Establishing learned associations between rewarding stimuli and the context under which those rewards are encountered is critical for survival. Hippocampal input to the nucleus accumbens (NAc) provides important environmental context to reward processing to support goal-directed behaviors. This connection consists of two independent pathways originating from the dorsal (dHipp) or ventral (vHipp) hippocampus, which have previously been considered functionally and anatomically distinct. Here, we show overlap in dHipp and vHipp terminal fields in the NAc, leading us to reconsider this view and raise new questions regarding the potential interactions between dHipp and vHipp pathways in the NAc. Using optogenetics, electrophysiology, and transsynaptic labeling in male and female mice, we investigated anatomical and functional convergence of dHipp and vHipp inputs in the NAc. Transsynaptic labeling revealed a subpopulation of dually innervated cells in the NAc medial shell, confirmed by independent optogenetic manipulation of dHipp and vHipp inputs during whole-cell electrophysiological recordings. Further analysis revealed closely apposed dHipp and vHipp inputs along dendritic branches, and simultaneous stimulation of both inputs elicited heterosynaptic potentiation. Comparison of observed and theoretical success rates suggests heterosynaptic interactions may occur presynaptically. Altogether, these results demonstrate that inputs originating from dHipp and vHipp converge onto a subset of NAc neurons with synapses positioned to enable rapid heterosynaptic interactions, indicating integration of these inputs at the single-neuron level. Exploring the physiological and behavioral implications of this convergence will offer new insights into how individual neurons incorporate information from distinct inputs and how this integration may shape learning.Significance statement Linking rewards to the contexts in which they are experienced is vital for survival. Hippocampal (Hipp) input to the nucleus accumbens (NAc) is essential for associating rewards with their environmental context to effectively guide motivated behaviors. This connection consists of two separate pathways originating from dorsal and ventral Hipp that have long been considered distinct. Here, we reveal a subpopulation of neurons in the NAc shell innervated by both Hipp subregions and heterosynaptic interactions that occur between dorsal and ventral Hipp-NAc synapses. These findings suggest that integration of distinct hippocampal information occurs at the single-neuron level, providing a critical mechanism underlying learning and motivated behavior while also opening new avenues for understanding how diverse contextual and reward signals shape decision-making.

Neurodegenerative disease profoundly affects structures and pathways responsible for memory, cognition, and higher-order processing. A foundational understanding of neuroanatomy and physiology is essential for recognizing how these disorders develop and how they are visualized with molecular imaging. Neurons, dendrites, axons, microtubules, and associated proteins, such as tau, form the structural basis for information transmission. Glial cells support neuronal health, regulate neurotransmission, maintain metabolic balance, and contribute to inflammatory responses that become dysregulated with aging. Brain regions such as the hippocampus, amygdala, prefrontal cortex, and limbic system coordinate memory formation, emotional encoding, working memory, and spatial navigation. The physiology of memory relies on encoding, consolidation, storage, and retrieval processes driven by neurotransmitters, such as acetylcholine, glutamate, serotonin, and dopamine. Synaptic plasticity enables adaptive strengthening or weakening of neural connections, whereas age-related changes contribute to natural cognitive decline. This article reviews the neuroanatomy and cellular physiology underlying memory to help understand neurodegenerative patterns and their appearance on advanced imaging.

Fornix subdivisions and spatial learning: a diffusion MRI study.

The hippocampal formation is a highly curved and topographically complex forebrain structure. This complex geometry presents persistent challenges for analyzing subregional, laminar, and connectivity patterns. Here, we present a computational workflow that generates curvilinear-coordinate flatmaps from Common Coordinate Framework (CCF) registered hippocampal and retrohippocampal regions by solving the Laplacian equation to derive geodesic streamlines. This transformation unfolds the hippocampus into a planar slab, bounded by the meningeal and ventricular surfaces, with the depth defined along the radial axis. We apply this transform to image volumes, single neuron reconstructions, and point data, including spatial transcriptomic and rabies tracing datasets, revealing topographic variations in the dorsoventral and radial axes that are obscured in the CCF coordinate space. As proof of principle, we use flatmaps to show connectivity loss in a mouse model of Alzheimer’s disease and track postnatal development of microglial distribution in the hippocampus. This work provides an efficient and accessible resource for visualizing hippocampal organization across development and disease, offering new opportunities to interrogate the structure and function of this important brain region.

