Progress In Neurobiology[JOURNAL]
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200 papers
BNST-projecting histaminergic circuits mediate state-dependent anxiety behavior through post-synaptic histamine H3 receptors on GABAergic neurons.
Lin W, Zhu X, Yu X … +7 more , Xia Q, Yan M, Li Y, Zheng Y, Wang Y, Cheng H, Chen Z
Prog Neurobiol · 2025 Oct · PMID 41046120 · Publisher ↗
Understanding the precise mechanisms underlying anxiety and anxiety disorders is crucial for identifying novel interventions. In this study, we report a histaminergic circuit targeting the bed nucleus of the stria termin...
Understanding the precise mechanisms underlying anxiety and anxiety disorders is crucial for identifying novel interventions. In this study, we report a histaminergic circuit targeting the bed nucleus of the stria terminalis (BNST) that mediates anxiety-like behavior in mice. First, we observed a significant decrease in both histamine signaling and histaminergic fiber activity in the BNST when mice entered an anxious environment. Selective modulation of the BNST-projecting histaminergic circuit mediated state-dependent anxiety behaviors: activation directly induced an anxiogenic effect on naive mice, while inhibition produced a significant anxiolytic effect in mice in an anxious state rather than normal state. Pharmacological intervention revealed that the inhibition of histamine H3 receptors (H3Rs), rather than histamine H1 receptors (H1Rs) or histamine H2 receptors (H2Rs), in the BNST abolished the anxiogenic effect of histaminergic circuit activation. Finally, through optogenetic manipulation of spatial-specific H3Rs, we identified a critical role for anxiety regulation by post-synaptic H3Rs in the BNST GABAergic neurons, rather than pre-synaptic H3Rs from upstream inputs. Together, our results revealed a histaminergic circuit targeting the BNST that mediates state-dependent anxiety-like behaviors through post-synaptic H3Rs. These findings provide new insights into the mechanism of anxiety and offer promising avenues for discovering novel pharmacological targets for the treatment of anxiety disorders.
NEIL3 shapes hippocampal network dynamics and fear memory through modulation of PV interneurons.
Fernandez-Berrocal MS, Døskeland DS, Saasen VL … +9 more , Bugaj AM, Kunath N, Heggedal M, Munir M, Marthinsen RC, Ekeli MD, Scheffler K, Bjørås M, Ye J
Prog Neurobiol · 2025 Oct · PMID 41015225 · Publisher ↗
The dynamic balance between excitatory and inhibitory (E/I) signaling is critical for hippocampal network function and memory processing. Here, we uncover a novel role for the DNA glycosylase Endonuclease VIII-like 3 (NE...
The dynamic balance between excitatory and inhibitory (E/I) signaling is critical for hippocampal network function and memory processing. Here, we uncover a novel role for the DNA glycosylase Endonuclease VIII-like 3 (NEIL3) in maintaining this E/I balance through its impact on parvalbumin-positive (PV⁺) GABAergic interneurons. NEIL3 deficiency leads to a selective reduction in PV⁺ interneurons and impaired perineuronal net (PNN) integrity, likely contributing to further PV⁺ neuron dysfunction. These changes result in altered hippocampal oscillatory dynamics, including increased beta and low gamma power, and reduced high gamma and ripple activity. These network alterations are accompanied by distinct effects on fear memory, as demonstrated using contextual and trace fear conditioning paradigms. NEIL3-deficient mice exhibited enhanced extinction of contextual fear memory but impaired extinction of trace fear memory. These findings suggest that the integrity of inhibitory networks plays differential roles in the spatial versus temporal aspects of fear memory extinction. Transcriptomic analysis further reveals dysregulation of genes involved in glutamatergic and GABAergic signaling. Among these, Gabra2 showed a marked downregulation, potentially driven by changes in promoter DNA methylation. This work identifies NEIL3 as an important regulator of the hippocampal inhibitory network, linking PV interneuron integrity and oscillatory coordination to distinct memory outcomes, and offers potential mechanistic insight into processes that may contribute to cognitive deficits in disorders characterized by E/I imbalance.
Transcriptomic shifts in Microtus ochrogaster neurogenic niches reveal psychiatric-risk pathways engaged by pair-bond formation.
