Sunday, August 17th, 2025

Time	Event
9:19a	An interneuronal CRH and CRHBP circuit stabilizes birdsong performance The performance of skilled behaviors requires a balance between consistency and adaptability. Although the neural mechanisms that regulate this balance have been extensively studied at systems and physiological levels, relatively little is known about how the molecular properties of motor circuits influence motor stability versus flexibility. Here, we characterize the region- and cell-type specific expression patterns of neuropeptide systems across the neural circuit that controls the learning and performance of birdsong, a model for skilled behavior. We identify a number of neuropeptide pathways with differential expression between song regions and surrounding areas that are not involved in song production or learning. One of the strongest enriched genes in song regions is corticotropin releasing hormone binding protein (CRHBP), whose product binds corticotropin releasing hormone (CRH), a neuropeptide implicated in neuronal excitability and plasticity. We find that the expression of CRHBP in the song motor pathway decreases upon deafening-induced song destabilization, increases during song acquisition, and increases the more a bird sings. CRH and CRHBP are expressed in distinct interneuronal populations in song motor regions, providing a local neuromodulatory circuit well-positioned to regulate song performance. Consistent with this role, genetic and pharmacological manipulation of the CRH pathway in the song motor pathway resulted in bidirectional modifications of song variability, with elevated CRHBP acting to maintain low variability and elevated CRH acting to increase variability. These data indicate that an interneuronal neuropeptidergic pathway maintains the stability of song, acting as a local mechanism that regulates the balance between motor consistency versus flexibility. (Comment on this)
9:19a	Synaptic Dysfunction and Compensation After NMDA Receptor Ablation in the Mouse Medial Prefrontal Cortex The glutamate hypothesis of schizophrenia posits that patients' symptoms arise from abnormal corticolimbic glutamatergic signaling, which is supported by evidence of abnormal expression of N-methyl-D-aspartate receptors (NMDARs) and decreased dendritic spine density in the prefrontal cortex (PFC). Pharmacological blockade of NMDARs in humans and animal models induces psychotomimetic symptoms, cognitive deficits, and decreased neural synchrony, with genetic knockdown of NMDARs providing further evidence of altered spine density and synaptic transmission. However, it is unknown how chronic loss of NMDARs in the PFC during adolescence - a developmental time period associated with significant synaptic pruning and symptom onset in patients - affects spine density and neurotransmission, and whether compensatory mechanisms emerge over time. In this study, we used in vivo genome editing to ablate expression of the Grin1 gene, which encodes the obligate GluN1 subunit of NMDARs, in neurons in the medial PFC of female and male adolescent mice. We assessed synaptic density and function in layer V pyramidal neurons at multiple time points using whole-cell patch-clamp electrophysiology, integrated with confocal imaging of dendritic spine architecture in recorded neurons. NMDAR ablation caused an early decrease in basilar dendritic spine density, followed by a rebound over baseline in spine density and a corresponding increase in AMPAR-mediated synaptic transmission. Inhibitory spontaneous neurotransmission was also increased, suggesting that synaptic compensation maintains an allostatic set point. Our findings demonstrate that NMDAR ablation initially disrupts local PFC networks, followed by recovery via compensatory processes that may be impaired in the disease state. (Comment on this)
9:19a	Theta-paced stimulation of the thalamic nucleus reuniens en-trains mPFC-HPC oscillations and facilitates the acquisition of extinction memories The nucleus reuniens (RE) is a midline thalamic nucleus interconnecting the medial prefrontal cortex (mPFC) and the hippocampus (HPC), structures known to be involved in aversive memory processes. Recent work indicates that the RE plays a critical role in the acquisition and retrieval of fear extinction memories. Specifically, the RE coordinates theta oscillations between the mPFC and HPC during extinction retrieval. Pharmacological inactivation of the RE impairs both mPFC-HPC theta coherence and the retrieval of extinction memory. Furthermore, theta-paced (8-Hz) optogenetic stimulation of the RE prevents fear renewal after extinction, a common form of fear relapse. However, it remains unclear whether theta-paced