Early development of the human pallium is shaped by transient cellular compartments that regulate the emergence of cytoarchitectonically distinct cortical types. At these stages, regional identity depends less on mature cortical layers-which form later in gestation-and more on the organization of transient compartments spanning from the pia to the ventricular surface. These early compartments arise within separate pallial sectors, including the medial pallium that produces the archicortex and mesocortex and the dorsal pallium that expands into the neocortex. Although recent studies have described molecular and cellular features within individual compartments, the spatiotemporal relationships among them that govern cortex-type specification remain insufficiently understood. We analyzed the distribution of proliferative, neuronal, fibrillar, and synaptic markers across the ventricular zone (VZ), subventricular zone (SVZ), cortical plate (CP), subplate (SP), and marginal zone (MZ) in prospective neocortical, mesocortical, and archicortical regions of the human fetal pallium. Development was examined across key phases: late preplate (7.5 PCW), initial CP formation (8 PCW), first CP condensation (9.5-12 PCW), SP formation (13-14 PCW), and the onset of typical fetal lamination (15 PCW). During the preplate phase, an expanded plexiform MZ containing the earliest TBR2+ and TBR1+ cells, along with tangential medial fibers, delineates the emerging archicortical (hippocampal) and mesocortical (entorhinal) sectors, which occupy much of the interhemispheric pallium. In contrast, the dorsal isocortical pallium shows a broad influx of TBR1+ neurons through abventricular compartments, while in the hippocampal primordium, these cells remain confined to the superficial zone. By 8 PCW, the first prospective pyramidal neurons form a disk-shaped CP in the midlateral neopallium, with a basal-to-dorsal gradient reflecting SVZ proliferative activity. At the same time, the ventral archicortex shows a distinct pattern characterized by MZ expansion, accumulation of "dormant" TBR2+ cells, absence of a defined CP, and progressive merging of the SVZ and MZ. Between 9.5 and 12 PCW, with the onset of the second proliferative wave, a CP emerges in the ventral hippocampal anlage. The future entorhinal mesocortex differentiates unusually early, displaying large multipolar "promoter" neurons in the superficial CP and the first appearance of a fibrillar lamina dissecans. By 13 PCW, hippocampal fields are discernible, and in the neocortex, the major developmental event is SP formation through merging of the deep CP and presubplate. Although hippocampal CP formation initially lags behind that of the neopallium, its subsequent differentiation-and that of adjacent transitional cortices-is accelerated. By 15 PCW, prospective archicortical, mesocortical, and neocortical sectors are clearly recognizable. Our findings suggest that cortex-type divisions arise from coordinated interactions among proliferative, migratory-fibrillar, synaptic, and postmigratory compartments. Allocortical regions exhibit distinctive developmental trajectories, including MZ enlargement, tapering of SVZ and SP and a characteristic tempo of CP formation. This compartment-based perspective highlights early transitional belt-like zones and spatiotemporal gradients across the pallium and identifies the ventral mesocortical (prospective entorhinal) area as an early organizing hub at the interface of allocortical and transmodal connectivity.