Ávila-González D, Lugo-Baca J, Camacho-Barrios F … +5 more , Castro AE, Arzate DM, Paredes-Guerrero R, Díaz NF, Portillo W
Prog Neurobiol · 2025 Oct · PMID 40972807 · Publisher ↗
Pair bonding (PB) is a stable affiliative relationship that confers profound behavioral and physiological advantages. The prairie vole (Microtus ochrogaster), one of the few socially monogamous mammals, provides a tracta...
Pair bonding (PB) is a stable affiliative relationship that confers profound behavioral and physiological advantages. The prairie vole (Microtus ochrogaster), one of the few socially monogamous mammals, provides a tractable model for dissecting the neurobiological substrates of social interactions. We previously showed that social co-habitation with mating (SCM) increases cell proliferation and neuronal differentiation in the subventricular zone (SVZ) and dentate gyrus (DG), implicating adult neurogenesis in bond formation. Here, we characterized the underlying molecular programs by bulk RNA-seq of the SVZ, DG and nucleus accumbens (NAc) at two time points, 48 h and 120 h, following SCM or isolated (control) housing. Across ∼ 18000 expressed genes, 286 differentially expressed genes (DEGs) emerged in the female SVZ and 540 in the females DG (120 h vs 48 h SCM), whereas male niches displayed markedly fewer transcriptional shifts, confirming pronounced sexual dimorphism. Gene ontology analysis revealed sustained upregulation of mitochondrial and oxidative-phosphorylation modules, coupled with downregulation of neurogenesis, synaptic plasticity, and cell migration pathways in females at 120 h. In vitro, SVZ-derived neurospheres from females mirrored these signatures: SCM increased the sphere number at 48 h, but neuronal output normalized by 120 h, indicating a transient neurogenic surge. Numerous zinc-finger transcripts and unannotated long non-coding RNAs were also regulated, hinting at vole-specific epigenetic controls. Strikingly, > 100 DEGs mapped to human psychiatric-risk loci. Autism disorder spectrum (ADS) and schizophrenia-associated orthologues (e.g., GRIN2A/B, KMT2A, UBE3A) were predominantly downregulated during bond consolidation in females, whereas isolation elevated major depressive disorder (MDD) markers (e.g., CACNA1H) in both sexes. These data suggest that pair-bond formation recruits transcriptional networks that overlap the genetic architecture of neuropsychiatric diseases, and that social isolation elicits an opposing, disorder-linked profile. Together, our results identified sex-specific, temporally phased molecular pathways that couple adult neurogenesis, energy metabolism, and psychiatric-risk gene networks to the establishment of enduring social bonds.
Neural entrainment by speech in human auditory cortex revealed by intracranial recordings.
Akkol S, Mishra A, Markowitz N … +6 more , Espinal E, Keshishian M, Mesgarani N, Schroeder C, Mehta AD, Bickel S
Prog Neurobiol · 2025 Oct · PMID 40930211 · Full text
Humans live in an environment that contains rich auditory stimuli, which must be processed efficiently. The entrainment of neural oscillations to acoustic inputs may support the processing of simple and complex sounds. H...
Humans live in an environment that contains rich auditory stimuli, which must be processed efficiently. The entrainment of neural oscillations to acoustic inputs may support the processing of simple and complex sounds. However, the characteristics of this entrainment process have been shown to be inconsistent across species and experimental paradigms. It is imperative to establish whether neural activity in response to speech is a result of combination of simple evoked responses or of entrainment of neural oscillations in human participants. In this study, 12 participants with intracranial electrodes listened to natural speech and neural entrainment as evidenced by oscillatory activity persisting beyond the evoked responses was assessed. Neural activity was recorded from 165 contacts in Heschl's gyrus and superior temporal gyrus. First, acoustic edges in the speech envelope induced coherence between speech and auditory cortex activity. Further, entrainment in the theta-alpha band outlasted the acoustic stimulation. This activity exceeded what could be expected from a simple evoked response. These findings suggest that speech has the potential to entrain neural oscillations in the human auditory cortex.
PDGFR mediates lumbar spinal stenosis-induced neuropathic pain by regulating JAK2/STAT3 signaling in activated macrophages.
Seo KJ, Park CS, Park MS … +3 more , Na WH, Lee JY, Yune TY
Prog Neurobiol · 2025 Oct · PMID 40914343 · Publisher ↗
Lumbar spinal stenosis (LSS) is one of the most common spinal disorders in elderly people and is often accompanied by neuropathic pain. Although our previous studies have demonstrated that infiltrating macrophage contrib...
