Progressive supranuclear palsy (PSP) is a severe neurodegenerative tauopathy defined by astrocytic tau inclusions and parkinsonism. The link between astrogliopathy and compromised cerebral fluid dynamics remains unclear. We generated a glial fibrillary acidic protein (GFAP)-e (2A-mMAPT (4R) cDNA) 1 mouse line (GFAP/tau Tg) with astrocyte-specific expression of 4-repeat (4R) tau to investigate mechanisms underlying astrocytic tau pathology as seen in PSP. Both male and female mice were used in this study. GFAP/tau Tg mice exhibited robust astrocytic hyperphosphorylated tau (p-tau) deposition and activation. Mechanistically, this pathology caused dysregulation of the dystrophin-associated complex (DAC), leading to a critical loss of Aquaporin 4 (AQP4) polarity and aberrant AQP4 distribution in perivascular end feet. This DAC-AQP4 axis disruption critically impaired cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange, subsequently causing deficient glymphatic fluid drainage and excessive ISF accumulation. This fluid stasis was correlated with a significant decline in the synaptic neurotransmitters dopamine (DA) and acetylcholine (ACh). Ultimately, these pathological events manifested as parkinsonian-like motor dysfunction and cognitive deficits in the transgenic mice. Our study clarifies a novel, sequential mechanism linking astrocytic 4R tauopathy to glymphatic circulation failure and neurochemical deficits that recapitulates key astroglial pathological features of PSP. These findings establish the glymphatic system as a compelling therapeutic target for treating neurodegenerative disorders linked to astrogliopathy.
The cochlear amplifier, mediated by outer hair cell-driven nonlinear mechanics, enables the remarkable sensitivity and dynamic range of human hearing. Cochlear compression is a defining feature of this active process and is known to deteriorate with hearing loss. Among individuals with normal audiograms, cochlear compression is generally presumed to be invariant, an assumption that has not been systematically examined. If incipient cochlear changes precede measurable threshold shifts, variability in compressive nonlinearity may represent an early peripheral correlate of emerging dysfunction and a potential mechanistic contributor to auditory processing differences. Whether cochlear compression varies meaningfully among individuals with normal audiograms, and what such variability reveals about the earliest stages of cochlear dysfunction, remains unknown. Here, we quantified compressive nonlinearity using distortion-product otoacoustic emission (DPOAE) input/output (i/o) functions with stringent signal-to-noise criteria, applying covariate-controlled mixed-effects models within a dimensional framework that treated compression as a continuous outcome to isolate structured individual differences (n =144 ears; male, 46). Compression metrics demonstrated substantial interindividual variability despite normal-hearing thresholds. Subtle differences in standard-frequency thresholds were associated with variations in cochlear gain. Extended high-frequency sensitivity, an index of basal cochlear integrity, showed additional associations with DPOAE i/o function, implicating basal vulnerability in shaping cochlear nonlinearity. Age-related effects were detectable even within a restricted young-adult cohort, indicating that cochlear operating characteristics may begin to diverge early in adulthood. These findings challenge the assumption of invariant compression in normal hearing and suggest that alterations in cochlear nonlinear processing may reflect incipient cochlear dysfunction that precedes overt hearing loss.
Growth hormone (GH) signaling contributes to pubertal development and reproductive function, yet the hypothalamic circuits mediating these effects remain incompletely understood. Kisspeptin and agouti-related protein (AgRP) neurons are key integrators of metabolic and reproductive cues and exhibit GH-responsive signaling pathways. We therefore investigated their contributions to the reproductive consequences of altered somatotropic signaling. Using genetic mouse models of chronic GH excess or deficiency, we examined the impact of altered GH signaling on pubertal maturation, fertility, and hypothalamic neuroendocrine function. Pubertal onset was unaffected in female mice, whereas males with either GH excess or GH deficiency exhibited delayed puberty. In contrast, GH hypersecretion selectively disrupted estrous cyclicity and impaired fertility in females. Female reproductive dysfunction occurred despite preserved kisspeptin signaling, as evidenced by the preservation of intrinsic electrophysiological properties of kisspeptin neurons and unaltered hypothalamic Kiss1 mRNA expression. Chronic GH excess increased hypothalamic Agrp mRNA expression and reduced Pomc and Tac2 mRNA expression compared to control mice; these transcriptional changes were prevented by AgRP-specific GH receptor (GHR) deletion, which also improved ovarian function. Notably, selective deletion of the GHR in AgRP cells markedly improved fertility in GH-hypersecreting females. Together, these findings identify AgRP neurons as a critical hypothalamic target through which chronic GH excess impairs female reproductive function. Our results further demonstrate that GH-induced infertility occurs independently of canonical kisspeptin-GnRH dysfunction, revealing a sexually dimorphic mechanism linking somatotropic signaling to reproductive competence. Significance Statement Reproductive dysfunction is a common consequence of chronic alterations in growth hormone (GH) secretion, but the underlying neural mechanisms remain poorly defined. We show that chronic GH excess induces a sexually dimorphic reproductive phenotype characterized by profound impairment of female fertility despite largely preserved kisspeptin neuronal function. In contrast, GH excess altered hypothalamic AgRP-associated pathways, and the selective deletion of GH receptors in AgRP neurons significantly improved fertility in GH-hypersecreting females. These findings identify AgRP neurons as key mediators of GH-induced reproductive dysfunction and reveal a previously unrecognized sexually dimorphic neuroendocrine mechanism linking somatotropic signaling, metabolic circuits, and female fertility.