Egocentric representations of the environment have historically been relegated to being used only for simple forms of spatial behaviour such as stimulus-response learning. However, in the many cases that critical aspects of policies are best defined relative to the self, egocentric representations can be advantageous. Furthermore, there is evidence that forms of egocentric representation might exist in the wider hippocampal formation. Nevertheless, egocentric representations have yet to be fully incorporated as a component of modern navigational methods. Here we investigate egocentric successor representations (SRs) and their combination with allocentric representations. We build a reinforcement learning agent that combines an egocentric SR with a conventional allocentric SR to navigate complex 2D environments. We demonstrate that the agent learns generalisable egocentric and allocentric value functions which, even when only additively composed, allow it to learn policies efficiently and to adapt to new environments quickly. Our work shows the benefit for egocentric relational structure to be captured, as well as allocentric. We offer a new perspective on how cognitive maps could usefully be composed from multiple simple maps representing associations between state features defined in different reference frames.

BackgroundThe Lieber Institute for Brain Development (LIBD) has one of the largest postmortem human brain banks for the study of neuropsychiatric disorders in the world. The postmortem evaluation involves neuropathological assessment for age-related protein accumulations, specifically phosphorylated tau (p-tau) and amyloid-β (Aβ).ObjectivePresent the LIBD semiquantitative assessment methodology for p-tau and Aβ by comparing proteinopathy by age and by apolipoprotein E (APOE) genotype.MethodsPostmortem brain tissue samples were from 1509 people aged 50 or greater (median age at death = 63 years; range = 50-102). Seven brain regions (four neocortical areas, hippocampal formation, midbrain, and cerebellum) were examined by routine histopathology, p-tau immunohistochemistry (AT8; hippocampus and four neocortical samples), and Aβ immunohistochemistry (BAM01; four neocortical samples). APOE genotyping was performed in a subgroup. Semiquantitative assessments include modified CERAD (Consortium to Establish a Registry for Alzheimer's Disease) and modified Braak approaches.ResultsThere were 63.8% rated as B1 (modified Braak I or II), 30.4% rated as B2 (modified Braak III or IV), and 5.8% rated as B3 (modified Braak V or VI). For those in their early 70 s, half had modified Braak stage III-IV ratings. For decedents in their 80 s, approximately 1 in 4 had modified Braak stage V-VI ratings. Aβ was present in 48.8% (C0 = 51.2%, C1 = 17.2%, C2 = 24.5%, and C3 = 7.1%). Age and APOE genotype were significant predictors of Aβ plaques.ConclusionsThe LIBD protocol assessing p-tau and Aβ burden identified significant associations with age and APOE genotype. More research is needed to understand the spectrum of age-related proteinopathy versus neurodegenerative disease neuropathology.

Spatial tuning is a hallmark property of neural firing in the hippocampal formation. Yet, that tuning is often less well correlated with the instantaneous current position of an animal than it is with an integrated version of the past or future state of the animal. Whether that encoding is biased towards past or future states and the extent to which it shows fixed versus multi-scale encoding varies across circuits and cell types. The temporal encoding properties of boundary vector cells of the subiculum are not well established. To address this here, we re-analyzed recordings of BVCs described previously by Lever et al. (2009) with multiple approaches. In the first, we asked if adding a temporal offset between the rat position and the spiking of a BVC increased the apparent spatial tuning in the firing rate map. We found that aligning BVC spiking with future states maximized the rate map spatial tuning. These results were mirrored in a second analysis that, instead of optimizing rate map spatial tuning, optimized how well the firing rate map predicted the BVC spiking. The second analysis also allowed us to ask whether that encoding is focused on a particular temporal horizon or whether the encoding captures behavior at multiple scales. To this end, for a given recording, we asked “How much time-integration of the behavioral state is the observed spiking most consistent with?” We observed a wide spectrum of time-constants of integration across cells, indicating that BVCs form a multiscale encoding of future states. The distribution of both offsets and integration rates observed across BVCs did not differ significantly from other, non-BVC, subiculum neurons. Taken together, these findings indicate that BVCs, along with other subiculum neurons, form a multi-scale encoding of future states.

