Feb · PMID 41390138 · Publisher ↗
Stroke is renowned for its high rates of disability and mortality. Ischemic stroke (IS), the most prevalent type, imposes a heavy burden on patients. In recent years, ferroptosis has garnered significant interest in the...
Stroke is renowned for its high rates of disability and mortality. Ischemic stroke (IS), the most prevalent type, imposes a heavy burden on patients. In recent years, ferroptosis has garnered significant interest in the field of neurological disease research and has been implicated in the pathophysiology of IS. This article provides a comprehensive review of the core mechanisms of ferroptosis. From the perspective of glia-neuron interactions, it explores iron metabolism, lipid peroxidation, and oxidative damage during IS, elucidating how these processes ultimately lead to ferroptosis and significant neuronal damage. Additionally, the emerging findings concerning the targets associated with ferroptosis in IS and related pharmacological therapies are described, thereby offering insights into innovative treatments for IS that focus on ferroptosis.
The YAP/SCAP/SREBP1 pathway in astrocytes: A novel target for treating neonatal hypoxic-ischemic encephalopathy.
Wang J, Dai C, Yuan H … +5 more , Tian Q, Xiao Q, Li X, Shi X, Dong Z
Prog Neurobiol · 2026 Feb · PMID 41390137 · Publisher ↗
Astrocytes play a significant role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE), contributing to neuroexcitotoxicity and inflammatory responses. However, the specific pathways through which astrocytes inf...
Astrocytes play a significant role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE), contributing to neuroexcitotoxicity and inflammatory responses. However, the specific pathways through which astrocytes influence neurons remain incompletely understood. In this study, we found that Yes-associated protein (YAP) was down-regulated and inactivated in hippocampal astrocytes in a hypoxic-ischemic brain damage (HIBD) rat model, as well as in astrocytes subjected to oxygen-glucose deprivation (OGD). Overexpression of YAP in astrocytes reduced neuronal death and improved motor, learning and memory dysfunction deficits associated with HIE. Further investigation demonstrated that YAP exerts neuroprotective effects by modulating lipid metabolism through the SCAP/SREBP1 pathway. Ultimately, activating YAP signaling by XMU-MP-1, a Hippo kinase MST1/2 inhibitor, partially restored brain tissue integrity and function, as well as improved motor, learning and memory functions in HIBD rats. In conclusion, our study has identified a novel YAP/SCAP/SREBP1 pathway that plays neuroprotective roles in HIE.
Place field dynamics in retrosplenial cortex compared to hippocampus.
Navratilova Z, Banerjee D, Muqolli F … +3 more , Zhang J, Gandhi SP, McNaughton BL
Prog Neurobiol · 2026 Feb · PMID 41386497 · Full text
The encoding, storage, and updating of memories in cortical networks are poorly understood. In retrosplenial cortex (RSC), cells respond to the animal's position as it traverses a real or virtual (VR) linear track. Most...
The encoding, storage, and updating of memories in cortical networks are poorly understood. In retrosplenial cortex (RSC), cells respond to the animal's position as it traverses a real or virtual (VR) linear track. Most position correlated cells (PCCs) in RSC require an intact hippocampus to form, but survive subsequent hippocampal damage. To examine whether RSC and hippocampal PCCs undergo remapping and spatial tuning development in parallel or sequentially, neuronal activity in RSC or CA1 was recorded using two-photon calcium imaging in mice running on VR tracks. RSC PCC activity underwent global remapping like CA1, with approximately the same dynamics of tuning development in the novel context. However, fields in RSC did not show place field expansion, in familiar or novel environments. Thus, while most properties of global remapping are shared between RSC and CA1, place field shift and expansion are notably restricted to hippocampus. Thus, our data suggests that RSC place specificity is either not 'inherited' directly from hippocampus or the hippocampal influence on RSC PCC formation may be restricted to hippocampal spikes occurring in the early phase of the theta rhythm (and thus late within the place field).
Developmental embedding of parvalbumin-positive interneurons drives local and crosshemispheric prefrontal gamma synchrony.
Offermanns A, Pöpplau JA, Hanganu-Opatz IL
Prog Neurobiol · 2026 Feb · PMID 41365479 · Publisher ↗
Gamma oscillations are critical for cortical cognitive processing. The ability to generate gamma oscillations evolves with age and requires cellular adjustments of the underlying neural networks. In the prefrontal cortex...