Lumbar spinal stenosis (LSS) is one of the most common spinal disorders in elderly people and is often accompanied by neuropathic pain. Although our previous studies have demonstrated that infiltrating macrophage contribute to chronic neuropathic pain in LSS rat model, the molecular mechanisms underlying macrophage activation and infiltration have not been fully elucidated. In this study, we examined the critical role of platelet-derived growth factor receptor (PDGFR) signaling pathway in neuropathic pain associated with macrophage infiltration and activation in LSS rats. The LSS rat model was induced by cauda equina compression using a silicone block placed within the epidural spaces of the L5-L6 vertebrae, with neuropathic pain developing four weeks after compression. We found that the PDGFR and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathways were upregulated in infiltrated macrophages at 28 days in the LSS model. Administration of the PDGFR inhibitor imatinib significantly alleviated LSS-induced macrophages activation and infiltration. Imatinib also reduced LSS-induced chronic mechanical allodynia and inhibited the expression of inflammatory mediators including tumor necrosis factor alpha (TNF-α), interleukin beta (IL-1β), interleukin 6 (IL-6), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Furthermore, imatinib significantly alleviated the activation of RAW 264.7 macrophage cell line by lipopolysaccharide (LPS). These findings suggest that PDGFR signaling mediates neuropathic pain by promoting macrophage infiltration and activation following cauda equina compression and may serve as a potential therapeutic target for neuropathic pain in LSS patients.
Rodent models of Alzheimer's disease: Critical analysis of current hypotheses and pathways for future research.
Singhaarachchi PH, Antal P, Calon F … +13 more , Culmsee C, Delpech JC, Feldotto M, Geertsema J, Hoeksema EE, Korosi A, Layé S, McQualter J, de Rooij SR, Rummel C, Slayo M, Sominsky L, Spencer SJ
Prog Neurobiol · 2025 Sep · PMID 40886908 · Publisher ↗
Alzheimer's disease (AD) was first described over a century ago. However, the mechanisms underlying the disease are not well understood to this day. This has negatively impacted our ability to create animal models to des...
Alzheimer's disease (AD) was first described over a century ago. However, the mechanisms underlying the disease are not well understood to this day. This has negatively impacted our ability to create animal models to design and test targeted reliable treatments for the disease. Amyloid β plaque accumulation, aggregation of neurofibrillary tangles, neuroinflammation, neurodegeneration, and, of course, cognitive decline, are few of the many observed pathological features associated with AD. However, there is a concern that the animal models of AD that are based on these frameworks may not be accurately representing AD in people. As such, the results from preclinical trials have not historically translated well to the clinic. In this article, we review the current major hypotheses to describe AD; we outline the major strengths and weaknesses of the commonly used rodent models used to replicate features of these hypotheses; and we provide a strategy for the field for future research.
Stimulus-driven rivalry among V1 neurons.
Wang J, Zhang R, Cai X … +3 more , Tang R, Dai Z, Lu HD
Prog Neurobiol · 2025 Nov · PMID 40846288 · Publisher ↗
Binocular rivalry (BR) is a fascinating phenomenon in which the presentation of two different images to each eye leads to alternating perceptual experiences. During BR, cortical activation is influenced by both stimulus-...
Binocular rivalry (BR) is a fascinating phenomenon in which the presentation of two different images to each eye leads to alternating perceptual experiences. During BR, cortical activation is influenced by both stimulus-related factors (e.g., image incongruence) and top-down cognitive processes such as attention. Disentangling the contributions of these factors has remained a challenge. Anesthetized animal models offer a unique opportunity to isolate purely stimulus-driven neural activity, eliminating confounds from higher cognitive and behavioral processes. Using two-photon calcium imaging, we recorded neuronal responses to BR stimuli in areas V1 and V2 of anesthetized macaques. We found that under BR stimulation, V1 neurons exhibited ongoing response fluctuations whose magnitude varied across cells and closely resembled activity patterns during physical stimulus alternation (SA). Key characteristics of these fluctuations mirrored those typical of perceptual BR. The strength of fluctuation in individual neurons correlated with their ocular dominance and orientation selectivity. Similar patterns observed in V2 suggest that such rivalry-like activity propagates along the visual hierarchy. Together, these results demonstrate that early sensory mechanisms in V1 can generate BR-like alternations independently of conscious processing.