The déjà vu phenomenon, despite its high prevalence in the general population, is a key symptom in patients with mesial temporal lobe epilepsy (MTLE), where it occurs in 50–80 % of cases. This lecture summarizes current concepts of the neurobiological and cognitive mechanisms of déjà vu, examining it through both the model of pathology (MTLE) and its occurrence in healthy individuals. Based on a review of the literature, the article demonstrates that the hippocampal system, particularly the parahippocampal gyrus, is the central neuroanatomical substrate of déjà vu. Direct evidence comes from studies of MTLE patients, where intracranial electroencephalography and electrical stimulation unequivocally link the onset of déjà vu aura to pathological activity in the mesial temporal lobe. Cognitive models (e.g., Dual Processing, Neural Delay/Mismatch, Global Matching hypotheses) interpret déjà vu as a temporary “glitch” in memory systems, involving a dissociation between the feeling of familiarity (mediated by the perirhinal cortex) and the mechanism of detailed contextual recollection (hippocampus). The contribution of specific subregions of the hippocampal formation (dentate gyrus, СА1–СА3 fields, entorhinal cortex) to pattern separation and completion processes, whose impairment underlies false recognition, is examined. Thus, the déjà vu phenomenon serves as a unique “window” into the mechanisms of memory function. The clinical model of MTLE demonstrates its direct link to pathological activity in the mesial temporal lobe, while cognitive models explain its occurrence in healthy people because of transient dysfunction of the same hippocampal mechanisms. Future research should focus on identifying specific electrophysiological patterns and clarifying the role of impaired inhibitory control and pattern separation mechanisms in the genesis of this phenomenon.

Fibronectin (FN1), a vital extracellular matrix protein, has been reported to be elevated in blood and cerebrospinal fluid in epileptic patients exhibiting recent seizure activity. A transcriptomic study from MTLE-HS patients has identified FN1 as a potential gene linked to MTLE. Nonetheless, the function of FN1 and the participation of the FN1/α5β1-Integrin/Src kinase signaling pathway are yet to be fully investigated in both pre-clinical and clinical investigations of TLE. Furthermore, its role in NMDA receptor-mediated hyperexcitability in TLE requires investigation. This study evaluates the contribution of the FN1/α5β1-Integrin/Src kinase axis in facilitating NMDA-induced hyperexcitability in temporal lobe epilepsy.Hippocampal formation and ATL tissues from MTLE-HS patients, as well as acute and chronic Li-pilocarpine TLE rat models, were examined using qRT-PCR, immunoblotting, and ex vivo immunolabeling to evaluate the expression of FN1, α5β1 Integrin, Src kinase, and NMDA receptor subunits. To assess the functions of FN1 and Src in NMDA receptor-induced hyperexcitability, siRNA-mediated knockdown was conducted in TLE rats. Following knockdown, behavioral assessments, molecular studies, and in vivo EEG were employed to examine the FN1/α5β1 Integrin/Src axis in seizure-related hyperexcitability.In MTLE-HS patients and TLE rat models, FN1 and Src kinase showed upregulation in both the hippocampal formation and ATL, together with increased α5β1 Integrin levels in rats. Elevated Src activity was associated with augmented phosphorylation of NMDA receptors. The siRNA-mediated knockdown of FN1 or Src diminished NMDA receptor phosphorylation and markedly reduced seizure activity in TLE animals.Our research suggests that FN1 has a role in MTLE pathophysiology and may regulate NMDAR-mediated hyperexcitability via the FN1/α5β1 Integrin/Src kinase pathway. This pathway regulates seizures via the hippocampal formation and anterior temporal lobe networks. The therapeutic potential of targeting this signaling pathway for epilepsy needs additional investigation.