Gamma oscillations are critical for cortical cognitive processing. The ability to generate gamma oscillations evolves with age and requires cellular adjustments of the underlying neural networks. In the prefrontal cortex, gamma oscillations emerge relatively late compared to other cortical areas and the developmental mechanisms underlying the generation of adult-like gamma oscillations are poorly understood. Here, we combine in vivo electrophysiology and selective optogenetic manipulations of parvalbumin- (PV) and somatostatin-positive (SOM) interneurons in the mouse medial prefrontal cortex of both hemispheres along development to investigate their role for the age-dependent maturation of gamma oscillations. We show that crosshemispheric gamma synchrony strengthens with age, in line with the previously reported increase in local gamma power. The inhibitory effect of PV interneurons follows a similar timeline, enabling them to functionally operate within the classical gamma frequency range from adolescence onwards. In contrast, SOM interneurons have an age-independent inhibitory function, modulating beta-band oscillatory activity along development. These data identify the SOM to PV interneuron shift as a mechanism of gamma ontogeny and emergence of crosshemispheric synchrony in the developing prefrontal cortex.
Altered somatostatin receptor 3 expression and functional dysregulation in tuberous sclerosis complex.
Scheper M, Gaeta A, Ruffolo G … +10 more , Lissner LJ, Le Bihan M, Anink JJ, Jansen FE, van Hecke W, Mühlebner A, Schubert D, Mills JD, Palma E, Aronica E
Prog Neurobiol · 2026 Jan · PMID 41352576 · Publisher ↗
Somatostatin (SST), a neuropeptide primarily synthesized by GABAergic interneurons, modulates neuronal excitability and synaptic transmission through its interaction with somatostatin receptors (SSTRs). Dysregulation of...
Somatostatin (SST), a neuropeptide primarily synthesized by GABAergic interneurons, modulates neuronal excitability and synaptic transmission through its interaction with somatostatin receptors (SSTRs). Dysregulation of SST signaling has been implicated in neurodevelopmental disorders, including tuberous sclerosis complex (TSC). However, its precise role in these pathologies remains incompletely understood. We investigated SST and SSTR expression across diverse brain cell types in control and TSC cortical samples using single-cell RNA sequencing (scRNA-seq). We conducted functional assessments of SST signaling using electrophysiological recordings in Xenopus laevis oocytes microtransplanted with human brain membranes. We pharmacologically modulated SST receptor activity to elucidate receptor-specific effects on GABAergic transmission. scRNA-seq analysis revealed that SST expression is predominantly confined to GABAergic interneurons, while SSTR1 and SSTR2 exhibit strong expression in both glutamatergic and GABAergic neuronal populations. In TSC samples, SSTR5 was upregulated in GABAergic neurons, SSTR2 in glutamatergic neurons, while SSTR3 was downregulated in both glutamatergic neurons and microglia. Functional experiments demonstrated that SST enhances GABAergic currents in control tissues through a receptor-mediated mechanism involving protein kinase C activation. In contrast, SST application in TSC samples resulted in a significant suppression of GABAergic currents. Pharmacological inhibition of SSTR3 further exacerbated this effect, suggesting a compensatory role for this receptor subtype. Our findings reveal a disruption of SST signaling in TSC, contributing to altered coordination of excitatory-inhibitory activity and epileptogenesis. Targeting SST signaling may represent a therapeutic strategy for restoring inhibitory network function in TSC and related disorders.
Divergence of cortical neurophysiology across different neurodegenerative disorders compared to healthy ageing.
Trubshaw M, Kohl O, Gohil C … +18 more , van Es MWJ, Quinn AJ, Yoganathan K, Edmond E, Proudfoot M, Zokaei N, Raymont V, Pitt J, Thayanandan T, Thompson AG, Talbot K, Hu MT, Perquin MN, Kocagoncu E, Rowe JB, Woolrich MW, Nobre AC, Turner MR
Prog Neurobiol · 2026 Feb · PMID 41349953 · Full text
Neurodegenerative diseases involve disruption of healthy brain network communication occurring before the emergence of symptoms. Magnetoencephalography (MEG) is sensitive to the magnetic fields generated by cortical neur...