Auditory regulation of hippocampal locomotion circuits by a non-canonical reticulo-limbic pathway.
Winne J, Nascimento G, Pedrosa R … +5 more , Nogueira M, Simões CS, Kullander K, Leão KE, Leão RN
Prog Neurobiol · 2025 Sep · PMID 40816704 · Publisher ↗
The ability to rapidly detect and respond to unexpected auditory stimuli is critical for adaptive behavior, especially during locomotion. Since movement suppresses auditory cortical activity, it remains unclear how salie...
The ability to rapidly detect and respond to unexpected auditory stimuli is critical for adaptive behavior, especially during locomotion. Since movement suppresses auditory cortical activity, it remains unclear how salient auditory information influences locomotor circuits. In this work, using in vivo calcium imaging, electrophysiology, chemo- and optogenetics, we investigate the path that relays loud broadband sounds to the dorsal hippocampus (dHPC) and modulates theta oscillations. We demonstrate that noise accelerates theta frequency and decreases its power, effects mediated by entorhinal cortex (EC) and medial septum (MS) inputs while independent of the primary auditory cortex. Activation of dorsal cochlear nucleus (DCN) neurons projecting to the pontine reticular nucleus (PRN) mimics noise-driven hippocampal responses, supporting a brainstem-limbic auditory processing route. Furthermore, noise selectively modulates CA1 pyramidal neuron and interneuron activity, reflecting diverse circuit dynamics. Finally, loud broadband noise stimulus increased theta coherence between the dHPC and the medial prefrontal cortex (mPFC), enhancing interregional synchronization. These results highlight the mechanisms in which the DCN filters behaviorally relevant sounds promoting acoustic motor integration in the hippocampus during locomotion, without direct influence of the auditory cortex.
Eye movements organize excitability state, information coding and network connectivity in the human hippocampus.
Leszczynski M, Espinal E, Smith E … +3 more , Schevon C, Sheth S, Schroeder CE
Prog Neurobiol · 2025 Sep · PMID 40816703 · Publisher ↗
Natural vision is an active sensing process that entails frequent eye movements to sample the environment. Nonetheless vision is often studied using passive viewing with eye position held constant. Using closed-loop eye-...
Natural vision is an active sensing process that entails frequent eye movements to sample the environment. Nonetheless vision is often studied using passive viewing with eye position held constant. Using closed-loop eye-tracking, with saccade-contingent stimulation and simultaneous intracranial recordings in surgical epilepsy patients, we tested the critical role of eye movement signals during natural visual processing in the hippocampus and hippocampal-amygdala circuit. Prior work shows that saccades elicit phase reset of ongoing neural excitability fluctuations across a broad array of cortical and subcortical areas. Here we show that saccade-related phase reset systematically modulates neuronal ensemble responses to visual input, enables phase-coding of information across the saccade-fixation cycle and modulates network connectivity between hippocampus and amygdala. The saccade-fixation cycle thus emerges as a fundamental sampling unit, organizing a range of neural operations including input representation, network connectivity and information coding. SUMMARY: Saccade-fixation cycle: a fundamental sampling unit, organizing input representation, information coding and network coordination.
Npas4 drives the effects of early social isolation on social behaviors and prefrontal parvalbumin neurons.
Jindal K, Ringland A, Fitzcharles S … +3 more , Redd C, Wheeler DG, Coutellier L
Prog Neurobiol · 2025 Sep · PMID 40812746 · Publisher ↗
Social behaviors mature during the adolescent period. Prefrontal parvalbumin (PV) neurons have been shown to play a critical role in this process, and their deregulation by early social isolation leads to social deficits...