RE stimulation can entrain theta oscillations in the mPFC and HPC, and whether such entrainment is sufficient to facilitate the acquisition of extinction memories. To this end, we performed theta-paced optogenetic stimulation of the RE in adult male and female Long-Evans rats during extinction training. Animals underwent auditory fear conditioning, extinction, and an extinction retrieval test, each separated by 24 h. During extinction, 8-Hz stimulation of the RE was delivered concurrently with the presentation of the conditioned stimuli (CS). Theta-paced stimulation of the RE during extinction training significantly decreased freezing behavior compared to the control group. Notably, this reduction in conditioned behavior was also evident during the subsequent stimulation-free retrieval test, suggesting that RE stimulation not only suppresses conditioned fear responses acutely, but also facilitates the acquisition of long-term extinction memories. In a separate set of animals, we observed that theta-paced RE stimulation markedly enhanced both neural activity and entrained oscillations in the mPFC and dHPC at 8-Hz. This work suggests that the RE oscillatory activity is critical for the acquisition of extinction memories through the modulation of hippocampal-prefrontal network dynamics. (Comment on this)
10:31a	Lead (Pb) exposure alters neural cell fate in the developing human brain The heavy metal lead (Pb) is a developmental neurotoxicant associated with cognitive and behavioral deficits, but the cellular mechanisms underlying these impairments remain unclear. Here we show that prenatal Pb exposure biases human radial glia fate, prolonging neurogenesis and suppressing astrogenesis. We used hiPSC-derived cortical organoids, primary human fetal tissue, and in vivo xenografts to demonstrate that Pb exposure alters radial glial differentiation. Pb-exposed organoids contain a higher proportion of neurons and fewer astrocytes. We validated this differentiation bias in primary radial glia from human cortices (GW16-20), observing Pb-associated reductions in astrocyte commitment via genetic lineage tracing. This correlated with increased H3K27me3, a repressive histone modification deposited by the histone methyltransferase complex PRC2, suggesting epigenetic reprogramming as a mechanistic link between Pb and neural cell fate commitment. Our findings indicate that prenatal Pb exposure impacts lineage commitment in the developing brain, which may contribute to cognitive and behavioral impairment. (Comment on this)
10:31a	Population trajectory analysis reveals divergent state-space geometries across three cortical excitatory cell types Understanding how cortical cell types differ in state-space geometry is central to linking circuit composition with population coding. Population neural trajectories provide a compact representation of high-dimensional activity, capturing both spatial configuration and temporal evolution. In the visual cortex, excitatory subtypes differ in laminar location, projection targets, and synaptic integration, yet most trajectory analyses pool mixed populations, obscuring subtype-specific contributions. Here, we compared trajectory geometries across three genetically defined excitatory subtypes-Cux2-CreERT2, Emx1-IRES-Cre, and Slc17a7-IRES2-Cre-in the mouse primary visual cortex, using large-scale two-photon calcium imaging data from the Allen Brain Observatory and five complementary structural metrics. Across all metrics, Cux2 neurons exhibited consistently smaller trajectory scales than the other two types, with medium effect sizes stable across time windows, stimulus orientations, and leave-one-out validation. Emx1 and Slc17a7 populations showed broadly overlapping profiles, with the largest differences emerging in the mid-response window, corresponding to the sensory integration phase of population dynamics. These findings reveal distinct geometric signatures imposed by excitatory subtypes: Cux2 circuits favor localized, stable representations, whereas Emx1 and Slc17a7 circuits support broader, distributed integration. This provides a framework for linking microcircuit composition to population-level dynamics under identical sensory conditions. (Comment on this)