Learning is associated with rapid microstructural changes in the human brain, yet the precise temporal dynamics of these changes remain unclear. Using dense temporal sampling of diffusion-weighted MRI (DW-MRI) combined with task-based fMRI, we assessed microstructural changes throughout a declarative learning paradigm and subsequent rest. Seventy-four participants (36 females) learned image-location associations across four encoding-retrieval repetitions while undergoing interleaved functional and DW-MRI acquisitions. A matched control group (N=37, 21 females) underwent a similar imaging protocol without learning. Dense sampling of DW-MRI acquisitions (2146 images across 22 time points in 127 min) revealed that learning-induced mean diffusivity (MD) decreases emerged shortly after learning onset and continued to develop during post-learning rest. The most robust change was localized to the left middle occipital/temporal gyrus, a region also showing functional activation during encoding and retrieval. Linear mixed-effects modeling further confirmed a significant group-by-time interaction, with MD reductions in the left middle occipital/temporal gyrus emerging as early as ≈7 min after learning onset, becoming robust by ≈35-40 min, and persisting throughout the extended post-learning period, while controls showed no changes. Our findings demonstrate that learning-related microstructural plasticity unfolds continuously from encoding to offline consolidation, with learning-induced structural changes emerging in functionally engaged regions. Dense temporal sampling of DW-MRI offers a powerful approach to bridge functional activation and structural remodeling, providing evidence of when and where experience-dependent plasticity occurs during memory formation. Significance Statement How quickly does the brain’s structure change when we learn? Using dense temporal sampling of diffusion-weighted MRI (DW-MRI; 2146 images) across more than 2 hours, we show that microstructural plasticity arises rapidly during learning and continues to develop during post-learning rest. These learning-induced changes are spatially precise and overlap with task-related functional activity. By capturing the entire progression of microstructural plasticity across the learning process, rather than just before and after a learning paradigm, our study provides insights into when and where learning-induced plasticity occurs, demonstrating that memory formation involves rapid, ongoing microstructural changes in functionally engaged regions.
The hippocampus is essential for learning and memory and interacts extensively with cortical and subcortical regions. Although the heterogeneity of intrinsic connectivity of hippocampal neurons is well established, the diversity of its extrahippocampal connectivity remains less understood. Such differential connectivity may contribute to functional diversity of hippocampal neurons in specific positions. Ventral CA1 (vCA1) and ventral subiculum (vSub) form strong reciprocal connections with the basolateral amygdala (BLA), a region critical for emotional and social regulation. Consequently, BLA–vCA1–vSub circuits have been implicated in anxiety-related and social behaviors. However, the functional connectivity from BLA to vCA1–vSub at the cellular and circuit levels is underexplored. To address this, we combined viral tracing with Channelrhodopsin-2 (ChR2)–assisted slice electrophysiology to examine BLA projections to vCA1–vSub in mice of either sex. We found that BLA inputs are not uniformly distributed along the transverse axis in vCA1-vSub. Instead, BLA selectively excites pyramidal neurons in distal vCA1–vSub while largely avoiding proximal vCA1 near CA2. BLA terminals strongly excited parvalbumin-expressing interneurons but only weakly recruited a small subset of somatostatin-expressing interneurons, generating robust disynaptic inhibitory synaptic currents in pyramidal neurons. Additionally, the same distal pyramidal neurons that receive BLA excitation also project back to the BLA. These findings reveal that BLA establishes cell-type- and subregion-specific excitatory connections within vCA1–vSub, highlighting a circuit architecture that may underlie functional heterogeneity in ventral hippocampal processing. Significance statement The hippocampus interacts extensively with cortical and subcortical regions, yet how long-range extrahippocampal inputs are organized across hippocampal subregions remains poorly understood. We examined projections from the basolateral amygdala (BLA) to the ventral hippocampus and found that BLA inputs selectively excite pyramidal neurons in distal ventral CA1 and ventral subiculum while largely avoiding proximal ventral CA1. BLA projections preferentially excite parvalbumin-expressing interneurons, provide disynaptic inhibition onto pyramidal neurons, and are reciprocally connected with the same pyramidal neurons in ventral CA1 and subiculum they excite. These findings reveal a highly selective connectivity pattern of amygdala–hippocampal circuits, providing a circuit framework for understanding how emotional information is routed through distinct ventral hippocampal pathways.