Social behaviors mature during the adolescent period. Prefrontal parvalbumin (PV) neurons have been shown to play a critical role in this process, and their deregulation by early social isolation leads to social deficits in adulthood. However, the molecular mechanisms by which early social isolation affects prefrontal PV neurons causing social impairments remain unclear. Here, we identified the neuronal-specific transcription factor Npas4 as a key player in this process. We first showed that social isolation results in aberrant adolescent developmental trajectories of Npas4 and PV expression in the prefrontal cortex (PFC) leading to prolonged downregulation of Npas4 and upregulation of PV, suggesting an Npas4-driven over-inhibition of prefrontal circuits following early social isolation. Using Npas4 knockout (KO) mice and iDISCO whole brain cFos mapping, we then further implicated Npas4-dependent reduction in prefrontal activity with appearance of sociability deficits in adulthood: Npas4 KO mice failed to show an age-increase in sociability and in activity of the anterior cingulate cortex (ACC) that we observed in wild-type mice during the transition from adolescence to adulthood. Finally, using a viral approach to restore prefrontal Npas4 expression during early adolescence, we were able to rescue the sociability deficits and aberrant expression of PV in the AAC induced by social isolation. Altogether, our findings identified Npas4 as a novel molecular mediator of early social isolation on social deficits, through the role it plays on the adolescent maturation of prefrontal PV neurons.
Interplay between circadian rhythms and epigenetics in neural stem cells and Alzheimer's disease.
Cunha Alves T, Musílek K, Monti B
Prog Neurobiol · 2025 Sep · PMID 40784542 · Publisher ↗
The circadian clock, as a molecular timekeeper, influences most behavioural and physiological processes. Numerous symptoms associated with neurodegenerative diseases, such as sleep disorders, anxiety, and mood alteration...
The circadian clock, as a molecular timekeeper, influences most behavioural and physiological processes. Numerous symptoms associated with neurodegenerative diseases, such as sleep disorders, anxiety, and mood alteration, are linked to circadian clock dysregulation. Dysregulation of the circadian system is increasingly implicated in the onset and progression of Alzheimer's disease, and emerging evidence highlights a bidirectional relationship between Alzheimer's disease and circadian clock disruption. A crucial point is that the circadian clock regulates adult neurogenesis, a process that is significantly impaired in Alzheimer's disease. Recent advancements suggest that the dynamic epigenetic mechanisms-including DNA and histone modifications as well as regulation by non-coding RNA-act as a critical regulation for circadian rhythms and neurogenesis. Therefore, research on circadian disruption and, particularly, focus on harmonising the circadian clock with neurogenesis in neurodegenerative diseases may also speed up the creation of innovative, circadian-based treatments to counteract the progress of neurological disorders from a new perspective. In this review, we explore potential epigenetic mechanisms linking the circadian system to neurodegenerative diseases, with a focus on Alzheimer's Disease.
Cortical hyperexcitability drives dying forward amyotrophic lateral sclerosis symptoms and pathology in mice.
Haidar M, Viden A, Daniel C … +17 more , Cuic B, Wang T, Rosier M, Tomas D, Mills SA, Govier-Cole A, Djouma E, Perera ND, Luikinga S, Rytova V, Barton SK, Gonsalvez DG, Palmer LM, McLean C, Kiernan MC, Vucic S, Turner BJ
Prog Neurobiol · 2025 Sep · PMID 40784541 · Publisher ↗
Degeneration of both upper motor neurons in the brain and lower motor neurons in the spinal cord defines amyotrophic lateral sclerosis (ALS), but how they are linked in ALS pathophysiology is unclear. Here, we uncover a...
Degeneration of both upper motor neurons in the brain and lower motor neurons in the spinal cord defines amyotrophic lateral sclerosis (ALS), but how they are linked in ALS pathophysiology is unclear. Here, we uncover a cortical origin of neurodegeneration in ALS mediated by upper motor neuron hyperexcitability. Chronic hyperexcitability of upper motor neurons induced by excitatory chemogenetics in healthy adult mice induced progressive motor deficits, weakness and core pathological hallmarks of ALS, including upper motor neurons loss, synaptic pathology, corticospinal tract degeneration and reactive gliosis. Importantly, upper motor neuron hyperexcitability and loss were sufficient to drive degeneration of lower motor neurons and their distal axons and neuromuscular junctions, associated with astrocyte and microglial activation in spinal cord. Cortical hyperexcitability also triggered cytoplasmic TAR DNA binding protein 43 (TDP-43) aggregation in upper motor neurons and lower motor neurons, placing hyperexcitability upstream of TDP-43 proteinopathy in ALS. These findings establish a cortical origin of ALS mediated by upper motor neurons, consistent with an anterograde mechanism of neurodegeneration throughout the central and peripheral nervous systems.
NCAM2 promotes targeting of APP from the cell surface to BACE1-containing recycling endosomes.