This article is a personal history of the background, ideas, and motivations behind the major discoveries from my lab in the past 27 years. Tracing the main themes back to my training as a graduate student and a postdoc, I discuss how all of our work has been influenced by a desire to use anatomical and computational literature to inspire and constrain the experimental questions we have addressed. The backstory of two fundamental discoveries made in the early days on my independent research program are described: (a) differences between DG, CA3, and CA1 population dynamics in relation to computational theories of pattern separation and pattern completion and (b) differences in the types of information conveyed to the hippocampus from its lateral and medial entorhinal cortex inputs. Also described are how these initial findings set the foundation for numerous subsequent discoveries as we followed the data from one experiment to the next, with the goals of understanding how information is represented and transformed through the hippocampal formation in support of spatial learning and episodic memory.

Comorbidity of autism spectrum disorders and anxiety disorders: Insights from neuronal circuitry studies.

ABSTRACTThe hippocampal formation is a functional entity that includes the hippocampus, subicular complex, and the entorhinal cortex, and has an essential role in learning and memory, emotional processing, and spatial coding. The well‐defined structure of hippocampal fields and the segregation of the connections have made this structure a favorite candidate for functional models that rely on fundamental information such as the number of neurons populating the hippocampal fields. Existing models on the rat rely on neuronal populations obtained from single studies, so we aimed to obtain more representative estimates by analyzing all available data. We identified 89 studies using reliable methodology that provided 264 stereological estimates of principal neuron populations. The resulting averages for males showed 1,000,000 neurons for the granule cell layer (GCL); 50,000 for the hilus; 210,000 for CA3; ~30,000 for CA2; 350,000 for CA1; and 300,000 for the Subiculum. Entorhinal cortex (EC) averages for both sexes showed 108,000 neurons in layer II; 270,000 in layer III; and 340,000 in layer V/VI. Most of those estimates are significantly different from those traditionally used in hippocampal models (e.g., ~2‐fold difference in EC layer II), revealing an updated architecture of the rat hippocampal formation that might help build more realistic models of hippocampal connectivity and function. Comparisons by age or sex were not reliable given the scarce data available from adolescents or females, while comparisons by strain showed inconsistent results, with similar populations in most fields but significant differences in CA3/CA2. The reliability of this finding is discussed.

ABSTRACTThe perirhinal and parahippocampal cortices are two prominent structures of the medial temporal lobe that play essential roles in memory and perceptual processes. In humans, major changes in memory capacities occur within the first 7 years of life, but the neurobiological substrates underlying these changes have long been hypothetical. Previous studies have shown that distinct regions, layers, and cells of the hippocampal formation, including the entorhinal cortex, exhibit different profiles of structural and molecular development. Here, to further understand the postnatal maturation of the medial temporal lobe, we implemented stereological techniques to characterize the structural development of the perirhinal and parahippocampal cortices in macaque monkeys. We found distinct, age‐related differences in volume, neuronal soma size, and neuron number in different layers and subdivisions. Volumetric data indicated a late maturation of areas 36r and 36c compared to areas 35, TF, and TH. There was also an earlier maturation of the superficial layers compared to the deep layers in areas 36r and 36c. We observed a transient increase in neuronal soma size at 6 months of age in several subdivisions. Additionally, we found a decrease in neuron numbers in both the perirhinal and parahippocampal cortices, but particularly in area 35 and layer III of area TF between birth and 6 months. These findings are consistent with the differential maturation of the rostral and caudal entorhinal cortex, which are interconnected with the perirhinal and parahippocampal cortices, respectively. Altogether, they support the theory that the differential maturation of distinct hippocampal circuits underlies the emergence of specific “hippocampus‐dependent” memory processes.