Neurodegenerative diseases involve disruption of healthy brain network communication occurring before the emergence of symptoms. Magnetoencephalography (MEG) is sensitive to the magnetic fields generated by cortical neuronal activity, and is the most spatio-temporally accurate method of directly assessing neuronal activity non-invasively. We used MEG to directly compare three neurodegenerative disorders with a large healthy cohort to characterise patterns of activity deviating from healthy ageing. Task-free MEG recordings were acquired from patients with Alzheimer's disease (AD, n = 29), Parkinson's disease (PD, n = 25), amyotrophic lateral sclerosis (ALS, n = 33) and healthy controls (HC, n = 191). Healthy ageing trajectories for metrics including spectral power (local neuronal recruitment), connectivity (long-range communication), 1/f exponent (power spectrum slope, which may reflect inhibition), and oscillatory speed were extracted. These metrics were compared pairwise between HC and patient groups, controlling for age and sex. The modelled trajectories of healthy ageing included increasing beta power and oscillatory speed, with reduced power spectrum slope. PD, AD, and ALS groups all showed reductions in beta power and slowing of oscillatory activity compared to matched HC. In AD, older patients showed lower beta power compared with younger patients. Compared with matched HC, the power spectrum slope was uniquely reduced in ALS, in contrast to the increase seen in PD and AD. Gamma connectivity increased in AD and ALS. MEG has unique potential as a source of biomarkers that might be used to detect deviation from healthy ageing if applied at an earlier presymptomatic stage of neurodegeneration than current tools permit. It might also provide outcome measures for prevention trials.
Respiratory coordination of excitability states across the human wake-sleep cycle.
Corzo AS, Tarrasó EB, Saltafossi M … +4 more , Berther T, Staudigl T, Kluger DS, Schreiner T
Prog Neurobiol · 2026 Jan · PMID 41349952 · Publisher ↗
While the respiratory rhythm is increasingly recognized as a key modulator of oscillatory brain activity across the wake-sleep cycle in humans, very little is known about its influence on aperiodic brain activity during...
While the respiratory rhythm is increasingly recognized as a key modulator of oscillatory brain activity across the wake-sleep cycle in humans, very little is known about its influence on aperiodic brain activity during sleep. This broadband activity indicates spontaneous fluctuations in excitation-inhibition (E:I) balance across vigilance states and has recently been shown to systematically covary across the respiratory cycle during waking resting state. We used simultaneous EEG and respiratory recordings over a full night of sleep collected from N = 23 healthy participants to unravel the nested dynamics of respiration phase-locked excitability states across the wake-sleep cycle. We demonstrate a robust phase shift in the coupling of aperiodic brain activity to respiratory rhythms as participants were transitioning from wakefulness to sleep. Moreover, respiration-brain coupling became more consistent both across and within participants, as interindividual as well as intraindividual variability systematically lessened from wakefulness and the transition to sleep towards deeper sleep stages. Our results suggest that respiration phase-locked changes in E:I balance conceivably add to sleep stage-specific neural signatures of REM and NREM sleep, highlighting the complexity of brain-body coupling during sleep.
Glycine and glycine transport control dendritic excitability and spiking.
Bohmbach K, Bauer V, Henneberger C
Prog Neurobiol · 2026 Jan · PMID 41297659 · Publisher ↗
Neuronal dendrites integrate excitatory input. They can perform local computations such as coincidence detection by amplifying synchronized local input and dendritic spiking. Extracellular glycine could be a powerful mod...
Neuronal dendrites integrate excitatory input. They can perform local computations such as coincidence detection by amplifying synchronized local input and dendritic spiking. Extracellular glycine could be a powerful modulator of such processes through its action as a co-agonist at glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype but also as a ligand of inhibitory glycine receptors (GlyRs). Similarly, glycine transporters (GlyTs), an emerging drug target for psychiatric and other diseases, could control dendritic integration through ambient glycine levels. Both hypotheses were tested at dendrites of CA1 pyramidal cells in acute hippocampal slices by pharmacologically analysing how glycine, GlyTs and GlyRs change the postsynaptic response to local dendritic excitatory input. Using microiontophoretic glutamate application, we found that glycine can indeed significantly increase dendritic excitability and dendritic spiking. We also uncovered that GlyTs are powerful modulators of dendritic spiking, which can limit the impact of glycine sources on CA1 pyramidal cells. Our experiments also revealed that GlyRs can have an opposite, inhibitory effect on the slow dendritic spike component. This directly demonstrates that glycine can dynamically enhance dendritic responsiveness to local input and promote dendritic spiking, while GlyTs and GlyRs have an opposing effect. Together, this makes glycinergic signalling a powerful modulator of the nonlinear integration of synaptic input in CA1 radial oblique dendrites.