Pfundstein G, Keable R, Hu S … +5 more , Al-Hadi M, Baker M, Schachner M, Leshchyns'ka I, Sytnyk V
Prog Neurobiol · 2025 Aug · PMID 40721030 · Publisher ↗
Convergence of amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) in endosomes initiates the production of amyloid-β (Aβ) peptides that accumulate in brains of Alzheimer's disease patients. APP and...
Convergence of amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) in endosomes initiates the production of amyloid-β (Aβ) peptides that accumulate in brains of Alzheimer's disease patients. APP and BACE1 are segregated in neurons, and mechanisms triggering their convergence have remained poorly understood, limiting therapeutic attempts to reduce Aβ production. Neural cell adhesion molecule 2 (NCAM2) is a cell surface localized protein, which increases Aβ levels via mechanisms that are not known. We show that APP binds to the extracellular domain of NCAM2. The intracellular domain of NCAM2 binds to the Rab11 adaptor protein Rab11-FIP5. The NCAM2/APP complex is endocytosed from the cell surface and targeted to BACE1-containing Rab11-positive recycling endosomes where it is processed. Convergence of APP with BACE1 is increased in transfected CHO cells and neurons expressing NCAM2. Consequently, the levels of amyloidogenic APP cleavage products are increased in cells expressing NCAM2. In NCAM2-deficient neurons, APP accumulates at the cell surface and in early endosomes, and APP levels in recycling endosomes are reduced. Aβ production is increased by Aβ oligomers and neuronal activity, and we show that the binding of NCAM2 to APP is increased in neurons treated with Aβ oligomers or after activation of synaptic NMDA receptors. Together, our data indicate that NCAM2 binds to APP and promotes APP targeting from the neuronal cell surface to recycling endosomes where APP is cleaved by BACE1. This novel mechanism regulating the convergence of APP and BACE1 in neurons can contribute to Aβ accumulation in Alzheimer's disease.
Astrocyte-interneuron interplay tunes neuronal excitability by enhancing the slow Ca -activated K current.
Expósito S, Alberquilla S, Martín ED
Prog Neurobiol · 2025 Aug · PMID 40681082 · Publisher ↗
Neurons have the unique ability to integrate synaptic information by modulating the function of the voltage-gated membrane ion channels, which govern their excitability. Astrocytes play active roles in synaptic function,...
Neurons have the unique ability to integrate synaptic information by modulating the function of the voltage-gated membrane ion channels, which govern their excitability. Astrocytes play active roles in synaptic function, from synapse formation and maturation to plasticity processes. However, it remains elusive whether astrocytes can impact the neuronal activity by regulating membrane ionic conductances that control the intrinsic firing properties. Here, we found that astrocytes enhance the slow Ca-activated K current (sIAHP) in CA1 hippocampal pyramidal neurons through the release of adenosine. Remarkably, our results indicate that interneuron activity plays a crucial role in this astrocyte-mediated modulation of sIAHP. Specifically, optogenetically stimulated hippocampal interneurons were found to evoke coordinated signaling between astrocytes and pyramidal neurons, relying on the activation of GABA and adenosine A1 receptors. In addition, the selective genetic ablation of GABA receptors in CA1 astrocytes prevented the potentiation of sIAHP and spike frequency adaptation in pyramidal cells following interneuron activation. Therefore, our data reveal the capability of astrocytes to modulate the intrinsic membrane properties that dictate neuronal firing rate, which in turn governs hippocampal network activity.
Cell-type-specific cholinergic control of granular retrosplenial cortex with implications for angular velocity coding across brain states.
Jedrasiak-Cape I, Rybicki-Kler C, Brooks I … +6 more , Ghosh M, Brennan EKW, Kailasa S, Ekins TG, Rupp A, Ahmed OJ
Prog Neurobiol · 2025 Aug · PMID 40639485 · Full text
Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving working memory, path integration, and head directio...
Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving working memory, path integration, and head direction encoding. The granular retrosplenial cortex (RSG) is important for spatially-guided behaviors, but how acetylcholine impacts RSG neurons is unknown. Here, we show that a transcriptomically, morphologically, and biophysically distinct RSG cell-type - the low-rheobase (LR) neuron - has a very distinct expression profile of cholinergic muscarinic receptors compared to all other neighboring excitatory neuronal subtypes. LR neurons do not fire persistently in response to cholinergic agonists, in stark contrast to all other principal neuronal subtypes examined within the RSG and across midline cortex. This lack of persistence allows LR neuron models to rapidly compute angular head velocity (AHV), independent of cholinergic changes seen during navigation. Thus, LR neurons can consistently compute AHV across brain states, highlighting the specialized RSG neural codes supporting navigation.
