Biology subjects

Amilhon, B.

Publications and source records attributed to Amilhon, B..

6 recordsLinked to original sources

bioRxiv2026

Median raphe input to dorsal CA1 shapes VIP interneuron recruitment and novelty-guided spatial memory

Vasoactive intestinal peptide-expressing interneurons (VIP-INs) gate hippocampal inhibition during novel experience, but the long-range signals that engage these cells remain poorly understood. Here we identify median raphe (MnR) projections as a brainstem pathway that tunes dorsal CA1 VIP-IN recruitment through coordinated glutamatergic and serotonergic mechanisms. Anatomical mapping and optogenetic recordings showed that MnR axons innervate multiple VIP-IN subtypes, while transcriptomic and pharmacological analyses revealed fast glutamatergic excitation together with serotonin receptor-dependent modulation of synaptic and intrinsic responsiveness. In vivo calcium imaging showed that novelty preferentially recruited a speed-coupled VIP-IN ensemble, and inhibition of MnR input selectively reduced the magnitude of this response. A hippocampal circuit model linked this pathway to dendritic disinhibition and place-cell recruitment. Behaviorally, inhibition of MnR input preserved exploratory engagement but disrupted the organization of spatial sampling and impaired object-location memory. Thus, MnR input organizes hippocampal disinhibition to support novelty-guided exploration and memory encoding.

neuroscience↗

bioRxiv2026

Anatomical organization and origins of VGLUT3-positive axon terminals in the lateral septum.

The lateral septum (LS) integrates afferents from multiple brain regions, including the raphe nuclei. The organization of these inputs contributes to the regionalization of LS functions, for example spatial coding in dorsal LS and emotional regulation in ventral LS. Raphe-LS projections include glutamatergic axons expressing the vesicular glutamate transporter type 3 (VGLUT3), which often form pericellular baskets around LS neurons. This study provides an anatomical characterization of the organization and origins of VGLUT3-positive (VGLUT3+) raphe inputs to the LS. We mapped VGLUT3+ axon terminal density across the rostro-caudal extent of the LS and quantified colocalization with serotonin (5-HT) using immunohistochemistry. Our results showed that VGLUT3 density was highest in the ventral LS, whereas VGLUT3/5-HT colocalization was strongest in the dorsal LS. Retrograde viral vector-mediated tracing identified predominant inputs from the median raphe and B9 neuron group. Interestingly, the ventral hippocampus, a functionally related region which is known to also receive raphe VGLUT3 inputs, showed collaterals with the LS. Additional VGLUT3+ inputs to the LS arose from the interpeduncular nucleus, bed nucleus of the stria terminalis, nucleus incertus and pontine central gray. Anterograde tracing revealed that inputs from these brain regions target distinct and largely non-overlapping domains in the LS. Our findings highlight multiple sources of VGLUT3+ inputs to the LS, beyond the raphe nuclei, and suggest that distinct VGLUT3 circuits could contribute to LS functional specialization.

neuroscience↗

bioRxiv2025

Beyond the straight path: high-density laminar recordings in the ventral hippocampus with curved microprobes

Neural circuits are organized within complex three-dimensional architectures. Most neural interfaces follow linear insertion trajectories, limiting their ability to achieve laminar recording in brain regions where neuronal layers lie approximately parallel to the insertion path. Here, we introduce a curved flexible neural interface that enables near-perpendicular alignment of the recording sites with the targeted neuronal layers. The device consists of a flexible Parylene-C neural probe, integrating 16 PEDOT:BF4-coated Au microelectrodes and a transient silk fibroin stiffener for controlled implantation. The electrodes exhibit low impedance at 1 kHz (29.2 {+/-} 2.5 k{Omega}) and were accurately positioned across the layers of the ventral hippocampus using a rotational implantation strategy. Chronic in vivo recordings demonstrate stable electrochemical performance and reliable acquisition of local field potentials over four weeks. This work establishes a strategy for anatomically matched neural interfacing, enabling high-resolution investigation of neural circuits that are challenging to study with conventional linear probes.

neuroscience↗

bioRxiv2025

Hyperexcitability of female serotonin neurons underlies sex-specific anxiety responses