The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases.
Lane-Donovan C, Paredes M, Kao AW
Prog Neurobiol · 2025 Dec · PMID 41253210 · Full text
In the last two decades, many gene mutations have been identified that when homozygous, lead to childhood neurological disorders, but when heterozygous, result in adult-onset neurodegenerative disease. A shared feature l...
In the last two decades, many gene mutations have been identified that when homozygous, lead to childhood neurological disorders, but when heterozygous, result in adult-onset neurodegenerative disease. A shared feature linking these genes? They encode proteins residing in or impacting the function of the lysosome, a key organelle in macromolecular degradation and recycling whose loss leads to the inability to manage proteostatic stress. Here, we propose that lysosomes connect a subset of genetic neurological and neurodegenerative disorders as they occur in two distinct life epochs-development and aging-that endure high levels of proteostatic and other physiological stresses. In this Perspective, we highlight the differing mechanisms of three genes that exemplify this link: glucocerebrosidase A (GBA: Gaucher's disease and Parkinson's disease), progranulin (GRN: neuronal ceroid lipofuscinosis and frontotemporal dementia), and tuberous sclerosis complex 1 (TSC1: tuberous sclerosis complex and frontotemporal dementia). We discuss why neurons seem particularly vulnerable to lysosomal dysfunction and ways in which lysosomes potentially contribute to selective neuronal vulnerability. Finally, as disrupted lysosomal catabolism of macromolecules connects these diseases of the nervous system, we propose that they be jointly conceptualized as "Lysosomal Clearance Disorders."
The neurobiology of major depressive disorder: Updates and perspectives from proteomics.
Spero V, D'Amelio S, Eligini S … +3 more , Molteni R, Banfi C, Cattaneo MG
Prog Neurobiol · 2025 Dec · PMID 41253209 · Publisher ↗
Major depressive disorder (MDD) is a widespread and disabling condition whose etiology and pathophysiology are not fully understood. Furthermore, pharmacological treatment of MDD poses challenging aspects, including dela...
Major depressive disorder (MDD) is a widespread and disabling condition whose etiology and pathophysiology are not fully understood. Furthermore, pharmacological treatment of MDD poses challenging aspects, including delayed therapeutic effects, ineffectiveness against the so-called "residual symptoms", and a high proportion of non-responder patients. On these bases, it is crucial to recognize the key molecular systems and mechanisms involved in the pathophysiology of MDD in order to improve diagnostic tools and develop more effective pharmacological strategies. In this context, proteomics is a highly effective tool for simultaneously identifying and quantifying a large number of proteins within biological samples. This review will describe and discuss proteomic data from stress-based experimental models of MDD as well as from human brains and bodily fluids (e.g., cerebrospinal fluid and plasma), with the aim of elucidating the neurobiological counterparts of this psychiatric disorder. These findings will be summarized in an attempt to provide comprehensive maps of the biological systems involved in MDD, offering new insights into the molecular basis of different disease subtypes and paving the way to personalized diagnostic and treatment strategies.
Effects of oxytocin receptor ligands on anxiogenic-like effect, social avoidance and changes on medial prefrontal cortex oxytocin receptor expression evoked by chronic social defeat stress in rats.
Canto-de-Souza L, Baptista-de-Souza D, Busnardo C … +1 more , Crestani CC
Prog Neurobiol · 2025 Dec · PMID 41238073 · Publisher ↗
We investigated the effect of systemic administration of the synthetic oxytocin (OXT) analog carbetocin and/or OXT receptor antagonists (atosiban and L-368,899) on social avoidance and anxiogenic-like effect in male rats...