10:31a	Theta-rhythmic attentional exploration of space Attention facilitates stimulus processing by selecting specific locations (spatial attention) or features (feature-based attention). It can be sustained on a given location or feature, or re-oriented between locations or between features, enabling attentional exploration. Sustained attention was associated with alpha (8-12Hz) oscillations. More recently, authors suggested that exploratory attention was instead related to theta (4-7Hz). To date, there is no systematic evaluation of attentional exploration across stimulus dimensions (space, features) in relation to theta oscillations. Using attentional cueing and electroencephalography (EEG) in humans, we assessed exploration of stimulus dimension during the (1) precue-to-stimulus (first attentional orienting) and (2) post-stimulus (during stimulus processing) trial periods. In the precue-to-stimulus period, we classified the cued dimension (attending to a location/feature) from EEG topographies to assess the neural dynamics of sustained and exploratory attentional orienting. Temporal generalization matrices showed oscillatory patterns of classification accuracies across time. When attention was sustained on a cued location but explored the feature dimension as the target feature was unknown, only the alpha frequency was observed. When attention was sustained on a cued feature but explored locations, both alpha and theta frequencies were observed. Focusing on post-stimulus theta oscillations revealed increased theta power in invalid trials (attention reorients from the precued distractor location/feature to the target, i.e., exploration) relative to valid trials in both feature-based and spatial attention conditions. Post-stimulus theta oscillations further predicted behavioral performance. Together, our results show that while alpha oscillations are associated with sustained attention regardless of the attended dimension, theta oscillations are specifically related to spatial exploration. (Comment on this)
10:31a	Parvalbumin interneurons mediate spontaneous hemodynamic fluctuations Resting-state hemodynamic fluctuations are closely linked to gamma-band neural activity, yet the cellular drivers of this neurovascular coupling remain unclear. Given their established contribution in generating gamma oscillations, parvalbumin (PV) interneurons are prime candidates for regulating spontaneous cerebral blood flow (CBF) dynamics. Using chemogenetic tools in awake PV-Cre mice, we modulated PV interneuron activity and measured effects on neural network activity, local field potentials (LFP), and hemodynamics. Two-photon (2P) calcium imaging confirmed effective PV modulation, which affected excitatory neuron activity. PV suppression reduced high-gamma power, increased low-frequency LFP activity, and elevated basal CBF. 2P vessel imaging showed increased basal arterial diameter and significantly greater diameter fluctuation power in deeper cortical layers enriched with PV cells, but not in superficial layers. PV suppression also significantly weakened the correlation between gamma LFP power and CBF. Despite increased apparent neuronal synchrony during PV suppression, its relationship to arterial dynamics remained stable, possibly due to compensatory regulation by subsets of PV-positive and PV-negative cells. These findings provide causal evidence that PV interneuron contribute to spontaneous neurovascular dynamics and mediate the link between gamma oscillations and resting-state hemodynamic signals, revealing their significant role in maintaining functional connectivity and vascular regulation during non-task-engaged brain states. (Comment on this)
10:31a	The inner ear's active process contributes to selective attention to speech in noise Humans are remarkably skilled at understanding speech in noisy environments. While segregation of different audio streams is mostly accomplished in the auditory cortex, it remains unclear whether the inner ear, where the sound detection occurs, already contributes to selective attention. In particular, the cochlea possesses an active process enabling it to amplify sound in a frequency-dependent manner. A physiological correlate of the active process are distortion-product otoacoustic emissions (DPOAEs) that can be measured non-invasively from the ear canal. Here we employed speech-DPOAEs that are connected to the spectral structure of voiced speech to show that these emissions are modulated by selective attention to one of two competing voices. We found that speech-DPOAEs evoked by the resolved harmonics of a voice were significantly reduced when that voice was attended as compared to when it was ignored. No such effect was observed for the unresolved harmonics of the target voice when the competing voice's harmonics in that range were unresolved as well, indicating that attentional modulation is specific to those components of voiced speech that are spectrally resolved. Our findings demonstrate for the first time that selective attention to speech in noise is already shaped by the inner ear's active process. (Comment on this)

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