To establish the relationship between circuit organization and information processing, many neuroscientists find it useful to reason in terms of neuron types. Hippocampome.org uses axonal and dendritic morphology as a foundational approach to classify neurons in the rodent hippocampal formation, including dentate gyrus, Cornu Ammonis, subiculum, and entorhinal cortex. For each identified neuron type, this open access knowledge base annotates essential properties, such as main neurotransmitter, membrane biophysics, firing patterns, molecular expression, and cell counts. Moreover, Hippocampome.org quantifies circuitry in terms of directional connection probabilities and synaptic signals between interacting neuron types. All properties are directly linked to peer reviewed experimental evidence and best-fitted with computational models. The resultant online resource provides an effective reference to design new experiments, analyses, and spiking neural network simulations. Here we illustrate the content and utility of Hippocampome.org with a focus on the subiculum, whose neuron type organization has received relatively less attention. Only 6 of the 180 Hippocampome.org neuron types are from the subiculum, compared to more than 60 in the adjacent area CA1. Specifically, we analyze the local subicular circuit and its broader interaction with the hippocampal formation with respect to both anatomical connectivity and signal transfer. Our results exemplify the potential added value of data integration in neuronal classification, while also highlighting the need for further research to fill existing knowledge gaps.

Neuropathologic features diagnostic of parkinsonian disorders infrequently occur in isolation; hyperphosphorylated tau (p-tau) and amyloid plaques are often observed in combination with α-synuclein deposition. Co-pathologies in neurodegenerative diseases are now recognized as the norm rather than an exception, but existing neuropathological assessment tools do not capture the complexity of concurrent co-pathologies. Characterization of this co-pathology is critical, as it has the potential to identify synergistic mechanisms. We developed a hierarchical cytoarchitectural classification system, which we applied to an autopsy series of military veterans with parkinsonism (n = 26), focusing on Lewy and neurofibrillary pathologies. We defined co-pathology as Type A (co-morbid), Type B (co-regional), Type C (co-cellular), or Type D (co-aggregate). The regional distributions of each co-pathology subtype were assessed using double-label immunohistochemistry in the frontal cortex, hippocampal formation, and midbrain. The frontal cortex demonstrated only subtypes A-C (no co-aggregates), whereas the midbrain and hippocampus showed all subtypes of copathology (A-D). In summary, we show marked differences in the prevalence and levels of mixed α-synuclein and tau pathology in this cohort. Our classification system has the potential to be applied broadly for the study of co-pathology in neurodegenerative disorders.

Although transcranial magnetic stimulation (TMS) is widely used in neuromodulation, conventional TMS struggles to achieve both depth and focal specificity. Temporal interference TMS (TI-TMS) offers a promising approach to enhance stimulation depth while reducing the focal area; however, current research remains largely simulation-based, with limited studies on system implementation and experimental validation in rodent deep brain regions. To address this, we developed a TI-TMS system based on a realistic mouse head model using finite element simulation. Electrophysiological recordings of local field potentials (LFPs) in the ventral hippocampal (vHPC) formation were performed to evaluate changes in θ rhythm power spectral density (PSD) and θ-γ phase-amplitude coupling (PAC) following stimulation. The results demonstrated that TI-TMS enhanced θ rhythm power and strengthened θ-γ PAC, indicating effective modulation of deep brain regions. This study establishes a functional TI-TMS system capable of effectively stimulating deep vHPC, providing an experimental basis for its application in precise neuromodulation of subcortical brain areas.