We investigated the effect of systemic administration of the synthetic oxytocin (OXT) analog carbetocin and/or OXT receptor antagonists (atosiban and L-368,899) on social avoidance and anxiogenic-like effect in male rats subjected to chronic social defeat stress (cSDS). Effect of cSDS and pharmacological manipulation of OXT system on expression of OXT receptor within the medial prefrontal cortex (mPFC) subregions [anterior cingulate (Cg), prelimbic (PL) and infralimbic (IL) cortices] was also evaluated. Our behavioral results indicated that cSDS, while not inducing social avoidance in the social interaction test, reliably induced anxiogenic-like effect as measured by the elevated plus maze test. Chronic systemic treatment with either carbetocin or atosiban, but not L-368,899, during cSDS protocol dose-dependently prevented the anxiogenic-like effect. Both atosiban and L-368,899 inhibited the anxiolytic effect of carbetocin in defeated animals, confirming OXT receptor-mediated effect. Also, cSDS increased OXT receptor levels within the Cg, which was inhibited by both atosiban and L-368,899 treatments. Conversely, cSDS did not affect OXT receptor within the PL and IL. However, carbetocin treatment increased OXT receptor expression within the PL and IL of defeated animals, an effect that was blocked by either atosiban or L-368,899. Taken together, our study provides evidence for the critical role of the OXT system and its pharmacological manipulation in modulating anxiogenic-like effects evoked by social stress. Furthermore, the region-specific modulation of OXT receptor expression within the mPFC by stress and OXT system pharmacological manipulation emphasize the complex and dynamic nature of OXT receptor regulation in brain regions crucial for emotional processing.
Inhibiting the JAK-STAT3 pathway in nucleus accumbens astrocytes alleviates cocaine-induced motor hyperactivity.
Arnoux I, Capano A, Yakoubi R … +4 more , Boulogne C, Ezan P, Escartin C, Rouach N
Prog Neurobiol · 2025 Dec · PMID 41223924 · Publisher ↗
Cocaine use disorder is a significant global health issue, and despite its widespread impact, effective treatments are lacking. While research has largely focused on the underlying neuronal mechanisms, the role of astroc...
Cocaine use disorder is a significant global health issue, and despite its widespread impact, effective treatments are lacking. While research has largely focused on the underlying neuronal mechanisms, the role of astrocytes, key regulators of synaptic transmission and plasticity, remains underexplored. Using a multidisciplinary approach that combines immunohistochemistry, electron microscopy, 3D cell reconstruction, viral gene transfer, and behavioral assays, we investigated the early adaptive responses of astrocytes to repeated cocaine administration. We report that cocaine administration induces astrocyte reactivity in the nucleus accumbens, characterized by structural remodeling, reduced synaptic coverage, and upregulation of reactivity-associated markers, including STAT3. Furthermore, we demonstrated that the JAK/STAT3 signaling pathway plays a critical role in the pathological structural astrocytic responses and in the cocaine-induced motor behavior. Our findings highlight astrocytes as pivotal players in the initial neural adaptations underlying cocaine-induced behavior. These data may provide a basis for the development of novel therapeutic strategies targeting astrocytes to address the structural and functional disruptions associated with cocaine exposure.
D1-type dopamine receptors are critical for GABAergic synaptic plasticity in CA1 mouse hippocampal SST interneurons and pyramidal cells.
Brzdąk P, Lebida K, Droździel P … +3 more , Stefańczyk E, Leszczyńska A, Mozrzymas JW
Prog Neurobiol · 2025 Dec · PMID 41207425 · Publisher ↗
Dopamine modulates brain functions such as memory and learning, and studies into underlying mechanisms have been largely focused on glutamatergic synapses and their plasticity. Much less is known about the dopaminergic m...