Mood and anxiety disorders display robust sex differences in prevalence, symptom profile, and treatment outcomes, yet the circuit mechanisms underlying this sex bias remain unclear. Here, we identify a serotonergic (5-HT) pathway from the median raphe region (MRR) to the ventral hippocampus (vHP) that drives sex-specific anxiety regulation in mice. Using a multimodal approach combining electrophysiology, fiber photometry, and optogenetics, we show that vHP-projecting 5-HT neurons (5-HTvHP) in the MRR are intrinsically hyperexcitable in females and exhibit delayed adaptation during exposure to aversive environments. At baseline, female mice displayed greater avoidance and reduced risk-assessment behavior. Optogenetic activation of this pathway selectively enhanced anxiety-like behavior and stress-related grooming in females, while leaving locomotion unaffected. Fiber photometry revealed that grooming episodes coincide with transient suppression of 5-HTvHP activity, suggesting an adaptive feedback mechanism to downregulate serotonergic tone under elevated anxiety. Moreover, activation of this pathway disrupted hippocampal theta dynamics during habituation to a novel arena exclusively in females, revealing serotonergic modulation of anxiety and novelty processing. These results were consistent with the identification of sex-specific M-currents, which constrained excitability in male MRR 5-HTvHP neurons, while being largely absent in females. Collectively, our findings uncover a hyperexcitable MRR-vHP serotonergic circuit that drives female-specific anxiety states, providing a mechanistic framework for understanding sex-specific vulnerability to mood and anxiety disorders.

neuroscience↗

bioRxiv2024

Secondary deficiency of neuraminidase 1 contributes to CNS pathology in neurological mucopolysaccharidoses via hypersialylation of brain glycoproteins

Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III and VII are associated with lysosomal accumulation of heparan sulphate and manifest with neurological deterioration. Most of these neurological MPS currently lack effective treatments. Here, we report that, compared to controls, neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of neurological MPS patients and in mouse models of MPS I, II, IIIA, IIIB and IIIC, but not of other neurological lysosomal disorders not presenting with heparan sulphate storage. We further show that accumulated heparan sulphate disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A (CTSA), {beta}-galactosidase (GLB1) and glucosamine-6-sulfate sulfatase (GALNS) necessary to maintain enzyme activity, and that NEU1 deficiency is linked to partial deficiencies of GLB1 and GALNS in cortical tissues and iPSC-derived cortical neurons of neurological MPS patients. Increased sialylation of N-linked glycans in brain samples of human MPS III patients and MPS IIIC mice implicated insufficient processing of brain N-linked sialylated glycans, except for polysialic acid, which was reduced in the brains of MPS IIIC mice. Correction of NEU1 activity in MPS IIIC mice by lentiviral gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioural traits, and reduced levels of the excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1-/PSD95-positive puncta in cortical neurons derived from iPSC of an MPS IIIA patient. Together, our data demonstrate that heparan sulphate-induced secondary NEU1 deficiency and aberrant sialylation of glycoproteins implicated in synaptogenesis, memory, and behaviour constitute a novel pathological pathway in neurological MPS spectrum crucially contributing to CNS pathology. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/587986v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@3905c3org.highwire.dtl.DTLVardef@1a9672corg.highwire.dtl.DTLVardef@b4911forg.highwire.dtl.DTLVardef@a3b190_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2022

Parallel streams of raphe VGLUT3-positive inputs target the dorsal and ventral hippocampus in each hemisphere.

The hippocampus (HP) receives neurochemically diverse inputs from the raphe nuclei, including glutamatergic fibers characterized by the expression of the vesicular glutamate transporter VGLUT3. These raphe-HP VGLUT3 (VGLUT3HP) projections have been suggested to play a critical role in HP functions, yet a complete anatomical overview of raphe VGLUT3 projections to the forebrain, and in particular the HP, is lacking. Using anterograde viral tracing, we describe largely non-overlapping VGLUT3-positive projections from the dorsal raphe (DR) and median raphe (MnR) to the forebrain, with the HP receiving inputs from the MnR. A limited subset of forebrain regions such as the amygdaloid complex, claustrum and hypothalamus receive projections from both the DR and MnR that remain largely segregated. This highly complementary anatomical pattern suggests contrasting roles for DR and MnR VGLUT3 neurons. To further analyse the topography of VGLUT3 raphe projections to the HP, we used retrograde tracing and found that VGLUT3HP neurons distribute over several raphe sub-regions (including the MnR, paramedian raphe and B9 nucleus) and lack co-expression of serotonergic markers. Strikingly, two-color retrograde tracing unraveled two parallel streams of VGLUT3-positive projections targeting the dorsal and ventral poles of the HP. These results demonstrate highly organized and segregated VGLUT3-positive projections to the HP, suggesting independent modulation of HP functions such as spatial memory and emotion-related behavior.

neuroscience↗