Tcf4 Deficiency causes recurrent seizures in mice.
Craciun L, DeNittis VR, Davis MT … +2 more , Paz JT, Saijo K
Prog Neurobiol · 2025 Aug · PMID 40619119 · Full text
Transcription factor 4 (TCF4) is essential for the normal development and function of the central nervous system. Haploinsufficiency of TCF4 due to deletions or mutations causes Pitt-Hopkins Syndrome (PTHS), a lifelong n...
Transcription factor 4 (TCF4) is essential for the normal development and function of the central nervous system. Haploinsufficiency of TCF4 due to deletions or mutations causes Pitt-Hopkins Syndrome (PTHS), a lifelong neurodevelopmental disorder characterized by seizures, autism, and intellectual disability. Previous studies have shown that various mutations, including deletion of exon 4 in the mouse Tcf4 gene in neural progenitors, neurons, or oligodendrocytes, did not reproduce the seizure phenotype. Here, we report that mice with a heterozygous deletion of Tcf4 in Aldehyde Dehydrogenase 1 Family Member L1 (Aldh1l1)-expressing cells-which resulted in approximately 60 % reduced Tcf4 expression in astrocytes and a 35 % reduction in other cell types, including neurons and oligodendrocytes-developed astrogliosis as early as postnatal day 4, followed by severe recurrent seizures beginning at three months of age or later, and exhibited shortened lifespans. Additionally, these mice showed increased neuronal activity in the cortex, hippocampus, amygdala, and hypothalamus in adulthood. Furthermore, single-nucleus RNA sequencing revealed widespread gene expression changes, including genes associated with epilepsy, in excitatory neurons, inhibitory neurons, astrocytes, and oligodendrocytes in our PTHS mouse model compared to wild-type controls. Overall, this is the first report of a PTHS mouse model exhibiting seizures, providing a valuable tool to investigate the mechanisms underlying PTHS pathogenesis and to develop therapies for PTHS and its associated epilepsy.
Cell types implement multiple coding schemes in distinct prefrontal cortex areas during goal-directed behavior.
Ceccarelli F, Ferrucci L, Londei F … +7 more , Arena G, Siano F, Di Bello F, Ramawat S, Tsujimoto S, Brunamonti E, Genovesio A
Prog Neurobiol · 2025 Aug · PMID 40609621 · Publisher ↗
Goal-directed behavior in complex environments relies on prefrontal (PF) microcircuits to generate, maintain in working memory (WM) and monitor choices. However, the cellular mechanisms underlying WM and choice monitorin...
Goal-directed behavior in complex environments relies on prefrontal (PF) microcircuits to generate, maintain in working memory (WM) and monitor choices. However, the cellular mechanisms underlying WM and choice monitoring remain conflictual and poorly understood. We investigated how distinct cell types represent choice, examining both coding magnitude and temporal coding schemes to distinguish between static and dynamic schemes across dorsolateral (PFdl), orbital (PFo), and frontopolar (PFp) prefrontal cortex in two macaques performing a Cued Strategy task. We consistently observed in putative interneurons both a higher coding magnitude than putative pyramidal neurons and a dynamic coding scheme across the PF areas. However, putative pyramidal neurons showed heterogeneous coding schemes, which in PFdl shifted from static to dynamic from WM to monitoring. PFo showed a similar dynamic scheme, and PFp was the only area with a static scheme during monitoring. Our results reveal rich population dynamics in PF microcircuits governed by pyramidal neurons.
FKBP5 deficiency selectively impairs NMDAR-dependent long-term depression via enhanced calcineurin activity: Implications for stress resilience.
Zhang S, Jeon YJ, Han JS … +2 more , Park H, Chung C
Prog Neurobiol · 2025 Aug · PMID 40578604 · Publisher ↗
The co-chaperone FK506 binding protein 51 (FKBP5) is known to negatively regulate glucocorticoid receptors (GRs), and its genetic polymorphisms have been implicated in stress resilience in clinical studies. FKBP5-deficie...