Dopamine modulates brain functions such as memory and learning, and studies into underlying mechanisms have been largely focused on glutamatergic synapses and their plasticity. Much less is known about the dopaminergic modulation of inhibitory plasticity at synapses formed by distinct GABAergic interneurons targeting different cells. Herein, we addressed the role of D1-type dopamine receptors (D1Rs) in inhibitory plasticity at synapses between interneurons (INs) and pyramidal cells (PCs), as well as between INs in the CA1 region. Activation and blockade of D1Rs increased and reduced the mIPSCs amplitude (measured from PCs), respectively, while the decay kinetics was prolonged, indicating a complex postsynaptic mechanism. We also checked the D1Rs effect on heterosynaptic NMDA-induced inhibitory long-term potentiation (iLTP) measured at PCs and found that blockade of D1Rs converted iLTP into inhibitory long-term depression (iLTD), whereas D1Rs activation slightly diminished iLTP. NMDA-induced iLTP in synapses formed by parvalbumin- (PV) positive INs on PCs was reduced to zero by SKF, while SCH converted iLTP to iLTD. Interestingly, NMDA-induced iLTP in the somatostatin- (SST) positive INs was reversed to iLTD by both SKF and SCH, while these compounds were ineffective on baseline activity, and these effects were mirrored by changes in gephyrin clusters. Thus, the impact of D1Rs on inhibitory plasticity observed at the SST INs and PCs showed differences with respect to baseline activity, NMDA-induced plasticity, and the kinetics of synaptic currents. Altogether, we show that D1Rs modulate inhibitory long-term plasticity in a manner dependent on the presynaptic and target neurons.
Opposing interictal dynamics in Alzheimer's disease and epilepsy.
Lisgaras CP, Scharfman HE
Prog Neurobiol · 2026 Jan · PMID 41192537 · Full text
Advanced EEG technology has revealed that epileptiform activity occurs more frequently in Alzheimer's disease (AD) than previously recognized, prompting debate over the utility of EEG in AD diagnostics. Yet, unlike epile...
Advanced EEG technology has revealed that epileptiform activity occurs more frequently in Alzheimer's disease (AD) than previously recognized, prompting debate over the utility of EEG in AD diagnostics. Yet, unlike epilepsy, epileptiform activity is not always observed in AD, leading to skepticism. Historically, this absence has been attributed to limited recording depth or insufficient recording duration. We tested an alternative hypothesis that certain types of epileptiform activity, specifically high frequency oscillations (HFOs, defined as 250-500 Hz fast ripples), inhibit interictal spikes (IIS), which are currently used to assess hyperexcitability clinically. We recorded wideband (0.1-500 Hz) hippocampal local field potentials in three AD (Tg2576, Presenilin 2, Ts65Dn Down syndrome model) and two epilepsy (intrahippocampal kainic acid, pilocarpine) mouse models during wakefulness and sleep. In both AD and epilepsy, HFOs consistently outnumbered IIS across behavioral states, age and recording contact. However, IIS and HFOs showed divergent relationships: a negative correlation between their rates was observed only in AD, in contrast to a positive correlation in epilepsy. HFOs preceded IIS at much shorter intervals in epilepsy than in AD. Co-occurrence of IIS with ripples did not differ between AD and epilepsy. These findings reveal a novel dissociation between clinically-relevant EEG biomarkers in AD and epilepsy. In AD, HFOs may inhibit IIS, which could lead to underestimation of hyperexcitability and hinder patient stratification for anti-seizure therapies. While non-invasive HFO detection remains challenging, we stress the need for wideband EEG/MEG, particularly in AD, to assess the full extent of hyperexcitability and biomarker interactions that would otherwise remain undetected.
Lateralized visuotopic organization in the macaque superior colliculus revealed by fMRI.
Sepe A, Panormita M, Zhu Q … +5 more , Li X, Leopold DA, Tamietto M, Bonini L, Vanduffel W
Prog Neurobiol · 2025 Nov · PMID 41086941 · Full text
The superior colliculus (SC) integrates multisensory inputs from retinal, subcortical, and cortical regions within a map of visual space to support orienting and interactive behaviors. While early models suggested that t...
The superior colliculus (SC) integrates multisensory inputs from retinal, subcortical, and cortical regions within a map of visual space to support orienting and interactive behaviors. While early models suggested that the SC primarily represents peripheral space for target detection, recent evidence highlights its significant foveal representation, essential for precisely targeting objects. Using ultra-high-resolution phase-encoding fMRI and spatially localized stimuli, we mapped the visuotopic organization of the SC in six macaques up to 40° eccentricity. In addition to confirming previous findings, we identified consistent interhemispheric asymmetries in the fMRI signal. The left SC, unlike the right, displayed a clear eccentricity map with a smooth rostro-caudal progression of responses to stimuli of increasing eccentricity from the fovea to the periphery. Conversely, the right SC showed no evidence of a pronounced eccentricity map and, instead, it exhibited more prominent polar angle maps and spatially broader fMRI responses to peripheral stimuli compared to the left SC. These lateralized responses were consistent across stimulus types and imaging protocols and were mirrored only in the intraparietal sulcus, a major cortical input to the SC. The observed asymmetry may derive from differences in magnification factor, intercollicular or surround inhibition between the left and right SC. Regardless of the underlying mechanism, our results suggest that functional lateralization in nonhuman primates may be more prevalent than previously recognized.