Background: Temporomandibular joint osteoarthritis (TMJOA) is a pathological condition marked by subchondral bone remodeling. Osteoarthritis can lead to TMJ pain, nevertheless, the relationship between nociceptive mechanisms and subchondral bone in TMJOA still unclear. Methods: In the present investigation, a rat TMJOA model was established via intra-articular administration of monosodium iodoacetate (MIA). Following the induction of MIA-triggered TMJOA, tissue samples were collected from the TMJ condyle, trigeminal system components including ganglion (TG) and nucleus caudalis (TNC), and hippocampal formation. Micro-computed tomography (Micro-CT) was employed to evaluate subchondral bone degeneration in the TMJ, while tartrate-resistant acid phosphatase (TRAP) staining was conducted to measure the activity of osteoclasts in the subchondral bone. Furthermore, immunofluorescence (IF) staining was performed to detect the expression of calcitonin gene related peptide (CGRP) in the TMJ subchondral bone. Afterwards, immunohistochemistry (IHC) was used to detect the expression of CGRP in the TG, TNC and hippocampus tissues. The experimental results were expressed as mean ± Standard Error of the Mean (SEM) values and two-way Analysis of Variance (ANOVA) with Student-Newman-Keuls post hoc testing was employed for statistical comparisons, adopting a significance threshold of p < 0.05. Results: Compared with the control group, Micro-CT results revealed progressive condylar degeneration over time. Consistently, MIA-induced TMJOA rats demonstrated a pronounced accumulation of TRAP-positive osteoclasts in the subchondral bone. The expression of CGRP in the TMJ subchondral bone, TG, TNC and hippocampus tissues was also obviously increased in MIA-induced TMJOA rats. Conclusions: MIA-induced rat TMJOA pain could be attributed to the augmented exprssion of CGRP in the TMJ subchondral bone, TG, TNC and hippocampus tissues. An elevated level of CGRP stimulated nociception which was implicated in the development of peripheral and central sensitization in TMJOA pain.

Long-lasting synaptic changes enable memory storage and regulate recall in the brain. Our previous work established that generation of multi-innervated dendritic spines (MISs), spines with typically two excitatory presynaptic inputs, underlies hippocampal memory formation in aged, but not young mice. The identification of MIS generation was done by ultrastructural analysis in hippocampal CA1 stratum radiatum 24 h after contextual fear conditioning (CFC). However, our analysis did not consider multi-spine boutons (MSBs), which were recently shown to increase in complexity (complex MSBs are pre-synaptic boutons connecting with more than two post-synapses) at a later time point after CFC in young age. Therefore, we re-analyzed our three-dimensional electron microscopy images and show that, unexpectedly, MSB complexity, decreases in CA1 stratum radiatum 24 h after CFC. The decrease in MSB complexity occurred both in young and aged mice, indicating that aging has no impact on this synaptic change. Considering that complex MSBs link the activity of multiple postsynaptic neurons, we suggest that after CFC a decrease in MSB complexity may be required for specific memory recall.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13041-025-01265-z.

Recombinant adeno-associated viruses (AAVs) capable of crossing the blood-brain barrier (e.g. AAV.PHP.eB) and encoding antibodies against amyloid beta peptides (Aβ) have potential to evaluate brain-wide gene immunotherapies in Alzheimer's disease (AD). Furthermore, leveraging astrocytic reactivity in response to Aβ pathology, the glial fibrillary acidic protein (GFAP) promoter could serve as a regulator of gene immunotherapy. Reactive astrocytes can regulate the expression of the recombinant anti-Aβ antibody (rSol) under the control of a GFAP promoter in the TgCRND8 (Tg) mouse model of amyloidosis. To study GFAP expression in Tg mice, GFAP mRNA levels were quantified using qPCR in the hippocampal formation at 3, 5, and 6 months (n=6 per group). Next, AAV.PHP.eB.GFAP.rSol-myc-tag and AAV.PHP.eB.GFAP.GFP were co-injected intravenously in Tg mice while non-Tg littermates and C57BL/6J mice served as controls. One-month post-injection, brain sections were processed for immunohistochemistry and RNAscope. GFAP mRNA levels doubled in 6-month-old compared to 3-month-old Tg mice. Brain-wide GFP expression in astrocytes confirmed efficacy of the GFAP promoter. Notably, brain cell transduction varied across Tg mice, peaking in the C57BL/6J line. Ly6A, a protein previously shown to facilitate AAV.PHP.eB entry into the brain, may explain this variability in transduction levels. We are currently examining Ly6A expression in our transgenic mouse line to determine the Tg background that will deliver the most efficient viral transduction. These results suggest that the GFAP promoter could control the production of therapeutics, such as rSol, in response to amyloid-induced astrocytic reactivity. Long-term studies will assess whether rSol prevents Aβ pathology progression in Tg-Aβ mice.