The co-chaperone FK506 binding protein 51 (FKBP5) is known to negatively regulate glucocorticoid receptors (GRs), and its genetic polymorphisms have been implicated in stress resilience in clinical studies. FKBP5-deficient animals are known to exhibit stress resilience, but minimal alterations in synaptic transmission were observed in the hippocampus. Given the crucial role of the hippocampus in GR regulation, we investigated the function of FKBP5 in the bidirectional synaptic plasticity in the hippocampus of male mice and found intact long-term potentiation (LTP) induction even in the absence of FKBP5. Furthermore, GR activation by corticosterone incubation blocked the LTP induction in controls but not in FKBP5 knockout (KO) mice. Interestingly, low-frequency stimulation (LFS) -induced long-term depression (LTD) was selectively impaired in male KO mice. Importantly, impaired LTD in KO mice was mediated by increased calcineurin expression, highlighting the importance of FKBP5 in regulating synaptic plasticity through its interaction with GR and calcineurin. Further research on the FKBP5-related signaling pathways may provide insights into the molecular mechanisms underlying stress resilience and potential therapeutic targets for psychiatric disorders associated with stress dysregulation.
CMTR1-catalyzed 2'-O-methylation promotes NMDA receptor signaling, long-term potentiation and memory.
Azeem S, Chang TT, Peng C … +3 more , Lee YL, Yeh NH, Huang YS
Prog Neurobiol · 2025 Aug · PMID 40571183 · Publisher ↗
Eukaryotic mRNA includes a 5'-end m7G cap to prevent degradation and enable cap-dependent translation. The first transcribed ribonucleotide undergoes additional 2'-O-ribose methylation by Cap Methyltransferase 1 (CMTR1)....
Eukaryotic mRNA includes a 5'-end m7G cap to prevent degradation and enable cap-dependent translation. The first transcribed ribonucleotide undergoes additional 2'-O-ribose methylation by Cap Methyltransferase 1 (CMTR1). Although this modification impacts gene expression, its physiological role remains largely unclear. High CMTR1 expression in the adult hippocampus prompted us to examine its role in learning and memory. In CMTR1-deficient hippocampi, numerous downregulated genes from transcriptome and proteome analyses were linked to glutamatergic synapses, including N-methyl-D-aspartate receptor (NMDAR) subunits. We generated CMTR1 conditional knockout mice targeting forebrain excitatory neurons and observed deficits in long-term potentiation (LTP) and spatial memory consolidation. D-cycloserine, an NMDAR allosteric agonist, restored memory consolidation and NMDAR hypofunction in these mice. Additionally, re-expression of wild-type, but not catalytically inactive, CMTR1 in hippocampal CA1 neurons rescued LTP and memory deficits. Our findings highlight the role of CMTR1 in regulating NMDAR signaling, which is critical for synaptic plasticity and memory consolidation.
Regulation of sociability by the cortico-habenula pathway in an animal model of depression.
Park H, Chung C
Prog Neurobiol · 2025 Aug · PMID 40571182 · Publisher ↗
Impaired sociability is a hallmark behavioral symptom frequently associated with depression. The medial prefrontal cortex (mPFC) is known to regulate both social behaviors and stress responses. Given the mPFC's projectio...
Impaired sociability is a hallmark behavioral symptom frequently associated with depression. The medial prefrontal cortex (mPFC) is known to regulate both social behaviors and stress responses. Given the mPFC's projections to the lateral habenula (LHb) and the abnormal hyperactivity of the LHb observed in depression, the mPFC-LHb pathway may play a pivotal role in mediating impaired social behaviors in depressive disorders. Recent studies have reported increased activity of the mPFC-LHb pathway in depressive animal models. However, how this pathway responds to social stimuli and the synaptic dynamics underlying this process remain unexamined. Utilizing an acute learned helplessness (aLH) mouse model, we demonstrated that exposure to non-social stress resulted in heightened excitability and enhanced excitatory synaptic transmission at mPFC-LHb synapses. Furthermore, during social interactions, aLH mice exhibited significantly elevated Ca transient signals in mPFC neurons projecting to the LHb. This synaptic enhancement was specifically observed in LHb neurons projecting to the ventral tegmental area (VTA). Importantly, optogenetic suppression of the mPFC-LHb pathway effectively restored sociability, underscoring its crucial role in the social deficits associated with depression. These findings highlight the mPFC-LHb pathway as a promising target for investigating the neural mechanisms underlying sociability deficits in depressive disorders.
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