Distinct Layer 6b transcriptomic subtypes parcellate the cortical mantle.
Kapustina M, Bristow BN, Cembrowski MS
Prog Neurobiol · 2025 Nov · PMID 41083138 · Publisher ↗
Layer 6b (L6b) neurons are a sparse population of deep neocortical neurons that govern both healthy and disordered brain states. L6b neurons have qualitatively been characterized as a thin lamina within the deepest layer...
Layer 6b (L6b) neurons are a sparse population of deep neocortical neurons that govern both healthy and disordered brain states. L6b neurons have qualitatively been characterized as a thin lamina within the deepest layer of the cerebral cortex, yet the precise cell-type-specific properties and spatial organization of these neurons across the cortical mantle remain unresolved. Here, we combine single-cell RNA sequencing, highly multiplexed fluorescent in situ hybridization, and single-cell spatial transcriptomics to comprehensively characterize L6b cell-type identity, molecular heterogeneity, and spatial organization. In doing so, we identify and spatially resolve multiple distinct L6b subtypes with unique molecular signatures. To investigate the spatial organization of these subtypes across the brain, we generated a single-cell spatial transcriptomics dataset comprising 450,496 cells, offering the most extensive spatial mapping of L6b subtypes to date. Using a data-driven approach to analyze this dataset, we identify that the spatial patterning of L6b varies across the cortical mantle according to a patchwork-like composition of subtypes, which can notably extend beyond the classically defined deep location of L6b for some subtypes. We also find that L6b neurons can be transcriptionally separable but spatially intermingled with Layer 6a neurons, illustrating that a deep location within the cortex is neither sufficient nor necessary for assessing L6b identity. Our work provides the most comprehensive cellular phenotyping of L6b to date, reveals a cell-type-specific spatial-molecular framework for interpreting L6b properties and function, and will guide future investigations on the role of L6b cell subtypes and molecules in brain health and disorder.
Evidence for the involvement of a fronto-striatal pathway in the processing of social reward.
Lin K, Coutellier L
Prog Neurobiol · 2025 Nov · PMID 41072650 · Publisher ↗
Social interactions are a hallmark of animal behavior and is essential for survival, cooperation, and reproduction. Despite its necessity, the neural mechanisms that drive social behavior, particularly the rewarding natu...
Social interactions are a hallmark of animal behavior and is essential for survival, cooperation, and reproduction. Despite its necessity, the neural mechanisms that drive social behavior, particularly the rewarding nature of social interactions, are not fully understood. Social behaviors are inherently rewarding, and this intrinsic value plays a key role in reinforcing and shaping social engagement. A growing body of work has sought to quantify social reward in rodents using behavioral paradigms such as social conditioned place preference and operant social motivation tasks, offering translational tools to probe underlying circuit mechanisms. Historically, this research has centered on the mesolimbic dopamine pathway, particularly the ventral tegmental area and its projections to the nucleus accumbens. However, emerging evidence supports a complementary role for prefrontal cortical (PFC) circuits in modulating social motivation and reward. The PFC integrates contextual and social information via distinct neuronal populations and exerts top-down control over behavior through its projections to subcortical targets such as the ventral striatum (vSTR). While prior research has implicated the PFC-vSTR pathway in general aspects of social behavior, its specific contribution to the encoding of social reward remains poorly defined. Here, we synthesize existing findings and propose a novel mechanism in which prefrontal parvalbumin (PV) interneurons regulate social reward by modulating PFC-vSTR output. We further consider how neuromodulators such as oxytocin and dopamine interact with this circuit to further influence social behavior. Elucidating the microcircuit-level control of social reward has significant implications for neuropsychiatric disorders, including autism spectrum disorder and schizophrenia, where social motivation and reward processing are often disrupted.
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